Antimicrobial Efficiency of Pistacia lentiscus L. Derivates against Oral Biofilm-Associated Diseases—A Narrative Review

Pistacia lentiscus L. (PlL) has been used for centuries in traditional medicine. The richness in antimicrobial biomolecules of Pll derivates can represent an alternative to chemically formulated agents used against oral infections. This review summarizes the knowledge on the antimicrobial activity of PlL essential oil (EO), extracts, and mastic resin against microorganisms being of relevance in oral biofilm-associated diseases. Results demonstrated that the potential of PlL polyphenol extracts has led to increasing scientific interest. In fact, the extracts are a significantly more effective agent than the other PlL derivates. The positive findings regarding the inhibition of periodontal pathogens and C. albicans, together with the antioxidant activity and the reduction of the inflammatory responses, suggest the use of the extracts in the prevention and/or reversal of intraoral dysbiosis. Toothpaste, mouthwashes, and local delivery devices could be effective in the clinical management of these oral diseases.


Introduction
The most prevalent oral diseases are strongly associated with a loss of microbial homeostasis and biofilm development.
Due to a microbiota involving carbohydrate-fermenting Streptococcus mutans and species of the genera Actinomyces, Lactobacillus, Dialister, Eubacterium, Olsenella, Bifidobacterium, Atopobium, Propionibacterium, Scardovir, Abiotrophia, Selenomonas, Veillonella, and Candida albicans biofilms on the tooth surfaces may cause dental caries [1]. At the gingival and subgingival margins, biofilm accumulation may lead to gingivitis, which occurs as an inflammatory infiltrate as a consequence of an imbalance of the host's immune response. A loss of eubiosis may increase the percent of proteolytic and anaerobic bacteria, e.g., Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Prevotella intermedia, all characterizing the periodontal disease [2][3][4]. Also, peri-implant diseases may develop due to the accumulation of bacteria [5]. Further, Porphyromonas, Fusobacterium, and Prevotella ssp. together with Tannerella forsythia and Veillonella spp. represent the most related oral bacteria in intraoral halitosis with the production of volatile sulfur compounds (VSCs) [6]. The compounds derived by the activity of Gram-negative anaerobic bacteria are supported by Gram-positive bacteria and fungi [7,8]. In comparison, Gram-negative anaerobic rods and proteolytic bacteria biofilm recur in endodontic and periapical infections related to pulp necrosis [9]. Regarding the yeast, Candida biofilm, with a high prevalence of C. albicans and/or C. glabrata in immunocompromised patients, leads to oral candidiasis that may have severe consequences under these pathological conditions [10]. Finally, Primary Herpetic related to pulp necrosis [9]. Regarding the yeast, Candida biofilm, with a high prevalence of C. albicans and/or C. glabrata in immunocompromised patients, leads to oral candidiasis that may have severe consequences under these pathological conditions [10]. Finally, Primary Herpetic Gingivostomatitis (PHG) and herpes labialis represent the most common clinical evidence of oral viral infections by the Herpes Simplex Virus type-1 (HSV-1) [11].
Accordingly, antiseptics are widely used to prevent and treat the above-mentioned conditions. Chlorhexidine digluconate is still the gold standard among antiseptics [12]. Nevertheless, tooth staining, calculus formation, and high cytotoxicity against human fibroblasts and osteoblasts have been described as side effects when using chlorhexidine [13,14]. Antibiotics, e.g., amoxicillin, metronidazole, and azithromycin, are applied in severe cases of periodontal disease, reporting side effects like nausea, vomiting, diarrhea, and others [15]. However, resistance to antimicrobials, which is associated with the use of these substances, has become a global problem.
Plant-derived substances have been considered to overcome the issues of antiseptics and antibiotics, plant-derived substances are highly discussed [16]. PlL, belonging to the Anacardiaceae family [17], has been used for centuries in traditional medicine. Almost the whole plant, including the leaves, fruits, wood, and mastic resin, has been utilized as a remedy for a large variety of diseases ( Figure 1). The richness in antimicrobial and antiinflammatory biomolecules might represent an alternative to chemically formulated therapies. Harsh growing conditions, dryness, and a warm environment influence on the genotype and richness of secondary metabolites of PlL. They are mainly represented by terpenoids in the EO, and flavonoids, phenolic acids, and derivatives in the polyphenols mixture of the extracts [17,18].
In ethno-pharmacology, different popular formulations of PlL, including the EO, the boiled extracts, the poultices of blossoms and leaves, patches of woods, and mastic resin, have been used [19][20][21][22][23][24][25]. Furthermore, PlL has been administered in the form of smoke, obtained by burning or boiling the soft wood and leaves, particularly in the cases of osteoarthritis, bronchitis, and allergies [21,25]. Moreover, using leaf extracts for beverages and mouthwash or direct chewing of the soft stems, leaves, or mastic is still used to antagonize toothache and gingival inflammation [24][25][26][27]. Additionally, powdered mastic can be applied to allow wound healing [19,20] and to antagonize gram-positive bacteria, including Staphylococcus aureus methicillin-resistant species [28], while the leaves EO acts with high Harsh growing conditions, dryness, and a warm environment influence on the genotype and richness of secondary metabolites of PlL. They are mainly represented by terpenoids in the EO, and flavonoids, phenolic acids, and derivatives in the polyphenols mixture of the extracts [17,18].
In ethno-pharmacology, different popular formulations of PlL, including the EO, the boiled extracts, the poultices of blossoms and leaves, patches of woods, and mastic resin, have been used [19][20][21][22][23][24][25]. Furthermore, PlL has been administered in the form of smoke, obtained by burning or boiling the soft wood and leaves, particularly in the cases of osteoarthritis, bronchitis, and allergies [21,25]. Moreover, using leaf extracts for beverages and mouthwash or direct chewing of the soft stems, leaves, or mastic is still used to antagonize toothache and gingival inflammation [24][25][26][27]. Additionally, powdered mastic can be applied to allow wound healing [19,20] and to antagonize gram-positive bacteria, including Staphylococcus aureus methicillin-resistant species [28], while the leaves EO acts with high antibacterial capacity against gram-negative rods as Escherichia coli, and Pseudomonas aeruginosa [29].
Anti-inflammatory and anti-ROS potency, and the capacity to target oral bacteria have led to the proposal of PlL derivates as a natural antimicrobial agent against oral diseases [18,[36][37][38].
Given the above considerations, after describing the major chemical constituents of PlL, the following overview discusses in-vitro studies on the antimicrobial activity of the EO, extracts, and mastic against microorganisms being of relevance in oral biofilm-associated diseases. Additionally, the clinical studies conducted to ascertain the scientifical value of PlL were summarized. Finally, we discussed the potential of PlL secondary metabolites as an oral agent and the greater indications they may have in preventing and treating oral diseases.

Phytochemical Constituents of Pistacia lentiscus
The growth environment, seasonability of harvesting, and type of material (edible or not edible parts of the plant) influence chemical differences of PlL oils and extracts between the Mediterranean regions [17] (Table 1).
Comprehensive studies have been conducted on the methanol and alcohol extracts of PlL leaves, alongside investigating their chemical characteristics. The high concentration of polyphenols in the extract is extremely attractive from a beneficial point of view. Polyphenols can antagonize oxidative stress and inflammation, exerting anti-cancer, antiobesity, and anti-diabetic character, further increased by cardiovascular, hepatoprotective and osteoporotic preventive effects [53,54]. Additionally, polyphenols have high value as anti-infective compounds [32,[55][56][57].
In the methanol extracts of PlL leaves from plants growing in Algeria, a number of 46 different molecules were identified [58]. Flavonoids, phenolic acids, and their derivatives were the most abundant, including myricetin glycoside, catechin, β-glucogallin, and quercitrin gallate. High doses of polyphenols in the ethyl acetate and methanol extracts of leaves were found by Romani and coworkers [59]. In that research, PlL polyphenols reached up to 7.5% of leaf dry. Furthermore, three major classes of secondary metabolites were recognized in the extract (i) gallic acid and galloyl derivatives of both glucose and quinic acid; (ii) flavonol glycosides, i.e., myricetin and quercetin glycosides; and (iii) anthocyanins, namely delphinidin 3-O-glucoside and cyanidin 3-O-glucoside. The leaf extract had greater content of phenols and flavonoids than that of the fruit, which conversely exhibited a higher number of tannins. A correlation between the polyphenols content and biological capacity of PlL extracts has been further strengthened by Garofulić and coworkers using a sophisticated microwave-assisted extraction (MAE) [60]. By MAE, the authors were able to isolate an increasing proportion of biomolecules, including the more heat-sensitive complex structures of flavonoid glycosides, procyanidins, and tannins, which proportionally raised the antioxidant capacity of the material. Very recently, a phytochemical study further confirmed the link between the content of phenol, flavonoid, and tannin to the antioxidant activity of extract [61].
Concerning the antimicrobial mechanism, it is proposed that the activity of polyphenols involves a membrane-disrupting mechanism, together with the inhibition of cell envelope synthetases, the nucleic acids synthetases, the bacterial virulence, the efflux pump, NADH-cytochrome C reductase, and ATP synthetase. All these cell disorders, further increased by an impairment of Quorum Sensing, lead microorganisms to inability to form biofilms [62][63][64].

In-Vitro Data on Oral Planktonic Microorganisms
Many laboratory studies attest to the antimicrobial activity of PlL derivates. The agar disc diffusion test (ADD) and the micro-broth dilution method determining the minimal inhibitory concentration (MIC) have been usually applied to quantify this capacity. More rarely, the minimal bactericidal/fungicidal concentration (MBC/MFC) and the time-killing assay were selected to measure the antimicrobial potency.
Commonly studied oral microorganisms vary from Gram-positive bacteria (Streptococcus spp., Enterococcus faecalis) to Gram-negative bacteria (Porphyromonas gingivalis, Fusobacterium nucleatum, Actinomyces spp. Tannerella forsythia), the yeasts Candida albicans and C. glabrata, and sometimes viruses, mainly represented by the herpes simplex virus. Concerning Streptococcus sp., many studies demonstrated the high sensitivity of S. mutans to PlL [37,68]. Moreover, periodontal pathobionts were strongly inhibited by the agent [36]. Conversely, some papers evidenced any or low antifungal activity of PlL derivates [37,67,[69][70][71][72], even if high capacity against the growth of Candida as laboratory as clinical isolate sp. was demonstrated very recently using the leaves EO [36].
Regarding the berry oil, Orrù and coworkers [37] found a selective inhibition of the agent toward different species of Streptococcus using the MIC and MBC/MFIC. S. agalactiae, S. intermedius, S. mutans, S. pyogenes were highly sensitive, and this correlated to the pathogenic profile of the bacteria.

In-Vitro Data on Biofilm Experiments
Orrù and coworkers also evaluated the capacity of PlL berry oil toward Streptococcus sp. in biofilm [37]. The results showed that the sensitivity of the bacteria was species-specific. Two probiotic strains of S. salivarius K12/M18 were non-sensitive to the oil. Conversely, the sensitivity of the pathogens S. agalactiae, S. intermedius, S. mutans, and S. pyogenes was correlated to the fatty acid profile of the oil. Chromatographic analysis of the growth medium containing the oil showed a significant increase in oleic, palmitic, and linoleic acids, which are already known for their antimicrobial capacity. In this context, it was said that PlL berry oil selectively inhibits the growth of pathogens by the fatty acid metabolic pathway while preserving the vitality of beneficial bacteria.

Research Related to Dental Caries
Many studies pointed to the activity of PlL against the cariogenic biofilm by carrying out in vitro and in vivo investigations (Tables 2-4). Most studies focused on the capacity to antagonize S. mutans as a key bacterium in the multifaceted events leading to the demineralization process [73,74]. Additional research included acidogenic microorganisms, i.e., Lactobacillus, acidic strains of non-mutans Streptococci, and Actinomyces [73]. Together these bacteria contribute to an increase in the biomass and extracellular polymeric substance (EPS) constituting the cariogenic biofilm.     In this context, one of the most studied materials has been the mastic resin, commonly used against toothache in popular medicine. The ability of mastic against the oral streptococci was mainly evaluated using the ADD, MIC, and MBC (Tables 2 and 3).
In this field, Aksoy and coworkers [76] assayed the capacity of mastic chewing in inhibiting the growth of Mutans streptococci and Lactobacillus spp. in saliva [76,84]. After mastic chewing, significantly lower bacteria were found in saliva samples in comparison to the control (p < 0.001). The results were related to the chemical content of terpinen-4-ol and α-terpineol in the mastic gum, which conferred relevant biological properties to the resin. The result asserted that mastic is a useful agent in preventing the disease.
The effectiveness of chewing mastic gum against the salivary counts of S. mutans was also reported by Preethi [85], who tested the capacity of the resin gum in a group of children compared to xylitol chewing gum. Mastic gum showed a statistically significant reduction of the bacterium in saliva in comparison to xylitol gum. The property to lower the cariogenic bacteria count in saliva was also attributed to the presence of PlL extract as a component of herbal toothpaste [87].
Further studies investigated the matter. Karygianni and coworkers [77] proved the antibacterial activity of three terpenoid acids derived from PlL resin extract: 24Zisomasticadienolic acid, oleanolic acid, and oleanonic aldehyde. The authors demonstrated that the acids had an inhibitory effect against S. mutans and other streptococci (S. sobrinus, S. oralis). Among the three compounds, the most active was the pentacyclic triterpenoid oleanolic acid, which not only possessed the greatest effect against S. mutans but also inhibited the yeast C. albicans as a cause of increased aggressiveness in cariogenic biofilm [74]. The antimicrobial mechanism of oleanolic acid was shown to disrupt the cell envelope leading to cell death. The interplay between natural compounds and Candida has been further elucidated using transmission electron microscopy (TEM) [88,89].
This study further supports the anti-cariogenic effect of the fatty acids of PlL oil, as reported by Orrù and coworkers in planktonic and biofilm cultures [37].
Further analysis attested to the antimicrobial activity of PlL EO of leaves targeting S. mutans and Lactobacillus acidophilus in adjunction to E. faecalis and F. nucleatum [90].

Research Related to Periodontal Disease
Many studies studied the capacity of PlL derivates against periodontal pathogens (Tables 2-4). Among them, several studies aimed to elucidate the antagonism of mastic toward P. gingivalis as a key bacterium in periodontal disease [77,91,92]. The antimicrobial activity of water-ether extracts of mastic was addressed by the presence of three major triterpenoid acids [77]. To validate this, 24Z-isomasticadienolic acid, oleanolic acid, and oleanonic aldehyde were screened as isolated fractions against P. gingivalis. F. nucleatum and Parvimonas micra. The acids showed different inhibitory capacities toward the bacteria, been the oleanolic acid the most effective.
Further, the capacity of mastic chewing against the total anaerobic bacteria in saliva was compared to that of a placebo gum [93]. The study was conducted on 20 young, healthy subjects. Unstimulated saliva was collected as a baseline sample. Then, each group used the assigned chewing gum for 10 min, and saliva was collected again at the end of 1, 2, 3, and 4 h after the chewing. The cultured saliva samples demonstrated a significant reduction in the total amount of anaerobic bacteria in the mastic group compared to the control.
Additionally, the sensitivity of P. gingivalis to PlL fruit extract and the leaves extract was carried out in one research [94]. Results demonstrated higher inhibition activity of the fruit extract toward the bacterium than the leaves extract. In the same study, the authors tried to identify the more potent antimicrobial fraction in the fruits fingerprint, which was mainly composed of gallic acid, catechin, 3,4-dihydroxyhydro-cinnamic acid, benzoic acid, salicylic acid, and luteolin. However, synergic activity between all the fractions was proved as responsible for the antimicrobial potency of the fruit extract.
Several studies also report on the biocompatibility of PlL extracts and oils as antimicrobial compounds. Cytotoxicity testing was conducted for a variety of cells, i.e., human immortalized keratinocytes [94], human gingival, periodontal ligament fibroblasts, gingival keratinocytes, and dysplastic oral keratinocytes [36], human osteoblastic cell lines, and mouse fibroblast cell lines [78]. However, any potential toxic effect on cell lines was ascribed to PlL derivates in the evaluations in addition to the antimicrobial capacity. Conversely, an increase in the viability of fibroblasts was reported by the WST-1 metabolic assay testing PlL EO [33]. Thus, all the reports show that the high biological character of PlL derivates occurs when used as oral antimicrobials.

Oral Halitosis
Mastic gum is an ancient remedy against oral halitosis [79], a common clinical sign of periodontal disease, dry mouth, smoking, alcohol consumption, and stress [74,95]. Halitosis derives from VSCs greatly produced by the Gram-negative anaerobic bacteria supported by the Gram-positive bacteria [7]. Furthermore, C. albicans can be involved in the production of VSCs [8], which accumulation in oral surfaces may also contribute to the development of cancer [96].
Several researchers focused on the activity of mastic gum in inhibiting the responsible oral bacteria for the production of VSCs (Tables 2 and 3). In this context, Sterer and coworkers [86] investigated the capacity of mastic gum as a component of palatal mucoadhesive tablets formulated to antagonize oral malodor and VSC levels. Using the ADD, the authors demonstrated the strength of mastic against P. gingivalis, C. albicans, and S. mutans, as pathogens involved in oral halitosis.

Candida Infection
The activity of PlL derivates against the yeasts in general, and Candida sp. in particular, has been widely investigated (Tables 2 and 3).
A high inhibiting effect on C. albicans was reported by examining the extracts. In this regard, the antifungal power was associated with the anti-antioxidant potency of an extract, which was further related to an increase in flavanols concentration [66,71,72,[80][81][82][83]. Further evidence concerns the amount of tannic acid. This phenol was more effective than nystatin and amphotericin, commonly used as antifungal agents. Moreover, linalool and α-terpineol were identified as potent antifungals in mastic water obtained by the steam distillation of mastic resin [97]. Also, the extraction solvent was reported as crucial in increasing the antifungal and antioxidant capacity of the agent [82].
Additional activity against C. albicans was reported by a poly-herbal mixture where PlL water extract was included as an ingredient of the paste. In this case, the significant capacity was comparable to that of fluconazole [98].
Conflicting data regarding the antifungal strength of PlL EO [37,71]. However, low MICs against C. albicans and glabrata, clinical isolate sp., were noticed by assaying PlL leaves EO [36]. The authors addressed such activity to the presence of six pharmacological terpenes, which were recovered in a concentration above 0.05%. In the same research, the authors demonstrated the capacity of the oil to inhibit COX2 and lowering LOX, supposing the capacity of the EO to antagonize the level of PGE2. In fact, the aggressiveness of Candida is strongly related to the ability to produce high quantity of fungal PGE2, which also exhibits cross-reactivity with that of the host [99][100][101]. The data could attest to important properties of the leaves EO against the yeast as COX-2 and LOX inhibitors are recommended to antagonize the biofilm development, resistance, and invasion of Candida.

Oral Virus Infection
Only two studies assessed the capacity of PlL derivates against HSVs. With the exception of the ethyl acetate extract, Suzuki and colleagues [102] reported the capacity of different PlL extracts. Moreover, Bouslama [103] described a significant activity of the methanol extract of the PlL stem against HSV-2. An explanation of these data could be found in the richness of polyphenols of PlL extracts and in their capacity to recover hormesis mechanisms.

Clinical Studies
A few numbers of studies documented the effectiveness of PlL derivates clinically. It was pointed to validate the popular capacity of mastic to antagonize toothache and gingival inflammation. With this intent, in a double-blinded, randomized study placebo-controlled, Takahashi and coworkers studied the ability of mastic chewing gum against tooth plaque formation and gingiva inflammation [93]. The study was conducted on 20 young volunteers with healthy periodontal. The plaque and gingival indices were recorded at baseline and at the end of the trial, during which a piece of mastic gum or of the placebo gum was chewed as the only oral hygiene device. The clinical data showed that the degree of plaque accumulation and gingival inflammation were significantly lower in the group of mastic chewing in comparison to the control.
Mastic resin was also included in a mixture of herbal polymers forming palatal mucoadhesive tablets in antagonism to oral malodor production and VSCs [86]. Results showed a significant reduction in malodor scores and VSC levels in the experimental group in comparison to the control.

Discussion
This review aimed to summarize the scientific knowledge on the antimicrobial capacity of PlL biomolecules toward oral biofilm-associated diseases. In view of the data, a second aim of this work was to suggest a possible use of PlL derivates as a health cure agent. This is in accordance with the need to find novel agents able to combat biofilms causing resistant bacteria and diseases.
Regarding our search, we found a great number of investigations that, together with the antimicrobial capacity, simultaneously reported on the wide biocompatibility, and the great antioxidant and anti-inflammatory properties possessed by PlL biomolecules. The evidence that natural molecules can exhibit several benefits at the same time strongly demonstrates their various working abilities in comparison to chemically formulated antimicrobial agents. In fact, natural antimicrobials can antagonize pathogens and behave in such a way as to regulate the altered environment. Furthermore, natural compounds can target bacteria by virulence/detrimental factors with biocide-free effects rather than the processes involved when employing chemical agents, leading to sustainable management of biofilm challenges. In such a way, natural antimicrobials can successfully counteract the alarming scenario of resistant bacteria.
The potential potency of polyphenol extracts has led to increasing scientific interest. Several trials confirm the value of these molecules in maintaining and recovering healthy status due to the management of the cell homeostatic systems. Polyphenols act as stressors to the exposed animal cells activating cell defense systems to control the redox environment, the proteostatic and metabolic homeostasis, the organelle turnover, and the inflammatory response [103]. As disturbance in homeostasis is also strongly related to the development of oral diseases, the high content of polyphenols of PlL extracts is particularly appealing in the search for new types of oral health care agents. Regardless of the parts of the plant they derive from, the extracts are among the richer extracts in polyphenols described in the literature. In the leaf extract, the molecules had a range of 7.5% of leaf dry weight, where the amount of galloyl quinic acid derivates, together with flavonol glycosides, greatly represented by myricetin derivates, and quercetin, in addition to anthocyanins are the main expressed agents. In addition to the antimicrobial properties, these chemical fractions confer to the extracts high antioxidant and anti-inflammatory capacity, together with anticancer, hepatoprotective, and hypercholesteremic characteristics.
Reviewing the literature, we found that the majority of the studies focused attention on the inhibitory effect of PlL derivates against cariogenic and periodontal bacteria in addition to C. albicans. Discordance data have been collected regarding S. mutans and other cariogenic microorganisms. The mastic resin and the EOs were the most active compounds against S. mutants and cariogenic bacteria in general. While, with the exception of mastic extract, the polyphenols of the leaves and the fruit were unable to block the bacteria.
Considerable antiseptic activity is reported against P. gingivalis and other periodontal pathogens by using all of the various derivates. Several studies attempted to isolate the most active biomolecules against P. gingivalis, but a synergic effect between all the fractions was necessary to stop the viability of the bacterium. Regarding the extract, laboratory studies demonstrated the greater efficacy of the fruit extract in comparison to that of the leaves. However, the latter showed the highest antioxidant capacity, which was related to a major content of flavonoids. A high anti-ROS property, and anti-inflammatory ability are still necessary to recover altered oral homeostasis by periodontal dysbiosis, and both these abilities work independently of the MIC. In fact, at dose ranges lower than the ascertained MIC, gallic acid-rich extract was able to downregulate gingipains expression by P. gingivalis, significantly affecting the release of inflammatory genes (i.e., COX-2) [104]. These data are consistent with the finding that sub-lethal concentrations of polyphenols have a proper time-dependent antibiofilm effect [60,105].
Concerning Candida sp., a great number of references cite PlL extracts as anti-Candida agents, whereas the EOs and mastic resin showed contrasting data. The high content of flavonoids in the extract is reported to be a determinant in eliminating the yeast. Among these biomolecules, the phenol tannic acid demonstrated higher antifungal activity than chemicals usually applied as chemotherapy agents. A considerable number of studies stressed ascertaining the MIC capacity of the polyphenols against cultivated species of Candida. While clinical species were rarely evaluated by studies, all of them analyzed biofilm. This suggests the need to investigate the capacity of biomolecules in such complex communities characterized by intrinsic resistance to host immune response and antimicrobial drugs. In this regard, in addition to cell growth inhibition, polyphenol properties are to be considered. Catechin and proanthocyanidins were found to react with spores and hyphae of the pathogenic fungi, interfering with quorum-sensing behavior. Additionally, natural phenols, as anti-inflammatory substances, are able to reduce the level of COX enzymes, thus interfering with the release of prostaglandin E2 (PGE2) expression, which is necessary to Candida in the formation of biofilm [106]. Given this evidence, a double effect can antagonize Candida oral infections using PlL polyphenols: a direct activity against the yeast and an indirect efficacy against its virulence, in addition to the absence of cytotoxicity, as it was largely verified in the studies.
Finally, this review has documented several clinical studies on the effectiveness of PlL derivates. However, the need to increase clinical knowledge demands trials to better understand the behavior of PlL polyphenols in oral health and diseases.

Conclusions
The positive findings regarding the inhibition of periodontal pathogens and C. albicans, together with the antioxidant activity and the reduction of the inflammatory responses, would strongly suggest the use of PlL polyphenols in the prevention and/or reversal of intraoral dysbiosis. In fact, the extract appears to be a significantly more effective agent than the other PlL derivates.
Toothpaste, mouthwashes, and local delivery devices could be effective in the clinical management of these oral diseases. Nanotechnology encapsulation will be useful in obtaining stable compounds able to transfer the pharmaceutical capacity of PlL derivates in the prevention and treatment of oral diseases.