Table 1.
Influence of proanthocyanidins or flavan-3-ols on periopathogens and their proteolytic enzymes.
| Source Plant (If Available)/Active Compound/Extract/Fraction | Periopathogen and Its Proteinase/Toxin | Results | Authors, Year | Ref. |
|---|---|---|---|---|
| Catechin | P. gingivalis | Catechin did not influence the growth of P. gingivalis at the concentration tested (20, 40, or 60 µM). | (Lee et al. 2020) | [19] |
| Pelargonium sidoides DC./root extract (PSRE) and proanthocyanidin fraction from PSRE (PACN) | A. actinomycetemcomitans |
|
(Jekabsone et al. 2019) | [20] |
| The buds of Castanopsis lamontii Hance/water extract (CLE) rich in epicatechin (EC) and procyanidin B2 (PB2). | P. gingivalis | MICs of CLE, EC, and PB2 against P. gingivalis were 0.625, 1.25, and >1.25 mg/mL, respectively. | (Gao et al. 2019) | [21] |
| c Cranberry fruit (Vaccinium macrocarpon Aiton)/proanthocyanidins (PACs) isolated therefrom |
A. actinomycetemcomitans, leukotoxin | PACs dose-dependently reduced leukotoxin gene expression (ltxB and ltxC, but not ltxA and ltxD) in the two strains of A. actinomycetemcomitans tested. | (Amel Ben Lagha et al. 2019) | [22] |
| Highbush blueberry (Vaccinium corymbosum L.) proanthocyanidins (PACs) | A. actinomycetemcomitans | At a concentration of 500 μg/mL, the PACs reduced the growth of A. actinomycetemcomitans by 62.5% The PACs at concentrations ranging from 500 to 3.9 μg/mL significantly and dose-dependently reduced biofilm formation. More specifically, 31.25 μg/mL of the PACs reduced the growth of bacteria by 23.83% and inhibited biofilm formation by 93.98%. PACs revealed a capacity to reduce biofilm viability, but not biofilm desorption at 500 μg/mL. PACs reduced LtxA cytotoxic towards macrophage-like cells by 100%, 95.4%, and 69.70%, at 125, 62.5, and 31.25 μg/mL, respectively. The PACs protected the oral keratinocytes barrier integrity from damage caused by A. actinomycetemcomitans. |
(Amel Ben Lagha et al. 2018) | [23] |
|
Camellia sinensis (L.) Kuntze/the commercial green tea extract polyphenol content of 98.42%, including 47.92% of (−)-epigallocatechin gallate (EGCG). |
P. gingivalis, Arg-gingipain, Lys-gingipain | 62.5 μg/mL of both the green tea extract and EGCG inhibited the degradation of type I collagen by a P. gingivalis culture supernatant by 91.1% and 94.5%, respectively. The green tea extract caused more significant inhibitions of both Arg-gingipain and Lys-gingipain activities than EGCG. More specifically, 125 μg/mL of the green tea extract and EGCG reduced Arg-gingipain activity by 61.82% and 16.46%, while Lys-gingipain activity was reduced by 51.28% and 7.97%, respectively. Green tea extract and EGCG enhanced the barrier function of a gingival keratinocyte model and exerted a protective effect against invasion by P. gingivalis. |
(Amel Ben Lagha et al. 2018) | [24] |
| Pelargonium sidoides DC./root extract (PSRE) composed mainly of various catechins and prodelphinidin oligomers; and proanthocyanidin fraction from PSRE (PACN) composed of prodelphinidin oligomers. | P. gingivalis | PSRE extract significantly reduced the viability of P. gingivalis, as well as S. salivarius in a dose-dependent manner, starting from the lowest tested concentration-0.02 g/mL (viability reduction by about 74% and 59%, respectively). After treatment with PACN, the P. gingivalis viability was not significantly decreased until using 0.05 g/mL. However, starting from this concentration the inhibition of P. gingivalis viability was stronger for PACN than for PSRE. Moreover, PACN was less effective against the commensal S. salivarius viability. | (Savickiene et al. 2018) | [25] |
| Camellia sinensis (L.) Kuntze Mixture of theaflavins (TFs) from black tea (theaflavin-3-gallate, theaflavin-3′-gallate, and theaflavin-3-3′-digallate, with more than 80% purity) | P. gingivalis | TFs dose-dependently inhibited the expression of genes: fimA, hagA, rgpA, and kgp. More specifically, TFs at 50 μg/mL inhibited the expression of fimA, hagA, rgpA, and kgp by 42%, 47%, 52%, and 53%, respectively. TFs also dose-dependently inhibited the adherence of P. gingivalis to keratinocytes and MatrigelTM (250 μg/mL of TFs inhibited adhesion by 73.9% and 64%, respectively). A treatment of gingival keratinocytes with TFs (31.25–125 μg/mL) significantly enhanced tight junction integrity and prevented P. gingivalis-mediated tight junction damage, as well as bacterial invasion. |
(A Ben Lagha and Grenier 2017) | [26] |
| Limonium brasiliense (Boiss.) Kuntze/70% acetone extract from rhizomes, rich in proanthocyanidins, gallic acid, and epigallocatechin-3-O-gallate/high amount of untypical double linked proanthocyanidins named samarangenins A and B | P. gingivalis, Arg-gingipain | Limonium brasiliense rhizomes (LBEs) at 100 μg/mL reduced the adhesion of P. gingivalis to the human epithelial KB cells by about 80% and at 20 μg/mL reduced the proteolytic activity of the arginin-specific Rgp gingipain by about 75%. | (de Oliveira Caleare et al. 2017) | [27] |
|
Camellia sinensis (L.) Kuntze/the commercial green tea extract with polyphenol content of 98.42%, including 47.92% of (−)-epigallocatechin gallate (EGCG). |
P. gingivalis; expression of several P. gingivalis genes involved in host colonization (fimA, hagA, hagB), tissue destruction (rgpA, kgp), heme acquisition (hem), and stress response (htrA) investigated | The MIC values of the green tea extract ranged from 250 to 1000 μg/mL, while for EGCG, they ranged from 125 to 500 μg/mL. Synergistic antibacterial effects were observed for the green tea extract or EGCG in combination with metronidazole. The combination of the green tea extract or EGCG and tetracycline resulted mostly in an additive effect. Both substances caused a dose-dependent inhibition of bacterial adherence to oral epithelial cells. Green tea extract and EGCG dose-dependently inhibited the expression of fimA, hagA, hag, rgpA, kgp, and hem. However, both compounds increased the expression of the stress protein htrA gene. Green tea extract and EGCG inhibited quorum sensing. |
(Fournier-Larente, Morin, and Grenier 2016) | [28] |
| Persimmon (Diospyros kaki Thunb.)/fruit extract (PS-M) contained 21.5 wt% of condensed tannin (proanthocyanidins). | Oral polymicrobial biofilms | The colony forming units (CFUs) were lower in all PS-M and CHX (chlorhexidine) groups compared to the control group. PS-M exerted a dose-dependent effect. PS-M at a dose of 4.0 wt% had the same effect as 0.2 wt% CHX. SEM revealed that the biofilm structures were considerably destroyed in the 4.0 wt% PS-M and 0.2 wt% CHX. | (Tomiyama et al. 2016) | [29] |
Rumex acetosa L/70% acetone extract from aerial parts., after removal of lipophilic compounds (RA1);
|
P. gingivalis, Arg-gingipain, Lys-gingipain | RA1 (5 to 15 μg/mL) reduced P. gingivalis adhesion to KB cells in a dose-dependent manner to about 90%. Galloylated flawan-3-ols and proanthocyanidins were confirmed to be responsible for this antiadhesive effect with (8) procyanidin B2-di-gallate being the lead compound. Ungalloylated flavan-3-ols and oligomeric proanthocyanidins (1,2,3,4,7,11) were inactive. RA1 and the galloylated proanthocyanidins (5,6,8,9,10,12,13) strongly interacted with the bacterial virulence factor Arg-gingipain, while the corresponding Lys-gingipain was hardly influenced. RA1 does not influence the gene expression of rgpA, kgp, and fimA. RA1 inhibited hemagglutination. In silico docking studies indicated that (8) procyanidin B2-di-gallate interacts with the active side of Arg-gingipain and hemagglutinin from P. gingivalis, and the galloylation of the molecule seems to be responsible for the fixation of the ligand to the protein. |
(Schmuch et al. 2015) | [30] |
| Camellia sinensis (L.) Kuntze/the commercial black tea extract (with theaflavin content of 40.23%); theaflavin (TF), theaflavin-3,3′-digallate (TFg), |
P. gingivalis, Prevotella intermedia, Fusobacterium nucleatum, A. actinomycetemcomitans |
MIC/MBC values (μg/mL) of black tea, TF, and TFg for P. gingivalis and P. intermedia were very similar, 500/1000, 125/500, and 250/500, respectively, and significantly higher for F. nucleatum, 2000/4000, 250/>1000, and 250/>1000, and A. Actinomycetemcomitans, 2000/8000, 250/>1000, and 500/1000. The black tea extract, theaflavin, and theaflavin-3,3′-digallate can potentiate the antibacterial effect of metronidazole and tetracycline against P. gingivalis. | (Telma Blanca Lombardo Bedran et al. 2015) | [31] |
| Vaccinium angustifolium Ait./70% ethanolic blueberry extract (phenolic acids, flavonoids, and procyanidins made up 16.6, 12.9, and 2.7% of the blueberry extract, respectively. | Fusobacterium nucleatum | The MIC of the blueberry extract against F. nucleatum was 1 mg/mL. This concentration also corresponded to the MBC. It was suggested that this property may result from the ability of blueberry polyphenols to chelate iron. Moreover, the blueberry extract at 62.5 μg/mL inhibited F. nucleatum biofilm formation by 87.5%. | (Amel Ben Lagha et al. 2015) | [32] |
| Epigallocatechin gallate (EGCG). | P. gingivalis | The MIC of EGCG was 500 μg/mL. EGCG at 500 μg/mL or 5 mg/mL significantly destroyed established P. gingivalis biofilms (in these concentrations of EGCG, adenosine triphosphate (ATP) levels were about 40% lower compared to the control). Damage of the cell membranes of P. gingivalis were frequently observed in these high concentrations. Moreover, EGCG at sub-MIC levels (10 μg/mL and 100 μg/mL) significantly inhibited P. gingivalis biofilm formation (ATP levels were more than 60% lower compared to the control); however, it did not damage the cytoplasmic membrane of P. gingivalis. |
(Asahi et al. 2014) | [33] |
| Cranberry Vaccinium macrocarpon Ait/non-dialyzable material (NDM) prepared from concentrated juice, rich in proanthocyanidins. | P. gingivalis and F. nucleatum mixed infection | NDM inhibited coaggregation between P. gingivalis and F. nucleatum in a dose-dependent manner (starting from 1 mg/mL). NDM inhibited P. gingivalis and F. nucleatum adhesion to human epithelial cells. The 4 mg/mL of NDM fully inhibited the adhesion of F. nucleatum and P. gingivalis onto the epithelial cells, leaving the cells entirely free of bacteria. | (Polak et al. 2013) | [34] |
| Vitis vinifera L./commercial proanthocyanidins from grapeseed extract (Leucoselect ®, Indena, Italy) combined with H2O2 and photo-irradiation. | P. gingivalis, S. mutans | A hydrogen peroxide photolysis system in combination with proanthocyanidin from grapeseed extract synergistically induced damage in P. gingivalis and S. mutans, leading to killing of these bacteria. | (Ikai et al. 2013) | [35] |
| Epigallocatechin gallate (EGCG). | A. actinomycetemcomitans | Antimicrobial activity was observed at >0.5 mg/mL of EGCG. Alpha-amylase reduced the antimicrobial activity of EGCG, and EGCG inhibited the activity of alpha-amylase. The reason was precipitated alpha-amylase by EGCG after adding to saliva. | (Hara et al. 2012) | [16] |
| Vaccinium macrocarpon Ait./A-type cranberry proanthocyanidins (APAC) and licochalcone A (LA)-chalcone, not proanthocyanidin. | P. gingivalis | APAC, at the highest concentration tested (50 μg/mL), did not affect the growth of P. gingivalis, whereas licochalcone A completely prevented growth at 10 μg/mL. When the two compounds were used in combination, P. gingivalis growth was inhibited in a synergistic manner. On the contrary, licochalcone A had no effect on the adherence of P. gingivalis to epithelial cells, but 50 μg/mL of APACs reduced bacterial adherence by approximately 25%. When used in combination, they acted in synergy to inhibit the adherence of P. gingivalis to oral epithelial cells. APACs at 25 μg/mL inhibited P. gingivalis collagenase by 66%. | (Feldman and Grenier 2012) | [36] |
| Myrothamnus flabellifolia Welw. (MF)/50% EtOH extract, rich in flavan-3-ols and oligomeric proanthocyanidins; epicatechin (EC), epigallocatechin (EGC), gallocatechin (GC). | P. gingivalis, Arg-gingipain, Lys-gingipain | MF dose-dependently (0.1–1.0 mg/mL) inhibited P. gingivalis epithelial cell attachment or invasion (by about 50% at 1 mg/mL); however, bacterial growth was not influenced. Reduced adhesion was observed after pre-treatment of bacteria, pre-treatment of KB cells, as well as co-incubation of bacteria together with KB cells in the presence of MF (0.1 mg/mL). The MF extract (1–1000 μg/mL) showed inhibition of bacterial haemagglutinin. The MF extract at 50 μg/mL reduced Arg-gingipain by 70–80% and also inhibited Lys-gingipain, but to a lesser extent. Fimbrillin (fimA) and Arg-gingipain (rgpA), but not Lys-gingipain (kgp), encoding genes were upregulated by 10 and 100 μg/mL of MF. EGC and GC at 3 mM reduced the P. gingivalis adhesion to KB cells by about 40%. EC, EGC, and GC inhibited hemagglutination in a dose-dependent manner (30–300 μM). A reduction of proanthocyanidin titers in the bacteria-free supernatant by about 40% after incubation P. gingivalis with proanthocyanidins was observed. | (Löhr et al. 2011) | [37] |
| Catechins: (+)-catechin (C), (−)-epicatechin (EC), (−)-gallocatechin (GC), (−)-epigallocatechin (EGC), (−)-catechin gallate (CG), (−)-epicatechin gallate (ECG), (−)-gallocatechin gallate (GCG), (−)-epigallocatechin gallate (EGCG). |
Eikenella corrodens | 1 mM of GC, EGC, CG, ECG, GCG, and EGCG significantly inhibited E. corrodens biofilm formation, whereas EC and C had no effect. Moreover, the catechins with the galloyl group (CG, ECG, GCG, EGCG) remarkably inhibited biofilm formation even at 0.1 mM, whereas the effects of catechins with only the pyrogallol-type B-ring (GC, EGC) were weaker, starting from 0.5 mM and 0.25 mM, respectively. Only catechins with the galloyl group revealed bactericidal activity at a 1 mM concentration; however, none of the catechins showed bactericidal activities at a 0.1 mM concentration, which suggests that catechins with the pyrogallol-type B-ring and/or the galloyl group inhibit biofilm formation at sub-MIC, by a mechanism other than bactericidal activity. As the research showed, this may by through the interference with the AI-2-mediated QS system in E. corrodens. | (Matsunaga et al. 2010) | [38] |
| Cranberry fruit (Vaccinium macrocarpon Ait.)/isolated A-type cranberry proanthocyanidins (AC-PACs), | P. gingivalis | AC-PACs inhibited biofilm formation by 45% and 60% at concentrations of 50 and 100 μg/mL and inhibited P. gingivalis adherence to epithelial cells by 37.5% and 54.1%, respectively. At these concentrations, AC-PACs also inhibited the adherence of P. gingivalis to Matrigel-coated polystyrene surfaces. The 25, 50, and 100 μg/mL of AC-PACs inhibited type I collagen degradation by a P. gingivalis culture supernatant by about 50%, 74%, and 89%, respectively. At all the concentrations tested (25–100 μg/mL), AC-PACs did not significantly affect the growth of P. gingivalis. | (Vu Dang La, Howell, and Grenier 2010) | [39] |
| Cranberry Vaccinium macrocarpon Ait/non-dialyzable material (NDM) prepared from concentrated juice, containing 65.1% proanthocyanidins. | Peptostreptococcus micros | Treatment of monocyte-derived macrophages, as well as oral epithelial cells with the cell wall of P. micros decreased their cell viability; however, adding the cranberry fraction (25–50 μg/mL) prior to treating cells with the P. micros cell wall dose-dependently protected these cell lines from the toxic effect. | (Vu Dang La, Labrecque, and Grenier 2009) | [40] |
| Same as above. | P. gingivalis | NDM significantly prevented the attachment of P. gingivalis to surfaces coated with type I collagen, fibrinogen, or human serum. NDM inhibited the biofilm formation of P. gingivalis; however, it had no effect on the growth and viability of bacteria. | (Labrecque et al. 2006) | [41] |
| Same as above. | Arg-gingipain, Lys-gingipain, dipeptidyl peptidase IV of P. gingivalis; trypsin-like protease of T. forsythia; chymotrypsin- like protease of T. denticola |
NDM dose-dependently inhibited the proteinases of P. gingivalis, T. forsythia, and T. denticola (10–150 μg/mL); however, the trypsin-like activity of T. forsythia was only slightly sensitive to NDM. 50 μg/mL of NDM significantly reduced the collagenase activity of P. gingivalis (by 30%) and the capability of P. gingivalis to degrade transferrin (by about 20%). Degradation of type I collagen and transferrin by P. gingivalis was completely or almost completely inhibited by 100 μg/mL and 150 μg/mL of NDM, respectively. |
(Charles Bodet et al. 2006) | [42] |
| Apple (Malus domestica L.)/apple fraction (AP) rich in proanthocyanidins; apple condensed tannin (ACT) isolated from AP; hops (Humulus japonicus Siebold & Zucc.)/hop bract polyphenol (HBP) fraction rich in proanthocyanidins; HMW-HBP (high molecular weight fraction) and LMW-HBP (low molecular weight fraction) separated from HBP; HMW-HBP mainly containing 8 to 22 mer proanthocyanidins; EGCG: (−)-epigallocatechin gallate. |
P. gingivalis, Arg- and Lys-gingipains | None of the fractions revealed bactericidal activity or suppression of bacterial growth at concentrations of 1 and 10 μg/mL. The studied fractions at 10 μg/mL significantly protected PDL (periodontal ligament) cells’ viability from the effect of P. gingivalis infection, although EGCG and LMW-HBT showed slightly lower effects than the others. Even at 1 μg/mL, AP, ACT, HBP, and HMW-HBP demonstrated protective effects. All of the fractions revealed significant inhibitory effects toward the proteolytic activities of Rgp and Kgp in a dose-dependent manner, with the ratios ranging from 70% to 95% at 10 and100 μg/mL. At lower doses (0.1 and 1 μg/mL), EGCG showed the greatest effect, followed by ACT and AP. |
(Inaba et al. 2005) | [43] |
| (−)-Epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), epicatechin (EC), (−)-gallocatechin gallate (GCG), catechin gallate (CG), gallocatechin (GC), (−)-catechin (C), gallic acid (G). |
P. gingivalis, Arg- and Lys-gingipains | Catechin derivatives, containing the galloyl moiety, which includes EGCG, ECG, GCG, and CG, significantly inhibited the Arg-gingipains’ activity. The IC50s ranged from 3 to 5 mM. Non-galloylated catechins, EGC and GC, moderately inhibited Arg-gingipains’ activity (IC50s, 20 mM), while EC, C, and G were not effective, with IC50 greater than 300 mM. Furthermore, some of the catechin derivatives (galloylated) also inhibited the Lys-gingipains’ activity, though to a lesser extent than the inhibition of the Arg-gingipains’ activity. | (Okamoto et al. 2004) | [44] |
|
Camellia sinensis (L.) Kuntze/Tea polyphenol mixture (TP), (+) catechin (C), (−) epicatechin (EC), (+) gallocatechin (GC), (−) epigallocatechin (EGC), (−) epicatechin gallate (ECG), (−) epigallocatechin gallate (EGCG), (−) gallocatechin gallate (GCG). |
Short-chain fatty acid (n-butyric and propionic acid), as well as phenylacetic acid production by P. gingivalis | The production of n-butyric and propionic acid in general anaerobic medium (GAM) was inhibited by TP in a dose-dependent manner; complete inhibition was seen at a concentration of 1.0–2.0 mg/mL. EGCG, a major component of tea polyphenols, inhibited the production of phenylacetic acid at 0.5 mg/mL. EGCG and other galloylated catechins, ECG and GCG, inhibited the reaction leading to the production of phenylacetic acid from L-phenylalanine and phenylpyruvic acid. However, C, GC, EC, and EGC did not inhibit those reactions. Moreover, the growth of P. gingivalis was inhibited by EGCG (strong at 0.5 mg/mL). | (Senji Sakanaka and Okada 2004) | [45] |
| Elm (Ulmus macrocarpa Hance)/extract (EE) (n-butanol fraction from extract of Ulmi cortex) containing 20% of procyanidins and the mixture of procyanidin oligomers (PO). | trypsin-like enzymes from T. denticola and P. gingivalis | Both EE and PO (0.1–0.01%) effectively inhibited the activity of the T. denticola proteases, whereas EE inhibited P. gingivalis proteases’ activity less than PO. PO, at a concentration of 0.1–0.01%, reduced the trypsin-like enzymes of T. denticola to 34–58% activity and the trypsin-like enzymes of P. gingivalis to 39–73% activity, whereas the same concentrations of the elm extract reduced the T. denticola enzyme activity to 40–89% and P. gingivalis to 49–91%. | (Song et al. 2003) | [46] |
|
Camellia sinensis (L.) Kuntze/the green tea catechin well-purified by Sunphenon ® (Taiyo Kagaku, Yokkaichi, Mie, Japan) prepared from Japanese green tea; details about the composition the of extract not provided. |
P. gingivalis, Prevotella species | The MICs of the green tea catechin for P. gingivalis, P. intermedia, and P. nigrescens were 1.0 mg/mL. The green tea catechin showed bactericidal effects against all three bacteria. However, a high concentration of catechin was used (4 mg/mL). | (Hirasawa et al. 2002) | [47] |
|
Camellia sinensis (L.) Kuntze/tea polyphenol mixture (TP) (+) catechin (C), (−) epicatechin (EC), (+) gallocatechin (GC), (−) epigallocatechin (EGC), (−) epicatechin gallate (ECG), (−) epigallocatechin gallate (EGCG), (−) gallocatechin gallate (GCG). |
P. gingivalis | EGCG completely inhibited the growth of three strains of P. gingivalis at concentrations of 250 or 500 μg/mL. The MICs for other polyphenols were 1000 μg/mL. TP at the concentration of 100 μg/mL reduced the adherence of P. gingivalis to human buccal epithelial cells by about 70%. All of the compounds inhibited the adherence of P. gingivalis to epithelial cells. However, the inhibitory effect was pronounced with catechin derivatives having a galloyl moiety: EGCG, GCG, and ECG (at 250 μg/mL, they almost completely inhibited the adherence of P. gingivalis to epithelial cells). Even at 7.8 μg/mL, EGCG or ECG reduced the adhered bacterial cells by about 70%. Inhibition of the adherence of P. gingivalis to epithelial cells was much more effective when EGCG was preincubated with bacteria than with epithelial cells. | (Sakanaka et al. 1996) | [48] |