Inflammation is an innate immune response of the body intended to eliminate the initial cause of tissue injury. Inflammatory responses play a major role in our body defence system against pathogens that also involve wound healing. Hence, inflammation is vital for our health and survival. The mouth provides a suitable environment for the growth of microorganisms. Thus, bacteria are present constantly in the mouth and some of these bacteria can trigger inflammatory response and implicated in oral disease. Most of the cases in periodontal disease are originated from bacterial dental plaque or biofilm accumulated on the teeth that induce host periodontal tissues inflammatory response (Hajishengallis et al., 2020). Both chronic gingivitis and periodontitis are chronic lesions that display inflammation and attempts at healing (Hasan and Palmer 2014).

The earliest process of inflammation involves its response against the invading microorganisms. In a susceptible host, invasion of periodontal pathogens particularly a group of specific Gram-negative anaerobic species in subgingival dental biofilm including Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola may result in chronic inflammation. These complex bacteria are predominantly found in deep periodontal pockets of patients with periodontitis (Kwon et al., 2021). The major component of the most Gram-negative bacteria present in the oral biofilm particularly lipopolysachharide (LPS) along with other virulence factors cause stimulation of mast cells and the release of vasoactive amines that cause vasodilation of blood vessels. The release of preformed tumour necrosis factor α (TNF-α) causes a subsequent release of inflammatory mediators in the gingival tissue (Hasturk et al., 2012; Yucel-Lindberg & Båge 2013). The chemoattractant proteins (chemokines) generated at this stage results in the initiation of the first line of defence, which are neutrophils that move and migrate to the site of microbial invasion. This process leads to the release of lysosomal enzymes that may also contribute to tissue degradation (Ge et al., 2015). Neutrophil infiltration is then followed by the activation of macrophages. Macrophages activation play a critical role in the elimination of the invaded bacteria, recruitment of other cells to the site of infection, removal of neutrophils excess, production of cytokines and chemokines and activation of lymphocyte-mediated adaptive immunity (Hasturk et al., 2012).

As lymphocytes and macrophages further invade the tissue, collagen content in gingiva is degraded but the bone at the site of lesion may still be intact. At this point, the associated damage is still reversible as it is still possible for gingival tissues to undergo repair and remodelling. In complete resolution with healing, the outcome of the inflammatory process can be restricted or cleared by the role of neutrophils and macrophages. The destructive inflammatory lesion that results in loss of local collagen due to accumulation of polymicrobial biofilm at the gingiva of the teeth is reversible upon resolution of the inflammation (Van Dyke et al., 2020). At this stage, the process of fibrosis and scar tissue formation may limit the infection but failure to clear the infection might establish a chronic inflammatory lesion.

It is noted that gingivitis is a major risk factor for periodontitis and it may develop into periodontitis in disease-susceptible individuals in which the host response is ineffective and dysregulated (Yucel-Lindberg and Båge 2013; Hajishengallis 2015). The pathogenesis of periodontal disease can be generally categorized into four stages, based on histopathological examination of the development of periodontal inflammation due to plaque accumulation. These stages are called 1) the initial, 2) the early, 3) the established, and 4) the advanced lesions. The advanced lesion which is also known as the destructive phase is clinically recognised as periodontitis where the inflammation extends deeper, with the formation of periodontal pocket, clinical attachment loss, collagen and bone loss (Hasan and Palmer 2014). The “established lesion” can persist for many years and the progression to an “advanced lesion” marks the transition from chronic and successful defence mechanism to destructive immunopathological mechanism or periodontitis. Recently, a new periodontitis classification scheme has been adopted according to the staging and grading system. Classification of periodontitis based on stages is dependent upon the severity of disease at presentation and the complexity of disease management. Meanwhile, classification of periodontitis based on grades reflect biologic features of the disease including analysis of the rate of periodontitis progression, risk for further progression, possibility of poor treatment outcomes and assessment of the risk that the disease or its treatment could affect the systemic health of the patient (Papapanou et al., 2018).

The exact factors that are responsible for the progression of periodontal diseases are unknown but chronic periodontal diseases involve the interaction of several components, which are the bacterial product or the pathogenicity factor, various cell populations and inflammatory mediators (Yucel-Lindberg and Båge 2013). Interaction between the host and microflora with time may result in dysbiosis of microbiome and dysregulation of host inflammation (Hajishengallis 2015). Colonization of Gram-negative bacteria up to 80% in the gingival sulcus during the establishment of periodontal disease form subgingival plaque, leading to periodontal pockets formation and gum recession (Palaska et al., 2013). Among the major pathogens, A. actinomycetemcomitants are more commonly detected in high levels in patients with aggressive periodontitis (Teles et al., 2013). The growth of pathogenic microbes within the dental plaque produces substances that could exacerbate inflammation, which may then lead to tissue destruction and even tooth loss. The immune-inflammatory mechanism in periodontal diseases is in part controlled by an individual’s susceptibility and interaction with environmental factors (Lamont et al., 2018).

The destruction of periodontal tissue and bone resorption are contributed by cellular activation, inflammatory mediators including cytokines, chemokines, prostaglandins and proteolytic enzymes particularly matrix metalloproteinases (MMP). The progression of periodontitis involves the release of prominent cytokines such as TNF-α, which is also involved at the early stage of inflammatory cascade, and IL-1 that are produced by the B-cell/plasma cell (Pan et al., 2019). These two cytokines may induce a number of inflammatory mediators such as IL-6, IL-8, MMP and prostaglandin E₂ (PGE₂), which is the most prominent prostaglandin implicated in the pathogenesis of periodontitis. IL-1 exerts different biologic effects on different cells and is an important biological mediator of autoimmune and inflammatory diseases. It plays a crucial role in both innate and adaptive immunity. Among first members of IL-1 identified include IL-1α and IL-1β (Dinarello 2018). 11 known members of IL-1 includes molecules with agonist activity such as IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ), receptor antagonists of IL-1Ra, IL-36Ra and two anti-inflammatory cytokines which are IL-37, and IL-38 (Dinarello 2018).

Dental biofilm dysbiosis will stimulate the release of IL-1 proinflammatory cytokines including IL-1α, IL-1β, IL-18, IL-36 from the oral junctional epithelium. These proinflammatory signals combined with bacterial products in the periodontal tissues in turn will stimulate both innate and adaptive immunity response. Hence, both complexes will promote release of inflammatory cell mediators into the periodontium (Papathanasiou et al., 2020). Virulence properties of periodontal pathogens such as lipopolysaccharides, stimulates the release of both IL-1α and IL-1β form oral epithelial cells hence resulting in periodontal destruction. Recently, it has been demonstrated that host defense peptides (HDPs) released from the gingival epithelium leading to accumulation of mast cells (MCs) that induces release of more pro-inflammatory cytokines. Therefore, enhancing further breakdown of periodontal tissue (Chompunud et al., 2020). IL-1β upregulates MMPs secretion hence contributing to augmented vasodilation, chemotaxis of inflammatory cells and degradation of collagen. In addition, osteoclastogenesis is also enhanced leading to elevated activity of bone resorption. A study reported that within gingival biopsies of active periodontal disease, there was reduced expression of inflammasome regulators while expression of messenger RNA (mRNA), NLRP3 and IL-1β were amplified (Aral et al., 2020).

Dendritic cells (DCs) release IL-18 that stimulates differentiation of T helper 1 cell (Th1) and T helper 17 cell (Th17) which in turn upregulates the release of IL-17, TNF-α, and IL-1β, hence contributing to further periodontal destruction. Elevated release of IL-1 proinflammatory has been associated with increased receptor activator of nuclear factor-κB ligand (RANKL) release, thus inducing osteoclasts progenitors responsible for alveolar bone resorption in periodontitis. However, IL-1 family members possessing anti-inflammatory properties play a defence role in periodontitis. Here, they will alleviate the magnitude of periodontal inflammation (Papathanasiou et al., 2020). The production of PGE₂ by the immune cells, fibroblasts and other resident gingival cells is associated with the formation of osteoclast via RANKL upregulation and osteoprotegerin (OPG) inhibition (Belibasakis & Guggenheim 2011).

Since the development of periodontitis is mediated by bacterial-induced inflammation that lead to an excessive host response, the use of conventional mechanical therapy and pharmacological adjuncts is therefore plausible to control the inflammation (Bartold and Van Dyke 2013). Evidence showed that, adjunctive antibiotics and other anti-inflammatory agents can be effective to inhibit or eliminate periodontopathogenic microorganisms and modulate the inflammatory response of the tissue (Da Rocha Júnior et al., 2015). The use of nonsurgical periodontal therapy with or without antimicrobials remains as standard of care that could mechanically removes dental biofilm but targeting only microbes does not equally favourable in all periodontal patients (Preshaw 2018). In addition, the use of adjunctive antibiotics is associated with the unwanted side effects and should only be recommended for progressive disease (Tilakaratne and Soory 2014). Some of the side effects associated with the most commonly used antibiotics in managing periodontal disease include nephritis, gastrointestinal problems, increased risk of allergy, allergic signs on the skin, disturbance in the nervous system and electrolytes imbalance (Heta and Robo 2018).

This is where other agents with similar properties and biological effects with fewer side effects can take its place in improving and managing periodontitis. In fact, One of the promising therapeutic approaches in managing periodontitis particularly in individuals with a higher risk for periodontitis is by modulation of host inflammatory mediators. The term ‘host modulation therapy’ was initially introduced by Golub et al., 30 years ago (Golub et al., 1998). In the last decades, the efficacy of HMT using anti-inflammatory and antioxidant agents in periodontitis was explored. The two major HMT categories accepted include firstly the modulation of the host’s inflammatory response via inhibition or resolution and secondly modulation of host’s pathologic collagenolytic response within the periodontal soft tissue along with alveolar bone (Van Dyke, 2017; Golub et al., 2018). The adjunctive use of host modulatory agents has been postulated to have a positive implication on the progression of periodontal disease particularly in susceptible patients and in individuals whom conventional therapeutic approach is ineffective (Balta et al., 2021). Recently, polyphenols have been documented to cause immunomodulatory effects by downregulating the proinflammatory cytokines, IL-1 and IFN-γ which could be beneficial to be used as adjunct therapeutic approaches in reducing the burden of various inflammatory diseases (Shakoor et al., 2021).

Quercetin is categorized as a flavonol, one of the six subclasses of flavonoids compounds (Li et al., 2016). The antimicrobial and anti-inflammatory properties of quercetin have been found to be effective to restrict inflammatory reaction in periodontitis. During acute and chronic inflammation in periodontitis, high amount of TNF-α generated by activated macrophages may lead to periodontal tissues degeneration (Noh et al., 2013). A study by Xiong et al. (2019) has demonstrated that all three doses of quercetin (5, 10 and 20 μM) attenuated the production of inflammatory mediators including TNF-α, IL-1β, IL-6, and IL-8 in Porphyromonas gingivalis (P. gingivalis) LPS-treated human gingival fibroblast. In addition, quercetin has been found to suppress LPS-induced nuclear factor kappa-B (NF-κB) activation in a dose-dependent manner (Xiong et al., 2019). Suppression of these inflammatory mediators and its signalling pathway could restrict the initiation and progression of periodontal disease (Muniz et al., 2015).

In an earlier study, Cheng et al. (2010) investigated the effect of quercetin on experimental periodontitis induced by LPS injection and silk ligation (Cheng et al., 2010). The study has reported that 5 days of oral quercetin treatment at the dose of 75 mg/kg reduced LPS-induced osteoclast formation, ligature-enhanced periodontal inflammation and subsequent alveolar bone loss. Inflammation was induced in the quercetin-administered group but not severe enough to cause alveolar bone loss as evidenced from bone micro-computerized tomography (μ−CT) evaluation. Quercetin decreased the area of inflammatory cell infiltration in connective tissue and narrowed connective tissue attachment. However, the findings also reported a similar attachment loss in both ligation and the ligation-plus-quercetin groups. The results indicated that alveolar bone loss may be prevented in the experimental periodontitis but quercetin was unable to prevent attachment loss, which questioned the beneficial effects of quercetin. The author postulated that the study duration might not be sufficient to observe the effect of quercetin on long-term attachment loss in chronic periodontitis.

In another study, the anti-inflammatory properties of 100 mg/kg quercetin were evaluated using a mouse periodontitis model induced by inoculation of A. actinomycetemcomitans (Napimoga et al., 2013). Subcutaneous treatment with quercetin has been found to reduce gingival pro-inflammatory cytokines (IL-1, TNF-α, IL-17), and down-regulate adhesion molecule ICAM-1 and osteoclastogenic cytokine RANKL production in A. actinomycetemcomitans-induced alveolar bone loss. Alteration in cell-mediated and humoral levels of adaptive immune defence is thought to be involved in the development of experimental bacterial-immune inflammation in periodontal tissue. The potential of quercetin in reducing bone loss was also demonstrated in a study by Taskan and Gevrek (2020). Osteoblastic activity was increased while osteoclastic activity, apoptosis and inflammation were decreased in ligature-induced periodontitis rats treated with quercetin. A study by Demkovych et al. (2021) was carried out to investigate the effects of quercetin on adaptive immunity in relation to the development of experimental bacterial-immune periodontitis. Intramuscular injection of water-soluble quercetin at a dose of 100 mg/kg for 7 days was found to normalize the cellular adaptive immunity indices and reverse the inflammatory process in the periodontal complex.

It was suggested that the inhibition of periodontal pathogen virulent factor could hamper the progression of periodontitis, prevent and control periodontal inflammation. The effect of quercetin on P. gingivalis virulent pathogenicity was demonstrated in a study by He et al. (2020). The study found that quercetin inhibits virulence and physiological properties of P. gingivalis as indicated by gingipain, hemolytic and hemagglutination activity. Quercetin also could modulate cell surface hydrophobicity, aggregation, biofilm formation and virulence gene expression. These findings suggested that quercetin might be beneficial in the treatment of periodontitis as it could impair the pathogenicity of P. gingivalis, a keystone pathogen for periodontal disease. Table 1 summarized the effects of quercetin in periodontal inflammation, in vivo and in vitro.

Resveratrol (trans-3,4,5-trihydroxystilbene) is a common stilbene found in berries, grape skin and in other plants (Gambini et al., 2015). Resveratrol has attracted substantial attention, as it possesses remarkable biological properties and this could be due to its molecular structure that confers its ability to bind to many biomolecules. Based on its promising anti-inflammatory and antioxidant properties, resveratrol has been studied for its prophylaxis and therapeutic potential in controlling periodontal disease. Resveratrol was shown to have a favourable effect on vascular inflammation induced by periodontal pathogen, P. gingivalis as it was able to inhibit NF-κB-dependent cell adhesion molecules in monocyte adhesion to the endothelium (Park et al., 2009). Casati et al. (2013) studied the effect of resveratrol that was administered continually on the progression of experimental periodontitis. Findings of the study showed that bone-loss value in ligated molars and unligated teeth in the control group were higher than in the treatment group that was administered with 10 mg/kg resveratrol for 30 days (19 days before periodontitis induction and 11 days after ligature placement). Resveratrol treated group also showed lower concentration of IL-17 in the gingival tissue. Modulation of IL-17 levels in gingival tissue that presents ligature-induced experimental periodontitis suggests the possible biologic mechanism of resveratrol during periodontal inflammation.

It is known that periodontitis is a multicomponent disorder that affects the supporting structures of the teeth including periodontal ligament and the alveolar bone. Bone loss values were found insignificant between resveratrol, curcumin and the combined groups in a study of continuous curcumin and resveratrol administration against the progression of experimental periodontitis. When compared with the placebo group, the concentration of IL-1 was lower in the combined group as revealed by immune-enzymatic assays. However, resveratrol, curcumin and combined groups showed higher IL-4 levels when compared to placebo group. The reduction in IFN-γ level was only observed in the resveratrol group and the difference in TNF-α levels among groups were not significant. Whether agents were added singly or in combination, both poplyphenolic compounds were able to attenuate alveolar bone loss in the experimental model of periodontitis. Nonetheless, the effects were neither synergistic nor additive (Corrêa et al., 2017). In another study, resveratrol derivative-rich melinjo seed extract was found to have a potent impact on inflammation-induced bone loss in a murine model of established periodontitis as indicated by a reduction in osteoclast differentiation (Ikeda et al., 2018) The production of IL-1β in gingival tissue was reduced but no significant changes in IL-6, TNF-α, and IL-17 levels were observed.

The antibacterial effects of resveratrol against periodontal pathogens P. gingivalis, T. forsythia and A. actinomycetemcomitans were studied by Cirano et al. (2016) in experimental model of periodontitis. The study however found that resveratrol does not exert positive effects on microbiological outcomes suggesting other mechanisms could contribute to its promising effect in controlling periodontitis. Nevertheless, in a recent study, resveratrol has been found to prevent biofilm formation and inhibit the virulence properties of P. gingivalis by reducing the expression of virulence factor genes including fimbriae and proteinases (Kugaji et al., 2019). The effect of resveratrol in in vivo and in vitro model of periodontal inflammation has been summarized in Table 2.

Curcumin, a yellow-coloured compound with low molecular weight is the main polyphenols extracted from the rhizome of turmeric plant, Curcuma longa L., (family: Zingiberaceae) (Wilken et al., 2011). This natural polyphenol has attracted considerable attention due to its nontoxicity and it has been used to treat various inflammatory diseases since long ago. Curcumin (diferuloylmethane) makes up 2–5% of turmeric and no adverse effects were found when it is given even as high as 8 g/day (Bhatia et al., 2014). Therapeutic potential of curcumin was observed in controlling inflammation and bone resorption in periodontitis. The antioxidant, antimicrobial, anti-inflammatory and analgesic properties of curcumin make them a suitable candidate for the management of periodontal diseases (Forouzanfar et al., 2020).

The possible mechanisms of curcumin involved in the suppression of periodontal disease reported in the existing studies are mainly based on its antibacterial and anti-inflammatory properties. In vitro studies have shown that curcumin can inhibit various periodontal pathogens growth such as A. actinomycetemcomitans, F. nucleatum, and P. gingivalis and the formation of biofilms (Shahzad et al., 2015). Curcumin has been found to have anti-biofilm and high antibacterial activity against P. gingivalis, which is considered as the main pathogen and major colonizer in host tissues (Shahzad et al., 2015; Izui et al., 2021; Kumbar et al., 2021). On the other hand, curcumin has low antibacterial activity against S. mitis, which is a part of the normal flora in the oral cavity and exert no threat to oral health. This result suggested that curcumin may have selective antimicrobial properties. In gene expression studies done by Kumbar et al. (2021), the virulence of P. gingivalis was reduced by curcumin as indicated by a reduce expression of genes coding for major virulence factors including adhesions and proteinases.

The occurrence and development of periodontitis involve the production of a vast number of inflammatory mediators. A recent study carried out by Xiao et al. (2018) showed that the production of IL-β and TNF-α were attenuated in rat gingival fibroblasts supplemented with 10 and 20 μM curcumin. The ratio of OPG/RANKL and the activation of NF-κB induced by LPS in vitro were also inhibited. In the same study, an in vivo ligation-induced experimental periodontitis showed that curcumin at the dose of 30 and 100 μg/g could alleviate gingival inflammation and modulated collagen fibre and alveolar bone loss as observed in histological and micro-CT results. An earlier study by Zhou et al. (2013) reported that intra-gastric curcumin administration at the dose of 100 mg/kg for 30 days could reduce alveolar bone loss in ligature-induced experimental periodontitis through the suppression of RANKL/RANK/OPG expression and its inflammatory properties (Zhou et al., 2013). Moderate bone resorption and root exposure, and mild bone loss were observed microscopically in curcumin treated animals. The expression of TNF-α and IL-6 in the gingival tissues of experimental rats treated with curcumin was significantly lower than the experimental periodontitis animal. In line with this study, several other studies also reported that curcumin can modulate the inflammatory response, suppress the pro-inflammatory cytokines particularly TNF-α and IL-6 in ligature-induced experimental periodontitis rat model (Guimarães et al., 2011) and LPS-induced periodontitis rat model (Guimaraes et al., 2012). Though curcumin is effective in inhibiting cytokine gene expression at mRNA and protein levels, the inhibition of NF-κB in the gingival tissue was only observed in the lower dose of curcumin (30 mg/kg), whereas p38 MAPK activation was not affected in both doses. Alveolar bone resorption was not prevented by daily dose of intragastric curcumin administration (30 and 50 mg/kg) for 15 days but its potential anti-inflammatory effect suggests their therapeutic potential in periodontal disease. Table 3 summarized the effects of curcumin in periodontal inflammation, in vivo and in vitro.

Proanthocyanidins are condensed tannins that take the form if oligomers or polymers of monomeric flavan-3-ols produced as an end product of flavonoid biosynthesis pathway (Rauf et al., 2019). The flavan-3-ols are catechin, epicatechin or their substituted derivatives. It is termed as condensed tannins for its capability to form insoluble complexes with carbohydrates and proteins (Balalaie et al., 2018). Proanthocyanidins are highly hydroxylated structures that is categorized according to the number of hydroxyl substitutions in the B ring in which one hydroxyl substitution refers to propelargonidin, two hydroxyl substitution refers to procyanidin and three hydroxyl substitution refers to prodelphinidin. The therapeutic potential of proanthocyanidins emerges from their unique chemical structure (Luca et al., 2020).

The antibacterial activity of proanthocyanidins has been substantially reported in literature (Nawrot-Hadzik et al., 2021). A study by Savickiene et al. (2018) revealed that proanthocyanidins had a unique antibacterial property that could selectively targets the keystone periodontal pathogens viability such as P. gingivalis while preserving the beneficial oral commensal S. salivarius. Lagha et al. (2018) reported the antibacterial and anti-biofilm effects of proanthocyanidins against A. actinomycetemcomitans. The treatment with proanthocyanidins reduced the growth of A. actinomycetemcomitans and resulted in a loss of bacterial viability as indicated by the damage to the bacterial cell membrane. Proanthocyanidins also possessed an anti-biofilm activity against P. aeruginosa as reported by Ulrey et al. (2014) and its anti-virulence potential was further investigated in a study by Maisuria et al. (2016).

Apart from its ability to inhibit biofilm formation and adhesion of periodontopathogenic bacteria, the therapeutic effect of proanthocyanidins with regards to periodontal disease include its potential to inhibit cytokine production by immune and mucosal cells and its capability to inhibit MMP production (Bonifait and Grenier 2010). Their capability to inhibit MMP and dentin cross-linker activity have been reported as an additional notable benefit of proanthocyanidins (Balalalie et al., 2018). The anti-inflammatory properties of proanthocyanidins were revealed by the attenuation of pro-inflammatory cytokines secretion (IL-1β, TNF-α, IL-6) as well as MMP-3 and MMP-9 secretion by macrophages stimulated with A. actinomycetemcomitans (Lagha et al., 2018). In another recent study, Jekabsone et al. (2019) demonstrated a strong antibacterial, anti-inflammatory and gingival tissue protecting properties of proanthocyanidins in periodontitis mimicking condition. Proanthocyanidins fraction has been found to have a stronger efficiency in suppressing caspases as indicated by the level of caspase-3 and caspase-8, and preventing mediator release as indicated by IL-8 and PGE₂ secretion from gingival fibroblast, and IL-6 secretion from peripheral blood mononuclear cells. In an earlier study, proanthocyanidins-enriched cranberry fraction has been shown to inhibit the production of MMP-3 and MMP-9 in LPS-induced gingival fibroblasts (Bodet et al., 2007). Gingival fibroblasts, the most abundant cells found in periodontal tissues are actively involved in the host inflammatory response to oral pathogens and is known to mediate local tissue destruction in periodontal disease. The productions of IL-6, IL-8 and PGE₂ by gingival fibroblast stimulated by LPS were inhibited with the treatment of proanthocyanidins-enriched cranberry fraction (Bodet et al., 2007). The effects of proanthocyanidins in in vivo and in vitro model of periodontal inflammation has been summarized in Table 4.