The Role of Nrf2 in the Regulation of Periodontitis, Peri-implantitis, Dentin Infection, and Apical Periodontitis

Abstract

The most frequent dental infections happen when bacteria enter the pulp and spread to the tissues. Dental caries arise from the dissolution of enamel and dentin by the acidic metabolites of oral streptococci. Dissolution leads to cavitation, which allows oral germs to enter the bloodstream. If left untreated, cavitation develops into bacterial invasion of the dental pulp. Dental plaque, also called dental biofilm, is associated with periodontitis. When the pulp is exposed, significant inflammation and necrotic foci occur as bacteria infect the tissue. Intravascular bacteria were identified in all instances, which may indicate an essential pathway for transmitting the infection via the pulp tissue. Also, bacteria buildup around a dental implant can result in peri-implantitis (PI), harming the adjacent bone and gums. Reactive oxygen species (ROS) are produced in excess when pathogens incite host immunological responses. Furthermore, osteogenic differentiation and bone formation depend on the regulated generation of ROS. Cells have complex antioxidant systems that carefully control the amount of ROS and prevent its harm. This mechanism activates transcription for multiple genes involved in antioxidant and cytoprotective functions through specific DNA sequences called antioxidant response elements (AREs). Nuclear factor erythroid-2-related factor-2 (Nrf2) is vital in safeguarding cells from oxidative and chemical harm by controlling various protective mechanisms. There is a potential preventive impact of Nrf2 on periodontitis. It is crucial to consider the involvement of Nrf2 in oral infectious illnesses to develop a substitute treatment strategy against antibiotic resistance. In this study, we have reviewed the diverse functions of Nrf2 in dental diseases, including periodontitis, PI, dentin, and oral root infections, to create a novel treatment approach. In this oral infection, the potential of various Nrf2 inhibitors was examined.

Introduction

Dental infections can spread to the surrounding tissues from their source in the tooth or the structures that support it [1]. Microorganisms in the oral cavity produce periodontal disease and dental caries, the two most common chronic infectious dental diseases [2]. In addition, certain invasive mouth bacteria that form dental plaque biofilms on the tooth surface cause periodontal infections. The host immune system’s reaction to inflammation is critical for worsening the disease [3]. It is widely recognized that periodontal disorders are infectious processes contingent upon the presence of bacteria, a host’s response, and additional genetic, environmental, and local variables. Porphyromonas gingivalis (P. gingivalis), Prevotella intermedia (P. intermedia), Tannerella forsythia (T. forsythia), Campylobacter rectus, and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) are among the most frequently encountered organisms associated with periodontal diseases (PDs), and the treponemes [4]. Periodontitis, also known as gum disease, is a harmful infection of the gums that causes damage to the soft tissue surrounding the teeth. If not appropriately treated, periodontitis can destroy the alveolar bone that supports the teeth, resulting in dental mobility or tooth loss [5]. Microbes can swell the tissues around the tooth’s crown when they enter the root canal system. The periapical inflammation and symptoms level are affected by how harmful the microbes are, how many there are, and how the host reacts to them [6]. Biofilms of microbes often form on the walls of root canals. However, different microbes can get into the dentine tubules differently [7].

Occasionally, dental implants may become infected, resulting in bone loss and soft tissue inflammation near the implant. This is frequently the result of peri-implantitis (PI) [8]. The gums and bone that support dental implants are affected by PI, an inflammatory condition similar to PD [9]. Germs and their protective biofilms are frequently not eliminated by conventional treatment procedures that rely on physical removal and chemical agents. These procedures have the potential to unintentionally result in the development of bacteria that are resistant to medications and disrupt the microbial balance of the mouth [10].

Inflammatory cells, including macrophages, neutrophils, and dendritic cells, swiftly detect, absorb, and consume germs upon their entry into the body through a process known as phagocytosis. Pathogens induce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), specifically NOX2. Through an increase in nitric oxide synthase (NOS), phagocytic cells facilitate the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Oxidative stress (OS) results from an imbalance between the concentrations of antioxidants and oxidants in cells. ROS and RNS are unstable free radicals that readily interact with biological macromolecules, causing damage to DNA, proteins, and lipids. Oxidants initiate the redox-sensitive nuclear factor kappa-B (NF-κB) signaling cascade, activating cell adhesion receptors, chemokines, and proinflammatory cytokines. This leads to the persistence of inflammation and the production of free radicals. In the context of infection, the significance of OS is still not fully understood. In essence, the proliferation of bacterial organisms has been demonstrated to be inhibited by OS for an extended period. Nevertheless, certain intracellular bacteria, such as Mycobacterium tuberculosis, Mycobacterium abscessus, and Mycobacterium avium, can thrive in oxidizing environments. In reality, Mycobacterium tuberculosis is more resistant to ROS than Listeria and Salmonella, as well as general bacteria and other intracellular parasites [11].

In response to an infection, the body releases cytokines, creating ROS and RNS, which damage proteins and DNA and eventually cause various disorders, including cancer. In response to these dangerous cytokines, the Nuclear erythroid-2-related factor-2 (Nrf2) pathway is turned on [12]. Moreover, host cells activate Nrf2, a powerful antioxidant defense mechanism, to reduce oxidative damage. Nrf2, a transcription factor, has been recognized as the principal controller of several genes that play a role in the antioxidant defense response [13, 14]. It stimulates the production of several downstream antioxidants, anti-inflammatory proteins, and detoxification enzymes by triggering the Kelch-like ECH-associating protein 1 (Keap1)-Nrf2-antioxidant response element (ARE) signaling pathway. It has been recognized that the Nrf2 signaling pathway is crucial for microbial infections [15].

When the Nrf2/keap1/ARE pathway is activated, it can stop the production of cytokines and chemokines that cause inflammation by working with the inflammasome NLRP3. By turning on Nrf2, inflammation can be reduced, making it easier for macrophages to do their job of phagocytosis more effectively. Ozone could be an excellent way to treat systemic bacterial illnesses, especially those caused by multidrug-resistant (MDR) pathogens, because it often increases Nrf2 activity and expression. Doctors may look into the effect of ozone because it may help activate Nrf2 expression, which is a reliable way to boost the natural immune system’s ability to fight off microbes. Activating Nrf2 can also start autophagy, a cellular process that helps the body’s natural defense by getting rid of bacteria inside cells and damaged organelles. Autophagy and phagocytosis are two processes that work together to get rid of trash and harmful substances from cells. The process of Nrf2-mediated autophagy makes it easier for macrophages to get rid of viruses inside cells [16].

Current research on PD, dental infections, and inflammation has emphasized these conditions’ anti-inflammatory, anti-OS, and anti-apoptotic properties [17]. Additionally, Nrf2 prevents OS, lowers osteoclast activation, and regulates periodontal cells’ growth, differentiation, and death to avoid periodontitis [13]. The restoration of damaged cell function is finally accomplished by increasing the mRNA expression of many antioxidant genes, including NQO1 and heme oxygenase-1 (HO-1), which Nrf2 activates. Therefore, to restore their diminished osteogenic potential and improve periodontal bone regeneration, activating Nrf2 in PDLSCs in a specific way is essential to inhibit inflammation-induced premature senescence [18]. For instance, periostin protects periodontal tissue, although its role in developing periodontitis is still debatable. Researchers focused on the role of periostin in periodontitis and the underlying mechanism. In rodent periodontal ligaments and lipopolysaccharide (LPS)-induced periodontal ligament fibroblasts (PDLFs), periostin expression is reduced. In PDLFs, LPS promoted the generation of ROS and the ensuing cell death, but N-acetylcysteine prevented this from happening. Periostin overexpression mitigated the inhibitory impact of LPS on nuclear Nrf2 expression, lowering PDLFs’ programmed cell death. Additionally, the Nrf2 inhibitor lessened periostin’s protective impact against LPS-induced cell death. LPS caused PDLFs to undergo programmed cell death by suppressing the Nrf2/HO-1 pathway and lowering the periostin expression. The implication is that periostin might be a viable target for periodontitis treatment [19]. Along with its anti-inflammatory and osteogenesis actions, ginsenoside Rg1 (GS-Rg1) is an active ginseng extract. The release of inflammatory factors IL-6 was markedly decreased, and the release of transforming growth factor TGF-β1 was markedly elevated after applying GS-Rg1. Furthermore, GS-Rg1 enhanced RUNX2 and OCN expression while decreasing osteoclast populations. GS-Rg1 was discovered to decrease Keap1 expression while increasing the associated protein Nrf2 expression. By acting on the Keap1/Nrf2 pathway, GS-Rg1 has the potential to relieve periodontitis. Finally, Zhou et al. offered the first evidence of GS-Rg1’s potential as a treatment for periodontitis in a preclinical setting [20].

This work comprehensively examines the current effects of Nrf2 on dental infectious disorders, including periodontitis, PI, infected dentin, and root canal reinfection. Additionally, we have covered the pros and cons of using Nrf2 as a therapeutic target for dental diseases. The information may be utilized to develop therapeutic options by targeting Nrf2 as a therapeutic target to cure dental infections.

Nfr2 in Bacterial Infection

The formation of oxygenated metabolites results from the final electron acceptor, oxygen, being employed in the mitochondrial energy metabolism of a cell. They are frequently referred to as ROS due to their strong reactivity. O^2.−, H₂O₂, OH.⁻, and singlet oxygen are among the most common examples [21, 22]. Most ROS are considered harmful due to their ability to damage cells. Consequently, several cellular defensive mechanisms are implemented to regulate and manage them. OS is defined as a state of imbalance between the systems that promote oxidation (prooxidant) and those that counteract it (antioxidant) [23]. The oxidation of numerous essential host macromolecules results from elevated levels of OS, which results in cellular injury [24].

A distinct type of microbial infection has also been demonstrated to increase OS significantly. It is intriguing to observe that this infection-induced OS is essential for activating innate immunity, which aids the body in combating harmful microorganisms. As a result, the preservation of the cellular components of the host cell and the conservation of a germ-free environment are contingent upon the effective management of OS within the cell [25]. Mammalian cells have evolved a unique antioxidative defense mechanism to mitigate the detrimental impact of OS. The purpose of this mechanism is to be deactivated in normal conditions [26]. Conversely, OS induces the activation of an oxidant-sensitive molecule, which subsequently stimulates the transcription of several genes involved in cytoprotection and detoxification. This function is facilitated by a transcription factor known as nuclear factor erythroid 2p45-Nrf2 [27].

This transcription factor is extensively researched and known for its ability to detect and respond to oxidants and electrophiles as an antioxidative agent. This protein comprises six conserved Nrf2-ECH homology (Neh) domains, comprising a basic leucine zipper structure [28]. Under normal conditions, it combines with KEAP1, a well-known negative regulator of Nrf2 [29]. The KEAP1 protein adapts the E3 ubiquitin ligase based on cullin-3. This complex, which consists of two Nrf2/KEAP1 units, regularly instructs Nrf2 to be ubiquitinated before being broken down by the proteasome [30]. Studies have shown that the twenty-five cysteine residues of KEAP1, particularly susceptible to conjugation by various ROS-inducing agents, are redox-sensitive. The oxidant-sensing mechanism of these residues is essential for regulating the E3 ubiquitin ligase activity. The ubiquitination (Ubq) of Nrf2 by KEAP1 was significantly reduced after it was conjugated [31]. Nrf2 can enter the nucleus and form a complex with several coactivators, including one of the tiny Maf proteins. This frees up the KEAP1-mediated restriction. The complex then attaches to AREs in the promoter regions. This makes it easier for several genes that protect cells and get rid of dangerous substances to be made. Some of these genes are HO-1, NAD(P)H quinone oxidoreductase-1 (NQO-1), glutamate-cysteine ligase catalytic and regulatory subunits (GCLC and GCLM), glutathione S-transferase (GST), uridine diphosphate glucuronosyltransferase (UDPGT), superoxide dismutase (SOD), catalase (CAT), glucose 6-phosphate dehydrogenase (G6PD), and glutathione peroxide (GSH) [32, 33]. The transcription factor, in turn, Nrf2 regulates the expression of genes involved in substance detoxification and the OS response, which governs the cell’s defense against toxic and oxidative assaults [34]. During a microorganism infection, phagocytic cells generate an abundance of oxidants that aid in eliminating pathogens but can also occasionally result in tissue damage [35].

Consequently, modulating OS may be a significant host-defense mechanism during an infection [36, 37]. Bacteria, viruses, and parasites have been shown to affect the Nrf2/Keap1 pathway in numerous biological systems [38]. In the absence of ROS, pathogens can also induce Nrf2 through agonism of the Toll-like receptor (TLR), as demonstrated by several studies. ROS are produced by various microbial infections, which can significantly activate Nrf2 [39]. Furthermore, the activation of Nrf2 is also protective against Staphylococcus aureus (S. aureus) and polymicrobial infections; however, the extent to which this is contingent upon developing disease tolerance remains uncertain [40].

The Nrf2-Keap1-ARE pathway is the primary regulator of phase II detoxification and antioxidant genes [41]. Detoxification is the most crucial technique for protecting the body’s cells from harmful substances, and many people worldwide are regularly exposed to high amounts of toxins [35]. The Nrf2/ARE-dependent gene is a critical cellular defense mechanism that activates phase II detoxification and antioxidant enzymes in response to OS or xenobiotic stress. This process functions as a crucial chemopreventive mechanism [42]. The Nrf2 protein, encoded by the NFE2L2 gene, regulates around 250 genes that play a role in maintaining cellular balance, including antioxidant proteins, detoxifying enzymes, drug transporters, and various cytoprotective proteins [43]. The successful interaction between Nrf2 and the ARE/EpRE (electrophilic response element) and the formation of a heterodimer between Nrf2 and minor Maf proteins (MafG, MafK, and MafF) are essential for the expression of Nrf2-controlled genes [44].

Ubq is a process wherein a protein containing 76 amino acids modifies substrate proteins covalently. All eukaryotic organisms, including yeast and humans, express this enzyme machinery. The three-step enzymatic cascade known as Ubq causes ubiquitin to be transferred from its C-terminal glycine to the ε-amino group of a lysine residue on the substrate. This process is facilitated by enzymes E1, E2, and E3. One of the most common changes to proteins after translation is Ubq. Most biological proteins will undergo Ubq at least once throughout their lifespan, since thousands of Ubq sites on thousands of proteins have been discovered [45]. Furthermore, Ubq is essential for many physiological functions, including innate and adaptive immunity, cell survival and differentiation, and many more [46]. Furthermore, separating Nrf2 from Keap1 inhibits its Ubq, increasing its half-life from 15 to 180 min. Nrf2 promotes the expression of genes that protect cells and detoxify toxins. This happens when Nrf2 forms a complex with coactivators and binds to the promoter regions (AREs) after entering the nucleus. Furthermore, activating Nrf2 improves the efficacy of the innate immune system, which can decrease or eliminate a variety of bacterial and viral illnesses [47]. Inflammation, an indispensable secondary defense mechanism of innate immunity, is crucial in eliminating invasive pathogens such as bacteria, viruses, fungi, and other parasites [48]. The inflammatory response may also stimulate the adaptive immune system, which results in lymphocytes producing either antibody-dependent or cell-mediated immune responses to eliminate the pathogenic insult. Nevertheless, the inflammatory processes may become uncontrolled, leading to cellular injury, tissue loss, and a chronic form of expression [49] (Fig. 1). An example of a condition where immunological imbalance or malfunction is thought to play a crucial role is recurrent oral ulcers (ROUs) of oral mucosa disease. These ulcers often recur and are infamously difficult to cure. Periplaneta americana extract (PAD), a raw ingredient used in Yunnan Baiyao toothpaste and Kangfuxin Liquid, has several growth factors that aid tissue healing. Among them are polypeptides and sticky sugar amino acids, which may promote granulation tissue formation and reduce wound surface inflammation. Li et al. examined the effect of PAD as a therapeutic for rats with recurrent mouth ulcers and clarified how the TLR4/NF-κB and Nrf2/HO-1 signaling pathways influence this action. In conclusion, PAD may restore normal serum IgA, IgG, and IgM levels and control the proportions of CD3⁺ and CD4⁺ cells in peripheral blood and the CD4⁺/CD8⁺ ratio. This helps keep the immune system in check. PAD reduces inflammation in the oral mucosa of ROU rats by increasing the expression of IL-2 and IL-10 while suppressing the production of IL-6, TNF-α, and IL-1β. Oral ulcer wounds may heal more quickly with PAD because it stimulates VEGF expression and granulation tissue formation. Additionally, PAD may stabilize OS and immunity in ROU rats by stimulating Nrf2/HO-1 signaling and inhibiting TLR4/NF-κB signaling. Thus, the therapy of ROU is affected by PAD’s symptoms [50].

Fig. 1.

Regulation of Keap1/Nrf2 signaling: a schematic representation. An adverse impact on the expression of Nrf2, Nrf1, and Nrf3. Protease activity maintains Nrf2 expression at a low level under typical conditions. After Keap1 binds to and sequesters Nrf2 in the cytoplasm, the Keap1-Cul3-Rbx1 complex ubiquitinates it, and the proteasome breaks it down. GSK-3 inhibits Nrf2’s activity and may promote Nrf2 degradation. To draw in the E3 ligase adaptor TrCP, GSK-3 phosphorylates Nrf2. Keap1 is not required for the ubiquitin-proteasome degradation of Nrf2, which GSK-3/-TrCP initiates. 4) Positive regulation of Nrf2: Nrf2 separates from Keap1 and moves to the nucleus in response to increased ROS levels, where it initiates the transcription of antioxidant genes, including HO-1 and NQO1 [52, 53]

By examining its interactions with Nrf2, Yu et al. investigated how overexpression of the breast cancer susceptibility gene 1 (BRCA1) affected oral cancer cells’ migration, proliferation, and death. Overexpression of BRCA1 increased the expression of Nrf2 and the transcripts and proteins produced by its target genes. CCK-8 and scratch test results showed that BRCA1 overexpression decreased cell proliferation and CAL-27 cell migratory potential. According to flow cytometry, overexpression of BRCA1 promoted cell mortality in a time-dependent manner, and the enzyme-linked immunosorbent assay showed that it decreased the levels of 8-OHdG expression in CAL-27 and DOK cells. According to immunohistochemistry studies, oral squamous cell carcinoma cells exhibited increased Ki-67 and Nrf2 target gene expression. Research using oral cancer cells verified that overexpressing BRCA1 might increase Nrf2 signaling pathway activity, decrease oxidative damage, and suppress cell growth, among other biological effects. Oral cancer may be linked to the BRCA1 and Nrf2 pathways [51].

Sampath et al. investigated how P. gingivalis impacts the expression of glycogen synthase kinase 3 beta (GSK-3β), Nrf2, tetrahydrobiopterin (BH4), and NOS in primary human aortic endothelial cells (pHAECs). P. gingivalis reduced the viability of pHAECs 24 h after infection. Endothelial NOS (eNOS), Nrf2, and time-dependently decreased levels of Phase II enzymes (HO-1, CAT, SOD-1) were all affected by Pg infection. The infected cells and media showed significant rises in the inflammatory markers (IL-1β, IL-6, and TNF-α). At 12 and 24 h, inducible NOS mRNA levels spiked, but they dropped at later times. The mRNA levels of dihydrofolate reductase (DHFR), an enzyme involved in eNOS production and the salvage pathway, decreased significantly, but the mRNA levels of GSK-3β were raised. According to researchers, periodontal bacterial infection may alter the endothelium GSK-3β/BH4/eNOS/Nrf2 pathways, which can impede vascular relaxation. To treat vascular illnesses caused by PD better, investigators need to better understand the variables that negatively impact endothelial cell function [54].

To better understand how a high-fat diet (HFD) causes hepatic steatosis in apolipoprotein E (ApoE) knockout (KO) mice, Wu et al. investigated the role of Fusobacterium nucleatum (F. nucleatum) in this process. Significant alterations were seen in ApoE KO mice with an HFD and infected with F. nucleatum. These alterations included increased body and liver weight, high serum and liver proinflammatory cytokines and lipid levels, neutrophil infiltration, fibrosis, apoptosis, OS, and lipid peroxidation in the liver. F. nucleatum also inhibits the Nrf2/Keap1 antioxidant pathway while activating de novo lipogenesis (DNL) and hepatic fat buildup. Finally, researchers showed that oral inoculation of F. nucleatum could impede the Nrf2/Keap1 pathway, which might lead to hepatic steatosis [55].

Infections with Candida albicans (C. albicans) and smoking both increase the likelihood of developing various oral illnesses. Cigarette smoking is strongly associated with C. albicans infection, according to many studies. Nevertheless, the precise process of maintaining this link is not yet known. To study the role of smoking in C. albicans infection, Ye et al. set up an infection model in rats and a co-culture model with and without smoke exposure using C. albicans and Leuk1 epithelial cells. Additionally, samples of oral mucosa were examined based on smoking status in both healthy persons and patients with oral leucoplakia. Scientists found that tobacco use caused redox dysregulation and OS in the mouth’s mucosa. The NLRP3 inflammasome was adversely regulated by smoking-induced Nrf2, which increased susceptibility to C. albicans and weakened the oral mucosal defensive response. The Nrf2 pathway may contribute to the pathogenesis of oral diseases by controlling an antioxidant response to exposure to cigarette smoke and lowering host immunity against C. albicans [56].

Researchers have shown that Clostridium butyricum (CB) improves the body’s ability to fight off dangerous substances and lessens the damage that OS does. Researchers looked into Enterotoxigenic Escherichia coli (ETEC) K88, used as a model for infectious organisms, and how CB can lower oxidative damage. Li et al. focused on the gut microbiota and the signaling pathway, including p62, Keap1, and Nrf2. When people were exposed to 4.4 × 10⁶ CFU/mL of CB before being infected with ETEC, their MDA levels went down, and their SOD and GSH-Px levels went up in the blood. Furthermore, this pre-treatment can significantly raise the mRNA expression levels of tight junction proteins and genes connected to the p62-Keap1-Nrf2 signaling pathway in the liver and jejunum of animals infected with ETEC K88. Also, the amount of Lactobacillus significantly increased after being given a dose of 4.4 × 10⁶ CFU/mL CB. When 4.4 × 10⁶ CFU/mL of CB was given to mice infected with ETEC K88, the amounts of short-chain fatty acids (SCFAs) in their cecum increased. A strong link was found between the quantities of SCFAs and reactive markers and the presence of Lachnoclostridium, Roseburia, Lactobacillus, Terrisporobacter, Akkermansia, and Bacteroides. Mice given 4.4 × 10⁶ CFU/mL CB before being exposed to ETEC K88 had less oxidant damage. This occurs when the cecal microbiota composition changes and the p62-Keap1-Nrf2 signaling cascade is accelerated [57].

The regular operation of the intestines is disrupted by ETEC, a significant gastrointestinal illness that is widely recognized. During the infection, tight-junction protein expression was downregulated, and serum diamine oxidase activity and D-lactate levels were significantly elevated in the small intestine’s middle portion. This pointed to an increase in intestinal permeability and a decrease in gastrointestinal function. In addition, the infection impeded the activation of Nrf2, which reduced the production of enzymes responsible for the synthesis of glutathione, SOD-1, and HO-1 in the intestine. As a result, there was a reduction in the levels of the antioxidant glutathione and an elevation in lipid peroxidation in both the gut and serum, suggesting the occurrence of OS. The infection produced cytokines, such as TNF-α and IL-6, that promote inflammation. Antibiotics helped reduce OS by increasing the colon’s antioxidant enzyme production and partly restoring glutathione levels. This medication enhanced the intestinal tract’s functioning by boosting the production of tight-junction proteins. The OS was effectively reduced, and glutathione supplementation restored tight-junction protein expression to normal levels. Researchers suggested that the body’s capacity to protect against antioxidants may be compromised and that OS levels in the intestine may increase due to diminishing Nrf2 activation. Following an infection, the function of the intestine can be improved by reducing OS [58].

Another study discovered that macrophages are critical in the innate immune defense process. Investigators looked at the impact of sulforaphane (SFN) on macrophages’ ability to destroy germs, as well as the precise biochemical pathways involved. Investigators also looked at how the microenvironment affects macrophage activation. Many studies have used THP-1, a human leukemia monocytic cell line, to examine the transport of nutrients and drugs and the processes and activities of monocytes and macrophages. In addition, a model of S. aureus infection was executed using macrophages derived from human THP-1 cells, primary human peripheral blood mononuclear cells, and primary mouse bone marrow. Deramaudt et al. showed that pre-treating macrophages with SFN effectively suppressed S. aureus survival within the cells by altering the p38/JNK signaling pathway and lowering S. aureus-induced cell apoptosis, which depends on caspases-3/7. This effect could be achieved by inhibiting the expression of microRNAs (miRs) 142-5p and 146a-5p. SFN, a well-known Nrf2 stimulator, was tested against Nrf2^−/− BMDMs to show that its inhibitory effect was independent of Nrf2. However, there has been a documented increase in the capacity of microbes to persist within macrophages that lack Nrf2. In response to S. aureus infection, SFN pretreatment inhibited the transcriptional expression of genes encoding proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and M1 markers (C-C motif chemokine receptor 7, IL-23, and iNOS). The p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) MAPK signaling pathways were activated by the S. aureus exposure. However, the activation of p38 and JNK was diminished by pretreatment with SFN. The prior treatment of two distinct inhibitors, SB203580 and SP600125, which target p38 and JNK, respectively, resulted in a decrease in the expression levels of S. aureus-induced proinflammatory genes, in comparison to the levels reported in macrophages pretreated with SFN. Additionally, the survival of intracellular S. aureus was significantly diminished in macrophages that were generated from THP-1 cells and treated with SB203580 or SP600125 before bacterial infection. Researchers suggest that the potential therapeutic method for treating S. aureus infection could be successful if SFN addresses both the p38/JNK-inflammatory response and S. aureus-induced apoptosis [59].

The Ingenuity Pathway Analysis demonstrated that Nrf2 signaling, a transcription factor essential for antioxidant responses, is predominantly upregulated in the blood exposed to S. aureus compared to Escherichia coli (E. coli). Additionally, distinct cytokine profiles were generated using pharmacological substances that predominantly targeted the Nrf2 pathway, contingent upon the specific type of bacterial infection. These data also emphasize the precise pathways that should be targeted to reduce bacterial-specific reactivity and illustrate the significant inflammatory dysregulation between E. coli and S. aureus [60].

Apart from their primary function in phagocytosis and pathogen killing, neutrophils have also been linked to the development of granulomas in many infectious illnesses. Reducing inflammation without sacrificing the host’s ability to fight germs, Nrf2 controls antioxidant protection in neutrophils. Araújo et al. examined the immunoexpression of Nrf2 and whether or not neutrophils were present in Paracoccidioides brasiliensis mycosis (PCM). A total of 39 instances of oral PCM were categorized based on the number of fungi, the existence of microabscesses, and whether the granulomas were loose or well-organized. Immunohistochemistry was performed using an Nrf2 antibody. Microabscesses and loose granulomas had neutrophils, but organized granulomas did not. The fungus was higher in instances with loose granulomas than in situations with both loose and well-organized granulomas. Neutrophils from loose granulomas and abscesses maintained consistent Nrf2 expression in their nuclei, even though the underlying material was well-organized. Scientists have postulated that neutrophils contribute to PCM formation, and Nrf2 may regulate the inflammatory response, which in turn helps neutrophil survival [61].

Nrf-2 has several beneficial roles and controls HO-1. Ginkgo biloba (G. biloba)’s anti-inflammatory properties have been connected to HO-1 expression. RAW264 was studied by Ryu et al. to determine if G. biloba’s anti-inflammatory qualities were linked to Nrf-2-mediated HO-1 synthesis; seven macrophage cells were treated with P. gingivalis LPS. To extract G. biloba, ethyl acetate (EGB) was used. Due to its anti-inflammatory properties, EGB decreased nuclear translocation of transcription factors, MAP kinase activation, and pro-inflammatory mediator levels. EGB also boosted HO-1 expression, transactivity, and nuclear Nrf-2 levels. Additionally, the impact of EGB on lowering pro-inflammatory mediator levels was reversed by the addition of SnPP. Researchers identified the mechanism by which EGB reduces inflammation as the up-regulation of Nrf-2 in RAW 264.7 cells triggered by P. gingivalis LPS [62].

The Role of Pathogenic Bacteria in Dental and Periodontal Infections

A distinct and intricate microbiota colonizes the oral cavity, forming a variety of biofilms on all mucosal and dental surfaces [63]. The primary etiology of dental infections is the invasion of the pulp by bacteria, which then spreads to the adjacent tissues. Infections can also affect the gums, resulting in gingivitis, which can progress to PD [64]. The microbiota in the oral cavity is incredibly diverse. The mouth’s humidity and temperature provide the ideal conditions for developing structured bacterial communities [65]. These biofilms develop on hard surfaces, such as teeth and the soft tissue of the stomatognathic system. It is important to emphasize that these communities are intricate structures that consist of a wide range of bacterial species with varying levels of harmfulness [66]. Dental plaque biofilms that contain periodontal pathogens can lead to PD. The disease’s manifestation is influenced by the virulence of the bacteria, the host immune system, and environmental factors such as smoking [67].

Compared to cariogenic infections, commensals have a clear advantage when the host’s diet lacks fermentable carbohydrates, particularly sucrose. Many oral health-related commensal bacteria can attach to saliva-coated tooth surfaces with more vigor, outgrow Streptococcus mutans (S. mutans) and other aciduric species, and thwart their establishment and proliferation in various ways. Conversely, sugar may significantly change the “microbial battlefield” by promoting acid production, manufacturing an extracellular polymeric substance (EPS) matrix, and creating isolated acidic microenvironments. S. mutans and other aciduric species may work together in these conditions to modify the biofilm community, structure, and metabolism to encourage caries development [68].

PD, a common health problem, is caused by an imbalance between bacteria and the host’s ability to defend against them, influenced by environmental factors. Research conducted in multiple countries suggests that the more severe forms of PD affect around 5–20% of the population. In recent years, mouth bacteria, especially periodontal infections, have been recognized as significant contributors to the development of other disorders, including respiratory illnesses [69]. Orofacial infections have been a source of concern for individuals since the inception of human history. Extraction of teeth, endodontic treatments, and surgery are the primary treatment options for the preponderance of oral infections with an odontogenic etiology [70]. Periodontitis is a global epidemic that affects over one billion individuals. The bacteria found in tooth plaque, including P. gingivalis, T. forsythia, Treponema denticola, P. intermedia, and A. actinomycetemcomitans, are the main cause of PDs [71]. Periodontitis, an inflammatory immune disease, also affects the periodontal ligaments and gums. Many illnesses, both communicable and non-communicable, are associated with periodontitis. These include diabetes, heart disease, rheumatoid arthritis, and cancer. Because inflammation, microbial byproducts, and bacteria may travel to other organ systems, periodontal disease and systemic disorders are believed to have an oral-systemic relationship. Swallowing saliva carries germs from the mouth to the digestive tract, where they cause dysbiosis and gastrointestinal problems. P. gingivalis, Klebsiella, Helicobacter pylori, Streptococcus, Veillonella, Parvimonas micra, F. nucleatum, Peptostreptococcus, Haemophilus, A. actinomycetomcommitans, and S. mutans are periodontal pathogens that can survive in the gut and cause dysbiosis there. Inflammation and dysplastic alterations brought on by gut dysbiosis are the root causes of gut dysfunction. Numerous studies have shown a connection between oral bacteria and the gut-microbiota axis and various gastrointestinal ailments, including Crohn’s disease, ulcerative colitis, inflammatory bowel disease, liver diseases, hepatocellular and pancreatic ductal carcinoma, and many more [72]. Furthermore, bacteria like the periodontal pathogens T. denticola and C. pneumoniae were found in postmortem Alzheimer’s disease brains, indicating that some periodontal infections may enter the brain across the blood-brain barrier in addition to inflammatory mediators. Studies on animals verified this by demonstrating that P. gingivalis was present in mouse brains. Additionally, older Alzheimer’s patients had greater antibodies against A. actinomycetemcomitans, P. gingivalis, T. forsythia, F. nucleatum, and P. intermedia than healthy controls. Additional longitudinal research will be required to establish a direct correlation between periodontal infections (and antibodies against them) and neurodegeneration in Alzheimer’s disease, even if these pathogens seem to be linked to Alzheimer’s disease symptoms [73, 74]. Furthermore, individuals with chronic renal illness had higher rates of C. albicans, P. gingivalis, T. forsythia, and T. denticola, which are linked to more severe chronic periodontitis [75].

After root canal treatment (RCT) fails, it is crucial to eliminate pathogens and diseased tissue, including Enterococcus faecalis (E. faecalis), one of the most often recovered species from the root canals. To achieve RCT’s objectives, the anatomical complexity of root canal systems should be filled with appropriate filling materials that have antibacterial, biocompatible, and sealing qualities. However, it has been shown that E. faecalis is resistant to the medication and filling materials [76].

Various bacteria are often found in peri-implant infections, and new research suggests that PI dysbiosis is comparable to alterations in periodontitis. Similar microbial pathogens, such as T. forsythia, P. gingivalis, several Fusobacterium species, including F. nucleatum, P. intermedia, P. nigrescens, and A. actinomycetemcomitans, were discovered in PI and periodontitis lesions in a systematic review on the condition. According to researchers, the microbiological makeup of PI is more complicated and has a different microbiological profile from periodontitis. This includes greater levels of enterics, various yeast species, Peptostreptococci, Streptococci, Treponema denticola, and Staphylococci [77].

Nevertheless, the prescription of antibiotics may be essential. The oral biofilm consists of various bacteria that interact cooperatively or competitively. Teeth offer durable, non-shedding surfaces where oral bacteria can accumulate and persist as dental plaque [78, 79]. Bacterial buildup and processing on the rigid surfaces of the inner cheeks are the main factors behind tooth decay, gum inflammation, gum disease, infections around dental implants, and mouth ulcers [80]. The oral epithelium is the protective barrier that divides the oral cavity from the outside world. The primary purpose of the oral mucosa is to protect against illnesses, wounds, and foreign objects [81–84]. By promoting proper oral hygiene, reducing alcohol and tobacco consumption, managing stress, and receiving comprehensive treatment to alleviate the adverse effects of oral biofilm, PD and its associated diseases can be prevented [85] (Fig. 2).

Fig. 2.

Several dental infections, including periodontitis, dentin, root infection, and PI

In the following sections, we have reviewed how to treat infectious dental conditions, such as periodontitis, PI, dentin, and root canal infection.

Periodontitis Surgical and Non-surgical Treatment Methods

The disparity of microorganisms in susceptible individuals is the cause of periodontitis, a prevalent, long-lasting inflammatory disease. Severe periodontitis is believed to affect more than 11% of adults worldwide [86]. Treatment for periodontitis aims to stop the disease’s development, reduce the chance of losing teeth, lessen its symptoms and perceptions, perhaps restore lost periodontal tissue, and educate people about the need to keep their periodontium healthy [87]. Given the lack of a single treatment technique that has conclusively proven to be superior, the use of additional antimicrobial chemotherapy is beneficial for almost all types of mechanical periodontal treatment [86]. The initial treatment of periodontitis is predicated on nonsurgical methods. Scaling and root planing (SRP) significantly reduce the subgingival microbial burden by eliminating dental biofilm, calculus, and bacterial endotoxins. In the non-surgical treatment of periodontitis, oral hygiene training is crucial for the patient to manage plaque through frequent mechanical removal. In this phase of treatment, it is imperative to address periodontal local and systemic risk factors, including tobacco consumption, occlusal interferences, and overhanging restorations (Clinical trial number: not applicable) [88]. Nonsurgical periodontal treatment has been demonstrated to manage periodontal infection and avoid disease progression in a substantial percentage of cases [89]. Nevertheless, for pockets exceeding a depth of 6 mm, it is often recommended to undergo surgical treatment in addition to systemic antibiotics and/or adjuvant medicines. When treating patients with aggressive periodontitis and chronic sickness (previously known as periodontitis), combining systemic antibiotic medication with traditional mechanical treatment produces superior clinical results compared to using SRP alone [90, 91].

Nevertheless, the clinician frequently employs empirical evidence to substantiate the use of antibiotics in conjunction with periodontal care. Amoxicillin (AMX) plus metronidazole (MTZ) is the most practical combination of antibiotics for lowering clinical parameters, such as bleeding on probing, probing depth in medium and deep pockets, and the rise in clinical attachment level [92].

For example, tooth roots’ concave and furcation regions are inaccessible to tools and harbor infection in PDs. Dental biofilm traps caused by defective restorations near the furcation region might cause periodontal illness. Retrograde periodontitis and furcation involvement (FI) may result from endodontic perforations that allow endodontic infection to move into the furcation region [93]. Furthermore, SRP, a method that scrapes the tooth surface inside the periodontal pocket to eliminate subgingival bacterial deposits, is successful in several clinical studies. Currently, no strategy has shown to be more efficient or successful than SRP in conjunction with systemic AMX and MTZ for the treatment of periodontal disease. Some proponents have proposed that these medications should be rationed for individuals with certain microbiological profiles. Unfortunately, there is little data to support clinical regimens that include bacteriology. Recolonization with a microbiota comparable to before treatment occurs in treated areas. The treatment plan, the pattern of periodontal microbe distribution in the mouth, and the patient’s oral hygiene habits all have a role in the severity and rate of recolonization. Additional work has to be done to improve treatments that deal with the colonization and recolonization of the periodontal pocket by microbes to reduce antibiotic use and the cumulative negative effects of recurrent therapy [94].

People with diabetes have an almost threefold greater chance of developing periodontitis, according to epidemiological research, making diabetes a key risk factor for the disease. The degree of hyperglycemia correlates positively with the severity of periodontitis. Immune system function, neutrophil activity, and cytokine biology are all implicated in the poorly understood processes that underlie the associations between these two disorders. New research suggests that diabetes and periodontitis are inversely related; that is, diabetes increases the incidence of periodontitis, and inflammation in the gums has a detrimental effect on glycaemic management. Diabetic persons with severe periodontitis had a twofold greater risk of macroalbuminuria and a threefold increased risk of end-stage renal disease compared to diabetic individuals without severe periodontitis. On top of that, diabetics with severe periodontitis have three times the risk of cardiorenal mortality compared to diabetics without severe periodontitis (defined as the combined risk of ischemic heart disease and diabetic nephropathy). Reductions in hemoglobin A1c of around 0.4% are linked with periodontitis treatment. Diabetes care plans should prioritize improving patients’ oral and periodontal health [95]. Combination pharmacological therapy for periodontitis is necessary for the inflammatory management in some individuals with systemic disorders, such as diabetes and periodontitis [96, 97]. In diabetic patients, for instance, a combination of SRP and systemic doxycycline is more effective than SRP alone in reducing gingival inflammation; nevertheless, this alone is insufficient to avoid periodontal tissue damage [98].

Peri-implantitis Surgical and Non-surgical Treatment Methods

The most common remedy for tooth loss and damage is dental implants. Even with technological advances, implant failure rates can still approach 23% when the underlying cause is a multispecies bacterial infection called PI. The 8.78% annual increase in implant placements makes implant failure due to bacterial infections a severe dental and general health concern [99]. The increasing antibiotic resistance of oral bacteria increases the risk of implant failure, requiring additional care to increase the success of dental implants. Deep soft tissue infections linked to implants are notoriously difficult to treat with antibiotics because of their widespread occurrence and frequent connection with methicillin-resistant S. aureus (MRSA). Incision, drainage, and continuous high-dose antibiotic treatment are usually necessary to accomplish this goal. It is more likely, though, that these strategies will aid in developing bacteria into superstrains. Bacterial communities, often known as biofilms, exhibit enhanced resistance to removal from subsurface sites, such as implants, due to their robust adhesion and rapid reproductive capacity. There is a growing number of instances where antibiotic treatment is not practical, leading to the development of persistent systemic infections in humans. Hence, it is imperative to find antibiotic-free techniques that can effectively treat infections that impact deep tissues at their original location [100].

PI can be treated using either non-surgical or surgical therapies. However, the effectiveness of these approaches is still uncertain due to insufficient reliable data [101]. Although the therapeutic efficacy of the nonsurgical approach is restricted, it is advantageous in mitigating soft tissue inflammation, including bleeding on probing (BoP) [102]. The access flap approach, which involves open flap debridement, reduces inflammation near the implant by directly executing debridement and exposing the implant surface [103].

Surgical treatment is advised for cases with bone deficiencies above the crest of the gum, with visible threads, in locations where appearance is not a significant concern. Implantoplasty is a surgical operation that aims to reduce or eliminate abnormal tissue pockets around dental implants. It incorporates techniques such as removing or reshaping the bone, adjusting the gum tissue, and modifying the implant surface if necessary [104]. Surgical procedures for PI produced superior results compared to non-surgical interventions [105]. The main goal of non-surgical treatment is to assist patients in effectively removing biofilm daily and thoroughly cleaning the implant, interrupting biofilm growth and eliminating calculus [106].

Dentin and Dental Root Infection Treatment Methods

Streptococci are frequently detected microorganisms that infiltrate dentin. Recent research indicates that streptococci can identify and attach to specific components, like collagen type I, in dentinal tubules. This enables the bacteria to proliferate and grow within the tubules. Particular bacterial groups may invade dentin with the help of specific interactions between other oral bacteria and invading streptococci [107]. There is a strong correlation between microorganisms in necrotic root canals and the formation of apical inflammatory lesions on intraoral radiography. Usually, the condition referred to as “primary apical periodontitis (AP)” is resolved with a root canal treatment that includes the removal of diseased tissues using chemical and mechanical methods, followed by filling the root canal. If root canals are not successfully treated, they might develop a persistent infection known as “secondary AP.” Additionally, roots treated for secondary AP have different microbial communities than untreated roots. Certain bacteria have demonstrated the ability to endure the impact of conventional antimicrobial medications and remain viable for multiple years in teeth that have undergone root canal treatment. Much research has been dedicated to studying Enterococcus faecalis (E. faecalis). This bacterium is commonly found as a single kind of bacteria in teeth that have undergone root canal treatment but is rarely seen in untreated root canals [108].

The surgical extraction of retained root tips is a common outpatient treatment performed by dentists and dental specialists. To effectively manage residual roots, one must understand dental morphology, current root removal procedures, indications, and contraindications [109]. To remove inflammatory or infected tissue inside a tooth, a widespread operation in modern dentistry is the root canal treatment, sometimes called endodontic treatment. Each tooth contains pulp, a sort of soft tissue that is located beneath the layers of enamel and dentin [110]. A root canal procedure involves the removal of diseased or inflammatory pulp tissue. The pulp chamber and root canal are thoroughly cleansed and refilled to protect the area from additional harm. The root canal treatment method is a good solution with numerous potential benefits for people who have severe inflammation or infection in the pulp of a tooth [111]. Without treatment, the infection may spread to cause substantial discomfort or the creation of an abscess behind the tooth, affecting the tooth’s strength and function [112].

Nrf2 in Periodontitis

Researchers clarified the processes behind Nrf2-mediated anti-apoptosis in periodontal ligament stem cells (PDLSCs) within the oxidative environment of periodontitis. Researchers employed PDLSCs treated with H₂O₂ to create an OS model. Researchers observed that elevated levels of MDA and ROS indicated OS during H₂O₂ treatment. The activation of downstream effectors, including HO-1, NQO1, and γ-GCS, was facilitated by the effect of H₂O₂ exposure on oxidative molecules, which stimulated Nrf2 signaling. Furthermore, OS-induced apoptosis is brought on by a decrease in Bcl-2 and an increase in caspase-9, caspase-3, Bax, and c-Fos levels. However, the caspase-8 concentrations did not change. The overexpression of Nrf2 raised cell proliferation and anti-oxidative levels, but the improved antioxidant impact did not lower the incidence of apoptosis. At the same time, overexpression decreased the molecular levels of caspase-9, caspase-3, Bax, and c-Fos but not caspase-8 and successfully stopped TUNEL staining. In contrast, the opposite outcome was obtained when Nrf2 expression was inhibited. Nrf2 inhibits intrinsic apoptosis, modifies OS, and activates oxidative enzymes to decrease PDLSCs [113] (Fig. 3).

Fig. 3.

The regulation of PLSC apoptosis by Nrf2 in periodontal disease. By regulating OS and inhibiting intrinsic apoptosis by inducing oxidative enzymes, Nrf2 mitigates PDLSCs [113]

Researchers discovered new therapeutic targets and how Nrf2 controls OS and inflammatory reactions in periodontitis. At first, researchers find that the periodontium goes through a redox mismatch because the Nrf2 signaling pathway is blocked. Low oxygen levels and bacterial events cause this. Then, researchers showed that stopping the PI3K/AKT/mTOR pathway, sequentially blocking crosstalk between the selective autophagy SQSTM1/p62 and Keap1/Nrf2 axis, strengthening Nrf2 Ubq degradation, and turning off Nrf2 nuclear translocation could stop the growth of hPDLCs and GSH levels, increase ROS production, lipid peroxidation levels, and pro-inflammatory cytokines like IL-6, TNF-α, and IL-17. Overexpression of Nrf2 and SQSTM1 can increase Nrf2 activity, protecting hPDLCs from worsening OS and inflammation. Furthermore, puerarin’s antioxidant and anti-inflammatory qualities have been proven in vitro and rodents with experimental periodontitis by mechanically weakening the negative feedback loop researchers discussed earlier. In general, researchers think that Nrf2-mediated redox homeostasis plays a key part in the development of periodontitis and suggest that puerarin could be used as a therapeutic target [114].

The researchers investigated the impact of P. gingivalis on the expression of glycogen synthase kinase 3 beta (GSK-3β), Nrf2, tetrahydrobiopterin (BH4), and NOS in primary human aortic endothelial cells (pHAECs). Endothelial NOS (eNOS), Nrf2, and Phase II enzymes (HO-1, CAT, SOD-1) mRNA expression levels were decreased by P. gingivalis infection in a time-dependent manner. The medium and the infected cells exhibited a substantial increase in inflammatory markers, including IL-1β, IL-6, and tumor necrosis factor-α. The levels of inducible NOS mRNA demonstrate a considerable increase at 12 and 24 h, followed by a decrease in the subsequent periods. This is a critical observation. mRNA levels of DHFR, an enzyme that is implicated in the production of BH4 (a cofactor of eNOS), decreased significantly, while GSK-3β levels increased. The GSK-3β/BH4/eNOS/Nrf2 pathways can be altered by periodontal bacterial infection, resulting in reduced vascular relaxation. The development of novel therapeutic medications for the treatment of vascular issues caused by PD could be facilitated by a greater understanding of the mechanisms that impede the normal functioning of endothelial cells [54]. Up to 80% of the plaque matrix in periodontal health comprises oral streptococci. Nevertheless, the periodontium is not frequently subjected to inflammation that causes damage. As a critical factor in their capacity to induce disease, oral streptococci generate H₂O₂. The antioxidant defense in mammalian cells is enabled by the activation of Nrf2 by H₂O₂. Researchers investigated whether the Nrf2 pathway in macrophages was activated by oral streptococci that generated H₂O₂ and if this activation affected the innate immune response. It has been shown that oral streptococci inhibit the normal immune response by reducing H2O2 levels and activating Nrf2. Inhibiting NF-ĸB, a crucial transcription factor that controls the pro-inflammatory response, activated the Nrf2 signaling pathway. Researchers showed that oral streptococci, previously believed to be passive spectators, may actively prevent inflammation to maintain periodontal health [115]. In addition, studies have shown that Nrf2 can decrease the transcription of genes linked with NLRP3, including pro-IL-1β and pro-IL-1α. This suggests that Nrf2 could be used as a pharmacological inhibitor for PD. Teles et al. discovered a correlation between these bacterial species and increased levels of proinflammatory cytokines, such as IL-1β and IL-18. Therefore, it is postulated that these bacteria, acting as pathogen-associated molecular patterns (PAMPs), have a role in the development and advancement of PD by stimulating inflammasome activity and directing the NLRP3-mediated inflammatory response (Clinical trial number: not applicable) [116]. Moreover, an in vitro experiment showed that periodontal pathogenic bacteria, including P. gingivalis, A. actinomycetemcomitans, and F. nucleatum, are accountable for the increased expression of NLRP3. Multiple signaling pathways have been demonstrated to both trigger and worsen the progression of PD. It is imperative to thoroughly investigate and understand these factors to regulate them effectively, as they may hold the secret to preventing or treating PD [116–118].

Polymorphonuclear leukocytes (PMN)-induced OS contributes significantly to the deterioration of periodontal health by damaging neutrophils and anaerobic periodontal bacteria [113, 119]. In addition, activated PMNs can potentially cause significant harm to gingival epithelial cells, as their oxidants and proteases can weaken periodontal tissues. Furthermore, the increase in the percentage of receptor activators of nuclear factor kappa B ligand (RANKL) to osteoprotegerin caused by ROS inhibits bone remodeling. This disruption leads to the formation of osteoclasts and the subsequent degeneration of alveolar bone [120]. The hyperactive and hyper-reactive PMN phenotypes are thought to be primarily caused by an impaired redox potential, specifically a loss of control over the Nrf2-mediated antioxidant system. Nrf2 is an important transcription factor that regulates genes responsible for anti-oxidative response elements, which are vital for maintaining the balance of periodontal tissue [121].

A different investigation has demonstrated that OS plays a substantial role in chronic periodontitis with diabetes mellitus (CPDM) [122]. Zhu et al. indicated the potential therapeutic advantages of baicalein (BCI) in treating OS-related disorders. The researchers intend to study the possibility of BCI in alleviating periodontal tissue damage linked with diabetes by changing the Nrf2 signaling pathway. The researcher’s results indicated a large increase in levels of ROS in both the high glucose (HG) and LPS groups. The glucose-potentiated (GP) group demonstrated the greatest levels of all the groups. Researchers noticed a significant drop in the messenger RNA (mRNA) levels of Nrf2, Cat, Gclc, SOD-1, and SOD-2 in both the HG and LPS groups, genes linked with ROS. The GP group had the greatest production of ROS, which was related to a much lower level of gene expression than the HG and LPS groups. Furthermore, the expression of pNrf2 demonstrated a similar pattern to that of the antioxidant genes. Before GP, the injection of different dosages of BCI (0.01, 0.1, or 0.5 µg/mL) significantly reduced ROS formation and the mitochondrial membrane potential. It was found that BCI had a considerable effect on the translocation of pNrf2 into the nucleus and the levels of gene expression for both pNrf2 and its target genes. Researchers showed that in the CPDM animal model, administering BCI at dosages of 50, 100, and 200 mg/kg increased pNrf2-positive cells in periodontal tissue and reduced alveolar bone loss [123].

OS may be lessened by resveratrol, a phytochemical having anti-inflammatory and antioxidant qualities [124]. Researchers predicted that resveratrol would reduce systemic OS and stop the development of periodontitis via activating the Nrf2/antioxidant defense pathways and the sirtuin 1 (Sirt1)/AMP-activated protein kinase (AMPK) pathway. By activating the Sirt1/AMPK and Nrf2/antioxidant defense pathways in inflammatory gingival tissues, Melinjo resveratrol supplementation decreased the resorption of alveolar bone. In addition, Melinjo resveratrol increased the body’s levels of nitrotyrosine, nitric oxide metabolism, proinflammatory cytokines, dityrosine, and 8-hydroxydeoxyguanosine. Researchers have shown that Melinjo resveratrol taken orally raises systemic oxidative and nitrosative stress and slows the development of ligature-induced periodontitis [125].

Paeonol is a phenolic molecule that comes from the Moutan Cortex. It has many health benefits, such as anti-inflammatory and antioxidant properties [126]. Researchers looked into how paeonol might help avoid periodontitis caused by ligation in rats and what those benefits might be. When 40 and 80 mg/kg of paeonol were injected into the abdominal cavity for 7 days, the expression of receptor activator of NF-κB ligand went down, the expression of osteoprotegrin went up, and the formation of osteoclasts was stopped. Paeonol can reduce inflammation by focusing on IL-1β, IL-6, and TNF-α. It can also lower OS in gingival tissues by controlling the amounts of SOD, MDA, GSH, and ROS. In addition, paeonol made Nrf2 start up faster. Using siRNA to target Nrf2 specifically made paeonol less able to stop NF-κB p65 from activating and subsequently gene expression. This shows how vital Nrf2 is to paeonol’s beneficial effects. By changing the Nrf2/NF-κB/NFATc1 signaling system, paeonol stopped the production of osteoclasts and the progression of bone damage in periodontitis [127].

In a separate investigation, magnolol, derived from the Chinese medicinal herb Magnolia officinalis, was found to be anti-inflammatory and to protect against periodontitis. Researchers explored whether magnolol reduces P. gingivalis LPS-induced inflammatory responses in RAW 264.7 macrophages and the involvement of HO-1. Magnolol substantially boosted p38 MAPK, Nrf2/HO-1 cascade, and ROS production. Decreasing p38 MAPK activity and ROS production inhibited magnolol-induced Nrf2 activation and HO-1 induction. Magnolol therapy successfully reduced inflammatory responses in macrophages activated by P. gingivalis LPS. Pro-inflammatory cytokines, prostaglandin E2, nitrite production, inducible NOS (iNOS) and cyclooxygenase-2 expression, NF-κB activation, and Nrf2 nuclear translocation and HO-1 expression/activity were all suppressed during this decrease. However, the anti-inflammatory effects of magnolol were significantly counteracted when tin protoporphyrin IX inhibited HO-1 function. Researchers suggested that magnolol, at least in part, inhibits P. gingivalis LPS-induced inflammation in macrophages via activating HO-1. This discovery boosts the potential clinical value of magnolol in treating periodontitis [128]. Also known to control macrophage homeostasis and cellular activity is the non-selective cation channel protein transient receptor potential vanilloid 1 (TRPV1). According to immunohistological research, mice afflicted with periodontitis had significantly lower levels of macrophage TRPV1 expression. These macrophages’ TRPV1 expression was shown to be efficiently elevated after treatment with capsaicin, a TRPV1 agonist. Using micro-computed tomography, capsaicin treatment also significantly reduced alveolar bone resorption compared to vehicle and healthy control groups. Li et al. demonstrated that capsaicin administration effectively reduced intracellular ROS levels by lowering LPS-induced TNF-α and IL-6 production in macrophages, which was mediated by NRF2 activation. According to researchers, a new way to treat periodontal disease might be using TRPV1 agonists, which modulate M1 macrophage activity and upregulate TRPV1 [129].

Significant antioxidant activity was shown by Ixeris dentata (IXD) and Lactobacillus gasseri medium (LGM), suggesting that they may be used to treat oxidative and inflammatory periodontitis. IXD/LGM decreased pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Additionally, it inhibited the activation of pro-inflammatory mediators such as nitric oxide, iNOS, and COX-2 while increasing the activation of AKT, Nrf2, and HO-1. Similarly, osteogenic proteins and mRNAs as alkaline phosphatase, collagen type 1 (COL1), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2) were elevated in response to IXD/LGM therapy. Hematoxylin and Eosin (H&E) staining and micro-CT analysis show that IXD/LGM positively affects inflammation and periodontal structure. Researchers suggested that IXD/LGM works via the Akt-Nrf2 pathway to decrease OS, periodontal inflammation, and the ensuing loss of alveolar bone. routes for HO-1 signaling. IXD/LGM may thus be employed as a substitute therapy for periodontitis brought on by oxidative/inflammatory stress [130].

NRF2 in Peri-implantitis

NFE2L2/Nrf2, Parkinsonism-associated deglycase (PARK7/DJ-1), KEAP1, and 8-hydroxy-deoxyguanosine (8-OHdG) expression levels in peri-implant mucosal tissues impacted by PI were evaluated and contrasted with samples of periodontally diseased and healthy tissue by Kasnak et al. The infiltration of inflammatory cells into the connective tissue and the disintegration of the epithelial spinous layer are characteristics of PI. PARK7/DJ-1 and 8-OHdG staining levels were considerably greater in patients with periodontitis and PI than in the control group. In both groups, NFE2L2/Nrf2 expression was comparable. KEAP1 was absent from every tissue sample [131].

Rehmannia glutinosa roots contain catalpol (CA), an anti-inflammatory and antioxidant. In the setting of type 2 diabetes (T2D), researchers examined the impact of CA on titanium implant (TI) osseointegration and clarified the pharmacological processes at play. High glucose and high lipid (HGHL)- induced OS causes osteoblast failure by reducing Nrf2 signaling through the AKT/GSK3β/FYN pathway. CA treatment reduced OS and reactivated AKT/GSK3β/FYN/Nrf2 signaling, significantly restoring HGHL-induced dysfunctions in MC3T3-E1 cells. This was confirmed by reduced apoptotic damage and increased osteoblast adhesion, proliferation, and differentiation. Furthermore, the beneficial effects of CA in vivo were corroborated by better TI osseointegration in T2D mice models, as demonstrated by microcomputed tomography and histological examinations. Nonetheless, the introduction of LY294002 substantially eliminated CA’s pro-osteogenic effects. CA treatment decreases the impairment in TI osseointegration in T2D conditions via activating the AKT/GSK3β/FYN pathway, which stimulates Nrf2. CA treatment has the potential to be a reliable therapeutic technique for implant repair in patients with T2D in the future, given its pro-osteogenic and antioxidative properties [132].

Investigators investigated the ability of TIs with micro/nanotopographies to reduce OS and promote bone regeneration in diabetic rats, which are widely utilized as an osteoporosis model. Furthermore, researchers studied the effects of these implants on cellular OS in models induced by H₂O₂, LPS, and hyperglycemia. The application of a TiO₂ nanotube (TNT) coating on TIs promotes better bone tissue formation and integration with the surrounding bone compared to the microscale sand blasted-acid etched topography (SLA) under OS due to increased activity of SOD-2, elimination of ROS within cells, and reduced cell death. The improved resistance to oxidation in TNT is primarily related to the overexpression of the forkhead box transcription factor O1 (FoxO1), which is inhibited in MSCs when FoxO1 is knocked down by shRNA. TNT indirectly lowers OS in macrophages, leading to a rise in the production of M2 morphologies under OS. These M2 phenotypes then release more IL-10, an anti-inflammatory cytokine, promoting osseoimmunity more efficiently than SLA. Investigators proposed a systematic assessment strategy for the future progress of bone biomaterials, while also proposing the prospective usage of TIs coated with TNTs in problematic settings [133].

NRF2 in Dentin and Dental Root Infection

Investigators identified xenogeneic extracellular matrices (xECM) as a possible solution to the shortage of donor matrices for allotransplantation by providing cell support. However, the negative impact of high OS and inflammation levels on seed and stem cell survival may be blamed for the poor success rate or failure of xECM-based organ transplantation [134]. To prevent the OS from destroying the roots, scientists created xenogeneic bioengineered dental roots (bio-roots) that included extracellular vesicles produced from human adipose-derived mesenchymal stem cells (hASC-EVs) [135]. Fu et al. showed that pretreatment with hASC-EVs reduced DNA damage, mitochondrial changes, cell apoptosis, and ROS generation. In addition, by activating the PI3K/Akt pathway and speeding up the translocation of NFE2-Nrf2 to the nucleus via KEAP1 degradation, hASC-EV treatment significantly decreased oxidative damage. Odontogenic and osteogenic cell differentiation, antioxidant ability, and cell proliferation were all enhanced by this. Inhibition of PI3K/Akt and suppression of Nrf2 resulted in decreased antioxidant capacity, indicating that the PI3K/Akt/Nrf2 pathway is partly responsible for these effects. Research using Sprague-Dawley rats found that hASC-EV treatment improved the bio-root’s antioxidant effect, increased the regeneration efficiency of periodontal ligament-like tissue, and made xenografts work better. In conclusion, hASC-EVs can potentially alleviate OS-induced bio-root resorption and degradation by acting as an antioxidant and immune modulator. This capability may be sped up by making and regenerating various intricate tissues and organs [135].

Dental pulp tissue has many mesenchymally derived dental pulp cells (DPCs), which protect it from environmental threats. HDPCs are pluripotent and can develop into odontoblasts, osteoblasts, endotheliocytes, and neurons. Cinnamaldehyde (CNM) has a range of functional qualities, including anti-cancer, antibacterial, anti-inflammatory, and antioxidant activity. Investigators investigated how CNM’s intracellular signaling systems influenced the OS response in hDPCs. CNM showed no cytotoxicity or morphological alterations at doses up to 50 µM. CNM treatment greatly increased cellular HO-1 protein levels and Nrf2 nuclear translocation. CNM-mediated Nrf2/HO-1 activation decreased ROS levels while protecting hDPCs from H₂O₂-induced OS, which causes apoptosis. Furthermore, siRNA-mediated decrease in HO-1 reduced CA-mediated cell protection against OS. Investigators showed that CNM protects hDPCs from OS by activating Nrf2 and boosting HO-1 levels. Researchers suggested CNM is a promising therapeutic drug for protecting cells from OS [136].

Yang et al. developed a mouse model using human periapical tissues to assess the role of ferroptosis in AP. Colocalization labeling verified that ferroptosis in macrophages amplifies the inflammatory bone loss linked to AP. The ferroptotic properties of this model were presented. Another feature was that Nrf2 levels declined in ferroptotic macrophages, and ROS levels dropped because Nrf2 overexpression enhanced FSP1. It was also shown that ferroptotic macrophages released TNF-α, which activated the p38 MAPK signaling pathway and caused a significant increase in ROS accumulation in macrophages. The capacity of mouse bone marrow stromal cells (BMSCs) to produce new bone was shown to be decreased by TNF-α released by ferroptotic macrophages, according to in vitro co-culture tests. Researchers’ results showed that the Nrf2/FSP1/ROS signaling pathway may be disrupted by the TNF-α autocrine-paracrine loop in ferroptotic macrophages, inhibiting bone formation in BMSCs. In AP, this leads to bone loss. Researchers have highlighted ferroptosis as a potential therapeutic target for inflammatory bone illnesses [137].

Song et al. determined how Nrf2 contributes to chronic apical periodontitis (CAP)-related bone resorption. E. coli LPS also helped create an inflammatory milieu at the levels of osteoclasts and osteoblasts. One way to analyze the proliferation and differentiation of osteoblasts and osteoclasts was to suppress the expression of Nrf2. The AP group had significantly greater Nrf2 expression than periodontal ligament tissue from healthy individuals. In the mouse AP model, Nrf2 expression increased as inflammation progressed. In LPS-induced inflammation, Nrf2 expression decreased, promoting osteoclast and osteoblast development and specialization. Nrf2 influences the development and specialization of osteoclasts and osteoblasts. It plays a part in the CAP process and might hasten the development of bone loss [138].

Conventional microbial identification methods have demonstrated the presence of E. faecalis in endodontic infections, particularly in the context of persistent/secondary infections. The subsequent presumption that this species is a significant factor in the failure of endodontic treatments led to the development of a variety of in vitro and ex vivo studies that tested protocols for removing E. faecalis from root canals [139]. Additionally, B. subtilis and Enterococcus faecium (E. faecium) decreased intestinal apoptosis, enhanced the downstream protective proteins HO-1 and Gpx4 expression, and controlled the OS pathway Keap1/Nrf2. Therefore, by boosting fecal metabolism and fortifying the colonic barrier, B. subtilis and E. faecium reduce colonic OS and inflammation in OA rats [140].

Peach gum polysaccharide (PGP) is a naturally occurring molecule with inherent antioxidant and anti-inflammatory properties. Researchers examined the potential protective benefits of PGP against pneumonia produced by E. faecium E745 to understand the underlying mechanism. PGP’s antioxidant benefits were validated by the normalization of MDA, SOD, and GSH levels, which happened due to the Nrf2 signaling pathway being activated. PGP lowered IL-6 and TNF-α levels in circulation, colon, and lungs, increased tight junction protein expression, and blocked the NF-κB signaling pathway. Furthermore, PGP increased the levels of propionate and butyrate, which influenced the formation of SCFA. The studies show that PGP reduces pneumonia by mending the intestinal barrier, increasing the production of SCFA, and decreasing inflammation and OS. Finally, researchers provided essential insights into the potential uses of PGP in managing inflammatory disorders [141] (Table 1).

Table 1.

Role of the NRF2 in dental infections

Dental infections	Explain the role of the NRF2	Ref
Periodontitis	Researchers discovered that BCI significantly impacted both the levels of gene expression for pNrf2 and its target genes and the translocation of pNrf2 into the nucleus. In the CPDM animal model, researchers showed that BCI at 50, 100, and 200 mg/kg reduced alveolar bone loss and enhanced the quantity of pNrf2-positive cells in periodontal tissue.	[123]
Periodontitis	Researchers suggested that resveratrol may activate the Sirt1/AMPK and Nrf2/antioxidant defense pathways, slowing the advancement of periodontitis and lowering systemic OS.	[125]
Periodontitis	Nrf2 inhibits intrinsic apoptosis, modifies OS, and activates oxidative enzymes to decrease PDLSCs.	[113]
Periodontitis	Paeonol accelerated the startup of Nrf2. When Nrf2 was directly targeted with siRNA, paeonol’s ability to prevent NF-κB p65 activation and consequent gene expression was diminished. This demonstrates the significance of Nrf2 to the positive effects of paeonol. By altering the Nrf2/NF-κB/NFATc1 signaling pathway, periodontal disease prevented the generation of osteoclasts and the advancement of bone destruction associated with periodontitis.	[127]
Periodontitis	GSK-3β levels rose, but DHFR mRNA levels, an enzyme involved in synthesizing BH4, an eNOS cofactor, dropped noticeably. A periodontal bacterial infection can change the GSK-3β/BH4/eNOS/Nrf2 pathways, which reduces vascular relaxation.	[54]
Periodontal health	Oral streptococci were observed to suppress the natural immune response by activating Nrf2 and diminishing the levels of H2O2. The Nrf2 signaling pathway was activated, inhibiting NF-ĸB, a critical transcription factor that regulates the pro-inflammatory response. This may actively prevent inflammation from maintaining periodontal health.	[115]
Peri-implantitis (PI)	Patients with PARK7/DJ-1 and periodontitis/PI had considerably greater levels of 8-OHdG staining than the control group. In both groups, NFE2L2/Nrf2 expression was comparable. None of the tissue samples contained KEAP1.	[131]
PI	Under T2D circumstances, CA therapy reduces the deficit in TI osseointegration via stimulating Nrf2 through activation of the AKT/GSK3β/FYN pathway. Given its pro-osteogenic and antioxidative qualities, CA therapy can potentially be a dependable therapeutic method for implant repair in patients with T2D.	[132]
PI	Because SOD is more active when a TNT coating is applied to TIs, this results in improved bone tissue production and integration with the surrounding bone when compared to microscale sandblast-acid etched topography (SLA) under OS.	[133]
Dental root infection	Scientists created xenogeneic bioengineered dental roots (bio-roots) using extracellular vesicles derived from hASC-EVs to shield the roots from oxidative destruction. The reduction in antioxidant capacity resulted from both Nrf2 suppression and PI3K/Akt inhibition, indicating a partial contribution of the PI3K/Akt/Nrf2 pathway to these effects.	[135]
Pulp infection	Studies on decaying tooth pulp have shown a higher frequency of the TRPA1 channel, suggesting a role for TRPA1 in the tissue’s defensive or reparative response to externally induced damage.	[142]
Apical periodontitis (AP)	Researchers showed that by interfering with the Nrf2/FSP1/ROS signaling pathway, the TNF-α autocrine-paracrine loop in ferroptotic macrophages can prevent bone formation in BMSCs. In AP, this results in bone loss.	[137]

Nrf2 Inhibitors in Dental Infections

Various disorders may be treated using Nrf2 inhibitors, which target the Nrf2 pathway. These molecules can be either natural or synthetic [143]. New NRF2 modulator drugs come with a slew of difficulties. The most important things to keep in mind are the following: finding the right illness indicators, keeping an eye on target interactions and pharmacodynamic responses, considering safety in the short and long term, and knowing how much variation there is in NRF2 activity and what it means. For a new treatment to have the greatest possible impact on patients, it must solve these problems while also ensuring their safety. Approving further NRF2 activators as innovative therapeutics in the future will be the ultimate measure of progress in tackling these difficulties [144]. Phytochemicals like quercetin and biochanin A have been shown in several studies to activate Nrf2. These Nrf2-activators have the potential to control nrf2-related pathways, which in turn might minimize alveolar bone resorption, suppress the body’s inflammatory and OS responses, and effectively treat periodontal disease symptoms. One possible therapeutic inhibitor of periodontitis is Nrf2, which is postulated to have specific functional consequences for the disease. In conclusion, it is important to address the issue of Nrf2’s impact on periodontitis [145].

When dental resin materials fail to polymerize or biodegrade fully, they produce resin monomers such as triethylene glycol dimethacrylate (TEGDMA), which may severely damage the pulp cells. Due to a lack of knowledge about the mechanism behind these events, there is currently no effective treatment option for this consequence. Research conducted by Wang et al. revealed that the bioactive compound notoginsenoside R1 (NR1), derived from Panax notoginseng, has a clear protective impact against mitochondrial apoptosis in the preodontoblast mDPC6T cell line, as triggered by TEGDMA. Pharmaceutical inhibitors of the Akt/Nrf2 pathway diminished NR1-mediated antioxidant cellular characteristics and worsened mitochondrial oxidative damage in cells treated with TEGDMA. Mitophagy was shown to be a possible downstream target of the Akt/Nrf2 pathway, and NR1 also boosted it. Mitophagy and NR1 protection on TEGDMA-exposed cells were reduced by blocking the Akt/Nrf2 pathway. Researchers concluded that one potential strategy for avoiding dental pulp damage caused by resin monomers is to activate the Akt/Nrf2-pathway-mediated mitophagy via NR1 [146]. Researchers explored if ED-71 can prevent LPS-induced pyroptosis in human gingival fibroblasts (HGFs) and, if so, to uncover the underlying mechanism. To improve the clarity of the explanation, researchers included three inhibitors: NAC, which inhibits ROS; MCC950, which inhibits NLRP3; and ML385, which inhibits Nrf2. Huang et al. showed the cytotoxic effect of LPS on HGFs using the CCK8 test. Along with the production of intracellular ROS, H2O2, and lactate dehydrogenase (LDH), LPS also enhanced the synthesis of the pyroptosis-associated proteins NLRP3, caspase-1, and IL-1β. LPS increased NLRP3, caspase-1, and IL-1β levels, which were decreased by NAC and MCC950 administration. Through activating the Nrf2/HO-1 signaling pathway, ED-71 pretreatment effectively decreased LPS-induced pyroptosis. ML385 prevented ED-71’s beneficial effects. Researchers demonstrated that, via activating the Nrf2/HO-1 pathway, ED-71 can prevent pyroptosis. Furthermore, it showed that ED-71 can repair LPS-induced pyroptosis via the NLRP3 inflammasome in HGFs. Researchers found that ED-71 may be an effective treatment option for periodontitis [147].

Xiong et al. assessed how curcumin (CUR) affects the Nrf2 signaling pathway and the osteogenic development of PDLSCs in an inflammatory milieu. PDLSCs were effectively identified and grown, creating an in vitro inflammatory milieu. According to CCK8 and ALP activity data, CUR at low concentrations was not harmful to PDLSCs in an inflammatory state. It also increased ALP activity, with 0.1 µmol/L being the ideal value. Subsequent research revealed that CUR increased ALP, COL1, and RUNX2 proteins and mRNA and ALP activity. The trend of osteogenesis and the change in Nrf2 level were comparable. Nrf2’s protein level dropped in the siNrf2 model. The LPS + CUR + siNrf2 group showed lower osteogenic indices and lighter ALP staining than the LPS + CUR group. In an inflammatory situation, CUR, which is linked to the Nrf2 signaling pathway, may reverse the osteogenic differentiation of PDLSCs [148].

Motivated by the adhesive qualities of mussels, researchers created mineralized and sticky hydrogel microspheres filled with the traditional chemical cordycepin (MMS-CY). MMS-CY may improve PDLSC mobility and draw them to the inflamed periodontal tissues by attaching themselves to the surface of the alveolar bone. Furthermore, MMS-CY restored the impaired osteogenesis and ligament-forming capacity of PDLSCs, suppressing the inflammatory stimulation. Additionally, MMS-CY had a strong inhibitory impact on osteoclastic activity. Mechanistically, MMS-CY decreased DNA damage and blocked the Nrf2 pathway, which causes premature senescence brought on by the inflammatory stimuli. Using the in vivo rat periodontitis model, MMS-CY enhanced periodontal bone regeneration by increasing osteogenesis and decreasing osteoclastic activity. Overall, scientists discovered that the multimodal approach could foster periodontal bone regeneration in cases of periodontitis by maintaining bone homeostasis and reducing inflammation-induced stem cell senescence [18]. Using 3-amino phenylboronic acid (PBA) and poly(vinyl alcohol) (PVA) to form a borate bond with hyaluronic acid, researchers developed an injectable hydrogel that reacts to ROS in a different study. Additionally, the periodontal microenvironment released the ROS-responsive hydrogel’s anti-inflammatory Fe-Que NPs and antibacterial drug minocycline hydrochloride (MH). This hydrogel (HP-PVA@MH/Fe-Que) has potent antibacterial properties. Additionally, the Nrf2/NF-κB pathway was regulated to eliminate ROS. To reduce inflammation, the periodontal microenvironment polarized macrophages to an M2 phenotype and enhanced the osteogenic differentiation potential of hPDLSCs. According to data from animal studies, HP-PVA@MH/Fe-Que may reduce inflammation and kill bacteria, reducing alveolar bone loss and boosting the synthesis of osteogenic components. Consequently, HP-PVA@MH/Fe-Que hydrogel showed encouraging anti-inflammatory, antibacterial, and ROS-scavenging qualities, making it a viable option for applications involving the healing of periodontitis [149].

Researchers showed that notopterol can stop the formation of osteoclasts, which stops the breakdown of alveolar bone in living things. The in vitro results showed that notopterol treatment decreased the production of inflammatory mediators like IL-1β, IL-32, and IL-8 in HGFs that LPS had activated. It is known that notopterol stops the stimulation of the NF-κB signaling pathway, which is a proinflammatory signaling pathway. Notopterol turns on the PI3K/Akt/NF-E2- Nrf2 signaling pathway in HGFs that LPS has activated. Notopterol also increased the activity of antioxidant genes like HO-1, NQO1, CAT, and glutathione reductase (GSR), which decreased the levels of ROS. This means that notopterol may help protect against reactive stress. MK-2206, a potent inhibitor, weakened notopterol’s antioxidant and anti-inflammatory effects by stopping Akt action. Researchers demonstrated that notopterol might treat periodontitis well by turning on the PI3K/AKT/Nrf2 pathway and stopping the NF-κB pathway in periodontal tissue [150].

Researchers developed a nano platform by incorporating baicalein (BA) into a flexible metal-organic framework (MOF) utilizing mesoporous prussian blue (MPB) nanoparticles. The baicalein loaded mesoporous Prussian blue (MPB-BA) nano platform is a reservoir and protective environment for the immunomodulatory medication BA, which is vulnerable to bacterial, inflammatory, and antioxidant influences. As a result, MPB-BA can utilize its antioxidant and anti-inflammatory characteristics to remove intracellular ROS, leading to the conversion of macrophages from the M1 to M2 phenotype and ultimately decreasing inflammation. The primary molecular process involves the excessive synthesis of phosphorylated Nrf2, which removes ROS and subsequently blocks the NF-κB signaling pathway. Furthermore, MPB-BA exhibited remarkable photothermal antibacterial efficacy against periodontal infections under near-infrared (NIR) light. The in vivo RNA sequencing data revealed significant antioxidant and anti-inflammatory pathways activation following MPB-BA therapy. Moreover, the therapeutic advantages of MPB-BA were validated compared to minocycline hydrochloride using immunohistochemical labeling of p-Nrf2 and p-P65 and micro-CT imaging. Investigators improved their understanding of how periodontitis is treated by altering the Nrf2/NF-κB signaling pathway using photothermal bioplatform-assisted immunotherapy [151].

Four-octyl itaconate (4-OI), a form that can pass through cell membranes, is a possible target for treating inflammatory illnesses. Researchers looked into whether 4-OI could help stop the underlying cause of periodontitis and whether it could also lower inflammation and protect against periodontal damage. Researchers showed that 4-OI treatment improves the periodontal microenvironment by reducing the inflammation caused by LPS. 4-OI turns on Nrf2, which lowers swelling and bone loss in the alveoli. This was proven by looking at samples from C57BL/6 mice with experimental periodontitis. To prove this, Nrf2 was turned off, which decreased the antioxidant action of 4-OI by reducing the activity of the following antioxidant enzymes. The molecular docking modeling also helped determine a likely way for Nrf2 to be activated. In Nrf2^−/− mice, 4-OI did not protect the maxillary bone from damage caused by periodontitis. This shows how vital Nrf2 is for treating gingivitis caused by 4-OI. The study showed that 4-OI can lower inflammation and OS by starting the Nrf2 signaling pathway and breaking up the KEAP1-Nrf2 complex. When applied locally, 4-OI has much therapeutic promise for stopping gum disease and reducing swelling in the area. Some people think this could make it easier to predict when periodontitis will happen [152].

Turmeric’s main ingredient, CUR, is found in minimal amounts in ginger. Many cruciferous veggies have SFN as a chemical, and it is found in them. People have gotten resveratrol from red wine, blueberries, grapes, and nuts. Some of the other plant substances are epigallocatechin gallate (EGCG), green tea extract, and ginseng fruit extract. Experiments done in living things and the lab have shown that all of these substances are good antioxidants and very good at reducing inflammation by activating Nrf2 in models of periodontitis. For example, BCI, the main chemical in Scutellaria baicalensis, can control the Keap1-Nrf2 system in two ways: one that doesn’t depend on Keap1 and one that does [153, 154].

Postbiotics are regarded as more reliable than probiotics in terms of clinical safety, and as such, they can be evaluated as potential agents that affect the host. The Nrf2 pathway has been demonstrated to be stimulated by various postbiotics, which leads to a reduction in oxidative damage and inflammation in periodontitis. In patients with high-risk or non-responsive periodontitis, the utilization of postbiotics as Nrf2 activators can be particularly advantageous. There is a dearth of evidence in laboratory studies that postbiotics can be employed to alter the body’s response to oral stimuli. In certain strains of Lactobacillus bacteria, linoleic acid can be converted into isomeric intermediates, which are fatty acids. The antioxidant response is influenced by ketoC, a fatty acid, through its action on the Nfr2-ARE pathway. KetoC therapy reduces ROS levels by increasing ERK phosphorylation, which results in the migration of Nrf2 into the nucleus. This, in turn, induces the expression of genes associated with antioxidants in gingival epithelial cells. The expression of HO-1 is regulated by Nrf2, a protein extensively investigated for its capacity to protect against freezing-induced injury and regulate the immune system. A surfactin derived from B. subtilis has been found by researchers to activate Nrf2 and increase the production of HO-1. The output of VCAM-1 caused by particulate matter is reduced by surfactant, which increases the activation of HO-1 in HGFs [155].

Despite its widespread usage in prosthodontics, the biocompatibility of cobalt-chromium (Co-Cr) dental alloys is still debated. Researchers looked into the potential molecular mechanisms of Co-Cr alloys on HGFs and osteoblasts in an in vitro model, particularly emphasizing NF-E2-Nrf2 pathways. The Co-Cr alloy significantly increased ROS generation and harmed HGFs and osteoblasts, as demonstrated by FACS and cell viability. Furthermore, Co-Cr alloys raised the levels of pro-inflammatory cytokines and other inflammatory mediators in both cells. According to a mechanistic study, co-Cr alloys upregulate antioxidant enzymes, including HO-1, and promote the Nrf2 pathway. Signaling pathways such as NF-κB, p38/ERK/JNK MAPKs, and JAK2/STAT3 were enhanced by Co-Cr alloys. In Co-Cr alloy-stimulated HGFs and osteoblasts, antioxidants and HO-1 inhibitors significantly decreased ROS production, inflammatory mediator activation, and NF-κB signaling. Researchers demonstrated that Co-Cr alloys upregulate downstream HO-1 and activate the Nrf2/ARE signaling pathway, which results in cytotoxicity and inflammation. Modifying these effects may be one way to control the inflammatory reactions to Co-Cr alloys [156].

Aseptic laxity (AL) is the main reason total hip arthroplasty (THA) fails and must be redone. When someone has AL, osteolysis is a big deal because it happens when wear particles come off of device surfaces. Even though previous studies have shown that wear particles always cause osteoblasts to die during the AL process, no one knows exactly how this happens. Osteoblast ferroptosis could be a new way for AL to work. CoCrMo nanoparticles (CoNPs) were created so researchers could look into how ferroptosis affects osteoblasts and calvaria loss in animal models. Periprosthetic osteolytic bone tissue was obtained from patients with AL after THA to confirm that osteoblast ferroptosis was genuine. According to the researchers'results, coNPs significantly triggered particle-induced osteolysis (PIO) in animal models and ferroptosis in osteoblasts. In a laboratory context, particle-induced ferroptosis was significantly reduced by a particular regulator known as ferrostatin-1. Also, CoNPs greatly reduced the production of Nrf2, a vital part of the antioxidant response, in osteoblasts. When Nrf2 was overexpressed in osteoblasts using siKeap1 or the Nrf2 promoter, Oltipraz, AREs increased greatly while ferroptosis decreased. Also, when Ferrostatin-1 and Oltipraz were used together, they greatly lowered the levels of osteolysis and ferroptosis in PIO animal models. The results show that CoNPs improve osteoblast ferroptosis by changing the Nrf2-ARE signaling pathway. Researchers showed a new way for PIO to work and a possible way to treat AL [157] (Table 2).

Table 2.

NRF2 inhibitors in various dental diseases

Dental infections	NRF2 inhibitors	Explain	Ref
Periodontitis	ML385	Researchers demonstrated that ED-71 can inhibit pyroptosis by triggering the Nrf2/HO-1 pathway. Furthermore, it demonstrates that ED-71 can restore LPS-induced pyroptosis by activating the NLRP3 inflammasome in HGFs.	[147]
Periodontitis	Notopterol	Investigators suggested that by activating the PI3K/AKT/Nrf2 pathway and inhibiting the NF-κB pathway in periodontal tissue, notopterol may be a useful treatment for periodontitis.	[150]
Periodontitis	MPB-BA	By eliminating intracellular ROS, MPB-BA can use its antioxidant and anti-inflammatory properties to change macrophages from the M1 to M2 phenotype, reducing inflammation.	[151]
Periodontitis	Four-octyl itaconate (4-OI)	Researchers showed that 4-OI can lower inflammation and OS by starting the Nrf2 signaling pathway and breaking up the KEAP1-Nrf2 complex.	[152]
HGF and osteoblasts	HO-1	Antioxidants and HO-1 inhibitors significantly reduced ROS production, inflammatory mediator activation, and NF-κB signaling in Co-Cr alloy-stimulated HGFs and osteoblasts. This is the first study to demonstrate that by upregulating downstream HO-1 and activating the Nrf2/ARE signaling pathway, Co-Cr alloys induce cytotoxicity and inflammation.	[156]
Osteoblast ferroptosis	CoCrMo nanoparticles (CoNPs)	CoNPs significantly reduced the production of Nrf2, an essential part of the antioxidant response in osteoblasts. When Nrf2 was overexpressed in osteoblasts using siKeap1 or the Nrf2 promoter, Oltipraz, AREs increased significantly while ferroptosis decreased. CoNPs improve osteoblast ferroptosis by changing the Nrf2-ARE signaling pathway.	[157]

The Role of the Nrf2 Activators in Dental Infections

Many synthetic or extracted compounds, often derived from plants, operate as Nrf2 activators. CUR, SFN, kahweol, resveratrol, garlic organosulfur compounds, zerumbone, epigallocatechin-3-gallate, carnosol, compounds based on cinnamon, lycopene, and cafestol are a few examples of natural Nrf2 activators [158]. For novel therapeutic applications, many electrophilic Nrf2 activators go through preclinical or clinical studies [159]. Furthermore, the activation of the Nrf2 signaling pathway depends on amino acids. Research has shown that several amino acids, including aspartate, glutamine, and glutamate, may increase the cell’s Nrf2 activity. The Nrf2 regulates glutamine absorption and metabolism as a nitrogen donor in the TCA cycle. Additionally, Nrf2 controls the expression of a crucial protein called ATF4, which is required to control the synthesis of asparagine and the glutamine SLC1A5 transporter, which prevents an excess of both asparagine and glutamine. Glutaminase, the cell’s Nrf2 target gene, is in charge of converting glutamine to glutamate [160].

At the compressive side of the periodontium, osteoclasts resorb the alveolar bone during orthodontic tooth movement. The effects of Nrf2 activation on osteoclastogenesis and, therefore, orthodontic tooth mobility and relapse were investigated by Kanzaki et al. Although catechin was only marginally affected, RANKL-mediated osteoclastogenesis was markedly reduced by SFN and EGCG. According to Western blot analysis, SFN and EGCG, but not catechin, increased the nuclear translocation of Nrf2 and the production of anti-OS enzymes like HO-1. Intracellular ROS were greatly reduced by SFN and EGCG, although catechin was only slightly reduced. Lastly, studies on animals showed that EGCG and SFN effectively stopped the movement of orthodontic teeth. SFN also prevented the recurrence. The researchers hypothesized that Nrf2 activation would be a therapeutic target for pharmacologic retention against relapse and anchoring enforcement in orthodontic therapy [161].

When it comes to Nrf2 activators, CUR has the best track record in terms of research, use, and safety, as well as its biological effects. A crucial mediator in the fight against OS, Nrf2, is also known to upregulate CUR [158]. Also, CUR inhibits ACSL4 and TfR1 expression while dramatically increasing GPX4 and SLC7A11 expression levels. Lastly, CUR prevents periodontal disease in rats caused by ligation by blocking ferroptosis [162]. In addition, CUR may enhance hPDLSC osteogenesis via a mechanism involving the PI3K/AKT/Nrf2 signaling pathway [163].

Many fruits and vegetables contain quercetin, a natural chemical with significant antioxidant properties. Reducing ROS, DNA damage, and cellular senescence, quercetin treatment of hPDLCs exposed to hydrogen peroxide boosted the expression of Nrf2, Nrf1, CAT, and HO-1. In addition, quercetin promoted osteogenesis in hPDLCs exposed to H₂O₂. In addition, there was a decrease in alveolar bone loss and an increase in Nrf2 and SOD expression in mice that were treated with quercetin for periodontitis. Consequently, quercetin may greatly enhance antioxidant status and prevent alveolar bone loss in periodontitis [163, 164].

KLF2, a transcription factor belonging to the Krüppel-like factor (KLF) family, regulates cell adhesion, proliferation, differentiation, and motility. Since overexpressing KLF2 may promote the osteogenic differentiation of hPDLSCs via Nrf2 activation, our finding supports the hypothesis that KLF2, via Nrf2, may be a viable target to increase the efficacy of PDLSC-based bone regeneration in periodontitis [165].

Tert-butylhydroquinone (T-BHQ), a Nrf2 activator, promoted osteogenic differentiation in PDLSCs treated with cyclic mechanical stretch and improved the microstructure of alveolar bone during orthodontic tooth movement in rats utilizing a micro-CT system. Nrf2 activation contributed to the osteogenic development of PDLSCs under cyclic mechanical strain. Since T-BHQ stimulates osteogenic differentiation in vitro and in vivo, it might be a good substitute for orthodontic tooth movement while alveolar bone reconstruction occurs [166]. Through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, Xi et al. demonstrated that Nrf2 activation in PDLSCs was implicated in cyclic mechanical stress-stimulated osteogenic differentiation. We found evidence of a protein-protein interaction between Nrf2 and Akt. Additionally, cyclic mechanical stress-stimulated osteogenic differentiation was linked to the protein-protein interaction between Nrf2’s downstream antioxidants, heme oxygenase 1 (HO1) and SOD-2. Orthodontic rats showed increased expression of osteogenesis markers after treatment with T-BHQ. One possible molecular target in orthodontics might be Nrf2 [167]. T-BHQ, an Nrf2 agonist, successfully reduced osteolysis and aberrant expression of antioxidant enzymes, inflammatory cytokines, and osteogenic factors downstream of Nrf2. Additionally, in a way sensitive to Nrf2 suppression, TBHQ significantly inhibited the unfavorable osteoblastogenesis and osteoclastogenesis that TiPs caused in cultured bone cells. Knockout mice for NFE2L2 showed significantly reduced osteoprotective effects of TBHQ compared to wild-type mice. Researchers pointed to Nrf2 suppression as a major cause of metal wear particle-induced osteolysis, and the methods that restore NRF2 effectively mitigate bone damage and may even lower the risk of metal implant loosening [168].

While Nrf2 activators aren’t unique in and of themselves, there are certain unique factors to consider due to Nrf2’s capacity to impact several biological processes. In a placebo-controlled Phase 3 clinical trial, four weeks after receiving bardoxolone methyl, patients with T2D and stage 4 chronic kidney disease had elevated serum levels of the liver injury markers γ-glutamyl transferase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). The slight augmentation of gene expression may not fully account for the limited number of patients who suffered 20-fold rises in blood ALT/AST levels after beginning treatment, even if Nrf2 activation was subsequently related to an increase in ALT in cultured cells and animals [144, 169, 170]. While studies of SFN have not shown comparable effects on circulating ALT/AST levels, clinical trials with DMF and omaveloxolone have. Therefore, it is yet unknown whether this is an accurate indication of the possibility of hepatotoxicity, an asymptomatic side effect of specific NRF2 activators, or a typical transcriptional response to Nrf2 activation in humans [144].

It is also important to consider how often to take an Nrf2 activator. According to tests conducted on mice, the effects of an Nrf2 activator may be felt for days after a single dosage. This is although the medication only has a half-life of a few hours. Treatment with an Nrf2 activator twice or thrice weekly for an extended period is enough to prevent non-neoplastic illness models in animals. Therefore, if you want to keep the advantages while avoiding some of the hazards, try taking your medication less often. More context-specific research, such as in the presence of oncogenic factors, is needed to confirm this hypothesis [144, 171, 172].

Many chronic illnesses are caused by inflammation and low-grade OS, and the Nrf2/KEAP1 system is a potential pharmaceutical target for controlling these processes. Researchers found many Nrf2 activators, most of which are electrophilic; some are even in the clinical trials phase. The delayed progress in medication development may be attributed to the pleiotropic effects of Nrf2 on cell physiology and the possibility of off-target effects caused by some Nrf2 activators. Research on Nrf2 inhibitors, which could significantly alter cancer treatments, is in its infancy. Future research should identify molecules with favorable pharmacokinetic and pharmacodynamic profiles to better target certain disorders [173].

Landscape and Future

Nrf2, the primary regulator of the antioxidant system, regulates the fate of cells, affecting their proliferation, differentiation, apoptosis, resistance to therapy, and the development of infectious diseases and dental infectious diseases [174]. Immune cells use ROS to inhibit infections, and the oxidative and antioxidant systems are in balance throughout periodontal health [175]. For example, ETEC is well-known worldwide as a serious bacterium that causes problems with the lining of the intestines and overall gut health. Intestinal damage and OS might result from an ETEC infection. Jin et al. used a piglet model of ETEC infection to examine the process of elevated OS and the possibility that restoring antioxidant defense may enhance intestinal integrity. Increased intestinal permeability and poor gut function were suggested by the infection-induced increases in serum diamine oxidase activity and D-lactate levels, as well as a decrease in the expression of the tight-junction protein in the mid-jejunum of the intestines. Additionally, Nrf2 activation was suppressed, and HO-1 and SOD-1 glutathione-synthesizing enzyme expression were downregulated in the intestines during the illness. As a result, OS was indicated by elevated lipid peroxidation in the serum and the intestines and a drop in the antioxidant glutathione level. The infection prompted the production of cytokines (IL-6, TNF-α) that promote inflammation. Antibiotic treatment alleviated OS by restoring glutathione levels and antioxidant enzyme expression in the gut. Intestinal function was improved, and this therapy boosted tight-junction protein expression. The expression of tight-junction proteins was repressed, and the expression of inflammatory cytokines was elevated when Caco2 cells were exposed to hydrogen peroxide, which induces OS. Supplemental glutathione significantly reduced OS, returning tight-junction protein expression levels to normal. Based on these findings, intestinal OS and a diminished antioxidant defense may arise from downregulation of Nrf2 activation. Intestinal function may be enhanced after an infection by reducing OS [176]. Moreover, CB may improve the transcriptional expression of tight junction proteins, decrease oxidative damage by ETEC K88, and increase the mRNA expression of genes linked to the p62-Keap1-Nrf2 signaling pathway. Furthermore, it could preserve the body barrier’s ability to function, lessen the oxidative damage brought on by ETEC K88, produce SCFAs, compete with dangerous bacteria for colonization sites, and promote the growth of Lactobacillus. Whether CB reduces oxidative damage via the p62-Keap1-Nrf2 signaling pathway is yet unknown [57].

Periodontal treatment aims to maintain a region devoid of inflammation and infection and, in specific cases, restore lost tissues through regeneration [177]. Although antibiotics and anti-inflammatory medicines are frequently employed as supplementary treatments for PD, it is crucial to mechanically disrupt the oral biofilm, especially for individuals with weakened immune systems. Recent research has shown that probiotics can reduce OS by activating Nrf2, which subsequently triggers the activation of antioxidant systems. Although antibiotics and anti-inflammatory medicines are frequently employed as supplementary treatments for PD, it is crucial to mechanically disrupt the oral biofilm, especially for individuals with weakened immune systems. Recent research has shown that probiotics can reduce OS by activating Nrf2, activating antioxidant mechanisms [178]. Periodontal pathogenesis is associated with diminished antioxidant capacity and elevated OS [179].

Although standard periodontal treatment is helpful in most cases, certain patients may not respond well to it. These individuals may benefit from additional medications that have direct and indirect effects on managing biofilm, such as changing the body’s immunological response [180]. The modulation of antioxidant capacity through adjunctive therapy models is a developing area of research in various medical disciplines, with a particular emphasis on Nrf2 activation. The mechanism at the root of the cellular injury caused by OS has been revealed through numerous studies of the transcription factor Nrf2 (Clinical trial number: not applicable) [181].

In cases of oral illness, the inflammasome may play a role in controlling an inappropriately large number of reaction pathways throughout the body, not just in the mouth. Understanding the NLRP3 inflammasome’s cellular and molecular biology and its connection to Nrf2 is essential to support its use as a possible medicinal target for treating and preventing inflammatory and immune diseases in the mouth. Researchers looked at what was known about NLRP3, how it might be involved in several inflammatory oral conditions, and how it might interact with Nrf2. This could lead to new ways to avoid diseases and target treatments in dentistry and oral health [117].

OS influences a diverse array of inflammatory illnesses. AP is a prevalent cause of osteolytic apical lesions (ALs), an immune system response to endodontic infection. The ligation of TLRs on the surface of phagocytes during endodontic infection triggers a variety of reactions, including activation, phagocytosis, the synthesis of ROS, the activation of humoral and cellular responses, and the production of inflammatory mediators such as cytokines and matrix metalloproteinases (MMPs). The emergence of OS within cells is caused by an increase in ROS, which disrupts the balance of normal redox reactions. The implications of ROS-induced molecular damage and altered redox signaling include bone homeostasis loss, increased pro-inflammatory mediators, and MMP overexpression and activation. This results in the breakdown of apical tissue. Conversely, OS has had a substantial impact on the evolution of atherosclerosis, leading to the establishment of a persistent inflammatory response in the artery walls. ROS are required for the host’s protection against endodontic bacterial assault and the control of cell signaling. Collectively, these pathways lead to the production and stimulation of MMPs, an inflammatory response, and disrupted bone homeostasis. In addition, the initial molecular evidence indicates a correlation between atherosclerosis and systemic OS in acute pancreatitis. Additional research is required to elucidate the intricate effects of ROS on the degradation of apical tissue and subsequent systemic illnesses, as well as the potential advantages of additional antioxidant interventions [182].

Researchers showed that the Nrf2 signaling pathway has a beneficial effect on preventing tissue damage caused by periodontitis. Furthermore, numerous medications designed to activate Nrf2 have made substantial strides in cellular and animal research. However, the precise relationship between Nrf2 and OS and the specific mechanism by which it contributes to the treatment of PD is still not fully understood. Additionally, insufficient clinical evidence supports the practical and effective clinical impact of Nrf2 activators. Although significant progress has been achieved in understanding the Keap1-Nrf2 signaling pathway, numerous unresolved issues remain [153]. These Nrf2-activators can potentially regulate Nrf2-related signaling pathways, relieving PD symptoms and decreasing alveolar bone loss. These pathways strongly connect with the growth and specialization of osteoclasts and osteoblasts. They have a role in bone-related disorders such as osteoporosis, osteoarthritis, and periodontitis by influencing the amount of bone and mineral density. It is possible to tentatively hypothesize that Nrf2 has distinct functional consequences for periodontitis, suggesting that Nrf2 could potentially be used as a therapeutic inhibitor. To summarize, further research is needed to understand the impact of Nrf2 on periodontitis [183].

Implant mucositis and PI are becoming more common. A recent study specifically looked into the underlying mechanisms of wound healing and the regeneration processes facilitated by ROS in PI. Compared to healthy persons, patients with PI have reduced expression of genes linked to osteogenesis, such as RUNX, Osterix, and β-Catenin, and increased expression of genes related to OS, such as NADPH oxidase and NOX4. This implies that the breakdown of the differentiated bone graft may be the reason for the loss of bone mass in inflammatory diseases like PI [184].

The findings from both trials provide compelling evidence that OS is a significant factor in the advancement of PI. Acknowledging that genetics, smoking, and food may influence the study’s findings is crucial. Nevertheless, there is an inconsistency in researchers’ findings when comparing PI with PD. The notable disparity between the two indicates that PI progresses due to distinct reasons or mechanisms compared to PD. Additional research is required to comprehensively understand the precise molecular and causal mechanisms underlying PI and the impact of OS on its advancement. Implementing anti-OS therapy can simplify the treatment of individuals with PI [185].

Further study will be required to understand better the regulatory mechanisms involved in oral streptococci’s generation of H₂O₂ and improve our understanding of how periodontal disease develops. Given that oral commensals naturally use the Nrf2 pathway to downregulate inflammatory responses, the investigation and identification of appropriate Nrf2 pathway modulators in the design of next-generation oral health care products for the prevention and treatment of oral inflammatory diseases is another fascinating area of additional research [115].

Conclusion

Targeting the Nrf2 antioxidant pathway could be a promising therapy technique for oral infectious illnesses such as periodontitis, AP, and PI. Nrf2 has been proven to have a vital role in infection response and protection in recent years. Activating immune cells with TLR ligands such as LPS activates Nrf2, reducing proinflammatory cytokines’ release. In severe periodontitis, the Nrf2 pathway is blocked, which leads to increased PMN levels and considerable oxidative damage. Therapeutic approaches targeting the transcription factor Nrf2 through the PI3K/Akt signaling pathway have been put forward for their anti-inflammatory and antioxidant benefits. Similarly, Nrf2 stops periodontitis by lowering OS, stopping osteoclasts from activating and managing periodontal cells’ growth, development, and death. This paper looks at the Nrf2 pathway’s structure and function and how it has recently been used to treat periodontitis. The goal is to discover more about how the Nrf2 pathway and OS are connected in the development and occurrence of periodontitis and to develop ideas for new drugs that target the Nrf2 pathway for treatment. More research is required to overcome concerns about PI and periodontitis treatment; however, researchers can offer a decisive answer. The role of Nrf in antibiotic-resistant bacteria (E. coli, S. aureus, A. actinomycetemcomitans, P. gingivalis, E. faecalis, and S. mutans) in dental infections, including periodontitis, PI, and periodontitis, should be widely investigated.

Authors' Contributions

M.A., M.Z., and R.J.A. designed the study validation with an original draft. Kh.G., Study supervision. S. K. G. Z., H. M., Searching and selecting suitable articles. W.M.T., M.A., M.J.J., S.GH., H.M., Writing and editing the original draft. All authors interpreted the data and reviewed and approved the manuscript.

Funding

There is no Funding.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

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Competing Interests

The authors declare no competing interests.