Phenolic compounds are a typical class of active ingredient found in a variety of natural plants. They have at least one aromatic ring structure linking one hydroxyl group. Three categories are frequently used to categorize phenolic compounds: lignans and tannins, which are polyphenols; low phenolic oligophenols including flavonoids, stilbenes, and coumarins; and monophenols (62, 63). Numerous studies have established that phenolic compounds have an antibacterial impact, and some researchers have outlined the antibacterial mechanisms in detail. The current generally held beliefs can be summed up as follows: 1. The phenolic compounds alter cell permeability and causes leakage of cellular contents by interacting with bacterial cell walls or membranes, as well as surface proteins; 2. Reactive oxygen species (ROS) are produced by phenolic chemicals, which enhances oxidative stress in bacterial cells; 3. Phenolic compounds prevent the synthesis of bacterial-related biological macromolecules, which inhibits the bacteria’s development and metabolism; 4. Phenolic substances prevent DNA and ATP from being synthesized; 5. The production of proteins or virulence factors necessary for bacterial survival and biofilm formation are weakened by phenolic chemicals (64). The positions and amounts of the hydroxyl and methoxy groups (65–67), as well as the amounts and locations of hydrophobic substituents such as isopentenyl, alkylamino, and alkyl chains (68, 69), are all intimately related to the aforementioned activities. Figure 2 depicts the chemical composition of phenolic compounds found in MFH plants that have antibacterial properties.

The primary active component of the essential oils of several MFH plants, including Syringa aromaticum (cloves) and Cinnamomum cassia (cinnamon), is eugenol, a widely available monophenol molecule (70, 71). At MIC concentrations, eugenol can reduce the planktonic activity of P. gingivalis in a time-dependent manner. After being exposed to eugenol, P.gingivalis cells exhibited atrophic changes and severe cell membrane destruction, as revealed by a scanning electron microscope(SEM). In addition, leakage of nucleic acids and proteins within cells can be observed, indicating that eugenol interferes with cell membrane permeability and integrity. The hydrophobicity of eugenol and the impact of hydroxyl groups are closely related to the aforementioned actions (43). The extremely reactive hydroxyl groups in eugenol can create hydrogen bonds with a specific target enzyme of bacteria, which can disrupt the activity of the enzyme and result in a malfunction of the cell membrane system (72). Besides that, eugenol can indirectly inhibit the production of bacterial virulence factors by P. gingivalis by down-regulating the expression of the fimA genes, the hemagglutinin encoding genes hagA and hagB and the gingipain genes rgpA, rgpB and kgp, thereby affecting bacterial colonization, copolymerization, biofilm formation and nutrient uptake (43).

As a traditional Chinese medicine, Glycyrrhiza glabra (licorice) has high medicinal value in its dry roots and rhizomes and can also be used in the daily diet (73). The research demonstrated that the licorice extract’s flavonoid known as glabridin had a potent antibacterial effect against P. gingivalis. Furthermore, glabridin and the antibacterial peptide -poly L-lysine work together to kill bacteria (47). Glabridin has a high affinity for DNA gyrase and dihydrofolate reductase (DHFR) and can be utilized as inhibitors of two enzymes, even though the antibacterial mechanism is still unknown. Glabridin’s phenolic hydroxyl generates two hydrogen bonds with certain amino acids at DNA gyrase’s ATP binding site, preventing the synthesis of nucleic acids, and the affinity is higher than ciprofloxacin. Glabridin’s affinity for DHFR is primarily mediated via a hydrogen bond and other factors and is slightly weaker than trimethoprim’s (74).

Fructus mori (mulberry), the fruit clusters of the mulberry tree, are juicy and delicious fruits rich in the polyphenolic compound resveratrol (75). Resveratrol is a common stilbene compound, which can kill P.gingivalis and can be found that the size and shape of bacteria are damaged to varying degrees through SEM (51). Despite the fact that there is currently no agreement on resveratrol’s antibacterial capabilities (76), the double bond between the two benzene rings and the location and number of hydroxyl groups in the resveratrol structure, according to some researchers, may be important components in resveratrol’s ability to inhibit bacteria (77, 78). Other studies have demonstrated that following resveratrol therapy, the expression of the P. gingivalis pili-related genes fimA II and IV decreased by more than 50%, and the expression of the gingipains-related genes rgpA and kgp also decreased (51). Resveratrol can impair P.gingivalis’ adhesion to the basement membrane model and prevent P.gingivalis from degrading type I collagen in a dose/time-dependent manner (54).

Curcuma longa (turmeric) is an ancient Chinese medicinal plant of the ginger family, whose dried roots can be used in everyday cooking as well as for medicinal purposes. Curcumin is a phenolic compound extracted from turmeric (79). At concentrations below the MIC, curcumin can considerably limit the activity of six different strains of P. gingivalis and reduce its adhesion ability (52). Similarly, the researchers stressed the significance of aromatic hydroxyl groups in curcumin’s antibacterial effect (80, 81). Studies have shown that curcumin can downregulate the gene expressions of fimA, hagA, hagB, rgpA, rgpB, and kgp, inhibit the formation of P. gingivalis biofilm and reduce bacterial adherence (52).

Saponins are composed of oligosaccharides partially linked with triterpenoids or steroidal aglycones, which can be divided into Triterpenoid saponin and steroidal saponin (82). They are prevalently present in plants as active compounds and have important pharmacological activities. Similar to surfactants, saponins include both hydrophilic and lipophilic groups. By lowering surface tension in aqueous solutions and producing micelles at crucial locations, these chemicals can alter the structure of biological macromolecules (44). Figure 3 displays the saponins from MFH plant sources that can be employed as antibacterial agents.

In China, Panax ginseng Meyer (ginseng) has an extended tradition of use in both food and medicinal. Ginsenosides are triterpenoid saponins isolated from ginseng (83). According to research, ginsenosides’ primary antibacterial targets are bacterial cell membranes, and their amphiphilic characteristics are essential for membrane binding and permeability (84). P. gingivalis treated with ginsenosides can show the damage of cell membrane system and the outflow of cell contents, and the membrane binding characteristics of ginsenosides also depend on the polarity of ginsenosides, that is, the number of polar sugar groups in the structure (85). High-polarity ginsenosides can be decalcified and dehydrated employing high temperature or biotransformation to reduce polarity and enhance affinity with bacterial cell membranes (44, 86, 87). According to studies, less polar ginsenosides, which contain just one glycosyl group, such as Rk3, Rh2, Rh4 and Rg5, exhibit a better bactericidal action than highly polar ginsenosides, which contain three glycosyl groups and include Rg1, Re, Rb1, Rb2, Rc and Rd. (MIC >500 g/mL). According to TEM images of F. nucleatum treated with ginsenoside Rh2, the cell membrane had been destroyed and the contents of the cell had leaked (44). Through experimentation, some researchers have demonstrated that high polar ginsenoside Rd can likewise have a lethal effect on P. gingivalis (MIC = 400 μM), but this concentration is quite considerable. Intriguingly, P. gingivalis might be limited or even destroyed after treatment with modest concentrations of ginsenoside Rd (100 and 200 μM). Low concentrations of ginsenoside Rd can also drastically reduce bacterial surface hydrophobicity and block the expression of fimA and kgp, which has an impact on bacterial adhesion, copolymerization, and biofilm formation (45).

The dried bark of the cinnamon tree, known as cinnamon, is a common element in Chinese cuisine and traditional herbal remedies. Cinnamaldehyde is an organic compound of olefine aldehydes extracted from cinnamon essential oil (Figure 4) (88). According to several researchers, the main cause of cinnamaldehyde’s antibacterial effects is the destruction of bacterial cell walls and membranes, which causes the contents of the cells to leak out. The interaction of hydrocarbons with hydrophobic bacterial cell membranes is thought to be the cause of this effect, but the antibacterial mechanism is not just restricted to this. It may also be connected to how cinnamaldehyde permeates bacteria and how it affects genetic material (89). In comparison to other chemicals lacking an aldehyde functional group, cinnamaldehyde had the strongest effect on removing Escherichia coli biofilm, leading Kot et al. to conclude that the antibacterial action of cinnamaldehyde may be derived from the aldehyde functional group it carries (90). The major component of cinnamon bark essential oil (CBEO), cinnamaldehyde, has been shown in experiments to have a substantial antibacterial impact on the cell wall and membrane of P. gingivalis. When P. gingivalis was exposed to CBEO and cinnamaldehyde, it developed uneven surfaces, folds, or damage that allowed intracellular proteins, DNA and RNA to leak out. Cinnamaldehyde at the sub-MIC level can inhibit the formation of 67.3% biofilm of P. gingivalis (46).

Aloe vera (aloe) is an edible herb of the lily family. Studies have shown that the gel prepared from mature fresh aloe leaf has an inhibitory effect on pathogens extracted from patients with subgingival stones, periapical abscesses, and periodontal abscesses, but only at a higher concentration. A low concentration of aloe gel does not show an antibacterial effect (91). In other studies, fresh aloe gel has an inhibitory effect on P. gingivalis, A. actinomycetemcomitans, and other periodontal pathogens, but the effect is not significant compared with S. mutans (49). However, both studies lack an analysis of the main active ingredients. When researchers used dried aloe powder extract, the outcomes were very different from those of fresh aloe gel and did not demonstrate any antibacterial activity against P. gingivalis. The reason might be that the dried aloe powder contains so little of the anthraquinone component aloe-emodin (Figure 4) (50). Anthracene and two carbonyl groups make form the chemical molecule known as anthraquinone. It is a typical chemical found in numerous plants. Its antibacterial activity primarily consists of impeding DNA synthesis and replication, compromising the integrity of cell membranes, preventing bacterial virulence factors, and preventing the development of biofilm (92–94). However, some academics have also asserted that Aloe-emodin is more likely to attach with peptidoglycan to destroy bacterial membranes and damage cell membrane permeability. Aloe-emodin consequently has more antibacterial effect against gram-positive bacteria than against gram-negative bacteria (95). This may also be one of the reasons why the outcomes of some studies on the bacteriostasis of aloe-emodin on P. gingivalis are not ideal. Aloe-emodin’s chemical composition also contributes to its antibacterial properties. According to several researchers, the antibacterial impact is directly tied to the aromatic hydroxyl groups on the anthracene core, and the antibacterial activity is further increased by the hydroxyl methyl groups the compound carries (96).

Foeniculum vulgare (fennel) is a traditional medicinal and culinary plant. Petroselinic acid extracted from fennel is an unsaturated fatty acid (Figure 4). Petroselinic acid induced the formation of moniliform OMVs-like particles on the surface of P. gingivalis, which, unlike naturally occurring OMVs, induced explosive degradation of the bacteria and leakage of cell contents and DNA. The accumulation of RagA and RagB in OMVs-like particles can lead to the reduction of RagA and RagB in P. gingivalis (55). RagA and RagB proteins are believed to have a part in the uptake of macromolecules like polysaccharides or glycoproteins (97, 98). In addition, fennel extract and petroselinic acid also showed inhibitory effects on gingipains (55). However, the relationship between the anti-P. gingivalis and its virulence factor effect of petroselinic acid and its molecular structure has not been elaborated. Some scholars have found that the antibacterial activity of unsaturated fatty acids can be affected by the length of the carbon chain, the degree of unsaturation, and the position and configuration of the double bond. Moreover, the virulence factor and its gene expression of Staphylococcus aureus were significantly inhibited by petroselinic acid, suggesting that there may be targets between petroselinic acid and these virulence factors, but this part has not been confirmed by molecular docking research (99).

In addition, some MFH plants have antibacterial activity. Some researchers have proposed that ethanol extract of Hibiscus sabdariffa L. (roselle calyx) has inhibitory effects on a variety of periodontal pathogens (48), but this study did not discuss the key active elements or the precise processes of roselle calyx. However, other researchers have hypothesized that protocatechuic acid, which, by generating ROS, damages DNA and causes lipid peroxidation in bacteria, changing the redox equilibrium (100), may be in charge of the roselle calyx’s antibacterial properties (101). More research is necessary to determine whether proto-catechuic acid has the same antibacterial impact against periodontal infections. Ethanol extract of Morus alba leaves can reduce the growth of periodontal pathogens in a dose-dependent manner (102). Similarly, diosgenin extracted from Trigonella foenum-graecum L. (fenugreek) also showed dose-dependent inhibition of P. gingivalis and P. intermedia (103). Yet neither study provided information on effective doses.

In conclusion, periodontitis-related bacteria have been found to be significantly inhibited by MFH plants and their active ingredients. In contrast to the direct killing of bacteria, the majority of MFH plants and their active ingredients appear to be more effective at preserving the stability and balance of the periodontal microenvironment by inhibiting bacterial accumulation, copolymerization, biofilm establishment, and the production and activity of bacterial virulence factors. Based on the aforementioned studies, several academics stress the significance of these active components’ chemical structures for their antibacterial activity. Each active ingredient’s antibacterial effect can be attributed to a unique bond or functional group in its chemical structure that can interact and bind with a particular bacterial structure or enzyme, disrupt the physiological function of bacteria result in abnormal bacterial activity or metabolism, and ultimately produce the desired antibacterial effect.

The aforementioned research still has some incomplete aspects in several areas, though. First off, rather than being primarily linked to the pathogenic properties of a specific bacterium, periodontitis tends to be more susceptible to abnormalities in the oral microbial ecosystem. The mouth cavity contains about 1,000 bacteria. Other microbes outside bacteria exist as well, including fungi, viruses, and archaea (104). Distinct strains of microbes can produce distinct active components due to differences in their surface properties and functional groups. Future research should take into account the variations between the harmful bacteria because the aforementioned tests mostly consider one or two of them. In addition, the aforementioned studies did not address whether the active components of some MFH plants can achieve the ideal antibacterial effect in vivo, whether the bactericidal effect is particular, or whether it can affect the stability of the overall microenvironment of the oral flora. Therefore, more research is required.

It has been demonstrated that cinnamaldehyde is a very effective anti-inflammatory medication (136). Cinnamaldehyde was found to diminish the P. gingivalis-activated NF-κβ signal pathway, which in turn reduced the expression of inflammatory factors and ROS generation in RAW264.7 cells. The same anti-inflammatory function has also been confirmed in Human periodontal ligament cells (HPDLCs). Cinnamaldehyde inhibits P. gingivalis-induced upregulation of pro-inflammatory cytokines in HPDLCs, including IL-6, IL-8, TNF-α and IL-1β. Downregulation of immune cell chemokines including monocyte chemoattractant protein 1 (MCP1), intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) is also observed. Meanwhile, cinnamaldehyde also promotes the expression of osteogenic differentiation markers in HPDLCs and improves oxidative stress status. Cinnamaldehyde also inhibits the phosphorylation of P65 and Iκβ and inactivates the NF-κβ signaling pathway (110). According to academics, the impacts of cinnamaldehyde can be summed up as follows: 1. Cinnamaldehyde can chelate metal ions and alter several signaling pathways; 2. The aldehyde functional groups carried by cinnamaldehyde can give hydrogen ions to neutralize free radicals, lowering oxidative stress and inflammatory reactions in tissues (137). Cinnamaldehyde can be given orally to mice with ligation-induced periodontitis to slow the rate of alveolar bone loss and the levels of inflammatory cells and oxidative stress in periodontal tissue (110).

Phenolic compounds are electron or hydrogen atom donors with aromatic rings and multiple hydroxyl groups, which can eliminate free radicals through hydrogen ion or proton transfer, inhibit lipid peroxidation, and inhibit the activation of pro-inflammatory cytokine-mediated inflammatory signaling pathways, reducing oxidative stress and inflammatory response (138, 139). They have developed into one of the areas of research that has received a lot of attention lately. MFH plant-derived phenolic compounds with anti-inflammatory, antioxidant, and bone resorption inhibition properties are shown in Figure 5.

In-vitro studies have demonstrated that resveratrol blocks the activation of human monoblastic leukemia cell transcription factors induced by P. gingivalis, and interfere with the NF-κβ signal pathway in a dose-dependent manner (54). Triggering receptor expressed on myeloid cells-1 (TREM-1) is closely associated with the production of IL-1β and TNF-α that contribute to the persistence of inflammatory pathways (140). Resveratrol significantly down-regulates the expression of TREM-1 mRNA and reduces the inflammatory response in THP-1 cells induced by P. gingivalis (54). Toll-like receptor-4 (TLR-4) is an LPS-specific cell sensor that inhibits LPS-induced osteoblast differentiation and bone remodeling (141). Resveratrol down-regulates LPS-stimulated elevated levels of TLR-4 in human gingival fibroblasts (HGFs), thereby reducing the inflammatory response (111). Matrix metalloproteinase (MMP) is a family of zinc-dependent endopeptidases whose main function is to cleave extracellular matrix proteins, reshape tissues and degrade extracellular matrix under physiological and pathological conditions, and is considered to be an important substance involved in periodontal tissue collapse and inflammatory response during the development of periodontitis (142). Cyclooxygenase-2 (COX-2) promotes the disease process of periodontitis by mediating the inflammatory process in periodontal tissues (143). Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream anti-invertases, such as heme oxygenase-1 (HO-1), are essential in resisting cellular oxidative stress and down-regulating the inflammatory response (144). Resveratrol has been shown to help reduce the inflammatory response and oxidative stress of rat periodontal tissue in vivo studies, decrease the protein levels of COX-2, MMP-2, and MMP-9 in rats with periodontitis, prevent the reduction of HO-1 and Nrf2, and effectively prevent alveolar bone loss by inhibiting osteoclast production (111).

Similarly, curcumin has shown superior anti-inflammation and antioxidant potential in vitro and in vivo. Curcumin downregulates COX-2 mRNA and protein expression in HGFs by inhibiting LPS-activated NF-κβ activation (112). Based on this, additional researchers have discovered that LPS can greatly upregulate IL-1β and TNF-α in rat gingival fibroblasts, and that curcumin can counteract this rise. In addition, the ratio of osteoprotegerin (OPG)/nuclear factor B receptor activator ligand (RANKL) increased in LPS-induced rat gingival fibroblasts treated with curcumin, and this bone protection feature was also demonstrated in rats with ligation-induced periodontitis (113). To treat rats with LPS-induced periodontitis, some researchers gave them an oral dose of the corn oil carrier that diluted curcumin each day. In periodontal tissue, downregulation of the expression of the IL-6, TNF-α, and prostaglandin E2 (PGE2) synthase genes was seen after 15 days. But curcumin can only block the pathway at a dose of 30 mg/kg (114). Additionally, more investigators discovered that the curcumin gel shell can minimize inflammatory infiltration and restrict bone absorption similarly to tetracyclines when used as an antibacterial supplementary treatment for scaling and root planning (SRP). Contrary to tetracyclines, interestingly, curcumin-treated rats showed iron deposits in their bone trabeculae, suggesting that curcumin may have the ability to encourage bone growth (145).

Zingiber officinale Roscoe (ginger) is a kind of herb of the ginger genus. Its rhizome is used as an essential cooking spice in the home and has a high medicinal value. Volatile phenolic compounds 6-Gingerol are the main irritating compounds present in ginger rhizomes. After heat treatment, they are prone to dehydration reactions to form 6-shogaol, which is also the source of the spicy flavor of ginger (146). Hyperglycemia in diabetes patients can induce protein glycosylation, and produce the advanced glycation end products (AGEs) that can damage periodontal tissue by increasing the oxidative stress of periodontal histiocytes and the expression of inflammatory-related factors (147). In vitro experiments showed that 6-shogaol can inhibit the generation of ROS in AGE-induced HGFs and upregulate the expression levels of two antioxidant factors, HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO1). In addition, 6-shogaol can also inhibit the phosphorylation of mitogen-activated protein kinases (MAPK) p38, ERK, and NF-κβ p65, as well as the production of pro-inflammatory cytokines (124). Other studies discovered that 6-shogaol blocked the MAPK signal transduction caused by RANKL in mice bone marrow macrophages (BMMs), which prevented the development of mice osteoclasts in a dose-dependent manner. Additionally, this research showed through in vivo tests that 6-shogaol can successfully stop bone loss and inflammation in the periodontal tissue of periodontally ligated mice (125).

Licorice isoliquiritigenin is a flavonoid compound. Some studies have suggested that isoliquiritigenin may reduce the levels of expression of RANKL-induced osteoclast-related genes and transcription factors in RAW264.7 and BMMs, and inhibit the differentiation of osteoclasts. And isoliquitigenin inhibits the activation of NF-κβ pathways and blocks the initiation step of the osteoclast formation process by inhibiting the binding of RANKL-stimulated receptor RANK and signal adapter molecule TRAF6. The expression of the c-Fos protein and nuclear factor of activated T cells c1 (NFATc1) has also been found to decrease. Animal studies have also supported isoliquiritigenin’s inhibitory effect on bone resorption. When isoliquiritigenin was administered intraperitoneally to mice, their bone loss was significantly reduced (118).

The dried rhizome of Pueraria lobata is a kind of traditional medicinal and edible plant. An isoflavone substance called puerarin is derived from P. lobata. Puerarin has been shown to suppress the activation of Akt, downregulate the expression of genes involved in osteoclast formation, and block the differentiation of RAW264.7 cells into osteoclasts caused by LPS and the release of proinflammatory substances. Puerarin can greatly reduce LPS-induced bone loss and the number of osteoclasts in the mice skull in later animal trials (129). According to an intriguing study, signaling pathways connected to Nrf2 may be able to shield periodontal tissue from oxidative stress in hypoxic conditions, preventing damage to the tissue. In typical conditions, Nrf2 can be weakened by Kelch ECH-associating protein 1(Keap1). Nevertheless, p62 and Nrf2 are regulated by a positive feedback loop. By strengthening its association with Keap1, p62 can prevent the degradation of Nrf2 by that protein, and the Akt/ mammalian target of the rapamycin(mTOR)signaling pathway influences the production of p62. Puerarin can indirectly prevent the ubiquitination degradation of Nrf2 mediated by Keap1 and enhance the nuclear translocation of Nrf2 in HPDLCs. It can also upregulate the production of p62 via stimulating the Akt/mTOR signaling pathway. Puerarin has additionally demonstrated in vivo studies that it can successfully stop alveolar bone loss in animals with periodontitis (130).

Magnolia officinalis is a member of the magnolia family whose dried stem bark, root bark and branch bark used in ancient Chinese medicine and can also be incorporated into the diet. Magnolia officinalis is the source of the plant polyphenol known as magnolol. According to studies, magnolol can trigger the Nrf2/HO-1 signaling pathway to reduce the oxidative stress and inflammatory response of RAW264.7 caused by LPS (132). In addition, magnolol significantly reduced the inflammatory response of periodontal tissue and alveolar bone loss and decreased the number of osteoclasts and the expression level of RANKL in experimental periodontitis rats. Magnolol also inhibited the expression of COX-2 and iNOS protein in gingival tissue, reduced the ratio of MMP-1/tissue inhibitor of metalloproteinases-1 (TIMP-1) and MMP-9/TIMP-1, and inhibited the destruction of periodontal tissue (133).

Epimedium brevicornu Maxim. (epimedium) is a Ranunculus Berberis plant whose dried leaves are used both medicinally and for food. Icariin is a flavonoid compound that is the main active ingredient in epimedium. 0.01 μg/mL icariin increased OPG in human periodontal cells and downregulated the expression level of RANKL, leading to a decrease in the RANKL/OPG ratio. In addition, icariin also increased the mRNA expression of core binding factor alpha1 (Cbfa1) and osteocalcin (OC) in a dose-dependent manner, and the icariin group at 0.01 μg/mL showed the highest expression, which had a bone-promoting effect; however, when the icariin concentration was greater than 0.1 μg/mL, the expression of Cbfa1 and OC was decreased (134). Icariin can also increase the protein and gene expression levels of alkaline phosphatase, which is downregulated by LPS in HPDLCs (135). Local injection of icariin can attenuate the inflammatory process in minipig periodontitis models, and levels of the pro-inflammatory cytokines IL-1β and IFN-γ were lower in the icariin group than in the control group. In addition, icariin can effectively promote the regeneration of periodontal fibers and bone tissue (148).

Psoralea corylifolia (psoraleae) is a traditional plant whose fruits can be eaten and used medicinally. Psoralen and angelicin, which are active components of psoraleae and are coumarin compounds, can, in a dose-dependent manner, block the release of IL-1β and IL-8 from monocyte-like THP-1 cells stimulated by P.gingivalis LPS. Additionally, psoralen and angelica can boost the expression of osteogenic proteins as well as the activity of alkaline phosphatase in HPDLCs. The osteoprotective activities of angelicin on the alveolar bone of periodontitis-affected mice were further supported by this work, although the in vivo effects of psoralen remain unaccounted for (53).

Schisandra chinensis (Turcz.) Baill is a traditional Chinese medicine in the magnolia family. Its fruit can be used as a medicine or as a daily food. The active ingredient of Schisandra chinensis is lignans, including gomisins and schisandrin (149). Gomisins G and J inhibit the activation of NF-κβ, downregulate the expression levels of TNF-α, IL-1β and IL-6, and induce HO-1 production by blocking the nuclear translocation of NF-κβ in RAW264.7 cells induced by P. gingivalis (126). HO-1 expression is mainly regulated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. In RAW264.7 cells induced by LPS of P. gingivalis, schisandrin can enhance Nrf2 nuclear translocation and HO-1 expression by inducing PI3K/Akt and ERK signaling pathways (128). However, there have been no reports on the in vivo anti-inflammatory effects of the active ingredients of Schisandra chinensis mentioned above.

The class of active compounds known as terpenoids, which are abundantly present in nature, is made up of isoprene structural units. They can be categorized as monoterpenes, sesquiterpenes, diterpenes, triterpenes, tetraterpenes, and polyterpenes based on how many isoprene units they contain. Terpenoids have been proven to have significant anti-inflammatory benefits (150). Terpenoids can suppress the development of osteoclasts and the oxidative stress on periodontal tissue as well as operate on a variety of targets in the signal pathway and diminish the generation of inflammatory cytokines. Figure 6 displays the MFH plant terpenoids having anti-inflammatory properties reported in this paper.

α-Iso-cubebenol is a cubebene sesquiterpene compound extracted from Schisandra chinensis (151). α-Iso-cubebenol mediated nuclear translocation and transactivation of Nrf2 in human macrophage THP-1 cells by promoting the PI3K/Akt and ERK pathways, induced HO-1 mRNA and protein expression in a time- and dose-dependent manner, and the anti-inflammatory effect of α-Iso-cubebenol can be reversed by the selective inhibitor tin-protoporphyrin of HO-1. In addition, α-Iso-cubebenol can also inhibit the nuclear translocation of NF-κβ and its activity, as well as inhibit the production of P.gingivalis LPS-stimulated pro-inflammatory cytokines (127). However, in-vivo research has not been done to further support the effects of α-Iso-cubebenol mentioned above.

Chaenomeles sinensis (Papaya) is a plant of the genus Papaya in the family of rosaceae. Its fruits are very common in daily life and can be eaten raw or used as a cooking ingredient and, after drying, can also be used as a medicine. β-cryptoxanthin is a carotenoid extracted from Papaya. In LPS-induced mice, β-cryptoxanthin can considerably reduce the amount of cranial bone resorption. Additionally, COX-2 and membrane-bound PGE synthase-1 (mPGES-1), two related enzymes that induce to production of PGE2 in the body, are downregulated by β-cryptoxanthin in osteoblasts. And β-cryptoxanthin also decreases the NF-κβ transcription activity. Molecular docking showed that β-cryptoxanthin competitively binds to the ATP-binding domain of inhibitor of NF-κβ kinase (IKKβ), inhibiting its activity and attenuating the activity of the LPS-induced NF-κβ pathway. In addition, β-cryptoxanthin inhibited RANKL-induced osteoclast differentiation and significantly reduced cathepsin K (CTSK) expression levels in RAW264.7 cells (123).But the effects of β-cryptoxanthin also lack proofs of in-vivo experiments.

Iridoid is a natural compound that often combines with sugars in plants to form iridoid glycoside. Eucommia ulmoides Oliv. is a plant whose bark is used in traditional medicine and food. Geniposidic acid (Figure 7), an iridoid glycoside extracted from Eucommia ulmoides, down-regulates MAPK phosphorylation and TLR2 expression in human gingival epithelial cells (HGECs) induced by P. gingivalis, inhibits IL-6 production. Additionally, Geniposidic acid can block the expression of genes linked to osteoclast differentiation in Bone marrow mononuclear cells (BMMC) in a concentration-dependent way. However, Geniposidic acid has no impact on IL-6 levels in BMMC, even though IL-6 is also linked to osteoclast differentiation. Geniposidic acid taken orally can reduce the inflammation of periodontal tissues and alveolar bone absorption in the mice of periodontitis caused by P.gingivalis (131).

Both the periodontitis inflammation response and bone resorption are improved by aloe-emodin and aloin derived from aloe (Figure 8). In rat models of periodontitis, aloe emodin has been suggested to lessen alveolar bone loss and periodontal inflammation. The mechanism may be the downregulation of aloe-emodin on acidic mammalian chitinase (AMcase) (119). AMcase is a hydrolase that cleaves glycoside saccharide bonds in chitin. Although humans cannot synthesize chitin, the expression level of AMcase is higher in inflammatory periodontal tissues than in normal periodontal tissues and is associated with the immune response to various inflammatory diseases (152). Aloin is also an anthraquinone compound extracted from aloe, composed of two types of diastereomers (153). Research has shown that aloin down-regulates IL-1β-induced IL-8 expression by inhibiting the phosphorylation of p38 and ERK in KB cells (120), but the anti-inflammatory mechanism in vivo has not been elucidated.

The saponin components derived from MFH plants also have anti-inflammatory effects (Figure 9). Ginsenoside Rd can downregulate the expression levels of osteoclast marker genes Acp5, Nfatc1 and Mmp9 induced by RANKL to inhibit osteoclast formation in vitro and downregulate the expression levels of inflammatory cytokines such as IL-1β, IL-6, and IL-8 in LPS-induced HGFs. Furthermore, in vivo experiments have shown that ginsenoside Rd can significantly inhibit alveolar bone resorption and destruction in mice models of periodontitis (45). Ginsenoside Rb3 inhibited the mRNA expression of Nfatc1, Mmp9, Ctsk and Acp5 and decreased the protein expression levels of MMP-9 and CTSK by inhibiting the RANKL-activated MAPK and NF-κβ signaling pathway in RAW264.7 cells. Besides that, ginsenoside Rb3 has the most significant inhibitory effect on the MARK/ERK pathway, suggesting that the ERK pathway may be the target of ginsenoside Rb3 (121). In experimental periodontitis rats stimulated by P. gingivalis LPS, Ginsenoside Rb3 inhibits alveolar bone loss and osteoclast differentiation as well (154). Activation of NLRP3 inflammasomes plays an important role in the production of pro-inflammatory cytokines and pyroptosis. Mitochondria are the key regulators of NLRP3 inflammasome activation. Mitochondrial homeostasis is closely linked to AMP-activated protein kinase (AMPK) and dynamin-related protein 1 (Drp1). Ginsenoside Rg1 can inhibit Drp1-mediated mitochondrial fission by activating AMPK, as well as block NLRP3-mediated pyroptosis of HPDLCs in a variety of ways (122). However, the in-vivo activity of ginsenoside Rg1 still needs further investigation.

High mobility group protein 1(HMGB1) is a group of non-histone chromosomal proteins that can be released from necrotic or damaged cells. It is highly expressed in periodontitis and can mediate bone resorption by promoting the differentiation of osteoclasts (155, 156). Glycyrrhizin, also known as glycyrrhizic acid, is a triterpenoid saponin isolated from the root of licorice (157). Glycyrrhizin can inhibit the expression of HMGB1, IL-6, and IL-1β in human periodontal ligament stem cells (PDLSCs) induced by TNF-α, according to in vitro investigations. In vivo test using a rat periodontitis model treated with glycyrrhizin revealed the downregulation of HMGB1, IL-6, and IL-1β in the gingival crevicular fluid and periodontal tissue (115). AGEs receptors (RAGE) in tissues and plasma of diabetic patients bound to HMGB1 are key in the association between periodontitis and diabetes (158). In diabetic mice with periodontitis, glycyrrhizic acid can suppress the production of HMGB1 and RAGE mRNA in the gingiva and serum and lessen the inflammatory response of the periodontal tissue (116). Glycyrrhetinic acid is the main metabolite of glycyrrhizin with two residues of glucose acid (157). According to the in-vivo Miles vascular permeability assay, glycyrrhetinic acid can prevent the rise in vascular endothelial permeability brought on by P. gingivalis LPS. Studies conducted in vitro have demonstrated that glycyrrhetinic acid impacts vascular endothelial permeability by preventing P. gingivalis LPS-promoted internalization of VE-cadherin of human microvascular endothelial cells (HMECs), which is the cause of the rise in vascular endothelial permeability. Additionally, by preventing the activation of NF-κβ, glycyrrhetinic acid can reduce the expression of IL-8, which increases vascular endothelial permeability in HMEC (117). Some researchers applied glycyrrhetinic acid locally to the gingival sulcus of the rat periodontitis model and found that glycyrrhetinic acid could effectively inhibit the formation of LPS-stimulated immune complex and inflammatory cell infiltration, and no loss of attachment was observed (159).

In addition to the secondary metabolites from MFH plants outlined above, several MFH plant extracts also have notable inhibiting impacts on periodontal tissue inflammation and bone resorption, such as Angelica dahurica, Ginkgo biloba, Houttuynia cordata, Chrysanthemum morifolium Ramat. (chrysanthemum), and Evodia rutaecarpa (160–164), although the active biological components they contain have not yet been identified. Table 4 lists the detailed effects of these extracts of MFH plants.

In conclusion, there is considerable biological activity and minimal toxicity in the extracts and secondary metabolites of MFH plants against periodontal tissue inflammation. Although there has been a substantial amount of in vitro and animal experimentation demonstrating the majority of the anti-inflammatory and anti-bone resorption benefits of MFH plants, clinical research is still in its infancy. Additionally, it is a difficult and time-consuming operation to identify and analyze the active components in some research that focus on extracts of MFH plants. There are still a lot of undiscovered linkages that need to be investigated, but some researches have established a causal link between the chemical makeup of some active chemicals and their anti-inflammatory and bone resorption action. However, the number of such studies is too limited. Furthermore, some researches indicate that the dosage or concentration of MFH plants is strongly related to their biological action, and high or low doses may significantly decrease or boost the biological activity of the active ingredient, such as large quantities of phenolic compounds that can cause oxidation (138). And different active component dosages may have various modes of action. For instance, various dosages of curcumin can influence various signal pathways and prevent the creation of certain pro-inflammatory substances (114). Therefore, dose control still requires special care from us.

Plant-based MFH products are frequently used in conjunction with periodontal therapy to help keep the therapeutic impact going strong. Babaei et al. (165) assigned 40 patients with chronic periodontitis to intervention and control groups and administered 1 g of Cichorium intybus L. (chicory) leaf methanol extract capsules and placebo capsules, respectively, twice daily for consecutive 8 weeks. Before the study, all subjects underwent non-surgical periodontal therapy. According to the findings, chicory leaf extract was able to significantly improve the depth of the periodontal pocket, increase total antioxidant capacity, uric acid and high-density lipoprotein cholesterol and decrease malondialdehyde, triglycerides, low-density lipoprotein cholesterol and total cholesterol levels in the intervention group compared to the control group and baseline (p < 0.05).

Twenty young adults with healthy periodontal conditions were recruited by Gao et al. (166) and divided into an intervention group and a control group before being given either Phyllanthus emblica L. gum or a placebo gum. It turns out that in the group of P. emblica gum, the generation of volatile sulfide was inhibited, and the overall bacterial count, S. mutans, and P. gingivalis counts were significantly reduced (p < 0.05). Assiry et al. (167)recruited 50 subjects with moderate gingival scores and fair plaque scores without systemic diseases and randomly assigned them to the intervention and control groups. The intervention group received Illicium verum (star anise) mouthwash, whereas the control group received colored placebos, twice daily. Results indicate that subjects in the I. verum intervention group significantly improved in mean gingival index, papillary bleeding index and microbial count (P 0.05) when compared to the control group and baseline (p < 0.05).

In summary, MFH plant-based functional foods and care items such as chewing gum, chewing tablets, mouthwash, toothpaste, and so on need to be enhanced in terms of flavor and taste while ensuring effectiveness, as adding MFH plant-based ingredients may result in an unpleasant odor and taste. How to strike the right balance between the degree of delicacy and the optimal clinical effect is one of the issues that need to be resolved. Future research should also take into account the low solubility issue with some active compounds generated from MFH plants. This issue can be resolved by developing a scientifically sound drug delivery system that will prolong the action duration inside the periodontal tissue and decrease drug loss.