Polyphenols in Oral Health: Homeostasis Maintenance, Disease Prevention, and Therapeutic Applications

Polyphenols, a class of bioactive compounds with phenolic structures, are abundant in human diets. They have gained attention in biomedical fields due to their beneficial properties, including antioxidant, antibacterial, and anti-inflammatory activities. Therefore, polyphenols can prevent multiple chronic or infectious diseases and may help in the prevention of oral diseases. Oral health is crucial to our well-being, and maintaining a healthy oral microbiome is essential for preventing various dental and systemic diseases. However, the mechanisms by which polyphenols modulate the oral microbiota and contribute to oral health are still not fully understood, and the application of polyphenol products lies in different stages. This review provides a comprehensive overview of the advancements in understanding polyphenols’ effects on oral health: dental caries, periodontal diseases, halitosis, and oral cancer. The mechanisms underlying the preventive and therapeutic effects of polyphenols derived from dietary sources are discussed, and new findings from animal models and clinical trials are included, highlighting the latest achievements. Given the great application potential of these natural compounds, novel approaches to dietary interventions and oral disease treatments may emerge. Moreover, investigating polyphenols combined with different materials presents promising opportunities for developing innovative therapeutic strategies in the treatment of oral diseases.


Introduction
Oral and periodontal diseases such as periodontitis are among the most common human diseases worldwide, leading to tooth loss and many other oral health complications [1].As reported by the WHO, the population suffering from untreated dental caries, severe periodontitis, and oral diseases has reached 3.5 billion worldwide [2,3].Oral health affects the quality of life significantly since poor oral health can affect one's ability to eat, speak, and socialize comfortably [4].Therefore, the prevalence of oral diseases has become a major global public health concern.During the past decade, intensive research has been conducted to prevent and treat oral diseases with nutrients, including identifying nutrients as dietary supplements and developing functional foods with health-promoting benefits.
Functional foods contain natural components that have been shown to prevent diseases and promote overall health.Modern diets such as ultra-processed foods and fruit juice beverages can reduce the influence of nutrients and their components in the oral cavity because they need to stay in the mouth for a longer period to exert their beneficial effects [5].Many fruits, vegetables, and other food sources have been found to contain these beneficial components.Among these, polyphenols, which are a group of chemical compounds containing at least one phenol moiety, have been found to play a significant role in promoting human oral health and overall well-being [6][7][8].These compounds have been extensively studied for their potential in preventing and treating dental issues.
Polyphenols are bioactive compounds that are naturally produced by plants, and essential in a wide range of plant functions.They contribute to the coloration of flowers, fruits, and seeds, which helps attract pollinators and seed dispersers [9].Polyphenols also act as signal molecules that mediate plant-microbe interactions and help to defend against pathogens and predators.They are secondary metabolites that are commonly found in all human diets such as fruits, vegetables, and beverages such as tea and cocoa [10].Polyphenols are well known for their potential health benefits for humans, including antioxidant, anti-allergic, anti-inflammatory, anticancer, antihypertensive, and antimicrobial effects [7,8,11].They come into direct contact with oral tissues before being absorbed and metabolized, demonstrating great benefits for oral health directly and indirectly.
Due to the rapid accumulation of polyphenols' functions studies in the field of oral health, several informative reviews have been published recently.The work of Flemming et al. provided a thorough introduction to the sources, and metabolic pathways of polyphenols, and their preventive effects in dentistry [10].However, they did not mention the treatment application of these molecules.Kovac et al. reviewed the therapeutic potential of flavonoids and tannins, which are two major active compounds of polyphenols.The article focused on the origins of the molecules and their effects on the microorganism that causes oral infectious disease [9].Some reviews emphasized the anticancer effect of polyphenols.For example, Trisha et al. discussed the benefits of tea polyphenols and covered a broad range of cancer types for their preventive functions [12], whereas Angellotti and colleagues selectively introduced the role of resveratrol in oral squamous cell carcinoma [13].However, no review discusses the prevention and treatment effect of polyphenols in different types of oral disease and discusses the mechanism and progression of animal or clinical trials for the commercialization of functional food products.
In this review, progressions regarding the effects of polyphenols on four types of oral health, dental caries, periodontal diseases, halitosis, and oral cancer, were summarized.The mechanisms for the prevention and treatment effect of food-based polyphenols were listed, and the studies of oral disease in animal models as well as human patients were discussed, demonstrating recent achievements in the field.As these natural nutrients showed great commercial potential, new approaches to dietary interventions and oral disease treatments might be found.Safe and long-term oral health management based on polyphenol products of different formats might be beneficial to the overall well-being of humans.

Dietary Polyphenols
Dietary polyphenols refer to a class of natural compounds found in food that exhibit various biological activities and health benefits.Dietary polyphenols constitute a large group of compounds encompassing thousands of different substances.They are mainly categorized into flavonoids, phenolic acids, lignans, and stilbenes [14].Each category includes numerous individual compounds that are present in various types of foods, such as fruits, vegetables, tea, red wine, and nuts (Table 1).Flavonoids are secondary metabolites derived from chalcones and fall into various subcategories, including flavanols, flavanones, flavonols, flavones, isoflavones, anthocyanins, proanthocyanidins, etc. [15].Non-flavonoids contain phenolic acids (like caffeic acid), lignans, and stilbenes (e.g., resveratrol).Tannins can be further divided into hydrolyzable tannins and condensed tannins [16].
One of the primary functions of dietary polyphenols is their antimicrobial [17] and antioxidant activity, which contributes to overall health.They can neutralize free radicals, reduce oxidative damage to cells and tissues [18], and help prevent chronic diseases such as cardiovascular diseases [19], cancer [20], and inflammatory conditions [21].Some polyphenols, such as flavonoids, are believed to be particularly beneficial for cardiovascular health.They can lower blood pressure, improve blood vessel function, and reduce the risk of heart disease and stroke [22].Previous studies suggest that dietary polyphenols may have potential benefits in cancer prevention and treatment.They can inhibit the growth and migration of tumor cells while supporting the healthy functioning of the immune system [23].These compounds also show anti-inflammatory effects and facilitate alleviating symptoms of inflammatory conditions [21].Moreover, dietary polyphenols may have Grapes, chocolate, red wine cocoa, berries, apples, apricots, black beans, green and black teas.
One of the primary functions of dietary polyphenols is their antimicrobial [17] and antioxidant activity, which contributes to overall health.They can neutralize free radicals, reduce oxidative damage to cells and tissues [18], and help prevent chronic diseases such as cardiovascular diseases [19], cancer [20], and inflammatory conditions [21].Some polyphenols, such as flavonoids, are believed to be particularly beneficial for cardiovascular health.They can lower blood pressure, improve blood vessel function, and reduce the risk of heart disease and stroke [22].Previous studies suggest that dietary polyphenols may have potential benefits in cancer prevention and treatment.They can inhibit the growth and migration of tumor cells while supporting the healthy functioning of the immune system [23].These compounds also show anti-inflammatory effects and facilitate alleviating symptoms of inflammatory conditions [21].Moreover, dietary polyphenols may have positive effects on blood sugar control, cognitive function, digestive health, and weight One of the primary functions of dietary polyphenols is their antimicrobial [17] and antioxidant activity, which contributes to overall health.They can neutralize free radicals, reduce oxidative damage to cells and tissues [18], and help prevent chronic diseases such as cardiovascular diseases [19], cancer [20], and inflammatory conditions [21].Some polyphenols, such as flavonoids, are believed to be particularly beneficial for cardiovascular health.They can lower blood pressure, improve blood vessel function, and reduce the risk of heart disease and stroke [22].Previous studies suggest that dietary polyphenols may have potential benefits in cancer prevention and treatment.They can inhibit the growth and migration of tumor cells while supporting the healthy functioning of the immune system [23].These compounds also show anti-inflammatory effects and facilitate alleviating symptoms of inflammatory conditions [21].Moreover, dietary polyphenols may have positive effects on blood sugar control, cognitive function, digestive health, and weight management, among other areas of health [24].

Oral Microbiota, Polyphenols, and Oral Health
Oral microbiota refers to the community of microorganisms that reside in the mouth.It is an essential component of the human microbiota and consists of hundreds to thousands of diverse species, including bacteria, fungi, viruses, and other microorganisms [25,26].These microorganisms colonize different areas of the mouth, such as the teeth, gums, tongue, and saliva, forming a complex ecological community that influences oral and systemic health [25,27].In the past century, medical research has primarily focused on studying bacteria in their planktonic phase.However, it is now widely recognized that oral microorganisms form biofilms [28,29].Dental plaque, which forms on non-shedding surfaces in the oral cavity, meets all the criteria for a microbial biofilm and undergoes a process called succession [26].When the delicate balance of the oral ecosystem is disrupted either due to an overload of microorganisms or a weakened immune system, a threat can be posed to local and systemic health.
The oral microbiota plays a crucial role in maintaining oral health by contributing to the digestion of food, protecting against harmful pathogens, and modulating the immune response [30].Certain bacteria in the oral produce acids that help regulate the pH and prevent the growth of harmful bacteria that thrive in acidic environments [31].Imbalances or dysbiosis in the oral microbiota can lead to oral diseases such as dental caries, periodontal disease, and oral infections.A significant alteration in the diversity and relative abundance of bacteria was found in the saliva of oral squamous cell carcinoma (OSCC) patients.These alterations can be used as biomarkers for the monitoring of the development, progression, and recurrence of oral cancer [32].Moreover, increasing evidence supports that many systemic diseases are associated with disturbances in the oral ecosystem, such as diabetes, cardiovascular diseases, and tumors [33].
As the human diet undergoes major shifts throughout evolution, a significant change was identified in the composition of the oral microbiota.The diet provides nutritional resources for the oral microbiota and also acts as a selective pressure, favoring the growth of organisms that are best adapted to utilize specific dietary resources derived from the host [34].Recent studies have been focused on exploring the potential of foods and diets in promoting oral health and preventing diseases.This has resulted in the development of foods and beverages that contain "functional ingredients", which offer additional benefits for maintaining oral health or preventing the onset and progression of dental issues.In the process of research, more and more studies have found that polyphenols play a critical role in oral health.Research on the relationship between diet polyphenols and oral health is essential for promoting oral health by targeting oral bacteria and biofilms, understanding the impact of food processing on polyphenol effectiveness, and exploring the potential systemic health benefits of maintaining good oral health.

Method for Literature Search
A comprehensive search of the literature was performed using PubMed, Web of Science, Embase, and Google Scholar.We focused on the articles examining the effects of polyphenols on various aspects of oral health, including dental caries, periodontal diseases, halitosis, and oral cancer.After the removal of the duplicates, reviews, comments, non-English articles, and those without full text, 188 research papers were obtained.The quality of these studies was evaluated and studies with insufficient experimental evidence or not closely related to the scope of this review were excluded.Finally, a total of 72 studies were selected for this review (Figure 1).

Polyphenols and Oral Health
Oral health is essential for preventing dental problems, maintaining overall health, and ensuring a good quality of life.To provide a comprehensive understanding of the impact of polyphenols on oral health, we will delve into the effects of these compounds on four aspects, including dental caries, periodontal diseases, halitosis, and oral cancer (Figure 2).

Polyphenols and Oral Health
Oral health is essential for preventing dental problems, maintaining overall health, and ensuring a good quality of life.To provide a comprehensive understanding of the impact of polyphenols on oral health, we will delve into the effects of these compounds on four aspects, including dental caries, periodontal diseases, halitosis, and oral cancer (Figure 2).

Figure 2.
Polyphenols in dental caries, periodontal diseases, halitosis, and oral cancers.In dental caries, polyphenols have been investigated for their antibacterial properties, effectively suppressing bacterial growth and adhesion.They also inhibit glycosyltransferase enzyme (GTF) activity, reduce the cariogenic impact of exopolysaccharides (EPS), and disrupt biofilm formation.In conditions involving inflammation, bleeding, and gum recession, polyphenols offer antimicrobial effects, enhance immunomodulation, and exhibit anti-inflammatory properties.They help mitigate oxidative stress, a critical factor in periodontal diseases.For halitosis, polyphenols possess antibacterial and antioxidant properties.In the meantime, they help reduce the volatile sulfur compounds (VSC), the primary source of halitosis.Regarding oral cancers, polyphenols have a multifaceted impact on oral cancer cells, including the inhibition of growth and division, decreased invasion and migration, enhanced apoptotic activity, and reduced expression of inflammatory cytokines such as IL-1β, IL-6, and IL-8.The small blue arrows indicate the upregulation/promotion or downregulation/inhibition of the biomarkers or behaviors.

Polyphenols and Dental Caries
Dental caries, also known as tooth decay or cavities, is a chronic oral disease with high prevalence among children and adolescents.It's a bacterial infectious disease that affects the hard tissues of the teeth and is caused by the interaction between bacteria, sugars, and carbohydrates in the mouth [35].Dental caries is caused by a microecological In dental caries, polyphenols have been investigated for their antibacterial properties, effectively suppressing bacterial growth and adhesion.They also inhibit glycosyltransferase enzyme (GTF) activity, reduce the cariogenic impact of exopolysaccharides (EPS), and disrupt biofilm formation.In conditions involving inflammation, bleeding, and gum recession, polyphenols offer antimicrobial effects, enhance immunomodulation, and exhibit anti-inflammatory properties.They help mitigate oxidative stress, a critical factor in periodontal diseases.For halitosis, polyphenols possess antibacterial and antioxidant properties.In the meantime, they help reduce the volatile sulfur compounds (VSC), the primary source of halitosis.Regarding oral cancers, polyphenols have a multifaceted impact on oral cancer cells, including the inhibition of growth and division, decreased invasion and migration, enhanced apoptotic activity, and reduced expression of inflammatory cytokines such as IL-1β, IL-6, and IL-8.The small blue arrows indicate the upregulation/promotion or downregulation/inhibition of the biomarkers or behaviors.

Polyphenols and Dental Caries
Dental caries, also known as tooth decay or cavities, is a chronic oral disease with high prevalence among children and adolescents.It's a bacterial infectious disease that affects the hard tissues of the teeth and is caused by the interaction between bacteria, sugars, and carbohydrates in the mouth [35].Dental caries is caused by a microecological imbalance in the biofilm of dental caries pathogens, with Streptococcus mutans (S. mutans) particularly involved [29,36].S. mutans is a Gram-positive bacterium and is recognized as the most important cariogenic bacteria in the oral cavity, secreting exopolysaccharides (EPS) to form a three-dimensional biofilm structure [37].Dental plaque biofilm appears where the bacteria attach and aggregate, protecting the bacteria and making them highly resistant to drugs and host immune defenses [38].
It is widely recognized that the consumption of dietary sugars, especially sucrose, is directly linked to the development of dental caries.The cariogenic bacteria metabolize sugars in the food and rapidly produce a large amount of organic acids, leading to microecological dysbiosis [39].The acid production resulting from the metabolism of sugars in the biofilm leads to a decrease in environmental pH, which is responsible for the demineralization of hard dental tissues [40].The bacteria produce acids that erode the enamel and dentin of the teeth, leading to the formation of cavities Therefore, effective methods to prevent the development of dental caries involve inhibiting the growth of pathogenic bacteria in the mouth, reducing the formation of EPS, and decreasing the content of biofilm.
As reported above, biofilms play a crucial role in the survival of S. mutans.Polyphenolic compounds can also interfere with the formation of biofilms, and protect the tooth from bacteria adherence [36,46,48,49].Catechins identified from hot steeping green or black tea showed inhibitory effects on biofilm formation and cell viability of S. mutans.and S. sobrinus [50].It was demonstrated that tart cherry (Prunus cerasus L.) fractions had a dose-dependent inhibitory effect on biofilm formation.Additionally, they also reduced the adherence of C. albicans and S. mutans to a hydroxylapatite surface as well as the adherence of F. nucleatum to oral epithelial cells [46].
The EPS-rich matrix plays a crucial role in bacterial adhesion to tooth surfaces and provides mechanical stability for acidogenic and aciduric bacteria [29,38].Therefore, EPS formation is essential for the pathogenesis of dental caries.Polyphenols have been reported to reduce the cariogenic effect of EPS in biofilm (Figure 2, Table 2) [47,51].Recently, a study showed that Lonicera caerulea fruit polyphenols (LCP) affect the characteristics of EPS produced by L. rhamnosus.Specifically, the addition of LCP increases galactose in EPS and disrupts the original aggregation state of EPS [45].However, LCP does not significantly affect the molecular weight and functional group composition of EPS.This suggests that LCP can alter the surface morphology, content, and composition of EPS produced by L. rhamnosus [45].These changes in EPS may contribute to reducing the cariogenic effect of EPS and biofilm formation.Schneider-Rayman et al. found that epigallocatechin-3-gallate (EGCG) exhibited the antibacterial and antibiofilm activity of S. mutans in a dose-dependent manner [52].At concentrations of 2.2-4.4 mg/mL, significant reductions were observed in S. mutans biofilm formation, DNA content, and EPS production.Furthermore, EGCG reduced the expression of genes involved in EPS production (gtfB, gtfC, and ftf) as well as genes involved in protection against oxidative stress (nox and sodA) [52].
In addition, polyphenols could inhibit the formation of glucan and biofilm from S. mutans by suppressing the activity of glycosyltransferase enzymes (GTF) (Figure 2, Table 2) [53][54][55].Goto et al. illustrated that Roasted Green Tea (RGT)-specific polyphenols had GTF inhibitory activity and a strong inhibitory effect on biofilm formed by S. mutans [53].A study in rats found that cranberry Proanthocyanidins (PAC) showed significantly less caries severity on smooth surfaces and sulcal surfaces.Furthermore, A-type PAC oligomers have shown effective inhibition of insoluble glucan synthesis by GtfB on saliva-coated apatitic surfaces.These PAC oligomers also had an impact on bacterial glycolysis [56].Additionally, polyphenols may inhibit S. mutans-mediated acidification.It reduces the glycolytic pH drop and lactate production thus protecting from dental caries [57].
It is worth mentioning that the following investigations report that polyphenols can prevent the development of dental caries in humans.An in vivo study was performed using saliva and dental biofilm samples collected from 75 healthy subjects.The use of polyphenolic mouthwash resulted in a significant reduction in bacterial taxa associated with oral diseases in both the refined sugar group and the unrefined sugar group [58].A one-year prospective human intervention study used fermented lingonberry juice (FLJ) as a mouthwash for 6 months, followed by a 6-month washout period.FLJ efficiently reduced visible plaques, S. mutans, and Candida levels, as well as caries risk [59].A randomized blinded clinical study with 60 healthy children of age 9-14 found that 0.5% Camellia sinensis extract exhibited antiplaque activity over the 2-week experiment period.In the treatment group, the salivary pH increase was sustained and significant, and oral hygiene was well improved [60].However, conventional anti-caries agents often exhibit limitations such as poor stability, low efficacy, or short residence time in the oral environment.It is critical to develop novel long-term strategies for the prevention of dental caries, especially for children and teenagers.

Polyphenols and Periodontal Diseases
Periodontal disease, including gingivitis and periodontitis, is a chronic inflammatory condition that affects the tissues surrounding and supporting the teeth, including the periodontal ligament, connective tissue, and alveolar bone [63].It is caused by the accumulation of dental plaque, a sticky film of bacteria, on the teeth and gingiva.Gingivitis is the early stage of periodontal disease, which is characterized by red, swollen, and bleeding gingiva [64].Untreated gingivitis can progress to periodontitis, a more severe form of gingival disease.
Periodontitis is a complex disease that involves ongoing interactions between bacteria and the immune and inflammatory responses of the host, which are influenced by genetic and environmental factors.The homeostasis or symbiosis of oral microbiota plays a crucial role in periodontal health, which is characterized by a state of dynamic equilibrium between periodontal microflora and a controllable immune/inflammatory response of the host [65].Dysregulation of the inflammatory response or stimulation of an imbalanced microbial community can disrupt the homeostasis in periodontal tissues.This dysbiosis results in an overgrowth of pathogenic bacteria and a decrease in beneficial bacteria, leading to a dysregulated and hyperinflammatory immune response [66].Pathogenic bacteria such as Porphyromonas gingivalis (P.gingivalis), are reported to be associated with periodontal diseases.These bacteria produce virulent factors such as gingipains and trigger the activation of host-derived proteolytic enzymes such as matrix metalloproteinases (MMPs) [67].The hyperinflammatory response is accompanied by the release of interleukin-1 (IL-1) superfamily members and the degradation of the extracellular matrix, which leads to chronic inflammation in the gingiva and the loss of alveolar bone [67,68].
Treatment for periodontal disease typically involves professional dental cleaning techniques to remove plaques and calculuses, scaling and root planing to remove bacteria from the periodontal pockets, as well as minimally invasive nonsurgical therapy (MINST) [65,68].In advanced cases, surgical procedures may be necessary to repair damaged tissues and restore oral health.Traditional treatments such as mechanical debridement and antimicrobial strategies suffer from limitations and adverse effects.Thus, there is a growing interest in exploring alternative adjunctive therapies for the prevention and treatment of periodontal disease.
In addition to their antimicrobial properties, polyphenols are also crucial in balancing oxidative stress and antioxidant activity in the oral cavity, which prevents the deterioration of periodontal tissue (Figure 2, Table 3) [80][81][82].Polyphenols derived from berries (Brand name: Orophenol ® ) showed inhibitory effects on the growth of P. gingivalis and reduced its hemolytic activity.Additionally, Orophenol ® suppressed the production of reactive oxygen species (ROS) by oral keratinocytes stimulated with P. gingivalis.and exhibited a protective effect against damages caused by P. gingivalis [81].A polyphenolic mixture extracted from the pomace of the Croatina grape variety also demonstrated antioxidant properties, downregulating inflammation in macrophages [80].A study focused on human gingival fibroblasts (HGFs) revealed that treatment with a polyphenolic fraction of L. caerulea berries (10-50 µg/mL) resulted in a decrease in ROS production, intracellular glutathione (GSH) depletion, and lipid peroxidation in lipopolysaccharide (LPS)-treated cells [82].
Polyphenolic components exhibit immunomodulatory and anti-inflammatory effects in periodontitis as well (Table 3).They modulate the host immune response, leading to a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines [6,83,84].Several inflammatory mediators such as interleukin-8 (IL-8), IL-6, tumor necrosis factor α (TNF-α), nuclear factor Kappa-B(NF-κB), and histamine are involved in this process along with the LPS produced by periodontal pathogens [85,86].PAC are rich in cranberry, wild berry, (Vaccinium angustifolium Ait.), blueberry, grape apples, cocoa, and green tea [71,87].Studies have reported that PAC can suppress inflammation by reducing the level of IL-1β, IL-6, IL-8, and TNF-α through the downregulation of the MAPK/AP-1 signaling pathway, and the inhibition of the transcription function of NF-κB.Similarly, the secretion of MMP-3, MMP-8, and MMP-9 was also inhibited in a dose-dependent manner [87][88][89][90][91].The research of Farzanegan et al. reported that the combination of resveratrol and silymarin effectively reduced the inflammatory effects of histamine on cultured HGFs through a decrease in the levels of IL-6, IL-8, TPA-1, and TNF-α [84].Ben Lagha and Grenier showed that the aflavins, and black or green tea extracts all inhibited the activation of NF-κB and caspase-1 as well as the release of IL-1β by monocytes/macrophages.Tea polyphenols have anti-inflammatory properties and help reduce gingival epithelial barrier dysfunction caused by TNF-α [83].Apple and hop bract polyphenols also inhibit P. gingivalis-mediated pMMP-9 activation and OSCC cellular invasion.Furthermore, polyphenols reduced the activation of heat shock protein 27 and Ets1 and NF-κB [92].The administration of resveratrol-quercetin reduced the inflammatory process in apical periodontitis, periapical bone resorption, and altered the expression of osteoprotegerin, IL-10, and tartrate-resistant acid phosphatase in rats [93].These findings indicate that the modulation of the immune response helps alleviate inflammation and promote tissue healing in periodontal disease.
Several clinical studies have investigated the effects of polyphenols on periodontal health (Table 3).These studies reported higher attachment levels, reduced inflammation, and decreased bone loss when treated with polyphenolic compounds.It is suggested that the specially formulated FLJ mouthwash may help relieve mild inflammation and proteolytic burden in the oral mucosa and periodontal tissues [59].A randomized clinical study in patients with periodontitis (stage III-IV) showed that combined use of PAC in MINST resulted in better clinical outcomes for moderate pockets.Moreover, MMP-3 concentration in saliva was increased when PAC was incorporated, compared with MINST alone.These results indicated that MMP-3 concentration in saliva can be used as a biomarker for the assessment of periodontal health [94].Additionally, a prospective, double-blind, randomized clinical trial conducted by Sánchez et al. also identified that oligomeric PAC can affect the condition of periodontal tissue [95].Despite the promising clinical findings, the heterogeneity of studies makes it difficult to determine the clinical applicability of polyphenols in periodontal disease treatment.
Overall, the ability of polyphenols to inhibit bacterial growth, reduce inflammation, and promote tissue healing makes them promising materials for the prevention and adjunctive therapies of periodontal disease (Figure 2).However, further research is needed to standardize the dosage, delivery methods, and formulations of polyphenols to optimize clinical outcomes.The exploration of polyphenols provides new options for therapeutic approaches in the management of periodontal disease.Decreased nuclear levels of IL-1b-activated NF-jB (p65) & AP-1 (phospho-c-Jun), inhibited IL-6 production.Reduction of ROS production, intracellular glutathione (GSH) depletion, and lipid peroxidation Inhibited LPS-induced up-regulation of IL-1β, IL-6 and TNF-α Suppressed expression of cyclooxygenase-2 (COX-2)

Polyphenols and Halitosis
Halitosis, commonly known as bad breath, is a dental condition characterized by an unpleasant and offensive odor emanating from the oral cavity.Halitosis is highly prevalent, including physiological or pathological halitosis.The latter can be classified further into oral or extraoral halitosis, depending on the source of the odor [102].Pathological halitosis is mainly caused by the presence of Gram-negative bacteria in the oral cavity that produces volatile sulfur compounds (VSC) such as hydrogen sulfide (H 2 S), methyl mercaptan (CH 3 SH), and dimethyl sulfide (C 2 H 6 S) [103,104].Other factors contributing to halitosis include poor oral hygiene, tongue biofilm, food impacts, gum diseases, dental abscesses, dry mouth, oral ulcers, respiratory infections, and other oral or systemic conditions [102,105].Treatments for halitosis include the improvement of oral hygiene, utilization of antibacterial mouthwashes, and medicinal plants with antimicrobial properties.
Polyphenolic compounds have been found to play an important role in the treatment of halitosis (Table 4).These compounds, which are naturally present in fruits, vegetables, and medicinal plants, possess antimicrobial properties and can help inhibit the bacteria that contribute to the unpleasant odor [103].Studies have shown that polyphenol-rich plant extracts, such as those from pomegranate, cinnamon, rosemary, and other medicinal plants, exhibit antibacterial activity against oral microorganisms, including those involved in VSC production [103,106].These extracts have been found to inhibit the growth of bacteria in the oral cavity and reduce the formation of VSC, addressing the root cause of halitosis.Liu et al. found that thinned-young apple polyphenols (YAP) exerted antibacterial effects by destroying the cell membrane of halitosis-related bacteria, including P. gingivalis, P. intermedius, and F. nucleatum [107].
The exact mechanisms by which polyphenols exert their antibacterial and anti-halitosis effects are still being investigated.However, their antioxidant properties are believed to play a role.Polyphenols can neutralize harmful free radicals and oxidative stress, which are known to contribute to oral health problems, including halitosis (Figure 2, Table 4) [103,108].Additionally, these compounds may interfere with bacterial metabolism and disrupt the formation of VSC.Morin et al. reported that green tea extract and its major constituent EGCG inhibited the growth of S. moorei by eradicating its pre-formed biofilms.Furthermore, the activity of β-galactosidase in S. moorei, which is crucial for VSC production, was inhibited in a dose-dependent manner by EGCG in green tea [106].According to the findings of a double-blinded and placebo-controlled clinical trial, the use of green tea mouthwash (green tea extract contains more than 80% of total catechins) for 4 weeks resulted in a significant reduction in VSC levels in individuals with gingivitis [109].Lodhia et al. demonstrated that green tea powder significantly reduced the concentration of both H 2 S and CH 3 SH gases in subjects after administration [110].Polyphenol-rich extracts from medicinal plants as an alternative treatment for halitosis offer a natural and safer approach compared to conventional mouthwashes that may have potential side effects.However, further research is needed to determine the optimal concentrations and formulations of these extracts for halitosis treatment, as well as their long-term effects.Incorporating polyphenols into oral care products or dietary supplements may provide a natural and effective solution for individuals suffering from bad breath.

Polyphenols and Oral Cancer
Oral cancers, particularly OSCCs, account for approximately 90% of head and neck cancers [111].OSCCs are characterized by the development of malignant cells in the squamous cells that line the oral cavity, including the lips, tongue, gums, lining of the cheeks, and floor of the mouth.The progression of OSCCs typically starts with changes in the normal oral mucosa, leading to the formation of precancerous lesions such as leukoplakia or erythroplakia [112].The development of these tumors is influenced by multiple factors, starting with the cancerous lesions of the normal mucosa and eventually progressing to metastasis.Among the main risk factors, excessive alcohol consumption and tobacco use are considered leading causes due to their proinflammatory effects [113].Despite advancements in therapeutic strategies such as chemotherapy, radiotherapy, and surgery, the 5-year survival rate of OSCCs was less than 50% [114].Therefore, novel relief agents and treatment approaches for OSCCs are a critical need.
In the past decade, the potential preventive and therapeutic effects of various polyphenols against OSCCs have been reported.Polyphenols interfere with the cell cycle and inhibit the invasion of cancer cells into other tissues and organs [12].They have been shown to have anti-inflammatory, antioxidant, and anti-carcinogenic effects as well [7] (Figure 2, Table 5).
Polyphenolic compounds found in green and black tea, such as catechins, theaflavins, polymeric thearubigins, and EGCG, suppress the growth and division of oral cancer cells in vitro [49,[115][116][117].Studies on hamsters and rats also showed similar effects.Administration of black tea polyphenols significantly decreased tumor incidence in the buccal pouch of male Syrian hamsters [118].Srinivasan et al. demonstrated that the treatment of green tea polyphenols declined the number of tumors, tumor volume, and OSCCs in 4-nitroquinoline-1-oxide -induced rats [119].Sharma et al. reported that the polyphenolic flavonoids found in defatted seeds of Azadirachta indica and Momordica charantia exhibited antiproliferative activity against Human oral epidermal carcinoma KB cells [120].A study by King et al. showed the dose-dependent inhibition of cellular proliferation in OSCC cells with grape seed PAC.In addition, the administration of PAC reduced the increased proliferation of OSCCs after transfection with HPV 16 (human papillomavirus 16) [121].
The effect of polyphenols on apoptosis in oral cancer cells has also been studied (Table 5).Treatment of OSCC cells with cranberry and grape seed extracts partially upregulated the expression of apoptosis-specific molecules, such as caspase-2 and caspase-8 [116].Specifically, treatment with PAC ranging from 50 to 70 µg/mL for OSCCs was found to increase caspase-2 and caspase-8 expression [122].Black tea polyphenols were also found to reduce the incidence of DMBA (7,12-dimethylbenz [a]anthracene)-induced hamster buccal pouch carcinogenesis by modulating biomarkers of cell proliferation, angiogenesis, and apoptosis [118].These results demonstrate that polyphenol-associated apoptosis is mitochondria-targeted and caspase 8 dependent.
Polyphenols interfere with the signaling pathways involved in oral cancer development and progression (Table 5).Fan et al. illustrated that anthocyanins from a species of black rice have the potential to inhibit the metastasis of CAL 27 cells.This nutrient reduces the expression of MMP-2, MMP-9, and NF-κB p65 through the suppression of the PI3K/Akt pathway and the inhibition of NF-κB [123].A study found that EGCG demonstrated a dose-dependent inhibitory effect on the invasion and migration of OC2 cells without causing cytotoxicity (ref).Additionally, EGCG was found to decrease the expression levels of MMP-2, MMP-9, and u-PA in a concentration-dependent manner [124].Moreover, it significantly inhibits the invasion, motility, migration, and secretion of MMP-2 and u-PA in SCC-9 oral cancer cells by attenuating p-FAK and p-Src.EGCG also inhibited the tumor growth of SCC-9 cells in vivo via cancer cell xenografted nude mice model [125].These findings suggest that polyphenols have the potential to inhibit the invasion and migration of oral cancer cells through the regulation of key proteins involved in these processes (Figure 2).
Evidence from human studies regarding the function of polyphenols has also accumulated.Recently, a randomized placebo-controlled phase 1 trial of APG-157 (a botanical drug containing multiple polyphenols, including curcumin) in oral cancer suggested that the material can be easily absorbed, showing an inhibitory effect on cytokines and tumorassociated microbes [126].APG-157 reduced the levels of IL-1β, IL-6, and IL-8 in the saliva of patients, and the analysis of microbial flora showed a decrease in Bacteroides species [126].These results illustrated that polyphenols are chemopreventive and are potential therapeutic agents against OSCCs.However, the bioavailability and handling of polyphenols can be challenging due to their unfavorable physicochemical properties.Further research is needed to develop effective drug delivery systems that can improve the clinical use of polyphenols in the treatment of OSCCs.

Discussion
Polyphenols have gained significant attention in biomedical fields due to their various beneficial properties, including antioxidant ability, antibacterial activity, and antiinflammatory activity.Moreover, numerous researches have shown that polyphenols play critical roles in maintaining oral health and oral microbiota, which benefits oral health and overall well-being for humans.However, it is important to note that the therapeutic activities of polyphenols are limited by their poor bioavailability.Polyphenols are typically applied in the form of mouthwashes, gels, or tinctures in oral infections, such as gel containing Scutellaria baicalensis(S.baicalensis) root extract (commercially known as Baikadent ® ) widely used in the treatment of oral inflammation (Figure 3).The direct contact of functional molecules with pathogens on the mucosa or teeth surface allows the antibacterial effects.However, the penetration of polyphenols into deeper regions of the oral mucosa may be limited, depending on the mucosal surface type and the duration of action.Additionally, the poor stability of certain polyphenols, such as EGCG from tea, further limits their potential application.

Discussion
Polyphenols have gained significant attention in biomedical fields due to their various beneficial properties, including antioxidant ability, antibacterial activity, and anti-inflammatory activity.Moreover, numerous researches have shown that polyphenols play critical roles in maintaining oral health and oral microbiota, which benefits oral health and overall well-being for humans.However, it is important to note that the therapeutic activities of polyphenols are limited by their poor bioavailability.Polyphenols are typically applied in the form of mouthwashes, gels, or tinctures in oral infections, such as gel containing Scutellaria baicalensis(S.baicalensis) root extract (commercially known as Baikadent ® ) widely used in the treatment of oral inflammation (Figure 3).The direct contact of functional molecules with pathogens on the mucosa or teeth surface allows the antibacterial effects.However, the penetration of polyphenols into deeper regions of the oral mucosa may be limited, depending on the mucosal surface type and the duration of action.Additionally, the poor stability of certain polyphenols, such as EGCG from tea, further limits their potential application.Further research is needed to explore the bioaccessibility of polyphenols and develop modern delivery systems to enhance their effectiveness.In addition, the stability and bioavailability of polyphenols can be improved through techniques such as nanoencapsulation, which protects sensitive ingredients from degradation and enhances their absorption across biological barriers.Recently, several studies have demonstrated the potential applications of polyphenols combined with different materials in the treatment of oral diseases (Figure 3).He et al. developed a programmed core-shell nanofiber that allows the sequential and controlled release of tea polyphenols and AdipoRon.The nanofibers can alleviate periodontal tissue inflammation and promote bone regeneration to repair periodontitis-related alveolar bone defects in vivo.These findings suggest that the programmed core-shell nanofibers have potential applications in the treatment of periodontitis [97].A ceramic granulated biomaterial containing phenolic molecules was considered an innovative regenerative approach in periodontal therapy [80].Nanovesicles in-situ gel based on the EGCG phospholipid complex improved its stability and bioavailability [61].Polyphenols-linked hydrogels are also new directions in the treatment of oral diseases for the gradual release of bioactive components [132,133].Ellagic acid (EA)-linked hydrogels were found to provide long-term sustained release of bioactive polyphenols and significantly suppress the CAL-27 human oral cancer cell viability [130].Using the oxidative self-polymerization principle, Qi et al. prepared polyphonic nanoparticles, which were encapsulated into thermosensitive type in-situ hydrogel.The effective constituent can be released continuously for 96 h under the periodontitis environment [96].It has been demonstrated that human-like collagen has properties that contribute to tissue healing and regeneration, including promoting collagen deposition, regulating growth factors, and reducing inflammation [134,135].Due to its outstanding biocompatibility, minimal immunogenicity, and ability of natural degradation polyphenols combined with human-like collagen have great potential in the treatment of oral diseases.
Polyphenols have a stimulating effect on host cells.Several studies suggested that polyphenols, such as EGCG, theaflavin, and resveratrol, can induce human beta-defensin (hBD) secretion in oral epithelial cells [136][137][138].Lombardo et al. found that tea polyphenols induced hBD secretion in gingival epithelial cells and protected hBDs from proteolytic degradation by P. gingivalis [136].When oral pathogens invade the oral tissues or biofilms form on the tooth surface, antimicrobial peptides are released to combat the pathogens and maintain microbial balance [137].In addition to their direct antimicrobial effects, antimicrobial peptides also have other beneficial functions in oral health, such as modulating the inflammatory response and promoting wound healing and tissue repair in the oral cavity [138].Polyphenol-induced antimicrobial peptides in the oral cavity regulate the oral microbiota and play a role in oral health.The interaction between polyphenol, pathogen, and host cells opens up a new research direction in the future.
The potential benefits of polyphenols in managing and treating oral diseases suggest that these molecules should be carefully evaluated in clinical settings.While there are many studies conducted in laboratory and animal models that demonstrate the potential benefits of polyphenols in oral health, strong evidence from well-designed clinical trials is still limited.Future research should focus on the applications in humans and evaluate the long-term benefits and safety of polyphenols in preventing and treating oral diseases.With the advances in precision medicine, there is a growing interest in personalized treatment approaches.Polyphenols, with their diverse pharmacological activities, could be tailored to individuals based on their specific oral health needs and microbial profiles.This personalized approach could lead to more targeted and effective oral health interventions.
While dietary polyphenols offer numerous benefits, they are not a panacea but rather should be part of a balanced diet.Various foods contain different types and amounts of polyphenols, and incorporating a variety of fruits, vegetables, nuts, and grains into your diet can maximize the benefits of dietary polyphenols.Additionally, the intake of dietary polyphenols should be moderate to avoid potential adverse effects, as excessive consumption may not always be beneficial and may even lead to digestive issues such as stomach upset, diarrhea, or constipation.Additionally, some individuals may be sensitive or allergic to specific polyphenols, resulting in adverse reactions such as skin rashes or headaches.Moreover, polyphenols can interact with medications, potentially reducing their effectiveness or causing unwanted side effects.Furthermore, utilizing polyphenolic lozenges, toothpaste, mouthwash, and other products to maintain good oral hygiene practices helps remove plaque, balance the oral microbiota, and prevent tooth decay and other oral disease.
It should be emphasized that tooth decay, gum disease, and bad breath often occur during aging and further exacerbate our health condition.Polyphenols possessing strong antioxidant properties can help combat oxidative stress, which is particularly important for aging.By reducing cellular damage and inflammation, polyphenols may function to slow the aging process.Several polyphenols such as curcumin, resveratrol, quercetin, EGCG, and tyrosol, were found to have anti-aging effects and could promote oral health by combating oxidative stress and inflammation [139].Therefore, polyphenols as functional foods might not only serve as a novel strategy to promote oral health but also prevent oral disease indirectly through their anti-aging effects.

Conclusions
Oral and periodontal diseases are primarily caused by an imbalance in the oral microbiome and the subsequent host immune response [30].The studies summarized in this review demonstrated the antimicrobial properties of the polyphenols, which help in inhibiting the growth of pathogenic microorganisms and maintaining a balanced oral microbiota.Polyphenols also have antioxidant and anti-inflammatory activities, reducing inflammation and oxidative stress in the oral cavity [6].Additionally, polyphenols can inhibit the attachment and biofilm formation of bacteria, preventing dental plaque formation and promoting oral hygiene [140].Overall, polyphenols are crucial for the maintenance of oral health and the balance of the oral ecosystem, which is vital for overall human health.Future studies should aim to reveal more information about the interaction between polyphenols, pathogens, and host cells.Long-term clinical studies of reliable polyphenol delivery systems and combination therapy with antibiotics will also be useful.
In summary, research on the functions, working mechanisms, and applications of foodoriginated polyphenols in oral health is important for the overall well-being of humans.The progressions in polyphenol-based microecology control and oral disease prevention highlight new directions for safe, convenient oral health maintenance.More importantly, the exploration of polyphenols opens up new avenues for the management of oral disease, and the achievements in animal studies and clinical trials provide insight to advance treatments and cost-effective healthcare strategies in the future.

Nutrients 2023 , 35 Figure 1 .
Figure 1.Flowchart of the search strategy and the literature selection process.

Figure 1 .
Figure 1.Flowchart of the search strategy and the literature selection process.

Figure 2 .
Figure 2. Polyphenols in dental caries, periodontal diseases, halitosis, and oral cancers.In dental caries, polyphenols have been investigated for their antibacterial properties, effectively suppressing bacterial growth and adhesion.They also inhibit glycosyltransferase enzyme (GTF) activity, reduce the cariogenic impact of exopolysaccharides (EPS), and disrupt biofilm formation.In conditions involving inflammation, bleeding, and gum recession, polyphenols offer antimicrobial effects, enhance immunomodulation, and exhibit anti-inflammatory properties.They help mitigate oxidative stress, a critical factor in periodontal diseases.For halitosis, polyphenols possess antibacterial and antioxidant properties.In the meantime, they help reduce the volatile sulfur compounds (VSC), the primary source of halitosis.Regarding oral cancers, polyphenols have a multifaceted impact on oral cancer cells, including the inhibition of growth and division, decreased invasion and migration, enhanced apoptotic activity, and reduced expression of inflammatory cytokines such as IL-1β, IL-6, and IL-8.The small blue arrows indicate the upregulation/promotion or downregulation/inhibition of the biomarkers or behaviors.

Figure 3 .
Figure 3. Current approaches and prospects of polyphenols-based oral hygiene.Diverse strategies are employed in polyphenols-based oral hygiene, ranging from conventional methods to cuttingedge developments in biomaterials.Current approaches include widely-used products for routine cleaning, e.g., toothpaste and mouthwash; saliva stimulation, e.g., chewing gum and lozenges; or even polyphenols-containing gels and tinctures.Emerging trends include the development of hydrogels, human-like collagen, and other new biomaterials, such as nanoparticles, programmed coreshell nanofibers, and ceramic granulated biomaterials.

Figure 3 .
Figure 3. Current approaches and prospects of polyphenols-based oral hygiene.Diverse strategies are employed in polyphenols-based oral hygiene, ranging from conventional methods to cuttingedge developments in biomaterials.Current approaches include widely-used products for routine cleaning, e.g., toothpaste and mouthwash; saliva stimulation, e.g., chewing gum and lozenges; or even polyphenols-containing gels and tinctures.Emerging trends include the development of hydrogels, human-like collagen, and other new biomaterials, such as nanoparticles, programmed core-shell nanofibers, and ceramic granulated biomaterials.

Table 1 .
Classification and chemical structure of major classes of dietary polyphenols.

Table 1 .
Classification and chemical structure of major classes of dietary polyphenols.

Table 1 .
Classification and chemical structure of major classes of dietary polyphenols.

Table 1 .
Classification and chemical structure of major classes of dietary polyphenols.

Table 1 .
Classification and chemical structure of major classes of dietary polyphenols.

Table 1 .
Classification and chemical structure of major classes of dietary polyphenols.

Table 2 .
Effects of polyphenols on dental caries.

Table 2 .
Cont.Attenuated the adherence of C. albicans and S. mutans to a hydroxylapatite surface as well as the adherence of F. nucleatum to oral epithelial cells.

Table 3 .
Effects of polyphenols on periodontal disease.

Table 4 .
Effects of polyphenols on halitosis.

Table 5 .
Effects of polyphenols on Oral cancers.