Fitoterapia Atual Como Tratamento Alternativo em Odontologia Estudos in Vitro, in Vivo e Clínicos PDF

European Journal of Pharmacology 889 (2020) 173665
Contents lists available at ScienceDirect
European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar
Current herbal medicine as an alternative treatment in dentistry: In vitro, in

vivo and clinical studies
Ehsan Tafazoli Moghadam a, 1, Mohsen Yazdanian a, 1, Elahe Tahmasebi a, *,
Hamid Tebyanian a, **, Reza Ranjbar a, Alireza Yazdanian b, Alexander Seifalian c, Ali Tafazoli d
a
Research Center for Prevention of Oral and Dental Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
b
Department of Veterinary, Science and Research Branch, Islamic Azad University, Tehran, Iran
c
Nanotechnology and Regenerative Medicine Commercialization Centre (NanoRegMed Ltd), The London Bioscience Innovation Centre, London, United Kingdom
d
Clinical Pharmacy Department, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
A R T I C L E I N F O A B S T R A C T
Keywords: Since the time that human population comprehended the importance of general health maintenance and the
Herbal medicine burden of disease, there has been a search for healing properties in the natural environment. Herbal medicine is
Oral health the use of plants with medical properties for prevention and treatment of conditions that can affect general
Dentistry
health. Recently, a growing interest has been observed toward the use of traditional herbal medicine alongside
Caries
Infections
synthetic modern drugs. Around 80% of the population, especially in developing countries relies on it for
healthcare. Oral healthcare is considered a major part of general health. According to the world health orga
nization (WHO), oral health is considered an important part of general health and quality of life. The utilization
of natural medications for the management of pathologic oro-dental conditions can be a logical alternative to
pharmaceutical methods due to their availability, low costs, and lower side effects. The current literature review
aimed at exploration of the variety and extent of herbal products application in oral health maintenance
including different fields of oral healthcare such as dental caries, periodontal maintenance, microbial infections,
oral cancers, and inflammatory conditions.
1. Introduction health issue (Organization W.H., 2017).

Besides conventional treatment methods, herbal agents have been
Oro-dental health has always been considered an inseparable part of extensively entered oral care products in recent years. These compounds
general health. The dimensions of oral health have been expanded, in have interesting medical and physicochemical characteristics. Nowa
accordance with broadening of the definition of health by WHO, with days, lots of manufacturers use herbal ingredients in their products to
inclusion of individual and social wellbeing. Because the oral health provide additional therapeutic characteristics. The earliest reports of
closely contributed to general wellbeing, it has gained more importance herbal drug application in oral health are related to Indian and Chinese
in recent years (Baiju et al., 2017). Every threatening factor to oral traditional medicine. It has been mentioned that Hippocrates suggested
health, will affect the quality of life, well-being, food selection, and a combination of alum, salt, and vinegar as a mouth rinse. Religious
psychosocial aspects of life, directly or indirectly. Considering their manuscript, Talmud, dating back about 1800 years, recommended using
worldwide prevalence, oro-dental pathologies and abnormalities are “dough water" and olive oil for oral health. Greek physician Pedanius
regarded as a significant public health challenges due to their impact on Dioscorides, proposed a combination of wine, milk and herbal extract of
individuals and society. The direct and indirect global costs of oro-dental olive tree leaves and pomegranate (Manipal et al., 2016). “Miswak”
problems were estimated around $298 and $144 billion respectively which is obtained from the Arak tree is one of the oldest known oral
(Listl et al., 2015). According to WHO, tooth decay is the most prevalent hygiene tools, but it is still being used in many Asian and African cul
nontransmissible disease and considered a significant global public tures since ancient times (Haque and Alsareii, 2015). At some instances,
* Correspondind author.
** Corresponding author.
E-mail addresses: elahe.tahmasebi.delfan@gmail.com (E. Tahmasebi), tebyan.hamid@yahoo.com (H. Tebyanian).
1
Both authors contributed equally to this work.
https://doi.org/10.1016/j.ejphar.2020.173665
Received 9 June 2020; Received in revised form 16 October 2020; Accepted 21 October 2020
Available online 22 October 2020
0014-2999/© 2020 Elsevier B.V. All rights reserved.
E.T. Moghadam et al. European Journal of Pharmacology 889 (2020) 173665
herbal medications are preferred over conventional drugs because of physiological metal ions like iron and prevent the activity of bacterial
their immense natural bio-characteristics, lower costs, availability, and metalloenzymes and consequent disruption of the bacterial cell mem
wide safety margin. In addition, many of the modern medications used brane and precipitation of membrane proteins (Reddy et al., 2007).
in dentistry are responsible for known side effects (Tartaglia et al., Several P. granatum products have exhibited an inhibitory effect on
2019). It is important to know that herbal medications are currently S. mutans and Streptococcus sanguinis (Millo et al., 2017).
used by about 80% of the world’s population for health-related pur Glycyrrhiza glabra, known as licorice, contains a considerable
poses, mostly by a majority of citizens at rural communities of devel amount of triterpene saponin glycyrrhizin as an active agent. An in-vitro
oping countries (Siddeeqh et al., 2016). study has shown a suppressant effect for its extracts or fractions on
Regarding oral health maintenance a huge number of studies have microbes like S. mutants (Bhadoria et al., 2019). Many other plants
focused on antimicrobial and anti-inflammatory properties of different including Aloe vera, Allium sativum, Azadirachta indica, Cimicifuga
natural agents. Antimicrobial topical medications have been recom foetida, Cinnamomum cassia, Citrus aurantiifolia, Cistus incanus, Citrus
mended as adjuncts for mechanical dental plaque control methods. Limon, Eucalyptus globulus, Galla chinensis, Houttuynia cordata,
Among them, chlorhexidine gluconate (CHX) is considered the most Mentha arvensis, Mimusops elengi, Mangifera indica, Mentha piperita,
common medication prescribed to fight harmful oral microorganisms Origanum dubium, Psidium guajava, Rosmarinus officinalis, Salvia
but it has some potential side effects including tooth staining, taste officinalis, Satureja hortensis, Scrophularia striata, Terminalia chebula,
alteration, increased mineral uptake into biofilm and calculus forma Tinospora cordifolia, Toddalia asiatica Lycii Radicis, Trachyspermum
tion, and irritation of oral mucosa (Gurgan et al., 2006; Sakaue et al., ammi, Vaccinium macrocarpon, Vaccinium vitisidaea and Zingiber
2018). Hence, the development of some new treatment protocols is officinale could be classified as the herbs for this indication. Inhibition of
required to safely manage these oral health problems. A logical ATP production or energy metabolism (Karioti et al., 2006), increasing
approach is exploring among the abundantly available medicinal plants the cell membrane permeability (Babaeekhou and Ghane, 2020;
in nature. The “naturally occurring” bio-active components in herbal Marchese et al., 2016; Saad et al., 2013), changing pH homeostasis
products can be beneficial with minimal side effects and maximum ef (Duarte et al., 2006), cell morphology deterioration (Azizan et al., 2017)
ficiency. Either as single ingredient products or in combinations, herbs (Fig. 1), cytoplasmic deregulation (Kim et al., 2017), enamel reminer
are proven to be safe and effective in the management of various oral alization enhancement (Zhang et al., 2016), inhibition of colony for
diseases (Sakagami et al., 2018). mation (Agarwal et al., 2019; Anand et al., 2015; Banavar Ravi et al.,
In this review article, we aimed to review the indications of herbal 2017; Dadpe et al., 2018; Hagh et al., 2019; Jain et al., 2016; Kar
medicine for different aspects of oro-dental maladies. Pre-clinical adağlıoğlu et al., 2019; Kokubu et al., 2019; Lekshmi et al., 2012;
studies have provided a basis for the determination of potential in Mahboubi et al., 2013; Mathai et al., 2017; Mistry et al., 2015; Patri and
dications of natural products in oral care. Therefore, they have a Sahu, 2017; Raghavan et al., 2018; Sekita et al., 2016; Shaheena et al.,
fundamental role in the development of research fields for herbal 2019; Shahriari et al., 2019; Thomas et al., 2015; Valones et al., 2016;
dentistry. Some of these laboratory workups are mentioned in this re Wittpahl et al., 2015; Yang et al., 2016) and colony adhesion (Bhadoria
view, to build a database of relevant literature for each topic. Regarding et al., 2019; Khan et al., 2010; Megalaa et al., 2018; Wang et al., 2016;
clinical implications, these treatment options are usually used as alter Zhang et al., 2015), are the observed mechanism of action for their
native therapies in dentistry. However, numerous clinical trials evalu natural compounds.
ated their efficiency and reached promising results. This fact has As a prototypical herbal agent to fight cariogenesis, Salvadora per
encouraged a large number of practitioners to employ herbal agents in sica (Miswak) which belongs to the Salvadoraceae family, is one of the
their routine clinical practice. Several outstanding studies in this field most popular cleaning tools among 182 species of plants used for hy
are discussed in the following section, separately for the specified gienic purposes as chewing sticks. The anti-cariogenic effect of S. persica
headings. might be due to chemical components in the plant’s structure, its me
chanical cleaning ability, or both of these traits working simultaneously.
2. Anti-cariogenic properties of herbal agents The effectiveness of Miswak related products is demonstrated against
anaerobic bacteria and facultative aerobes, multidrug-resistant, and
2.1. In-vitro and animal studies biofilm-forming bacteria like E. coli, Streptococcus pyogenes (Al-Ayed
et al., 2016), S. sanguinis, and Streptococcus mitis (Abdulbaqi et al.,
Microorganisms are etiologic factors in the occurrence of carious 2016).
lesions (Bradshaw and Lynch, 2013). Streptococcus mutans and Lacto
bacillus acidophilus are known to be the principal microorganisms 2.2. Clinical trials
involved in dental caries (van Houte, 1993) and a significant correlation
has been identified between the salivary numbers of these microor The anti-cariogenic properties of many plants have been the subject
ganisms and dental caries prevalence (Damle et al., 2016). Other culprit of several studies with human subjects. These clinical trials focused on
phylotypes for such pathologies include Fusobacterium, Dialister, Pre bacterial pollution, rate of eradication, and growth inhibition in biologic
votella, Atopobium, Streptococcus, and Pseudoramibacter (Rocas et al., samples, obtained from clinical settings. Stevia rebaudiana is an herbal
2016). The inhibition of the activity of these bacteria minimizes the risk natural sweetener with growing popularity. Besides saving teeth from
of dental caries. The application of herbal extracts against these mi sugar-enriched food products, researchers have found valuable anti
crobes has been investigated, extensively. The highlights of recent bacterial properties for it. Results of a randomized controlled trial (RCT)
in-vitro research on the application of herbal medications in dentistry conducted on twenty-two adult participants showed anti-cariogenic ef
fields are summarized in Table 1. ficacy for it. Compared to 10% sucrose solution, Stevia leaf extract
Camellia sinensis (Tea plant) is one of the most effective ones, in this prevented plaque pH acidification, which is a risk factor for enamel
regard. (Chacko et al., 2010). Active ingredients for these effects are demineralization (Siraj et al., 2019). Ocimum sanctum is another
stated to be caffeine, theobromine, theophylline, theanine, and free candidate for the management of dental caries. It’s been suggested that
amino acids (Graham, 1992). Also, polyphenols and their gallic acid the linolenic acid found in O. sanctum is responsible for its antibacterial
derivatives such as catechin, epicatechin, gallocatechin, epicatechin property (Singh et al., 2005). Accordingly, in a clinical trial on 60
gallate, and epigallocatechin gallate (EGCG) are other tea antibiotics high-risk patients, anti-cariogenic efficacy of O. sanctum mouthwash
(Yam et al., 1997). was evaluated against sodium fluoride mouthwash and it presented the
Tannin and phenolic compounds with antimicrobial properties can fastest reduction in salivary S. mutans colony count, while it was not as
also be found in Punica granatum. These Polyphenols bind to effective on salivary PH as sodium fluoride (Megalaa et al., 2018).
2
Table 1
Summary of in vitro studies for the application of herbal medicine in dentistry.
Scientific name Product Experiment Outcomes Ref/Year
Anti-cariogenic properties of herbal agents

Zingiber officinale n-hexane, ethyl acetate, Antimicrobial analysis such as biofilm Methanol and ethyl acetate extracts (Babaeekhou and
methanol, and aqueous inhibition, time-kill kinetics, and exerted the best antibacterial property Ghane, 2020)/2020
extracts adherence inhibition was conducted against S. mutants and S. sobrinus
Satureja hortensis S. hortensis extract and its Antibacterial activity against S. mutants Insignificant antibacterial activity was (Hagh et al.,
essential oil (EO) was evaluated by the disc diffusion observed in Aqueous and methanolic 2019)/2019
method extract groups, but the EO significantly
inhibited the growth of S. mutants
Salvia officinalis glass-ionomer cement (GIC) Antibacterial activity against S. mutants A concentration-response relationship was (Shahriari et al.,
modified with of S.officinalis and L. casei was evaluated by agar disc observed in using the test material against 2019)/2019
extract diffusion method S. mutants and L. casei
Psidium guajava P. guajava leaf extract used Herbal toothpaste was studied for its The dentifrice formulation showed (Shaheena et al.,
in herbal toothpaste antimicrobial activity against, S.aureus, S. efficiency against the tested bacteria 2019)/2019
mutants, Bacillus subtilis, S. oralis, and
Proteus vulgaris
Vaccinium vitis-idaea Polyphenol-rich fraction Evaluation of biofilm formation ability The herbal component significantly (Kokubu et al.,
and bioactivity of S. mutants, S. sobrinus, decreased biofilm formation of the tested 2019)/2019
and S. sanguinis bacteria
Tinospora cordifolia Ethanolic extract Seven different concentrations were 40 μl volume at 2% concentration of the (Agarwal et al.,
prepared and tested against S. mutans in herbal extract showed the greatest 2019)/2019
brain-heart infusion agar medium bacterial activity against S. mutans
Glycyrrhiza glabra/Terminalia G.glabra and T.chebula The anti-adherence property of the herbal Both herbal extracts have significant anti- (Bhadoria et al.,
chebula extracts extract was evaluated using a glass adhesive and antimicrobial activity 2019)/2019
surface adherence test against S. mutans, With the higher results
belonging to the T. chebula group
Origanum dubium/ Combination of O. dubium An Agar diffusion test was conducted to The addition of essential oils increases the (Karadağlıoğlu
Cinnamomum cassia and C. cassia essential oils determine antibacterial activity against S. toothpaste antibacterial property against et al., 2019)/2019
with herbal toothpaste mutans S. mutans
Trachyspermum ammi T. ammi oil serial dilution and disc diffusion method T. ammi oil shows significant antibacterial (Dadpe et al.,
was used for evaluation of T. ammi efficacy against cariogenic bacteria 2018)/2018
antibacterial efficacy compared to CHX
Mentha piperita M. piperita Leaf Extract Anti-microbial activity of the M. piperita M. piprerita showed the best results (Raghavan et al.,
was tested by the disc diffusion method against S. mutans followed by A. 2018)/2018
actinomycetemcomitans, and C. albicans
respectively
Camellia sinensis the esterified derivative of The number of colony-forming units was EGCG can be used as an antibacterial (Melok et al.,
EGCG assessed for evaluation of EGCG efficiency component against cariogenic bacteria 2018)/2018
against cariogenic bacteria such as S. mutans
Psoraleae semen P. semen ethanolic extract protein leakage evaluation and scanning P. semen extract is considered a potential (Kim et al.,
electron microscopy was conducted to natural agent against cariogenic bacteria 2017)/2017
determine the efficacy of P. semen against such as S. mutans
bacterial cell membrane
Punica granatum P. granatum gel agar well diffusion method was used for P. granatum gel showed efficacy against S. (Millo et al.,
evaluation of P. granatum against mutans and S. sanguinis but it wasn’t 2017)/2017
cariogenic bacteria such as S. sanguis, S. effective against L. casei
mutans, and L. casei
Galla chinensis G. chinensis water and Different herbal extraction methods were In comparison, the ethanolic extract of G. (Huang et al.,
ethanolic extract compared by the pH-cycling regime and chinensis was more potent in reducing 2017)/2017
polymicrobial biofilms model to evaluate enamel demineralization than the aqueous
efficacy for inhibition of enamel extract
demineralization and biofilm activity
Allium sativum/Mentha alcoholic extracts The good diffusion method was used for M. indica extract shows higher (Banavar Ravi
arvensis/Mangifera indica/ evaluation of antibacterial activity antibacterial effects against cariogenic et al., 2017)/2017
globulus Labill against S. mutans bacteria followed by G. labill
Zingiber officinale/Allium Herbal extract The good diffusion method was used for A. sativum showed the greatest (Mathai et al.,
sativum/Citrus limon evaluation of antibacterial activity antimicrobial effect against S. mutans 2017)/2017
against S. mutans individually. A. sativum and C. limon
showed the greatest zone of inhibition in
combination
Galla chinensis G. chinensis crude aqueous Anticariogenic efficacy of G. chinensis G. chinensis shows potential efficacy in (Zhang et al.,
extract was evaluated by tests like Keyes’ caries remineralization of enamel caries lesions 2016)/2016
diagnosis and scoring technique and the in the animal model
mineral density analysis on molar animal
teeth
Rosmarinus officinalis alcoholic extract dentifrice single-disc diffusion technique was used The herbal dentifrice showed considerable (Valones et al.,
for evaluation of herbal dentifrice against efficacy against S. mutans, S. oralis, and L. 2016)/2016
cariogenic bacteria rhamnosus
Salvadora persica S. persica aqueous and Agar dilution and minimum inhibitory Methanol extract shows more efficacy (Al-Ayed et al.,
methanol extracts concentration methods were employed than aqueous extract as a natural 2016)/2016
for evaluation of both extracts against medicament against the tested bacteria
antibiotic-resistant bacteria
Salvadora persica S. persica aqueous and Agar well diffusion method and two-fold The alcoholic extract showed more (Siddeeqh et al.,
alcoholic extracts broth dilution method were used for efficacy against cariogenic bacteria such 2016)/2016
(continued on next page)
3
Table 1 (continued )
evaluation of herbal extracts against as S. mutans and S. mitis in comparison

cariogenic bacteria with aqueous extract
Aloe vera Aloe vera leaf extract Agar and broth microdilution method was Antimicrobial activity was observed at (Jain et al.,
used for antibacterial evaluation 100% and 50% concentrations. No 2016)/2016
significant effect was observed in lower
concentrations
Houttuynia cordata H.cordata ethanolic extract Antibiofilm activity of H.cordata extract H. cordata showed great antibiofilm (Sekita et al.,
was evaluated against oral pathogens activity against microorganisms such as F. 2016)/2016
nucleatum, S. mutans, and C.albicans
Galla chinensis orthodontic adhesive cement An Agar diffusion test was conducted to The herbal extract demonstrated (Wang et al.,
containing G. chinensis determine antibacterial activity against S. significant antibacterial activity against S. 2016)/2016
extract mutans mutans in a concentration-dependent
manner
Acacia nilotica/Murraya Ethanolic extracts Agar diffusion test under anaerobic All the herbal extracts showed significant (Chandra Shekar
koenigii/Eucalyptus hybrid/ conditions was conducted to determine activity against both bacterial species but et al., 2016)/2016
Psidium guajava antibacterial activity against S. mutans the greatest results were obtained by the
and L. acidophilus combination of all herbal extracts
Toddalia asiatica/Cortex Lycii/ Herbal mouthwash An Agar diffusion test was conducted to The herbal gargle shows an inhibitory (Yang et al.,
Cimicifuga foetida/Toddalia (LongZhang Gargle®) determine antibacterial activity against S. effect at 16% and bactericidal activity at 2016)/2016
asiatica mutans 32% concentration. The herbal mouth
rinse significantly reduced acid
production
Camellia sinensis/Salvadora Herbal aqueous extracts Broth microdilution method was used for C. sinensis exhibited more efficacy than S. (Abdulbaqi et al.,
persica antibacterial evaluation persica water extract. Their combination 2016)/2016
showed synergistic activity against S. mitis
and S. sanguis
Cistus incanus C.incanus accelerated A live/dead assay was conducted for Exposure to C. incanus extract inhibits S. (Wittpahl et al.,
solvent extract evaluation of C. incanus herbal extract mutans colonization on enamel samples 2015)/2015
exposed to oral fluids
Azadirachta indica/Mimusops Herbal methanolic extract After allowing bacterial biofilm formation A. Indica, M. elengi herbal extracts show (Mistry et al.,
elengi on tooth substrate, the antimicrobial considerable antibacterial efficacy against 2015)/2015
efficacy of herbal extract was evaluated dentinal bacterial biofilm
by counting colony-forming units
Camellia sinensi/Alium Herbal mouthwash Agar diffusion test was conducted to A combination of A. sativum and C. (Thomas et al.,
sativum/Citrus aurantiifolia determine antibacterial activity against S. aurantifolia showed the most efficacy 2015)/2015
mutans and C. albicans against C. albicans. In comparison with
CHX, all herbal extracts were less effective
against S. mutans
Anacardium occidentale/ Herbal ethanolic extract An Agar diffusion test was conducted to In comparison with povidone-iodine- (Anand et al.,
Mangifera indica determine antibacterial activity against S. based mouth rinses, both herbal extracts 2015)/2015
mutans and E. faecalis showed greater efficacy against the tested
bacteria
Herbal medicine and periodontal health maintenance
Acacia chundra//Adhatoda Ayurvedic herbal extract ELISA test was conducted for evaluation Results revealed that the extract has a (Chang et al.,
vasica/Mimusops elengi/ of IL-8 production by immortalized modulatory effect on gingival epithelial 2020a)/2020
Piper nigrum/Pongamia gingival keratinocytes after herbal extract cell IL-8 production in presence of F.
pinnata/Quercus infectoria/ treatment nucleatum LPS and pro-inflammatory
Syzygium aromaticum/ signal
Terminalia/Zingiber
officinale
Hippophae rhamnoides H. rhamnoides pulp oil Biofilm Ring Test was conducted for The mouthwash was not effective against (Smida et al.,
mouthwash evaluation of H. rhamnoides efficacy C. albicans but it showed bactericidal 2019)/2019
against P. gingivalis, C. albicans, and S. property against P. gingivalis and S.
gordonii gordonii
Camellia sinensis C. sinensis water extract immunohistochemistry was conducted for Irrigation with C. sinensis extract showed (de Almeida et al.,
evaluation of IL-1β, TNF-α, and IL-10 lower inflammatory responses, lower 2019)/2019
expression in dental furcation of rat’s expression of IL-1β and TNF-α, and
tooth boosting in the expression of IL-10
Cinnamomum zeylanicum/ Herbal ethanolic extracts Agar diffusion test was performed for C. zeylanicum showed the best results (Saquib et al.,
Salvadora persica evaluation of the antibacterial property of against T. forsythia. The combination of S. 2019)/2019
the herbal extract against A. persica with metronidazole exerted the
actinomycetemcomitans and T. forsythia best synergistic effect against A.
actinomycetemcomitans
Acacia nilotica/Murraya Herbal ethanolic extract An Agar diffusion test was conducted to In comparison, all herbal extracts (Chandra Shekar
koenigii/Eucalyptus hybrid/ determine antibacterial activity against P. (individually and in combination) were et al., 2018)/2018
Psidium guajava gingivalis and F. nucleatum effective against the tested bacteria but
not as much as CHX mouthwash
Camellia sinensis The herbal extract of green Broth microdilution assay was conducted F. nucleatum adherence ability to oral (Ben Lagha et al.,
and black tea for evaluation of antibacterial property tissues was decreased by tea extract, 2017)/2017
against F. nucleatum in green and black theaflavin, and EGCG treatment
tea
Allium sativum/Ziziphora Z. clinopodioides and A. The broth macro dilution method and disk Ziziphora essential oil showed promising (Pakdel et al.,
clinopodioides sativum essential oil diffusion technique were conducted to results against S. aureus. A. sativum didn’t 2017)/2017
evaluate the activity of essential oils on show significant results
S. aureus and P. aeruginosa.
Aloe vera Acemannan
4
ELISA and real-time PCR was conducted Interleukin-6/-8 expression, and p50/DNA (Thunyakitpisal
for evaluation of interleukin- 6 & 8 binding in gingival fibroblasts is increased et al., 2017)/2017
expressions after treatment with after acemannan treatment
acemannan
Houttuynia cordata The decoction of dried H. The microbial broth dilution method was the antimicrobial property was observed (Sekita et al.,
cordata leaves used for evaluation of H. cordata against methicillin-resistant S. aureus 2017)/2017
antibacterial property And F. nucleatum as well as a modulatory
property on IL-8 expression by human oral
keratinocytes
Ocimum Sanctum O. sanctum ethanolic extract Agar well diffusion method was used for O. sanctum extract can be effective against (Eswar et al.,
evaluation of O. sanctum antibacterial periodontal pathogens like A. 2016)/2016
property actinomycetemcomitans
Polygoni Multiflori 2,3,5,4- Evaluation of modulatory property of Expression of cytokines was inhibited after (Chin et al.,
Tetrahydroxystilbene-2-O- THSG on inflammatory responses caused treatment with THSG in human gingival 2016)/2016
beta-glucoside (THSG) by P. gingivalis in gingival fibroblasts fibroblasts
Boswellia serrata/Nigella sativa Antibacterial activity of both herbal B. serrata and N. sativa herbal extracts are (Maraghehpour
extracts against A. both significantly effective against the et al., 2016)/2016
actinomycetemcomitans was evaluated tested bacteria
by the broth microdilution method
Morus alba ethanolic extract Antibacterial efficacy of the ethanolic Although M. alba extract shows significant (Gunjal et al.,
extract was assessed by estimating antimicrobial properties against 2015)/2015
minimum inhibitory concentration periodontal pathogens, it is not as effective
against common periodontal pathogens as CHX
amellia sinensis C. sinensis solution Expression of interleukin-10, tumor C. sinensis administration can be used as an (Gennaro et al.,
necrosis factor and RANKL in diabetic rats adjunctive treatment in periodontal 2015)/2015
were evaluated after treatment with C. diseases complicated by diabetes
sinnensis solution by
immunohistochemistry
Vitis Viniferea Commercially available The modified agar dilution millpore Results of the study showed significant (Shrestha et al.,
grape seed extract “Breko method was conducted for evaluation of antibacterial property against S. aureus 2012)/2012
exGrape seed OPC 30®” seed extract antibacterial property against
S. aureus, E. coli, C. albicans, and K.
pneumonia
Herbal medications and endodontic treatments
Myrtus Communis/Eucalyptus Methanolic extracts in Agar diffusion technique, tube dilution A combination of herbal extract with (Raoof et al.,
Galbie combination with calcium test, and microtiter plate assay were calcium hydroxide couldn’t inhibit 2019)/2019
hydroxide powder conducted for evaluation of antibacterial E. faecalis biofilm formation and activity
activity against E. faecalis
Piper nigrum/Piper longum/ Herbal extracts with The intra-canal medicaments (extracts) The greatest antibacterial results were (Kalaiselvam et al.,
Zingiber officinale methylcellulose were packed inside the tooth. After five obtained by the CHX group followed by 2019)/2019
days, the remaining microbial load was calcium hydroxide, The herbal extracts
determined by using real-time PCR showed significant but less effective
antibacterial properties against E. faecalis
Angelica archanglica/Asurum Fufang Bingpeng irrigant PCR, high-throughput sequencing The herbal irrigant removed intracanal (Shi et al.,
European analyses, and antibacterial test were debris, successfully opened dentinal 2019)/2019
conducted to evaluate the efficacy of the tubules, and reduced E. faecalis intracanal
herbal irrigant against E. faecalis count
Glycyrrhiza glabra/Tinospora Endodontic sealers combined An Agar diffusion test was conducted for ZOE based sealer with G. glabra extract (Saha et al.,
cordifolia/Mimusops elengi with herbal extracts evaluation of endodontic sealers showed the greatest bacterial activity 2019)/2019
combined with herbal extracts
Emblica officinalis/Terminalia Triphala extract Dental canals were examined after rinsing The use of Triphala as a final rinse solution (Susan et al.,
bellirica/Terminalia chebula with Triphala extract for evaluation of the during biomechanical root canal 2019)/2019
smear layer by field emission scanning preparation is beneficial in reducing the
electron microscope smear layer
Ricinus communis/Aloe vera/ Herbal extracts the efficacy of herbal extracts against Herbal extracts showed significantly lower (Varshini et al.,
Citrus limon E. faecalis was assessed using confocal antimicrobial efficacy than calcium 2019)/2019
microscopy hydroxide
Morinda citrifolia M. citrifolia juice Disc and well diffusion tests were 100% M. citrifolia juice showed the highest (Singh et al.,
conducted for evaluation of M. citrifolia antibacterial efficacy against both test 2019)/2019
against intracanal bacteria such as E. organisms
faecalis and C. albicans
Morinda citrifolia/Camellia Herbal extracts The tube dilution method was used for NaOCl exerted the greatest efficiency (Divia et al.,
sinensis/Triphala evaluating antibacterial efficacy of herbal against E. faecalis. Triphala showed 2018)/2018
extracts against E. faecalis and then the significant antibacterial activity compared
results were compared to NaOCl efficacy to NaOCl but M. citrifolia didn’t show the
same results
Cymbopogon citratus/Mentha NaOCl herbal solution (9:1 A combination of 6% NaOCl and herbal The study showed that 9:1 ratio (9 ml of (Pradhan et al.,
piperita/Ocimum sanctum ratio) extracts was tested for pH and chlorine NaOCl and 1 ml of herbal extracts) is the 2018)/2018
content most effective combination for chlorine
content which can be used as an intracanal
irrigant
Psidium guajava/Anacardium Herbal extracts An Agar diffusion test was conducted for Among the herbal extracts, P. guajava and (Noushad et al.,
occidentale/Carica papaya/ evaluation of herbal extracts against A. occidentale showed statistically 2018)/2018
Aloe vera E. faecalis and C. albicans significant activity against E. faecalis and
C. albicans.
But less than NaOCl
5
Andrographis paniculata/ Alcoholic extracts Agar diffusion test was conducted for The highest antibacterial activity against (Dedhia et al.,
Azadirachta indica/Curcuma evaluation of herbal extracts against C. albicans was for the A. paniculata 2018)/2018
longa S. aureus and C. albicans and then the group. Compared to NaOCl, A. paniculata
results were compared to NaOCl efficacy showed the same results against S. aureus
Morinda citrifolia/Emblica M. citrifolia extract/Triphala Colony-forming units of E. faecalis and C. All groups showed significant (Choudhary et al.,
officinalis/Terminalia juice albicans were evaluated after intracanal antimicrobial efficiency, But among them, 2018)/2018
bellirica/Terminalia chebula irrigation with Triphala juice, M. citrifolia CHX showed the most long-lasting results.
extract and CHX
Curcuma longa/Azadirachta Alcoholic extracts Agar diffusion test was conducted for CHX or A. indica exhibited the greatest (Joy Sinha et al.,
indica evaluation of herbal extracts against antibacterial activity when used as 2017)/2017
E. faecalis and then the results were endodontic irrigants against E. faecalis,
compared to NaOCl and CHX efficacy followed by sodium hypochlorite.
Aloe vera/Phyllanthus emblica/ Aloe vera Juice/Amla Juice/ Evaluation of colony-forming units, after All groups showed significant results (Mukka et al.,
Ocimum sanctum/ Pancha Tulsi. rinsing E. faecalis-contaminated gutta- against E. faecalis with the most promising 2017)/2017
percha cones with herbal ingredients results belonging to Pancha Tulsi
Aloe vera/Ocimum sanctum Combination of zinc oxide Evaluation of antimicrobial efficacy of The addition of eugenol to zinc oxide (Jaidka et al.,
with herbal extracts Aloe vera and O. sanctum combination showed better efficacy than herbal 2017)/2017
with zinc oxide against E. faecalis combinations of zinc oxide
Curcuma longa C. longa gel Evaluation of anti-bacterial property of C. As a control group, CHX gel showed better (Vasudeva et al.,
longa against E, faecalis infection found in results than C. longa 2017)/2017
dentinal tubules
Ocimum sanctum/Azadirachta Herbal extracts Evaluation of E. faecalis colony-forming A. Indica showed the best results against (Bhardwaj et al.,
indica/Tinospora cordifolia units after treatment with herbal extracts the tested bacteria with O. sanctum in the 2017)/2017
2nd order
Syzygium aromaticum/A. Herbal oil Evaluation of antimicrobial efficacy of All herbal oils showed significant efficacy (Hugar et al.,
sativum/Azadirachta. Indica/ herbal oils against E. faecalis- against E. faecalis except A. indica 2017)/2017
Ocimum. sanctum contaminated endodontic files
Cymbopogon citratus/Ocimum C. citarus oil/O. basilicum Broth microdilution method was used for C. citarus exerted the most promising (Makade et al.,
basilicum/Camellia sinensis oil/obicure tea extract evaluating the antimicrobial efficacy of results against E. faecalis among other 2017)/2017
herbal extracts against E. faecalis found on groups
gutta-percha cones
Azadirachta Indica/ Herbal extracts A polymerase chain reaction test was C. Myrrha extract showed the same results (Anand et al.,
Commiphora Myrrha/ conducted for evaluating the as CHX did against E.faecalis with A. 2016)/2016
Glycyrrhiza Glabra antimicrobial efficacy of herbal extracts indica in the 2nd order
against E. faecalis
Emblica officinalis/Psidium Alcoholic extracts The Agar disk-diffusion method was used BioPure MTAD® exerted the best results (Dubey,
guajava for evaluating the efficiency of herbal against E. faecalis. Both herbal extracts 2016)/2016
extracts and BioPure MTAD® against showed significant results.
E. faecalis
Morinda citrifolia,/Azadirachta Aqueous extracts An Agar diffusion test was conducted for In order from highest to lowest efficacy, (Babaji et al.,
indica/Aloe vera evaluating herbal extract’s efficacy the antibacterial properties belonged to 2016)/2016
against E. faecalis NaOCl, M. citrifolia, A. indica, and Aloe
vera groups respectively
Ocimum sanctum/ Herbal extracts A polymerase chain reaction test was All herbal extracts showed promising (Gupta-Wadhwa
Cinnamomum zeylanicum/ conducted for evaluating the results against E. faecalis but not as et al., 2016)/2016
Syzygium antimicrobial efficacy of herbal extracts efficiently as NaOCl
against E. faecalis
Azadirachta indica/Ocimum Ethanolic extract An Agar diffusion test was conducted to In order from highest to lowest efficacy, (Chandrappa et al.,
sanctum evaluate the antibacterial efficacy of the antibacterial properties belonged to 2015)/2015
herbal extracts against E. faecalis CHX, A. indica, and O. sanctum,
respectively
Allium sativum Water extract fluorescence microscopic analysis and 70% concentration of A. sativum exerted (Birring et al.,
microbial viability assay were used for the most promising results against 2015)/2015
evaluation of antibacterial efficacy E. faecalis
against E. faecalis
Ferula gummosa F. gummosa essential oil Broth micro-dilution evaluation and disk 50 μg/mL concentration of the herbal oil (Abbaszadegan
diffusion test were conducted to evaluate showed more efficacy against E. faecalis in et al., 2015)/2015
the antibacterial efficacy of F. gummosa comparison with 5% NaOCl
oil
Herbal medicine and anti-fungal properties
Curcuma longa Curcumin extract Evaluation and comparison of Curcumin C. longa extract didn’t show the significant (Nosratzehi et al.,
efficacy with nystatine against C. albicans anti-fungal property 2019)/2019
by using agar diffusion test
Nigella Sativa Alcoholic extract Candida colony count evaluation was N. sativa showed promising but less (Ariamanesh et al.,
conducted after rinsing C. albicans- effective anti-fungal properties compared 2019)/2019
contaminated acrylic resin specimens to nystatine
with N. sativa extract
Acacia catechu extract/ Arowash liquid mouthwash® Evaluation and comparison of the herbal The herbal mouthwash showed less anti- (Nagappan et al.,
Glycyrrhiza glabra/Syzygium mouthwash’s efficacy with CHX against fungal efficacy compared to CHX 2019)/2019
aromaticum C. albicans by using broth macro-dilution
and agar well diffusion tests
Equisetum giganteum/Punica Combination of herbal Evaluation of the herbal extracts’ efficacy Herbal extracts can be successfully added (Almeida et al.,
granatum ethanolic extracts with against C. albicans by confocal laser to denture adhesives because of their anti- 2018)/2018
denture adhesive scanning microscopy analysis, colony- fungal properties against C. albicans
forming units count, cell viability
6
analysis, and scanning electron

microscopy
Centratherum anthelminticum/ herbal oils used in a soft liner Evaluation of anti-fungal property by disk A combination of herbal oils with soft (Muttagi and
Ocimum sanctum/Linum diffusion method liners showed promising results against C. Subramanya,
usitatissimum Evaluation of soft liner’s surface albicans. It also upgraded wettability and 2017)/2017
roughness by scanning electron minimized liner’s surface roughness
microscopy
Terminalia bellirica/Terminalia Triphala extract Evaluation of anti-fungal property of Compared to CHX, Triphala showed better (Sushma et al.,
chebula//Emblica officinalis Triphala by counting colony-forming results against C. albicans 2017)/2017
units
Isodon flavidus Methanolic extract Evaluation of anti-fungal property of I. I. Flavidus exerted anti-fungal results (Li et al.,
flavidus by biofilm breakdown assay against T. rubrum but was ineffective 2016)/2016
against C. albicans and T. rubrum against C. albicans
Zingiber officinale Ethanolic extract Evaluation of anti-fungal property of Z. Z. officinale showed promising results (Aghazadeh et al.,
officinale by microdilution method against both Candida species 2016)/2016
against C. albicans and C. krusei
Lippia citriodora Aqueous and ethanolic Evaluation of anti-fungal property of L. Ethanolic extract showed better anti- (Ghasempour et al.,
extract citriodora by the disk and well diffusion fungal characteristics than aqueous 2016)/2016
tests extract against C. albicans
Centratherum anthelminticum/ Seed oils Evaluation of anti-fungal property of C. anthelminticum and O. sanctum both (Aghazadeh et al.,
Ocimum sanctum herbal oils by disc diffusion and broth exerted antifungal activity against 2016)/2016
microdilution methods Candida species
Azadirachta indica Aqueous and alcoholic Evaluation of anti-fungal property of A. A. indica alcoholic extract showed the (Joy Sinha et al.,
extracts indica extracts against C. albicans found same results against C. albicans compared 2015)/2015
in dentinal tubules to 0.2% CHX
Zataria Multiflora 0.5 mg/ml Z.multiflora Evaluation of anti-fungal property of Z. Z. multiflora exerted antifungal activity (Aghili et al.,
extract multiflora herbal extract against C. against Candida species found on 2015)/2015
albicans by mean viable microbial count elastomeric ligatures
Origanum dubium Origanum oil combined with Evaluation of anti-fungal property of O. O. dubium can be used effectively against (Srivatstava et al.,
tissue conditioner dubium herbal extract against C. albicans C. albicans in tissue conditioner without 2013)/2013
by agar punch well method significantly affecting mechanical
properties
Anti-inflammatory and wound healing properties
P. ginseng/G. glabra/Z. jujuba/ Hangeshashinto Evaluation of the effects of Hangeshashinto helps in the treatment of (Miyano et al.,
P.ternata/Z. officinale/ Hangeshashinto on scratch induced oral ulcerative mucositis by increasing 2020)/2020
Scutellaria/Coptis wound healing in vitro and in vivo oral keratinocyte migration
P. ginseng/G. glabra/Z. jujuba/ Hangeshashinto (TJ-14) Evaluation of stomatitis grades in rats Treatment with Hangeshashinto showed (Ozawa et al.,
P.ternata/Z. officinale/ with oral mucositis after treatment with the considerable antimicrobial property 2020)/2020
Scutellaria/Coptis Hangeshashinto and resolved induced oral stomatitis
symptoms in rats
Schisandtrin chinensis Schisandrin C Evaluation of reactive oxidative stress and Schisandrin C showed promising results in (Kim and Yi,
nitric oxide production in dental pulp minimizing inflammation and oxidation 2018)/2018
cells by muse cell analysis
Camellia sinensis Herbal extract Evaluation of inflammatory cell C. sinensis significantly decreases (Zaheer et al.,
infiltration in oral epithelium after inflammatory cell infiltration in the oral 2017)/2017
treatment with C. sinensis herbal extract in epithelium in rats
rats by histological analysis
P. ginseng/G. glabra/Z. jujuba/ Hangeshashinto Evaluation of COX-1 and 2 productions by Hangeshashinto successfully minimized (Kato et al.,
P.ternata/Z. officinale/ periodontal ligament fibroblasts after production of COX-2 but was not effective 2016)/2016
Scutellaria/Coptis treatment with Hangeshashinto in COX-1 production
Antineoplastic properties in herbal medications
Geranium thunbergii Geraniin Evaluation of anti-neoplastic property of A considerable reduction in MMP-2 (Yeh et al.,
Geraniin against SCC cells by western blot production by oral neoplastic cells was 2019)/2019
assay observed after treatment with Geraniin
Vernonia cinerea 8α-tigloyloxyhirsutinolide- Evaluation of anti-proliferative property 8αTGH showed significant promising (Pouyfung et al.,
13-O-acetate ( of 8αTGH against SCC cells by SRB results against oral SCC cell lines 2019)/2019
colorimetric method
Syzygium cumini Herbal extract Evaluation of anti-proliferative property Apoptosis induction in SCC cell lines was (Ezhilarasan et al.,
of S. cumini against SCC cell lines by MTT observed after treatment with S. cumini 2019)/2019
assay
Camellia sinensis EGCG Evaluation of anti-proliferative property Apoptosis induction in SCC cell lines was (Yoshimura et al.,
of EGCG against SCC cell lines by observed after treatment with EGCG 2019)/2019
immunohistochemical Ki 67 staining
Eclipta prostrata Herbal extract Evaluation of E. prostrata property on E. prostrata significantly minimized SCC (Liao et al.,
metastasis promoting proteins production cell migration and decreased MMP-2 2018)/2018
in SCC cell lines production.
Ferula persica Methanolic extract Evaluation of COX-2 presence in blood Treatment with F. persica significantly (Vosoughhosseini
serum in rats with SCC by enzyme-linked reduced COX-2 serum levels et al., 2018)/2018
immunosorbent assay after treatment
with F. persica
Rheum palmatum Herbal extract Evaluation of R. palmatum herbal extract R. palmatum significantly minimized SCC (Chen et al.,
against SCC cell metastasis by western cell metastasis ability by reducing MMP-2 2017)/2017
blot and gelatin zymography production
Nigella sativa/Aloe vera/ Herbal extracts Evaluation of anti-neoplastic property of N. sativa extract significantly minimized (Amjed et al.,
Salvadora persica herbal extracts against HeLa cell lines HeLa cells’ growth 2017)/2017
Salvia miltiorrhiza Herbal extract
7
Evaluation of apoptosis-inducing S. miltiorrhiza herbal extract was able to (Yang et al.,

property of S. miltorrhiza extracts against promote cell apoptosis via the caspase 2017)/2017
oral neoplastic cells by western blotting pathway
analysis
Gynostemma pentaphyllum Gypenosides Evaluation of Gypenosides’s effects on Gypenosides significantly increased the (Lu et al.,
cell viability and apoptosis, and oral apoptosis rate in oral neoplastic cell lines 2017)/2017
neoplastic cell DNA
Embelia ribes Embelin Evaluation of anti-neoplastic property of Embelin significantly induced both (Lee et al.,
Embelin against SCC cells by western blot autophagy and apoptosis in oral squamous 2017b)/2017
and flow cytometer analysis neoplastic cell lines
Allium sativum A. sativum L. cultivars, Evaluation of reactive oxygen species A significant anti-neoplastic activity (Szychowski et al.,
Harnaś and Morado formation in SCC cell lines after treatment against SCC cells was observed related to 2018)/2018
with A. sativum extract reactive oxygen species formation
Cudrania tricuspidata Cudraxanthone H Evaluation of anti-proliferative property A concentration and time-dependent (Lee et al.,
of Cudraxanthone H against SCC cell lines antiproliferative effect was observed 2015)/2015
by western blotting and fluorescent against SCC cell lines
nuclear staining
Bone regeneration and herbal medicine
G. glabra/V. vinifera/A. Mecsina hemostopper® Evaluation of hard tissue regeneration by Mecsina hemostopper significantly (Ozyurt et al.,
officinarum/U. dioica/S. using histologic and radiologic analyses induced alveolar bone healing process in 2018)/2018
aromaticum/S. vulgaris/ after treatment with the herbal agent and rats as well as laser therapy
H. perforatum low-level laser therapy in rats
Morinda citrifolia Aqueous extract Evaluation of osteogenic differentiation in M. citrifolia aqueous extract significantly (Gu et al.,
human periodontal ligament cells after improved osteogenic differentiation in 2018)/2018
treatment with M. citrifolia periodontal ligament cells in laboratory
settings
Aloe vera Acemannan Evaluation of bone formation after tooth Bone marrow cells proliferation, (Boonyagul et al.,
extraction by dual-energy X-ray differentiation, and activity was increased 2014)/2014
absorptiometry and histologic analysis after treatment with Acemannan in dental
sockets
Fig. 1. Alteration and disruption in the morphological appearance of S. mutans due to the formation of crystalline structures around bacterial cells (white arrows).
(A) Normal S. mutans cells. (B) S. mutans treated with Amoxicillin. (C) S. mutans treated with O. stamineus herbal extract. (D) S. mutans treated with F. deltoidea
herbal extract. Reprinted with permission from ref (Azizan et al., 2017), Copyright 2017, with permission from MDPI (https://doi.org/10.3390/mole
cules22122135).
Glycyrrhiza species have been extensively evaluated for this indi G. uralensis lollipops for three weeks in high-risk pre-school children
cation. A study based on licorice products conducted in 2018 on enamel drastically reduces salivary S. mutans count compared to the control
blocks embedded on Hawley’s appliances worn by participants revealed group. This licorice lollipop not only preserved the diversity of the oral
that using G. glabra extract lollipops can be an effective method in microbiome, it also had a healthy modulatory effect on it (Chen et al.,
reducing S. mutans count in children. Although, there was no significant 2019). Another licorice trial showed the same results in children,
effect on enamel structural characteristics, this study lacked a control regarding the efficacy of sugar-free lollipops (Almaz et al., 2017).
group to confirm the results (Krishnakumar et al., 2018). Glycyrrhiza In minimally invasive dentistry and post excavating setting, a clinical
uralensis is widely used in China as a natural food sweetener. The use of study demonstrated a significant reduction in S. mutans count in dentinal
8
samples with Aloe vera and Melaleuca alternifolia herbal extracts (Patri 3. Herbal medicine and periodontal health maintenance
and Sahu, 2017). Tea mouthwashes are major extemporaneous and
commercial products for caries fighting with outstanding anti-microbial 3.1. In-vitro and animal studies
efficacy in clinical practice. In a clinical trial on 40 preschool children,
participants were divided into herbal mouthwash and control groups. Periodontal pathologies are common multifactorial oral conditions
Twice daily administration of 8 ml/day of C. Sinensis mouthwash for with an incidence rate of over 46% among American citizens (Eke et al.,
one month induced a significant decrease in salivary S. mutans count 2015). Gingivitis and periodontitis induced by plaque are categorized
after 2 and 4 weeks follow-up periods (Salama and Alsughier, 2019). among the most prevalent periodontal problems which can have a
Another study showed similar results with a combination of C. Sinensis negative correlation with the oral-health related quality of life (Jansson
and Propolis extract in school children (Abdelmegid et al., 2015). This et al., 2014). It is essential to know that plaque accounts for 20% of the
herb in both forms of steeping green and black tea can be effective direct risk of developing periodontitis (Lang and Bartold, 2018). The
against salivary S. mutans. Catechins found in green tea turn into thea main known bacteria related to the occurrence and progression of
flavin and thearubigin through the enzymatic oxidation process of plaque-induced gingivitis and periodontitis are P. gingivalis, Bacteroides
making black tea. Theaflavin decreases the fermentation process of forsythus, Actinobacillus actinomycetemcomitans, Treponema denticola,
sugars in the oral cavity which can prevent PH reduction and subse Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum
quently enamel demineralization (Armidin and Yanti, 2019). Another (Colombo and Tanner, 2019). Bacterial presence induces stimulation of
plant used for making drinks, Coffea arabica and related species (Coffee the immune system and pro-inflammatory cytokines production and
plant), is rich in chlorogenic acid, a phenolic compound with known consequently creation of reactive oxygen species (ROS). This prolonged
antibacterial activity. An RCT showed that 2% green coffee bean extract inflammatory condition leads to degradation and destruction of the
is as capable as CHX mouthwash against S. mutans proposed to be periodontal structure (Silva et al., 2015). Not only these pathologic
attributed to chlorogenic acid without any reported side effects (Yadav conditions can result in tooth loss, they also are related to a higher risk of
et al., 2017). systemic problems like cardiovascular diseases and diabetes (Chang
A randomized controlled parallel triple-blind clinical study on 30 et al., 2020b; Voinescu et al., 2019). Using topical medications with
young adult participants compared plain S. persica and 0.5% Sodium antimicrobial and anti-inflammatory agents alongside mechanical pla
Fluoride (NaF) impregnated Miswak sticks on salivary S. mutans count. It que removal techniques is considered an effective approach in peri
was indicated that both groups reduce the bacterial load of S. mutans in odontal health maintenance. Among these treatment protocols, using
saliva without a synergistic antibacterial effect (Raina et al., 2017). herbal extracts in mouthwash forms has been the subject of many
Another RCT compared the antibacterial properties of M. indica and studies, as well.
CHX mouthwashes after 5 days of administration. Although using M. Polygonum multiflorum Thunb contains a bioactive compound,
indica mouthwash once daily was able to reduce salivary S. mutans, S, named stilbene 2, 3, 5, 4-tetrahydroxystilbene-2-Oβ-D-glucoside (THSG)
mitis, and S. salivarius count, CHX mouthwash showed higher efficacy (Qian et al., 2020) which is capable of pro-inflammatory cytokine sup
(Bhat et al., 2017). To boost the clinical efficiency of herbal extract, pression. THSG reduces the production of inflammatory cytokines at the
some labs have tried producing complex formulations as cocktail presence of P. gingivalis LPS from gingival fibroblast cells (Chin et al.,
mouthwashes (Shah et al., 2018). Triphala is a multi-component tradi 2016). Ocimum sanctum, a plant with considerable amounts of essential
tional herbal medicine containing Emblica officinalis, Terminalia bel oils of antibacterial value (Joshi, 2013), yielded antibacterial properties
lirica, and T. chebula. Clinical use of Triphala mouthwash is against A. actinomycetemcomitans (Eswar et al., 2016). Morus Alba
significantly capable of reducing salivary S. mutans count (Saxena et al., extract which is rich in tannin and phenolic and triterpene compounds is
2017). effective against A. actinomycetemcomitans, P. gingivalis, and T. forsythi
A comparative double-blind evaluation of four fluoride-containing (Gunjal et al., 2015). Boswellic acids are tripenes usually found in
chewing sticks (Alchornea laxiflora, Zanthoxylum zanthoxyloides, Boswellia serrata with known antimicrobial properties (Raja et al.,
Anogeissus leocarpus, and Masularia acuminate) with a non-herbal 2011). Boswellia serrata and Nigella sativa (black cumin) possess similar
fluoridated dentifrice, exhibited an increased concentration of salivary effects (Maraghehpour et al., 2016).
fluoride in all study groups but among them, Z. zanthoxyloides showed C. sinensis extract which is a potent inhibitor of periodontal inflam
the highest increase in salivary fluoride (Emeke et al., 2019). Xerostomia mation reduces cytokines, TRAP-positive multinucleated osteoclasts,
and decreased salivary flow rate can be a potential risk factor for dental hence, decreases alveolar bone resorption in an animal model of peri
caries (Quilici and Zech, 2019). Linum usitatissimum’s seed is rich in odontitis (de Almeida et al., 2019). Such effects are proposed to be
proteins, unsaturated oils, and fibers. When hydrated, the lining cells of related to EGCG found in C. sinensis that inhibits DNA methyltransferase
L. usitatissimum seeds release a considerable amount of mucilage, which (DNMT) and subsequently induces differentiation of naïve CD4+ cells
makes a gelatinous capsule surrounding the seed. This water-soluble into regulatory T cells (Tregs). Tregs are important in interleukin-10
mucilage is made of heavy polymers with viscoelastic properties expression which acts as a protective anti-inflammatory agent (Gen
which can be used in patients suffering from xerostomia. Combination of naro et al., 2015). This mechanism of action is depicted in Fig. 2. The
L. usitatissimum and M chamomile extract can act as an efficient natural aflavins, a bioactive compound found in C. sinensis leaves, also have a
saliva for alleviating xerostomia side effects (Morales-Bozo et al., 2017). modulatory effect on F. nucleatum-induced NF-κB activation in mono
Accordingly, S. persica extract has a significant effect on parotid salivary cytes. Theaflavin’s antibacterial activity against F. nucleatm has shown
flow rate due to its strong taste. Five minutes of chewing to be higher than EGCG (Ben Lagha et al., 2017). It can also decrease
persica-containing gum increase saliva flow rate and boost the concen subgingival biofilm formation (Kaplan et al., 2009). Resveratol is a
tration of fluoride ions in the oral cavity, act as two efficient mechanisms bioactive component commonly found in Polygonum multiflorum which
in decreasing dental caries, comparable to sodium fluoride-containing exhibits anti-osteoblastogenesis quality. Resveratrol and THSG can
chewing gums. This shows that fluoride present in S. persica extract reduce the expression of pro-inflammatory cytokines, such as
can successfully be ionized in the oral cavity. (Mortazavi et al., 2019). A interleukin-1 which is involved in the pathogenesis of periodontitis
summary of recent clinical trials for the application of herbal medicine (Chin et al., 2016). Peri-implantitis is a multifactorial pathologic situa
in dentistry is depicted in Table 2. tion related to loss of supporting bone around implants which leads to
implant failure. S. aureus and P. aeruginosa are considered two factors
involved in peri-implantitis etiology (Persson and Renvert, 2014). An
in-vitro study compared the antibacterial efficacy of Ziziphora (from
Labitae or Lamiaceae family) and A. sativum against these two bacteria.
9
Table 2
Summary of clinical trials for application of herbal medicine in dentistry.
Scientific name Product Number of Methodological approach Result Ref/Year
participants
Anti-cariogenic properties of herbal agents

Camellia sinensis Herbal mouthwash 40 Quantitative microbiological laboratory C. sinensis extract mouth rinse (Salama and Alsughier,
cultivation assay. Comparison of S. caused a significant decrease in S. 2019)/2019
mutans bacterial count found in saliva mutans bacterial load in saliva
before and after mouth rinse
administration in pre-school children
Camellia sinensis Green and black tea 60 Comparison of S. mutans bacterial count In comparison, green tea herbal (Armidin and Yanti,
mouth rinse found in saliva before and after mouth rinse showed higher efficacy 2019)/2019
C. sinensis mouth rinses administration in reducing S. mutans count than
black tea mouth rinse
Glycyrrhiza glabra Liquorice Lollipop 37 Quantitative PCR & 16S rRNA gene The herbal lollipops are beneficial (Chen et al.,
containing analysis. in salivary S. mutans load 2019)/2019
Glycyrrhizol A Comparison of salivary S. mutans reduction without changing
bacterial counts before and after the phylogenic diversity
consumption of lollipops in pre-school
children
Stevia rebaudiana Stevia aqueous 22 Pre-post study design/PH analysis No significant change was observed (Siraj et al.,
solution/Cerovia after using S. rebaudiana extract 2019)/2019
powder
Salvadora persica Persica chewing gum 44 Evaluation of salivary fluoride ion Both the fluoride ion concentration (Mortazavi et al.,
concentration after using the herbal gum and salivary flow rate increased 2019)/2019
by hexamethyldisiloxane diffusion after using persica containing gum
method.
Alchornea laxiflora/ Fluoride containing 20 double-blind cross-over study design/ Among different chewing sticks Z. (Emeke et al.,
Zanthoxylum chewing sticks Comparison of fluoride ion zanthoxyloides showed the highest 2019)/2019
zanthoxyloides/ concentration detected in saliva before mean salivary fluoride increase
Anogeissus leocarpus and after using herbal chewing sticks
with spectrophotometry
Terminalia chebula/ Ethanolic extracts 60 /Comparison of salivary PH and S. Sodium fluoride mouth rinse (Megalaa et al.,
Ocimum sanctum mutans load before and after showed the highest efficacy in 2018)/2018
administration of herbal extracts and increasing salivary Ph compared to
sodium fluoride mouth rinse in high-risk herbal mouth rinses. T. chebula
patients group showed higher efficacy in S.
mutans load reduction than O.
sanctum after a week
Glycyrrhiza glabra Liquorice Lollipop 20 Comparison of salivary S. mutans and L. The herbal lollipop showed efficacy (Krishnakumar et al.,
acidophilus bacterial counts before and in S. mutans load reduction but did 2018)/2018
after the herbal lollipop administration not show antimicrobial property
against L. acidophilus
Terminalia chebula T. chebula mouth rinse 45 Double-blind RCT/Comparison of S. The herbal mouth rinse was more (Shah et al.,
(Oratreat®) mutans bacterial load detected in saliva effective in bacterial load reduction 2018)/2018
before and after herbal mouth rinse and than CHX
CHX administration by colony-forming
units count
Glycyrrhiza glabra Herbal lollipop (Dr. 108 Double-blind RCT/Comparison of The herbal G. glabra lollipops are (Almaz et al.,
John’s herbal salivary S. mutans bacterial counts beneficial in salivary S. mutans 2017)/2017
lollipop®) before and after the consumption of load reduction in high-risk children
lollipops in high-risk children by colony-
forming units count
Salvadora persica 0.5% Sodium fluoride 30 randomized controlled concurrent Both groups showed the same (Raina et al.,
impregnated miswak parallel triple-blind study/Comparison efficacy in S. mutans load reduction 2017)/2017
and plain miswak sticks of unstimulated salivary S. mutans
bacterial count before and after chewing
sticks administration
Melaleuca alternifolia/ Tea tree oil/Aloe vera 40 Controlled pre and post-study/ CHX as a control group exerted the (Patri and Sahu,
Aloe vera gel Evaluating the anti-microbial efficacy strongest efficacy against 2017)/2017
after caries excavation and topical cariogenic microorganisms
application of herbal medicaments on followed by M. alternifolia
dentinal specimens by total viable count
analysis
Mangifera indica mango leaf mouthwash 20 RCT/Comparison of S. mutans bacterial Using herbal mouthwash (Bhat et al.,
load detected in saliva before and after significantly reduced S. mutans 2017)/2017
herbal mouth rinse and CHX count but not as well as CHX
administration by colony-forming units
count
Coffea arabica Herbal extract 45 Parallel RCT/Comparison of S. mutans C. Arabica showed the same (Yadav et al.,
bacterial load detected in saliva before efficacy as CHX in decreasing 2017)/2017
and after herbal mouth rinse and CHX S. mutans salivary load
administration by colony-forming units
count
Terminalia Chebula/ Herbal aqueous 40 Linear randomized cross over study/ All groups showed significant (Saxena et al.,
Terminalia Bellirica/ extracts and Triphala Comparison of S. mutans bacterial load antimicrobial efficacy but the 2017)/2017
Embilica Officinalis detected in saliva before and after herbal highest results were obtained by
10
participants
mouth rinses individually and in using the combination of all herbal

combination by colony-forming units extracts
count
Camellia sinensis Herbal mouthwash 30 Cross-sectional study/Comparison of S. Administration of C. sinensis (Abdelmegid et al.,
mutans bacterial load detected in saliva mouthwash significantly reduced 2015)/2015
before and after herbal mouth rinses in salivary S. mutans count
school children by colony-forming units
count
Herbal medicine and periodontal health maintenance
Melaleuca alternifolia/ Aloe vera and M. 152 Double-blinded RCT/Comparison of PI Recorded periodontal indices were (Kamath et al.,
Aloe vera alternifolia mouthwash and GI before and after using herbal improved after herbal mouthwash 2020)/2020
mouthwashes in children administration
Melaleuca alternifolia Herbal mouthwash 42 PI, GI, BOP, and Probing Depth The herbal mouthwash was more (Ripari et al.,
efficient in improving periodontal 2020)/2020
indices compared to CHX with no
side effect
Melaleuca alternifolia M. alternifolia 60 Double-blinded crossover RCT/gingival The herbal mouth rinse showed the (Casarin et al.,
nanoparticle crevicular fluid volume and the Quigley same anti-inflammatory efficacy 2019)/2019
& Hein plaque index comparison before compared to CHX without affecting
and after herbal mouthwash taste sensation
administration
Psidium guajava 0.15% Guava mouth 60 Double-blinded three-arm parallel RCT/ Although P. guajava mouth rinse (Nayak et al.,
rinse PI, GI, and antioxidant production significantly improved PI and GI, it 2019)/2019
comparison before and after using herbal did not exert significant change in
mouthwashes and CHX antioxidant level
Scrophularia striata hydroalcoholic extract 50 RCT/BOP, PI, and pocket depth Compared to Listerine mouth rinse, (Kerdar et al.,
comparison before and after, mouth S. striata showed higher efficacy in 2019)/2019
rinse administration in patients suffering improving the periodontal status
from chronic periodontitis
Ligusticum chuanxiong/ Rhizoma Chuanxiong 120 Parallel allocation RCT/OP, BI, and GI Administration of the herbal (He et al., 2019)/2019
Imperata cylindrica and Rhizoma comparison before and after using herbal toothpaste showed considerable
Imperatae dentifrice dentifrice efficacy in periodontal indices
improvement
Taraxacum Pudilan extract- 120 Double-blinded parallel RCT/BOP, BI, The herbal dentifrice showed (Cheng et al.,
mongolicum/ containing dentifrice PI, and GI comparison before and after significant efficacy in improving 2019)/2019
Corydalis bungeana/ using herbal dentifrice gingival and periodontal indices
isatidis seu and BOP
Baphicacanthii/
Scutellaria baicalensis
Punica granatum/ Herbal extract 80 Double-blinded RCT/PI and salivary P. granatum mouth rinse exerted (Mishra et al.,
Terminalia chebula/ mouthwash buffering capacity comparison before the highest substantivity among all 2019)/2019
Vitis vinifera and after using herbal mouthwashes groups. The least significant results
belonged to V. vinifera mouth rinse
group
Salvadora persica/ Herbal mouthwash 100 RCT/Bonded bracket plaque index The best results concerning the (Niazi et al.,
Azadiractha indica comparison before and after using herbal improvement of plaque index 2018)/2018
mouthwashes in orthodontic patients belonged to the S. persica mouth
rinse group
Rheum glycyrrhiza Daiokanzoto 23 RCT/PI, GI, and tongue coating index A significant improvement was (Moriyama et al.,
comparison before and after observed in periodontal status (GI 2018)/2018
intervention in patients undergoing and PI) after mouthwash
chemotherapy administration
Camellia sinensis C. sinensis mouthwash 30 RCT/probing depth and periodontal A significant improvement was (Taleghani et al.,
indices comparison before and after observed in periodontal status (BI 2018)/2018
using herbal mouthwash and probing depth) after
mouthwash administration
Carica papaya Herbal toothpaste/ 100 RCT/Interdental bleeding index A significant improvement was (Saliasi et al.,
mouthwash comparison before and after using herbal observed in the interdental 2018)/2018
mouth rinse and toothpaste bleeding index in both groups. A
synergistic effect was reported in
using the combination of both
mouth rinse and dentifrice
Salvadora persica/ Herbal HiOra® 40 RCT/Modified sulcular bleeding index, A significant improvement was (Siddeshappa et al.,
Terminalia bellerica/ mouthwash PI, and GI were evaluated in participants observed in periodontal status (All 2018)/2018
gandhapura taila/ before and after using an herbal mouth indices) after mouthwash
peppermint satva/ rinse administration
Yavani satva
Salvadora persica S. persica containing 100 Single blinded parallel RCT/approximal A significant improvement was (Saliasi et al.,
toothpaste plaque index and sulcus bleeding index observed in both periodontal 2018)/2018
comparison before and after using herbal indices
dentifrice
Aloe vera 99% aloe juice 390 RCT/GI and PI comparison before and Aloe vera juice can be as effective (Vangipuram et al.,
after using herbal mouthwashes and as CHX in periodontal indices 2016)/2016
CHX improvement
52
11
participants
Carica papaya/Ananas Dentifrice containing Single blinded, parallel RCT/GI and PI The herbal toothpaste can be (Tadikonda et al.,
comosus/Azadirachta Papain, Bromelain, S. Comparison before and after using effectively used in orthodontic 2017)/2017
indica/Salvadora persica, and A. indica herbal toothpaste in patients undergoing patients for periodontal health
persica orthodontic treatment maintenance
Cymbopogon citratus C. citratus oil 45 Three-arm parallel RCT/periodontal C. citratus mouth rinse can be (Subha and Pradeep,
mouthwash indices and cardiovascular serum beneficial in cardiovascular serum 2017)/2017
biomarkers comparison before and after markers and periodontal indices
using herbal mouthwash improvement
Barleria prionitis Herbal mouthwash 30 Double-blind RCT/Quigley and Hein A significant improvement of (Gupta et al.,
plaque index comparison before and plaque index was recorded in both 2016)/2016
after using herbal mouth rinse and CHX groups with the higher efficacy
belonging to CHX mouthwash
Arimedadi (Herbal Arimedadi oil mouth 45 Double-blinded parallel RCT/GI and PI The herbal mouth rinse was as (Mali et al.,
combination) rinse comparison in participants before and potent as CHX in GI and PI 2016)/2016
after using herbal mouth rinse and CHX improvement
Anacardium occidentale 10% herbal 30 RCT/GI and PI comparison in A. occidentale mouth rinse was as (Gomes et al.,
mouthwash participants before and after using potent as 0.12% CHX in GI and PI 2016)/2016
herbal mouth rinse and CHX improvement
Azadirachta indica A. Indica chip 10% 20 Split-mouth design/Microbiological The presence of A. indica chips (Vennila et al.,
analysis (polymerase chain reaction test) significantly decreased P. 2016)/2016
after placing the herbal chip in gingivalis load in periodontal
periodontal pockets pockets
Emblica officinalis/ Triphala mouthwash 90 Double-blinded RCT/Oral hygiene A significant improvement of (Pradeep et al.,
Terminalia bellirica/ index-simplified, PI, and GI comparison periodontal indices was recorded in 2016)/2016
Terminalia chebula before and after using an herbal mouth the herbal mouth rinse group
rinse
Baccharis Herbal mouthwash 12 Cross over triple-blind RCT/PI The herbal mouth rinse (Pedrazzi et al.,
dracunculifolia evaluation before and after using an significantly improved PI in 2015)/2015
herbal mouth rinse participants
Herbal medicine and anti-fungal properties
Camellia sinensis Green tea mouthwash 22 RCT/lesion size and fungal colonies C. sinensis can be as effective as (Ghorbani et al.,
0.5% count analysis after treatment with nystatin in alleviating denture 2018)/2018
C. sinensis mouth rinse and nystatin stomatitis symptoms
suspension 100,000 U/ml in patients
suffering from denture stomatitis
Anti-inflammatory and wound healing properties
Aloe vera Aloe vera powder 40 Cross-sectional randomized Aloe vera extract can be used as an (Nimma et al.,
capsule 500 mg interventional method/standardized adjunct therapy agent for socket 2017)/2017
index by Landry, Turnbull, and Howley healing improvement after dental
assessment after third molar surgery in extraction
patients treated with foam gel soaked in
Aloe vera extract
Glycyrrhiza Glabra Aqueous extract 37 Double-blind RCT/Oral mucositis G. glabra extract significantly (Najafi et al.,
mouthwash indices comparison before and after alleviated mucositis symptoms and 2017)/2017
using G. glabra in patients undergoing improved wound healing
radiotherapy
Curcuma longa Curcumin extract 20 RCT/Oral mucositis indices before and C. longa extract significantly (Patil et al.,
mouthwash after using C. longa in patients alleviated mucositis symptoms and 2015)/2015
undergoing radio-chemotherapy improved wound healing
Halitosis and herbal medicine
O. sanctum O. sanctum mouthwash 45 Double-blinded parallel RCT/VSC O. sanctum showed significant but (Sharma et al.,
concentration before and after using less efficacy in reducing VSC 2019)/2019
herbal mouthwash, CHX and hydrogen concentration than other mouth
peroxide mouth rinses rinses
Echinacea augustifolia/ Herbal muco-adhesive 40 RCT/VSC concentration analysis by Malodor grades and VSC (Sterer et al.,
Pistacia lentiscus/ tablet spectrophotometry concentration were significantly 2013)/2013
,/lavandula improved after herbal tablet
augustifolia/ administration
salviaofficinals
Camellia sinensis C. sinensis mouthwash 60 Double-blind RCT/VSC concentration C. sinensis significantly decreased (Rassameemasmaung
and PI evaluation VSC concentration detected in the et al., 2013)/2013
breath
Curcuma zedoaria/ aqueous solution 30 Cysteine challenge testing for VSC Both groups showed considerable (Farina et al.,
Camellia sinensis mouthwash evaluation efficacy in reducing VSC 2012)/2012
concentration but CHX maintained
long-lasting results
Analgesic properties in herbal medicine
Scutellaria baicalensis/ phytotherapeutic drug 82 Triple blind RCT/Postoperative pain Using the herbal drug significantly (Isola et al.,
Aesculus (Baicalin/bromelain/ score evaluation in patients undergoing reduced visual analogue pain 2019)/2019
hippocastanum escin) 3rd molar surgery scores in patients after their
surgery
Punica granatum P. granatum gel 60 Double-blind RCT/Visual analogue scale P. granatum application (Tavangar et al.,
analysis in patients suffering from significantly decreased pain relief 2019)/2019
aphthous stomatitis duration compared to the control
group
12
participants
Echinacea purpurea E. purpurea tablets 50 Controlled trial/Visual analogue scale E. purpura administration (Khozeimeh et al.,
(114 mg) analysis, the severity of symptoms and significantly improved pain scores 2018)/2018
healing process after herbal drug and clinical symptoms in patients
administration in patients suffering from with aphtous ulcres
aphthous stomatitis
Zingiber officinale 500 mg ginger rhizome 67 Double-blind RCT/Postoperative pain Z. officinale can be as efficient as (Rayati et al.,
powder capsule score and C-reactive serum level Ibuprofen in pain control after 3rd 2017)/2017
analyses in patients undergoing 3rd molar surgery in clinical settings
molar surgery
Zingiber officinale Mucoadhesive paste 15 Double-blind RCT/Pain intensity and Z. officinale significantly decreased (Haghpanah et al.,
inflammatory zone evaluation in pain experience in patients but was 2015)/2015
patients suffering from aphthous ulcers ineffective in alleviating the other
signs
Camellia sinensis 5% C. sinensis 97 RCT/Visual analogue scale and mouth C. sinensis can be effective in (Shahakbari et al.,
mouthwash opening range assessment after using alleviating the patient’s discomfort 2014)/2014
herbal and CHX mouthwash in pericoronitis
Camellia sinensis C. sinensis mouthwash 44 Split-mouth double-blinded RCT/ C. sinensis administration (Eshghpour et al.,
Postoperative pain score evaluation in significantly improved pain scores 2013)/2013
patients undergoing 3rd molar surgery compared to the control group after
3rd molar surgery
Vital Pulp therapy and herbal medicine
Myristica fragrans/ Herbal gel 20 Evaluation by clinical and radiological Pulpotomy treatment using herbal (Mali et al.,
Terminalia chebula analyses using M. fragrans and T. gels in primary teeth showed the 2018)/2018
chebula as primary teeth pulpotomy same success rate as using
medicaments formocresol
Curcuma longa Turmeric Powder 15 Clinical and Radiological Evaluation was Pulpotomy treatment using (Purohit et al.,
conducted after using turmeric powder turmeric powder in primary teeth 2017)/2017
for primary teeth pulpotomy resulted in proper clinical and
medicament radiographic success
Aloe vera Acemannan 42 Clinical, radiographic, and histologic Compared to calcium hydroxide, (Songsiripradubboon
analyses after direct pulp capping using acemannan as a direct pulp et al., 2016)/2016
treatment with the herbal agent in capping agent resulted in better
primary teeth histological responses and
biocompatibility
Ziziphora essential oil showed a significant effect against S. aureus

compared to vancomycin while no considerable effect was reported
against P. aeruginosa. The aqueous and alcoholic extracts of A. sativum
showed no significant efficacy in this manner (Pakdel et al., 2017).
As mentioned, laboratory experiments have demonstrated peri
odontal preservation properties for numerous other herbal extracts or
compounds, such as Acadia chundra, A. nilotica, Adhatoda vasica,
Cinnamomum zeylanicum, E. hybrid, Glycyrrhizae radix, H. cordata,
Hippophae rhamnoides, M. koenigii, P. guajava, Pongamia pinnata,
Quercus infectoria, Syzygium aromaticum, S. persica, M. elengi, P.
nigrum, T. chebula, Vitis vinifera, and Z. officinale.
Inhibition of inflammatory pathways (Chang et al., 2020a; Sekita
et al., 2017), anti-microbial effects (Chandra Shekar et al., 2018; Saquib
et al., 2019; Shrestha et al., 2012; Smida et al., 2019; Watanabe et al.,
2019) and radical scavenging (Yadav et al., 2015) are common features
in almost all of their mechanisms of actions.
Phenolic compounds, flavonoids, quinones, steroid/triterpenoids
and tannins, tocopherols, carotenoids, vitamins, phytosterols, resvera
trol, aempferol, quercetin, myricetin, anthocyanins, monomeric cate
chin and epicatechin, gallic acid, and procyanidins are the main
bioactive compounds in these species.
3.2. Clinical trials
The use of herbal products in periodontal health maintenance has

Fig. 2. C. sinensis polyphenols induce naïve CD4+ Tcells differentiation into
been explored in many clinical trials with uncertainty in results. All of
Tregs by reducing DNMT activity and consequently reactivation of FoxP3. The
presence of Tregs is mandatory for regulating inflammatory responses and the agents in this field of research had shown promising results at pre-
inteleukin-10 production. Reprinted with permission from ref (Gennaro et al., clinical stages, as mentioned before.
2015), Copyright 2015, with permission from PLOS ONE (https://doi.org M. alternifolia is recognized for its antibacterial and anti-
/10.1371/journal.pone.0134784). inflammatory properties. Results of a randomized crossover trial
showed administration of a mouth rinse containing M. alternifolia ex
tracts nanoparticles for 4 days can be as capable as CHX in reducing
gingival crevicular fluid. The unpleasant taste was the only reported side
13
effect of using M. alternifolia (Casarin et al., 2019). A similar study re and Pradeep, 2017). Several other clinical studies have demonstrated
ported total safety without any adversity for this product (Ripari et al., positive outcomes in chronic periodontitis, moderate to severe gingivitis
2020). Another study on 30 subjects with chronic periodontitis showed and microbial plaque eradication from products such as 0.15% P. gua
using C. sinensis mouthwash after scaling and root planing (SRP) for six java extract, Baccharis dracunculifolia mouthwash, Aloe vera juice
weeks has a superior effect on improving the probing index than SRP mouthwash, M. alternifolia oil mouthwash, and 6% Triphala mouth
alone. Regarding the saliva acidity, C. sinensis mouthwash is more wash (Kamath et al., 2020; Nayak et al., 2019; Pedrazzi et al., 2015;
effective in increasing salivary pH than CHX and sodium fluoride Pradeep et al., 2016; Rabbani et al., 2006; Taleghani et al., 2018; Van
mouthwashes (Taleghani et al., 2018). gipuram et al., 2016).
Barleria prionitis is a medicinal plant native to India. An RCT failed
to show superiority for 50% B. prionitis extract mouthwash versus 12% 4. Herbal medicine and anti-fungal properties
CHX in reducing plaque and gingival scores after 3 days of the experi
ment (Gupta et al., 2016). 4.1. In-vitro studies
Anacardium occidentale extract contains tannins that inhibit the
cyclooxygenase (COX) and arachidonic acid metabolic pathways (Mota The prevalence of oral fungal infections has changed dramatically in
et al., 1985). The extract containing mouthwash has presented the same recent years (Gleiznys et al., 2015). These changes are mainly related to
efficacy in reducing plaque index (PI) and bleeding index (BI) as CHX, the increase in predisposing factors like immune-compromising situa
with lower rates of side effects (Gomes et al., 2016). Scrophularia striata tions such as HIV infection, endocrine disorders, using immunosup
is a plant commonly found in Iran. Clinical use of S. striata mouthwash pressive drugs and prolonged antibiotic therapies, malnourishment,
twice daily for two and four-week periods decreased PI, pocket depth, using dentures, etc. (Gleiznys et al., 2015). Candida is considered a
and bleeding on probing (BOP) in patients with mild to moderate natural flora in the human oral cavity but it can cause pathogenic con
chronic periodontitis with better efficacy compared to Listerine ditions due to some host and microbial virulence factors like protection
mouthwash. (Kerdar et al., 2019). Among trials that evaluated the against defense system and adhesion ability to host tissue (Garcia et al.,
sulcular bleeding index, Azaripour A et al. (2017), used an S. 2011; Murciano et al., 2012). C. albicans is responsible for most of the
persica-containing dentifrice which showed to be more effective in oral candidiasis cases (Astvad et al., 2015). Unfortunately, Candida in
reducing this index in patients with gingivitis after three weeks fections have become more resistant to azoles day by day, so, finding
follow-up in comparison with conventional toothpaste (Azaripour et al., alternate effective medicines against these infections seems necessary
2017). (Whaley et al., 2016). In this way, in vitro studies have taken the lead in
Combination products have been used for this indication as well. finding curative approaches and herbal agents have shown beneficial
Arimedadi oil contains Rubia cordifolia, Sesamum indicium, A. catechu, effects in these procedures.
and S. aromatics which is an Indian traditional medicine that has shown Among natural resources, Z. officinale ethanolic extract has a
comparable efficacy to CHX in improving gingival and plaque indices. considerable anti-biofilm effect against C. albicans and C. krusei. Inter
However, it has an unpleasant taste which can cause a challenge for its estingly, the herbal extract of Z. officinale possessed greater antifungal
acceptability among consumers (Mali et al., 2016). Ligusticum chuan activity compared to common antifungal drugs like nystatin and flu
xiong which is a flowering plant of the carrot family contains bioactive conazole (Aghazadeh et al., 2016). Sesquiterpenes are highly oxygen
compounds such as tetramethylpyrazine, senkyunolide A, and ferulic ated compounds found in herbal essential oils which can be responsible
acid. A combination of L. chuanxiong and Imperata cylindrical in a for the plant’s antifungal property (Dolara et al., 2000). Phytosterols of
dentifrice exhibited a significant decrease in GI, BI, and BOP % scores Centratherum anthelminticum seed oil (Aghazadeh et al., 2016), Lippia
compared to the control group without any reported adverse effect (He citriodora ethanolic extract (Ghasempour et al., 2016) Fladin A, and
et al., 2019). Daiokanzoto is a traditional herbal Japanese medicine lophanic acid of Isodon flavidus (Li et al., 2016) have presented prom
which consists of Rheum rhabarbarum (with bioactive components ising anti-fungal activities.
including anthraquinones) and G. glabra. Daiokanzo administration A. indica extract containing nimbidin, nimbin, azadirachtin, mar
significantly improves PI and GI and decrease in F. nucleatum colony golone, and cyclictrisulphide as active ingredients can act through
count in patients undergoing chemotherapy (Moriyama et al., 2018). interfering with the respiratory chain in C. albicans. This process mini
Herbal medicine has come to the aid of producing functional devices mizes fungal adhesion ability to dentin surface (Joy Sinha et al., 2015).
like dentifrices or therapeutic chips. An herbal dentifrice, containing Acrylic prosthetic dentures and tissue conditioners which are usually
Carica papaya, has shown promising results in clinical settings. It was as reservoirs for adherence and colonization of Candida species (Garg
capable as a sodium lauryl sulfate-free enzyme-containing dentifrice in et al., 2012) can cause mucosal irritation and denture stomatitis. Herbal
decreasing bleeding on the interdental brushing index after 4 weeks of antifungal agents can be added to denture soft liners and tissue condi
follow-ups (Saliasi et al., 2018). Vennila K et al. (2016) also found that tioners. Origanum vulgare oil containing 4-terpineol, carvacrol, and
using 10% A. indica extract on nonabsorbable chips placed in peri thymol with antifungal and antibacterial properties is a suitable candi
odontal pockets, as an adjunctive therapy besides SRP can be a suc date via decreasing fungal filament formation and germination without
cessful approach in the treatment of patients with chronic periodontitis. compromising bond strength (Srivatstava et al., 2013). The addition of
This study proved the efficacy for A. indica extract in reducing P. granatum and Equisetum giganteum extracts which are known to
P. gingivalis count in subgingival plaque samples compared to the contain polyphenolic ingredients to denture adhesives interferes with
administration of SRP alone in 3 weeks (Vennila et al., 2016). attachment and colonization of C. albicans biofilm on the acrylic resin
Periodontal maintenance and plaque control is also a major concern (Almeida et al., 2018). C. anthelminticum and O. sanctum seed oil can
in patients undergoing fixed orthodontic treatments. S. persica mouth also be added to soft liners which considerably reduces surface rough
wash is more capable of improving the modified bonded bracket plaque ness and minimizes glucose absorption into the soft liner structure which
index than CHX and A. indica extract mouthwashes in patients under can interfere with C. albicans adhesion ability to surfaces (Muttagi and
going orthodontic treatment (Niazi et al., 2018). A clinical study con Subramanya, 2017). Ariamanesh H et al. (2019) evaluated the anti
ducted in 2017 on 45 patients suffering from chronic periodontitis fungal potency of N. sativa extract against C. albicans biofilm on the
showed the combination of local periodontal treatment and adminis acrylic resin surface. The study indicated a concentration-dependent
tration of 0.2% C. citratus (twice daily for three months) results in a anti-fungal activity for N. sativa extract (Ariamanesh et al., 2019).
more significant decrease in cardiovascular biomarkers like C - reactive Zataria multiflora rich in phenolic compounds like carvacrol, thymol,
protein and low-density lipoprotein and a significant rise in high-density and eugenol, has shown significant growth inhibition for C. albicans on
lipoprotein level compared to local periodontal treatment alone (Subha artificially contaminated orthodontic elastomeric ligatures. (Aghili
14
et al., 2015). more biocompatible components. The addition of O. sanctum liquid

extract to zinc oxide powder (1:4 ratio) shows the same efficacy as zinc
4.2. Clinical trials oxide eugenol in E. faecalis inhibition. This may be due to the high
concentration of eugenol and methyl eugenol as bioactive components
The number of clinical studies on anti-fungal agents for dentistry in these species (Jaidka et al., 2017). A combination of G. glabra with
research is limited. A randomized clinical trial on patients suffering from resin-based and zinc oxide eugenol-based endodontic sealers showed
denture-related stomatitis showed that using 15 ml of 0.5% C. sinensis promising results against E. faecalis, too (Saha et al., 2019). Mukka PK
mouthwash, four times daily can be as effective as receiving nystatin et al. (2017) showed that Phyllanthus emblica juice and a commercially
suspension 100,000 u/ml, in reducing stomatitis lesion size and available herbal disinfecting drop containing O. sanctum extract can be
decreasing Candida colony count (Ghorbani et al., 2018). Another RCT used for chairside decontamination of gutta-percha cones before end
conducted for 60 edentulous patients with dentures in 2017 proved odontic obturation (Mukka et al., 2017). Another study showed C. cit
using Triphala for denture cleansing for one month is as effective as ratus extract, basil oil, and obicure tea extract can be effective against
0.2% CHX mouthwash in reducing C. albicans load found on removable E. faecalis as disinfecting agents for gutta-percha cones, with the best
prosthetic dentures (Sushma et al., 2017). results belonging to C. citratus (Makade et al., 2017). Another author
states that immersion of contaminated endodontic K-files in A. sativum,
5. Herbal medicaments and endodontic treatments S. aromaticum, and O. sanctum C. citratus oils causes a considerable
decline in bacterial load obtained from endodontic file surfaces (Hugar
5.1. In vitro studies et al., 2017).
Bacterial pathogenesis is the primary factor responsible for end 5.2. Clinical trials
odontic infections. Enterococcus faecalis is one of the most common
bacteria found in infected root canals and cases of failed root canal Regarding clinical settings, using triphala in anatomically curved
therapies with the need for retreatment (with the prevalence from 24% root canals as an irrigating agent in RCTs shows promising results. It also
to 77%) (Choudhary et al., 2018). It is a gram-positive bacterium with can act as a chelating agent because of its citric acid-rich content which
the ability to survive in most unfavorable environments (Evans et al., can be beneficial in the removal of the smear layer during canal
2002). E. faecalis can alter host responses, control pH homeostasis, and debridement and cleaning (Susan et al., 2019).
contains lytic enzymes. It can adhere to dentin and invade dentinal tu
bules and shows the capability to survive to Sodium hypochlorite con 6. Anti-inflammatory and wound healing properties
centrations (NaOCl) of up to 6.5% which is commonly used as an
intracanal irrigant during root canal treatment (Kayaoglu and Ørstavik, Herbal remedies are well-known for their traditional use for their
2004). Therefore, finding an irrigating agent against E. faecalis with high soothing effects. Dentistry practice has benefited a lot from such po
penetrative ability for dentinal tubules, has a great importance. Many tentials. A large number of plant products have been introduced to have
pre-clinical studies have tried to find an appropriate herbal and natural tangible anti-inflammatory effects. Some researchers have used single-
substitutes for intracanal irrigating agents but, unfortunately, clinical ingredient products and others have utilized complex formulations.
data is scarce. Chisandra chinensis and its major lignan Schisandrin C possess anti-
Birring OJ et al. (2015) found out that A. sativum 70% herbal extract inflammatory properties by suppressing Interleukin-1β and Tumor ne
can be as effective as NaOCl 5.25% against E. faecalis with considerable crosis factor-α expression. It also diminishes nitric oxide production by
dentin penetration. Allicin is one of the main important antibacterial human dental pulp cells in the presence of bacterial LPS, so it can help
components of A. sativum (Birring et al., 2015). treating oral related inflammations such as pulpitis (Takanche et al.,
In an attempt to create an herbal sodium hypochlorite solution, 2018).
Pradhan MS et al. (2018) added 10% extracts of three herbal species (C. In an animal study, C. sinensis extract exerted a significant reduction
citarus, M. piperita, and O. sanctum) to 6% sodium hypochlorite. The in nicotine-induced damage, in terms of inflammatory cell infiltrates in
authors suggested that this combination might have a synergistic anti the buccal mucosa (Shahbaz et al., 2017). Matricaria recutita or cham
bacterial effect without compromising pH and chlorine content (Prad omile extract inhibits COX-2 and synthesis of inflammatory mediators,
han et al., 2018). Another herbal extract with the same efficacy as NaOCl such as prostaglandin E2 and reported to be useful in the treatment of
and CHX is obtained from A. indica which can be used in further studies oral mucositis (Gomes et al., 2016). The topical application of Aloe vera
for more evaluations (Joy Sinha et al., 2017). However, another on the extraction site significantly enhances the wound healing process
experiment using A. indica and O. sanctum extract in comparison with which can be due to improving collagen and proteoglycans production
CHX against E. faecalis didn’t show matching results (Chandrappa et al., by fibroblasts and wound tensile strength (Nimma et al., 2017). Isatis
2015). In comparison with A. indica and O. sanctum, T. cordifolia shows indigotica extract reduces the severity of oral mucositis caused by ra
antibacterial property against E. faecalis but with less efficacy (Bhardwaj diation (Baharvand et al., 2017). This can be an important implication
et al., 2017). for cancer trials. An in-vivo study showed using curcumin mouth rinse
Fufang Bingpeng (a combination of Angelica archanglica and Asu for patients with oral mucositis following radio-chemotherapy shows
rum uropeumis extracts with borax and weathered sodium sulfate) is better efficacy than CHX mouthwash in improving the oral mucositis
considered an effective antibacterial agent. A study showed significant assessment scale (Patil et al., 2015).
results against E. faecalis, P. intermedius, P. gingivalis, and F. nucleatum. Hangeshashinto (a traditional Japanese herbal medicine) consists of
Furthermore, it was proved that Fufang Bingpen shows lower cytotox Coptis rhizome, ginseng, G. glabra, jujube, Pinellia ternata, processed
icity to L929 cells in comparison with NaOCl as well as significant ef ginger, and Scutellaria root. Glycyrrhizin is a bioactive agent found in
ficiency in removing debris and opening dentinal tubules in root canal G. glabra which acts as a potent anti-inflammatory agent in Hang
(Shi et al., 2019). Another comparative experiment between NaOCl, eshashinto and makes it the most common traditional medicine pre
Triphala, C. sinensis, and M. citrifolia against E. faecalis showed Triphala scribed for stomatitis in Japanese hospitals (Hara et al., 2019). Efficacy
can be as effective as NaOCl (Divia et al., 2018). of G. glabra has been confirmed in the alleviation of oral mucositis
Zinc oxide eugenol has been considered a common material for root symptoms during head and neck radiotherapy (Najafi et al., 2017). This
canal obturation in deciduous teeth for a long time (Sweet, 1930). But herbal medication exerts its wound healing mechanism by escalating
due to some drawbacks like irritating periapical tissues or bone necrosis cell proliferation rate and cell migration in epidermal keratinocytes and
(Sarrami et al., 2002), there have been attempts to replace eugenol with fibroblasts, thus helping the formation of granulation tissue (Ozawa
15
et al., 2020). Ingredients found in Hangeshashinto minimize the inter COX-2 is frequently expressed in oral cancers and precancerous le
leukin 1β-induced prostaglandin E2 production in human oral kerati sions which plays a role in malignancy etiology (Hsu et al., 2015).
nocytes by suppression of COX-2 expression (Kato et al., 2016; Miyano Achieving the suppression of overexpression of COX-2 in neoplastic le
et al., 2020; Sunagawa et al., 2018). Hence, Hangeshashinto can be sions is a promising method in the treatment of SCC. An animal study
administered in the treatment of stomatitis caused by anti-tumor agents evaluated the efficacy of F. persica in decreasing COX-2 levels in induced
and radiation therapy, as well (Ara et al., 2018). SCC but did not find any significant outcome (Vosoughhosseini et al.,
2018). Formononetin is a flavonoid found in plants like Astragalus
7. Antineoplastic properties in herbal medications membranaceus (Tay et al., 2019) and Trifolium pretense (Ong et al.,
2019). Formononetin can induce both extrinsic and intrinsic apoptotic
Head and neck cancers are ranked among the top 10 most common pathways in SCC cells (Oh et al., 2020). Gynostemma pentaphyllum is
malignancies in the world with an incidence rate of 4.84 per 100,000 commonly used in Chinese traditional medicine. Gypenosides are the
persons in 2017 (Ren et al., 2020). Delayed clinical diagnosis, poor main bioactive components of G. pentaphyllum. SCC cell’s exposure to
prognosis, limited and expensive therapeutic alternatives are among the gypenoside causes chromatin condensation and DNA damage. It also
problems we face against oral cancers (Rivera, 2015). Patients suffering induces G2/M phase arrest and apoptosis in SCC cells in a
from oral squamous cell carcinoma (OSCC) are currently treated with concentration-dependent manner (Lu et al., 2017). S. cumini is an
conventional treatment techniques such as radiotherapy, chemotherapy, evergreen tropical tree with known anti-cancer properties (Barh and
and surgery. Despite these endeavors, OSCC still has a considerable Viswanathan, 2008; Goyal et al., 2010). Treatment with S. cumini in
mortality rate (Ren et al., 2020) so there is a necessity to find new duces intracellular ROS accumulation and cell cytotoxicity in OSCC cell
therapeutic approaches and medications, with the administration of lines. (Ezhilarasan et al., 2019). Embelia ribes is a medicinal plant rich in
herbal medicaments being one of the most promising antineoplastic Embelin (2, 5-dihydroxy-3-undecyl-1, 4-benzoquinone). Embelin is a
treatment modalities (Lee et al., 2017a). bioactive component with the ability to deactivate an X-linked inhibitor
Signal transducer and activator of transcription 3 (STAT 3) is a of apoptosis protein. It’s been observed that there is a significant in
transcription factor responsible for tumoral and metastatic activity in crease in the presence of autophagic vacuoles in Embelin-treated SCC
OSCC (Masuda et al., 2010). Inhibition of activated JAK/STAT signaling cell lines. Embelin exerts its anti-neoplastic effects against SCC cells by
is a considerable therapeutic target for cancer treatment. 8α-tigloylox both autophagy and apoptosis (Lee et al., 2017a). EGCG induces
yhirsutinolide-13-O-acetate (8αTGH) is a bioactive component found in caspase-3 and -7 activation enzymes which act as an executioner of
Vernonia cinerea species which can inhibit STAT3 phosphorylation in apoptosis in cellular structure. In another animal experiment, EGCG
OSCC (Pouyfung et al., 2019). The caspases-8 and 9 are proteins treatment resulted in a 45.2% reduction in tumor size. EGCG, found in
responsible for extrinsic and intrinsic pathways of apoptosis. A. catechu C. sinensis, also significantly minimizes cell proliferation by imple
extract increases caspases-8 and 9 gene expression which can induce menting its effect on cell cycle progression and apoptosis (Yoshimura
apoptosis in SCC-cells. Cell cycle analysis also showed that A. catechu et al., 2019). Isoliquiritigenin is a polyphenolic metabolite found in
treatment causes a concentration-dependent accumulation of cells in G. glabra which acts as a novel inhibitor of tumor angiogenesis and can
S-phase. Hence, SCC cells lose their ability to duplicate due to DNA be evaluated as a cancer chemotherapeutic agent in future studies(Sidhu
damage (Lakshmi et al., 2015). The presence of proteolytic enzymes is et al., 2020).
necessary for metastasis of cancer cells to break down the extracellular
matrix. Matrix metallopeptidase (MMP)-2 and 9 are two proteolytic 8. Analgesic properties in herbal medicine
enzymes with the strongest correlations with the invasion and metas
tasis of neoplastic cells (Farina and Mackay, 2014; Xu et al., 2010). Oral pain is a very common manifestation of numerous clinical
Eclipta prostrate is a plant, native to China, Japan, and India. E. pros presentations and pathologies in dental patients. Oral lesions and sur
trata extract diminishes migration and invasion of SCC cells by inhibi gical wounds are on the top rank etiologies (Hargitai, 2018). Bromelain
tion of MMP-2 expression. Blocking MMP-2 expression can be a is an enzyme extract mainly found in Ananas comosus which possesses
promising strategy for the prevention of SCC metastasis (Liao et al., anti-inflammatory effects. The Bromelain mechanism of action is exer
2018). Another in vitro study showed low doses of Rheum palmatum ted via inhibition of pain mediators such as prostaglandin E2 and sub
extract exert the same anti-invasive and anti-metastatic mechanism stance P (Onken et al., 2008). Baicalin is another natural molecule found
among SCC cell lines (Chen et al., 2017). Geraniin is an ellagitannin in Scutellaria baicalensis with anti-inflammatory activity. Escin is
belonging to hydrolysable tannin group. It can be found in different considered a natural mixture of triterpene saponins which can be found
plant species such as Nephelium lappaceum (Abdul Ahmad et al., 2017). in plant species like Aesculus hippocastanum.
Enzymatic activity of MMP-2 can be minimized by geraniin in a An RCT conducted by Isola G et al. (2019) showed a combination of
concentration-dependent manner. It is suggested that the anti-migration baicalin (190 mg), bromelain (50 mg), and escin (30 mg) exerted sig
effect of geraniin on SCC cells is due to inhibition of MMP-2 expression nificant analgesic properties after 3rd molar removal surgeries,
(Yeh et al., 2019). Cudraxanthone H from Cudrania tricuspidata is a compared to Ibuprofen 600 mg (Isola et al., 2019). Z. officinale is a plant
prenylated xanthone, obtained from methanol extract of C. tricuspidata known for analgesic properties with minimal adverse effects (Lobina
root. Cudraxanthone H in 20μM dosage inhibited primary and meta et al., 2019). The plant contains natural constituents that inhibit pros
static OSCC cell viability. At lower doses, it results in apoptosis which taglandin synthesis. Another clinical trial revealed that administration
was observed as alterations in nuclear morphology and an increasing of Z. officinale (500 mg powder 4 times daily) can be as effective as
percentage of cells in the sub-G1 phase of the cell cycle (Lee et al., 2015). Ibuprofen 400 mg in reducing postoperative pain after third molar
A. sativum is a plant rich in natural antioxidants. It is known that removal surgery (Rayati et al., 2017). Shahakbari et al. (2014) showed
reactive oxygen species (ROS) can activate the mitochondrial-dependent that after a 7-day follow-up, C. sinensis mouthwash 5% causes a signif
intrinsic apoptotic pathway and consequently induce apoptosis (Simon icant improvement in pain scores and the number of painkillers needed
et al., 2000). A. sativum significantly induces ROS production in SCC in patients with acute pericoronitis in comparison with CHX 0.12%
cells (Szychowski et al., 2018). Salvia miltiorrhiza is commonly used in (Shahakbari et al., 2014). C. sinensis mouthwash also improves visual
traditional Chinese medicine. S. miltiorrhiza treatment (5–10 μg/mL) analogue scale scores in patients experiencing postoperative pain after
causes approximately 50% reduction in SCC cell proliferation. The 3rd molar removal surgery compared to placebo mouthwash (Eshgh
mechanism of action involves elongation of the G0/G1 and the short pour et al., 2013). G. officinale extract provides anti-inflammatory
ening of the S phase. Induction of cell cycle G0/G1 arrest leads SCC cells properties, so it has been the subject of a clinical study for aphthous
to apoptosis (Yang et al., 2017). stomatitis treatment. After 10 days of monitoring results indicated that
16
topical administration of herbal mucoadhesive paste containing G. involves using a topical medication or a dressing on the exposed dental
officinale extract significantly reduces the severity of pain, but does not pulp to induce reparative dentin production without compromising its
show clinically significant efficiency in reducing ulcer diameter vitality. Ca (OH)2 compounds are the gold standard materials for pulp
compared to the placebo group (Haghpanah et al., 2015). P. granatum capping in human teeth (Schröder, 1985). But due to reported draw
mucoadhesive gel also shows promising results in experienced pain backs (Shahravan et al., 2012), some studies have tried to find herbal
reduction during aphthous stomatitis lesion healing compared to the substitutes for pulp capping materials. Acemannan (b- (1–4) acetylated
placebo (Tavangar et al., 2019). Echinacea purpurea is a plant native to polymannose), the bioactive component of Aloe vera, stimulates the
North America. It contains alkaloids, polysaccharides, and chicoric acid proliferation, differentiation, and mineralization of both animal and
with a modulatory effect on immune system responses. Administration human dental pulp cells. An animal study examined the effect of ace
of E. purpurea tablets (114 mg) for six months shows a significant mannan on intentionally exposed dental pulp that induced deciduous
reduction in pain experience, number of lesions, and recurrence rate in dental pulp cell proliferation and differentiation. It also increased dentin
patients suffering from recurrent aphthous stomatitis which can be sialoprotein synthesis and mineralization and formation of complete or
attributed to the improvement of the immune system and inhibition of partially complete mineralized dentin in “dog tooth” (Songsir
hyaluronidase enzyme (Khozeimeh et al., 2018). Oral lichen planus is a ipradubboon et al., 2017). Histopathological response to acemannan as
chronic inflammatory mucocutaneous pathologic condition with a direct pulp capping medicament in human primary teeth included the
various symptoms like a severe burning sensation, erythema, and pres presence of odontoblast-like cells under a complete homogenous dentin
ence of ulcerative lesions in the oral cavity. Curcumin gel obtained from bridge formation and lack of inflammatory cell presence which are the
C. longa plant shows anti-inflammatory and anti-oxidant activity. It is criteria for successful treatment in microscopic observations (Songsir
suggested that 1% curcumin gel can decrease pain and burning sensation ipradubboon et al., 2016). Another clinical study showed that using C.
of oral lichen planus and can be used as a maintenance herbal medicine longa powder instead of Ca (OH)2 in primary teeth vital pulpotomy
after an initial course of corticosteroid therapy (Thomas et al., 2017). resulted in clinical and radiographic success without reports of failure
Regarding the combination products, Gingerol and shogaol are the main after six months of follow-up (Purohit et al., 2017). The same protocol
bioactive compounds found in the herbal medication, Hangeshashinto. was used for the evaluation of T. chebula and Myristica fragrans seed
These two components inhibit the function of voltage-dependent sodium powders. The researchers suggested that both powders can be used as
cellular channels and subsequently reduce the expression of substance P biocompatible medicaments in vital pulpotomy (Mali et al., 2018).
which is considered an important nociceptive signal transmission
modulator in sensory neurons (Abdel-Aziz et al., 2006). Hangeshashinto 11. Bone regeneration and herbal medicine
can be used as an effective topical analgesic medicine in patients
suffering from oral mucositis (Hitomi et al., 2017, 2019; Zieglgäns Bone regeneration therapy is an obligation for many dentistry pro
berger, 2019). cedures. Herbal medicine has entered this field as well, in recent years.
Acemannan is the major polysaccharide found in Aloe vera gel. Ace
9. Halitosis and herbal medicine mannan significantly stimulates bone marrow stromal cells, expression
of vascular endothelial growth factor, and bone mineralization. An an
Halitosis is defined as a disagreeable and unpleasant odor emanating imal experiment showed that the application of acemannan sponge on
from the mouth air and breath. More than 31% of the population suffer rat tooth socket after extraction increases the rate of new bone formation
from halitosis (Silva et al., 2018). This condition results from volatile and presence of osteoblasts and osteocytes in the socket healing area.
molecules (like sulfur compounds, aromatic compounds, and Bone mineral density analysis showed better results concerning bone
nitrogen-containing compounds) which can be produced by patholog density after 30 days compared with a control group (Boonyagul et al.,
ical or nonpathological factors (Aylikci and Colak, 2013). Solobacterium 2014). It has been also suggested that acemannan sponge can be used as
moorei is an anaerobic bacterium that is closely related to halitosis a biomaterial for helping bone formation in sinus lift surgeries (Trinh
(Haraszthy et al., 2007). C. sinensis extract and EGCG can efficiently et al., 2020). This bioactive component also improves local gingival
exert bactericidal activity against S. moorei, as well as reducing bacte defense by up-regulating interleukin-6 and interleukin-8 mRNA and
rial adherence to oral epithelial cells (Morin et al., 2015). Clinical protein expression in human gingival fibroblasts, so it can be beneficial
studies show C. sinensis mouthwash can reduce volatile sulfur com as an immune-boosting agent in both healthy and immunocompromised
pounds (VSCs) which are responsible for oral malodor compared to patients by improving their innate immune systems function (Thunya
0.012% CHX (Farina et al., 2012; Rassameemasmaung et al., 2013). kitpisal et al., 2017). Aqueous leaf extract of M. citrifolia contains two
Antibacterial essential oils like p-cymene, thymol, β-caryophyllene, and major components, rutin, and kaempferol3-O-rutinoside. These two
γ-terpinenecan can be found in Plectranthus amboinicus species. components significantly increase the proliferation and osteogenic dif
Nazliniwaty N et al. (2016) proved that P. amboinicus mouthwash has ferentiation of human osteoblast-like cells. Osteogenic differentiation
antibacterial activity against S. aureus which can be responsible for plays a crucial part in bone remodeling and periodontal regeneration. It
bacterial-induced halitosis (Nazliniwaty and Laila, 2019). P. granatum has been suggested that M. citrifolia extract induces matrix mineraliza
extract also showed great antibacterial efficacy against VSC producing tion in human periodontal ligament cells and alkaline phosphatase
bacteria like P. micra, P. gingivalis, and F. nucleatum and inhibits VSC expression (Gu et al., 2018). Mecsina herbal hemostopper is a combi
formation in a salivary sediment model (Veloso et al., 2020). Adminis nation herbal product which consists of G. glabra, S. aromaticum, V.
tration of a herbal mucoadhesive tablet containing four herbal extracts vinifera, Alpinia officinarum, Urtica dioica, Thymus vulgaris, Hypericum
(Echinacea augustifolia, Pistacia lentiscus, Lavandula augustifolia, and perforatum, and Mentha arvensis. An animal study showed promising
salvia officinals) significantly reduced VSCs and improves judged odor alveolar bone healing properties with co-administration of Mecsina and
scores compared to placebo tablets in patients suffering from halitosis 9 low-level laser therapy (Ozyurt et al., 2018).
h after product application (Sterer et al., 2013).
12. Conclusion
10. Vital pulp therapy and herbal medicine
Herbal medicine has gained considerable popularity during the past
Nowadays non-invasive vital pulp therapy has gained popularity due decade. Many researchers in the field of dentistry and pharmacology
to giving dentists the possibility to preserve tooth structure and avoid have dedicated their time and resources to evaluation of natural prod
more aggressive treatment techniques like pulpectomy, especially in ucts, discovering their bioactive compounds and finding applications for
pediatric dentistry. Among vital pulp therapies, direct pulp capping them in various aspects of oral health maintenance. In this article, we
17
tried to make a comprehensive review of recent scientific studies about by colleagues at the Research Center for Prevention of Oral and Dental
medicinal plants and their current status in the field of dentistry. Poly Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran.
phenolic compounds such as flavonoids and tannin are among common
bioactive ingredients found in herbal extracts with promising beneficial References
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European Journal of Pharmacology 889 (2020) 173665

Contents lists available at ScienceDirect

European Journal of Pharmacology

Current herbal medicine as an alternative treatment in dentistry: In vitro, in

1. Introduction health issue (Organization W.H., 2017).

Anti-cariogenic properties of herbal agents

evaluation of herbal extracts against as S. mutans and S. mitis in comparison

analysis, and scanning electron

Evaluation of apoptosis-inducing S. miltiorrhiza herbal extract was able to (Yang et al.,

Anti-cariogenic properties of herbal agents

mouth rinses individually and in using the combination of all herbal

Ziziphora essential oil showed a significant effect against S. aureus

3.2. Clinical trials

The use of herbal products in periodontal health maintenance has

et al., 2015). more biocompatible components. The addition of O. sanctum liquid

The authors would like to acknowledge the useful comments given

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