Journal of Traditional Chinese Medical Sciences (2018) 5, 58e63

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://www.elsevier.com/locate/jtcms

Effects of Zingiber officinalis (WILLD.)

ROSC. Membranes on minor recurrent
aphthous stomatitis: a randomized
pragmatic trial
Qian Du a, Shenglou Ni a, Lin Guo a, Wenjie Song a, Kun Zhao a,
Ni Liu a, Xinrong Wang a, Xun Ma a, Yanling Fu a,*,
Quanming Tan b

a
Beijing University of Chinese Medicine, Beijing 100029, China
b
Singapore Thong Chai Medical Institution, Thong Chai Building 169874, Singapore

Received 8 January 2018; received in revised form 8 February 2018; accepted 18 February 2018
Available online 17 March 2018

KEYWORDS Abstract Objective: To evaluate the effects of dried ginger rhizome (DGR; Zingiber officina-
Dried ginger rhizome lis (WILLD.) ROSC.), prepared as a membrane, in minor recurrent aphthous stomatitis (miRAS)
membrane; treatment and explore its mechanism of action by detecting changes in levels of epidermal
Recurrent aphthous growth factor (EGF) and tumor necrosis factor (TNF)-a in saliva.
stomatitis; Methods: Fifty-nine miRAS patients were enrolled in this study. The number of participants in
Epidermal growth the dried ginger rhizome membrane (DGRM) group was 30, and 29 were in the placebo mem-
factor; brane (PM) group. Sixty sealed envelopes containing either type of membrane were coded
Tumor necrosis randomly. Investigators and participants were blinded to group assignments. A visual analog
factor-a scale (VAS) was used for pain, follow-up information for healing time, and enzyme-linked
immunosorbent assays to measure the concentrations of EGF and TNF-a.
Results: In terms of VAS, there was a significant difference between pre- and post-DGRM treat-
ment (P < .001), but not so for the PM group (P > .05). A significant difference was observed in
the healing time between the two groups (6.08 (2.712) vs. 8.04 (2.142) days). The mean heal-
ing time in the DGRM group was shorter than that in the PM group (P < .05). In both groups, the
salivary EGF concentration decreased significantly after treatment (P < .05), but the mean
level in the DGRM group was significantly lower than that in the PM group (P < .05). The mean
TNF-a level in both groups was increased significantly after treatment (P < .05), but patients
who used DGRMs had a significantly lower level than that in the PM group (P < .05).

* Corresponding author.
E-mail address: fuyanling@bucm.edu.cn (Y. Fu).
Peer review under responsibility of Beijing University of Chinese Medicine.

https://doi.org/10.1016/j.jtcms.2018.02.004
2095-7548/ª 2018 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Effects of Zingiber officinalis membranes on miRAS
Conclusion: The present study provides evidence that DGRMs are effective treatment for RAS.
Dried ginger rhizome has obvious effects on pain relief, shortening of healing time, reducing
the EGF level in saliva, and has an inhibitory effect on TNF-a release.
ª 2018 Beijing University of Chinese Medicine. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
Introduction
Recurrent aphthous stomatitis (RAS) is a relatively common
disease affecting the oral mucosa. According to epidemio-
logic data, 2%e66% of the worldwide population is affected
by RAS.1‒2 It is characterized by painful, recurrent ulcera-
tions of the oral mucosa and can be classified clinically into
three categories based on the diameter of mouth ulcers:
minor (<1 cm), major (>1 cm), and herpetiform. Minor
recurrent aphthous stomatitis (miRAS) is the most common
manifestation, and occurs in 75%e80% of patients. Ulcers
due to miRAS are <1 cm in diameter (usually 2e5 mm) and
heal spontaneously in 7e14 days. Although common, RAS
has an unpredictable disease course.3‒4
The exact pathogenesis of RAS is not known,5e9 but
inflammation plays an important part in it. Considerable
evidence suggests that focal immune dysfunction exerts a
significant influence. Thus, anti-inflammatory and immu-
nosuppressant drugs have been administered widely to
miRAS patients. However, efficacious therapies that can
prevent repeated bouts of ulceration are lacking. Main-
stream treatments aim at alleviating pain, reducing func-
tional disability, and facilitating healing.10,11 Traditional
Chinese medicine (TCM) could be used to treat RAS.
Dried ginger rhizome (DGR; Zingiber officinalis (WILLD.)
ROSC.) is a common dietary adjunct contributing to the
taste and flavor of foods, and is also an important Chinese
herb. Dried ginger rhizome is a frequently used ingredient
in TCM-based treatment of RAS.12
Some studies have shown that DGR has anti-inflammatory,
antioxidant, analgesic and antiseptic effects.13e15 Yang et al
reported that DGR is a transient receptor potential cation
channel subfamily V member 1 (TRPV1) agonist. Initially,
DGR can sensitize sensory endings within inflamed tissue and
produce a “warm” feeling, then desensitize the tissue and
relieve pain.16,17 Some researchers have shown that water
extracts of DGR have good effects against pain caused by
different stimuli, and can reduce the pain caused by
inflammation.18 Luo et al used a component of DGR,
6-gingerol,19 to treat oral stomatitis in mice, and showed a
shortened healing time and improvement of the cure rate.20
We evaluated the effects of a water extract of DGR, in
the form of an oral membrane, on miRAS.
Methods
Ethical approval
This was a double-blind, placebo-controlled clinical prag-
matic trial undertaken at the Beijing University of Chinese
59
Medicine (BUCM; Beijing, China). The study was approved
by the Ethics Committee of BUCM (2017BZHYLL0308). All
participants were informed of the purpose, general con-
tents, and data use of our study. The trial was registered in
the Chinese Clinical Trial Registry (ChiCTR-OPR-17013127).
Patient selection
This was an exploratory study so the patient cohort was
small. Participants were selected from the general popu-
lation of Beijing using flyers posted at various locations as
well as e-mails to universities. People were enrolled after a
diagnosis had been made by Professor Yanling Fu in the Guo
Yi Tang Outpatient Department of BUCM in 2017.
Inclusion criteria were: (i) age > 18 years; (ii) a clear
history of RAS occurring no less than four times a year; (iii)
presentation with one or two ulcers measuring
10 mm in
diameter for
48 hours and yet to receive treatment; (iv)
ulcers that took > 5 days to resolve without treatment.
Individuals were excluded if they: (i) had underlying
systemic disease(s) or a history of immunologic disorder(s);
(ii) were taking immunomodulatory agents or systemic
nonsteroidal anti-inflammatory drugs < 1 month before
study commencement;4 (iii) were smokers; (iv) were preg-
nant; (v) were (or had a history of) abusing drugs or alcohol;
(vi) could not provide written informed consent.
Preparation membranes
Dried ginger rhizome (DGR; Z. officinalis (WILLD.) ROSC.)
was purchased from a Tong Ren Tang outlet in Beijing. Using
a ratio of DGR: water of 1:10, medicinal components were
extracted by boiling in water for 6 hours. Then, extracts
were filtered, concentrated, dried, ground and stored.
The resulting powder was mixed with polyvinyl alcohol
(PVA)1788 and prepared into a dried ginger rhizome mem-
brane (DGRM). A placebo membrane (PM) containing the
resulting powder at one-tenth the concentration of DGR
and PVA1788 was prepared after we failed to create a DGRM
at one-twentieth concentration of DGR.21,22 There were no
other ingredients in either type of membrane.
In dry storage, both types of membrane are non-
adherent and can be applied readily as required. Upon
contact with saliva at a lesion site, a sticky hydrogel is
formed which adheres to the mucosa.
The prepared membranes were cut into squares of size
1.5 cm, and sealed in small plastic bags. The latter were
encoded by a research pharmacist (Lin Guo) so that in-
vestigators and patients were both blinded to the type of
membrane contained within.
60
We selected three pieces of membranes randomly to
test for 6-gingerol, which is the main component of DGR
as listed in the Pharmacopoeia of People’s Republic
of China.23 A 6-gingerol measurement standard
(Y12A8H41703, Shanghai, China) was used, and the mean
content was 0.0535 mg.
Randomization and masking
The research pharmacist numbered 60 opaque and sealed
envelopes. She assigned the DGRM group or PM group (1:1
distribution) randomly based on a random number table
(excluding repeating numbers). Researchers distributed
envelopes containing the drugs in sequence and maintained
records of the number assigned to each patient. The
research pharmacist did not participate in other activities
during the study.
Interventions
Patients were required to undergo intervention within
48 hours of aphthous stomatitis onset. Baseline parameters
were recorded during the first visit. The application of a
membrane was demonstrated to participants. They were
instructed to use one membrane piece each time twice
dailydno less than 30 minutes apart from eating and before
sleepduntil it dissolved. Usually, the membrane dissolved
in 20e30 minutes. Drinking, eating or talking during mem-
brane application was prohibited. The total duration of
treatment for each patient was the healing time of aph-
thous stomatitis.
Therapeutic evaluation
Patients were required to provide two saliva samples. One
sample was collected at the first visit (i.e., before treat-
ment) and the other was just after healing.
We measured the levels of epidermal growth factor
(EGF) and tumor necrosis factor (TNF)-a in saliva. The pain
level was recorded before application of the first mem-
brane and 1 day after treatment using a visual analog scale
(VAS), which is a tool can be used to indicate the degree of
pain. It consisted of a 10-cm horizontal line, and the end of
the line is (0) indicating “no pain” and the other end is (10)
denoting “unbearable pain”. The investigators recorded
the patient’s tolerance to the membranes including the
DGRM and any adverse reactions that may be associated
with the membranes.
Saliva collection and measurement of EGF and
TNF-a
Saliva was collected from fasting patients under standard
conditions between 9 AM and 11 AM Patients were pro-
hibited from drinking water during the entire sampling
process.
Unstimulated whole saliva (3 mL) was collected using
sterile plastic centrifuge tubes. Samples were centrifuged
for 10 minutes at 4 C (428  g), and stored at 80 C for
further analyses.
Q. Du et al.
For determination of salivary levels of EGF and TNF-a,
we used a Human EGF enzyme-linked immunosorbent assay
(ELISA) kit (HU9916; BioTSZ, San Francisco, CA) and Human
TNF-a ELISA kit (HU9890; BioTSZ).
Statistical analyses
Data were analyzed using SPSS v20.0 (IBM, Armonk, NY) and
expressed by mean (standard deviation). Statistical ana-
lyses were used Wilcoxon ranKolmogorov-Smirovum test.
P < .05 was considered significant.
Results
Fifty-nine individuals were recruited for our study. They
were assigned randomly to the DGRM group (n Z 30) and PM
group (n Z 29). Their mean age was 29.47 (8.93) years. Ten
people withdrew due to 3 cases suffering from common
cold and 7 people failing in contact. Finally, 49 patients
were evaluated at the last visit: 26 and 23 in the DGRM and
PM groups respectively.
VAS and healing time
The VAS for ulcers before treatment between the DGRM
group and PM group was well-matched upon study entry.
However, there was a significant difference between
before treatment and after 1 day of treatment in the DGRM
group (P Z .000), but there was no significant difference in
the PM group (P Z .337) (Table 1).
A difference was also observed in the healing time be-
tween the two groups (6.08 (2.712) vs. 8.04 (2.142) days,
respectively) (Fig. 1). The healing time in the RZM group
was shorter compared with that in the PM group (P Z .002).
Epidermal growth factor level
There was no significant difference in the salivary level of
EGF at the first visit between the two groups (P > .05).
However, the EGF concentration of the two groups after
healing decreased significantly (Table 2). The EGF level
after healing in DGRM group was significantly lower than
that in the PM group (P Z .024), suggesting that the DGR
could reduce the EGF level in saliva significantly.
Tumor necrosis factor-a level
No significant difference in the salivary level of TNF-a
before treatment between the two groups was displayed
(P > .05). In the two groups of patients after healing, the
Table 1 Change in the VAS between the two groups.
Group BT AOT P
DGRM group (n Z 30) 2.73 (0.944) 1.33 (1.155) .000
PM group (n Z 29) 2.52 (1.122) 2.35 (1.143) .337
DGRM: dried ginger rhizome membrane; PM: placebo mem-
brane; BT: before treatment; AOT: after 1 day of treatment;
VAS: visual analogue scale.
Effects of Zingiber officinalis membranes on miRAS 61

Discussion

DGR and pain relief

Our study showed that the change in ulcer-based pain in the

DGRM group was significantly different before treatment
and after 1 day of treatment (Table 1), suggesting that
DGRMs had an obvious analgesic effect. Pain affects the
quality of life of RAS patients. Severe pain can lead to
eating problems and, subsequently, inadequate nutrition.
The mechanism of action of RAS is not known, but pain
relief is one of the main principles for treating RAS.24
Dried ginger rhizome is an “acrid” and “warm” herb,
Figure 1 Healing time of patients in the two groups. DGRM: which may form part of its effect on pain relief. Yang et al
dried ginger rhizome membrane; PM: placebo membrane. showed that DGR is a strong agonist of TRPV1 channels that
can produce a warm feeling through sensitization of the
sensory endings in inflamed tissue before desensitizing the
tissue towards pain.16 Hitomi et al proposed that 6-gingerol
Table 2 Differences in salivary levels of EGF before and 6-shogaol, extracted from DGR, could inhibit the
treatment and after healing in the two groups. stimulant-induced release of substance P and generation of
Group BT (pg/mL) AH (pg/mL) P action potentials in cultured rat sensory neurons to elicit
DGRM group 49.64 (12.070) 26.44 (10.870) .000 analgesic effects.25 Li et al compared the concentrations of
(BT: n Z 30; five components (zingerone, 6-gingerol, 6-shogaol, 8-
AH: n Z 26) gingerol, and 10-gingerol) and antioxidant activity of
PM group 45.64 (13.260) 33.82 (11.370) .001 fresh, dried, stir-fried and carbonized ginger extracts, and
(BT: n Z 29; found DGR to be maximal in both parameters.26 Ma et al
AH: n Z 23) designed rat experiments that showed water extracts of
DGR to have good antipyretic analgesic effects, possibly by
EGF: epidermal growth factor; DGRM: dried ginger rhizome inhibiting the activity of ring oxidase and lipoxygenase and
membrane; PM: placebo membrane; BT: before treatment; AH:
reducing the amount of prostaglandins and leukotrienes
after healing.
generated. The identity of the exact antipyretic component
within water extracts of DGR, the pathways through which
it modulates the temperature-regulating center and pain
Table 3 Differences in salivary levels of TNF-a before response, and other pharmacologic effects have yet to be
treatment and after healing in the two groups. elucidated.18
Group BT (pg/mL) AH (pg/mL) P
DGRM group 32.21 (6.837) 38.18 (7.840) .002
DGR and levels of EGF and TNF-a in saliva
(BT: n Z 30;
AH: n Z 26)
The protective properties of saliva are not limited to
PM group 29.33 (6.245) 44.64 (5.960) .000
cleaning, flushing, cushioning, lubrication and mineral
(BT: n Z 29;
supplementation. Saliva can deliver various anti-viral, anti-
AH: n Z 23)
bacterial, anti-fungal and multiple skin-growth factors of
TNF: tumor necrosis factor; DGRM: dried ginger rhizome mem- the human body itself. Therefore, considerable attention
brane; PM: placebo membrane; BT: before treatment; AH: after should be paid to the qualitative and quantitative analyses
healing.
of saliva.27 We measured levels of EGF and TNF-a in saliva.
The stability of the epithelial layer of the oral mucosa is
dependent upon the relative rates of proliferation of the
saliva concentration of TNF-a was significantly higher than basal cell layer and sloughing of the keratinocyte layer. If
that before treatment (Table 3). However, at the last the former decreases or the latter increases, the mucosal
collection, for patients who used a DGRM, the TNF-a level epithelium thins and becomes prone to ulceration. Under
was significantly lower compared with that of the PM group normal physiologic conditions, the oral epithelium is pro-
after treatment (P Z .002), suggesting that DGRMs may tected by the mucosal defense systems, including salivary
have inhibitory effects on TNF-a expression. secretions. The basic function of saliva is to protect and
maintain the integrity of the mucous membranes of the oral
and upper gastrointestinal tracts.28 Considerable evidence
Adverse drug effects suggests that salivary EGF has a preventive effect against
oral mucosal diseases and can prevent oral mucosal injury,
Adverse drug effects (e.g., hypersensitivity, infection, thus maintaining the integrity of oral mucosa. In addition,
taste-bud malfunction) were not observed in any partici- EGF is beneficial to mucosal repair and healing, and is
pant (Fig. 2). involved in repair mechanisms.29e31
62 Q. Du et al.

Figure 2 Photographs of an ulcer before (A) and six days after treatment (B).

The EGF concentration was higher in both groups pre- obvious effects on pain relief, shortening of healing time,
treatment (Table 2), which was likely due to the body’s reducing the EGF level in saliva, and has an inhibitory ef-
anti-ulcer response. However, the time needed for the EGF fect on TNF-a release. Recurrent aphthous stomatitis
level to decrease was shorter in the DGRM group, which treatment could be achieved through analgesia, promotion
paralleled the faster healing of wounds using DGR (Fig. 1, of wound healing, and immune suppression.
Table 2). This finding suggests that EGF is beneficial to ulcer
healing. Funding
The TNF-a level was higher in both groups post-
treatment, suggesting that oral ulcers could activate the
The clinical trial was supported by Beijing University of
body’s immune system. However, the level of TNF-a after
Chinese Medicine Research Project (2010072220010).
treatment in the DGRM group was lower than that in the PM
group, suggesting that DGRMs may have had an inhibitory
effect on TNF-a expression (Table 3). Conflicts of interest
Recurrent aphthous stomatitis seems to be regulated
mainly by the immune system. However, the part of the None declared.
immune system involved in its pathogenesis as a reaction to
a still-unknown antigen is not clear.32 TNF-a participates in Author contributions
inflammation and the immune response. Several studies
have highlighted a possible role for TNF-a, and its increased
Qian Du designed the study, took part in the whole process
production could predispose individuals to RAS. Song et al
including participants enrollment, data analyses, etc., and
found that mean levels of TNF-a in patients with major,
wrote the manuscript. Yanling Fu designed the study,
minor, and herpetiform types of RAS were significantly
revised the manuscript and provided fund support. Shen-
higher than those in healthy controls. TNF-a level may also
glou Ni offered valuable advice on the study design, guided
be associated with the severity and stage of RAS.33 It has
the statistical analyses partly, and revised the manuscript.
been assumed that the therapeutic effect of thalidomide
Lin Guo assisted in creating the DGR membranes, was in
and corticosteroids in RAS is regulated through their ability
charge of blinding and grouping, and partly measured drug
to inhibit TNF-a production. Taken together, these obser-
concentrations. Xun Ma measured drug concentrations. Kun
vations suggest that increased production of TNF-a could
Zhao, Ni Liu and Xinrong Wang were responsible for the
predispose individuals to RAS. Some researchers have sug-
distribution of drugs to patients and collected samples.
gested that TNF-a, a pro-inflammatory cytokine, gets
Wenjie Song recorded and analyzed data. Quanming Tan
involved in the inflammatory process, and is closely related
carefully polished the article.
to the clinical manifestations and recurrent nature of oral
ulceration. Patients with active RAS display high levels of
TNF-a and its receptor in serum, so the positive response of Acknowledgements
complex aphthous stomatitis to TNF-a inhibitors is not
surprising.34,35 We are grateful to Professor Jian Ni and Associate Professor
Xingbin Yin (Beijing University of Chinese Medicine; BUCM)
Limitations for their advice on DGRM preparation, and to Professor
Jianxin Chen (BUCM) for his expertise in statistical analyses.
This is a small size clinical trial with a high rate of with-
drawal. We measured levels of EGF and TNF-a in saliva but References
other components of saliva need to be evaluated too. We
focused only on 6-gingerol, but other components in water 1. Hamedi S, Sadeghpour O, Shamsardekani MR, Amin G,
decoctions need to be investigated in future studies. Hajighasemali D, Feyzabadi Z. The most common herbs to cure
the most common oral disease: stomatitis recurrent aphthous
ulcer (RAU). Iran Red Crescent Med J. 2016;18(2):e21694.
Conclusion 2. Haghpanah P, Moghadamnia AA, Zarghami A, Motallebnejad M.
Muco-bioadhesive containing ginger officinale extract in the
The present study provides evidence that DGRMs are management of recurrent aphthous stomatitis: a randomized
effective treatment for RAS. Dried ginger rhizome has clinical study. Caspian J Intern Med. 2015;6(1):3e8.
Effects of Zingiber officinalis membranes on miRAS
3. Lalla RV, Choquette LE, Feinn RS, et al. Multivitamin therapy
for recurrent aphthous stomatitis: a randomized, double-
masked, placebo-controlled trial. J Am Dent Assoc. 2012;
143(4):370e376.
4. Babaee N, Mansourian A, Momen-Heravi F, Moghadamnia A,
Momen-Beitollahi J. The efficacy of a paste containing Myrtus
communis (Myrtle) in the management of recurrent aphthous
stomatitis: a randomized controlled trial. Clin Oral Investig.
2010;14(1):65e70.
5. Han JY, He ZW, Li K, Hou L. Microarray analysis of potential
genes in the pathogenesis of recurrent oral ulcer. Int J Clin Exp
Pathol. 2015;8(10):12419e12427.
6. Natah SS, Konttinen YT, Enattah NS, Ashammakhi N,
Sharkey KA, Häyrinen-Immonen R. Recurrent aphthous ulcers
today: a review of the growing knowledge. Int J Oral Max-
illofac Surg. 2004;33(3):221e234.
7. Jiang N, Luo L, Liu L, Sun XQ, Jiang X, Cai Y. Soluble pro-
grammed death-1 and soluble programmed death ligand 1
protein expression and immune status in patients with recur-
rent aphthous ulcer. West China J Stomatol. 2017;35(3):
286e290 [Chinese].
8. Chen J, Ding WJ. Correlation between microbial and immune
mechanisms of recurrent oral ulcer and traditional Chinese
medicine. Chin J Exp Tradit Med Formulae. 2016;22(13):
202e207 [Chinese].
9. Wang ZX. Epidemiological analysis of correlation of the
gastrointestinal diseases and recurrent apthous ulcers. Gen J
Stomatol. 2016;3(3):148 [Chinese].
10. Altenburg A, El-Haj N, Micheli C, Puttkammer M, Abdel-
Naser MB, Zouboulis CC. The treatment of chronic recurrent
oral aphthous ulcers. Dtsch Arztebl Int. 2014;111(40):665e673.
11. Jiang XW, Zhang Y, Zhang H, Lu K, Yang SK, Sun GL. Double-
blind, randomized, controlled clinical trial of the effects of
diosmectite and basic fibroblast growth factor paste on the
treatment of minor recurrent aphthous stomatitis. Oral Surg
Oral Med Oral Pathol Oral Radiol. 2013;116(5):570e575.
12. Lü JJ, Wang YG, Wang SZ, Yang Q. Analysis on composition
rules of prescriptions in treating recurrent oral ulcer based on
traditional Chinese medicine inheritance support. Chin J Exp
Tradit Med Formulae. 2016;22(5):231e234 [Chinese].
13. Long QJ, Xu XQ. Literature analysis of chemical components
and pharmacological actions and processing of ginger. Res
Pract Chin Med. 2015;29(1):82e83 [Chinese].
14. Chrubasik S, Pittler MH, Roufogalis BD. Zingiberis rhizoma: a
comprehensive review on the ginger effect and efficacy pro-
files. Phytomedicine. 2005;12(9):684e701.
15. Jung HW, Yoon CH, Park KM, Han HS, Park YK. Hexane fraction
of Zingiberis Rhizoma Crudus extract inhibits the production of
nitric oxide and proinflammatory cytokines in LPS-stimulated
BV2 microglial cells via the NF-kappaB pathway. Food Chem
Toxicol. 2009;47(6):1190e1197.
16. Yang Z, Gao L, Zhao HX, Lu C, Li J. Thermal channel: cell and
molecular biology significance of “treating cold with heat,
treating heat with cold”. Chin J Basic Med Tradit Chin Med.
2014;20(10):1358e1361 [Chinese].
17. Yang Z, Gao L, Zhao HX, et al. Thermal channel theory and
mechanism of Lizhongwan for warm spleen and stomach for
dispelling cold. Inf Tradit Chin Med. 2014;31(6):33e35
[Chinese].
63
18. Ma XQ, Zhao XM. The antipyretic-analgesic effects of aqueous
extract from dried ginger. J Shandong Med Coll. 2011;33(5):
327e329 [Chinese].
19. Semwal RB, Semwal DK, Combrinck S, Viljoen AM. Gingerols
and shogaols: important nutraceutical principles from ginger.
Phytochemistry. 2015;117:554e568.
20. Luo X, Zhong PL, Zhang X, Zhang J. Effect of gingerols on oral
ulcer. Med Aesthet Cosmetol. 2015;5:699e700 [Chinese].
21. Wu J. Placebo control and clinical trial of Chinese medicine. J
Chin Integr Med. 2010;8(10):906e910 [Chinese].
22. Sakai N. Clinical trials of traditional Chinese Medicine. Liu JJ,
Guo YM, trans. Prog Jpn Med. 2003;24(2):91e93 [Chinese].
23. Chinese Pharmacopoeia Commission. Pharmacopoeia of Peo-
ple’s Republic of China (2015 Edition). Beijing, China: China
Medical Science Press; 2015:14e15.
24. Hoseinpour H, Peel SA, Rakhshandeh H, et al. Evaluation of Rosa
damascena mouthwash in the treatment of recurrent aphthous
stomatitis: a randomized, double-blinded, placebo-controlled
clinical trial. Quintessence Int. 2011;42(6):483e491.
25. Hitomi S, Ono K, Terawaki K, et al. [6]-gingerol and [6]-
shogaol, active ingredients of the traditional Japanese medi-
cine hangeshashinto, relief oral ulcerative mucositis-induced
pain via action on Naþ channels. Pharmacol Res. 2017;117:
288e302.
26. Li YX, Hong Y, Han YQ, Wang YZ, Xia LZ. Chemical character-
ization and antioxidant activities comparison in fresh, dried,
stir-frying and carbonized ginger. J Chromatogr B Analyt
Technol Biomed Life Sci. 2016;1011:223e232.
27. Gu Y, Guo RC, Li HM, Chang HQ. The research for change of the
secretory capacity of salivary gland in RAU. West China J
Stomatol. 1996;14(4):272e273 [Chinese].
28. Castagnola M, Picciotti PM, Messana I, et al. Potential appli-
cations of human saliva as diagnostic fluid. Acta Otorhinolar-
yngol Ital. 2011;31(6):347e357.
29. Rahim MA, Rahim ZH, Ahmad WA, Hashim OH. Can saliva pro-
teins be used to predict the onset of acute myocardial
infarction among high-risk patients? Int J Med Sci. 2015;12(4):
329e335.
30. Adis‚en E, Aral A, Aybay C, Gürer MA. Salivary epidermal growth
factor levels in behçet’s disease and recurrent aphthous sto-
matitis. Dermatology. 2008;217(3):235e240.
31. Gu Y, Zhang G, Lin M. Quantity research on epidermal growth
factor in saliva and epidermal growth factor receptor in biopsy
samples of recurrent aphthous ulcer patients. West China J
Stomatol. 2008;26(1):36e39 [Chinese].
32. Sun M, Fu SM, Dong GY, Wu D, Wang GX, Wu YM. Inflammatory
factors gene polymorphism in recurrent oral ulceration. J Oral
Pathol Med. 2013;42(7):528e534.
33. Song AY, Liang L. The expression and clinical significance of
TNF-a of saliva in patients with recurrent aphthous ulceration.
Chin J Lab Diagn. 2012;16(7):1216e1218 [Chinese].
34. Sand FL, Thomsen SF. Efficacy and safety of TNF-a inhibitors in
refractory primary complex aphthosis: a patient series and
overview of the literature. J Dermatolog Treat. 2013;24(6):
444e446.
35. Boras VV, Lukac J, Brailo V, Picek P, Kordic D, Zilic IA. Salivary
interleukin-6 and tumor necrosis factor-alpha in patients with
recurrent aphthous ulceration. J Oral Pathol Med. 2006;35(4):
241e243.