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An “essential herbal medicine”—licorice: A review of phytochemicals and its effects in combination preparations
Journal Pre-proof An “essential herbal medicine”—licorice: A review of phytochemicals and its effects in combination preparations Maoyuan Jiang, Shengjia Zhao, Shasha Yang, Xia Lin, Xiguo He, Xinyi Wei, Qin Song, Rui Li, Chaomei Fu, Jinming Zhang, Zhen Zhang PII:
S0378-8741(19)30411-8
DOI:
https://doi.org/10.1016/j.jep.2019.112439
Reference:
JEP 112439
To appear in:
Journal of Ethnopharmacology
Received Date: 30 January 2019 Revised Date:
26 November 2019
Accepted Date: 26 November 2019
Please cite this article as: Jiang, M., Zhao, S., Yang, S., Lin, X., He, X., Wei, X., Song, Q., Li, R., Fu, C., Zhang, J., Zhang, Z., An “essential herbal medicine”—licorice: A review of phytochemicals and its effects in combination preparations, Journal of Ethnopharmacology (2020), doi: https://doi.org/10.1016/ j.jep.2019.112439. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
An “essential herbal medicine”—licorice: a review of phytochemicals and its effects in combination preparations Maoyuan Jianga, #, Shengjia Zhaoa, #, Shasha Yanga, XiaLina, Xiguo Hea, Xinyi Weia, Qin Songb, RuiLia, Chaomei Fua, Jinming Zhanga, Zhen Zhanga, * a
Pharmacy College，Chengdu University of Traditional Chinese Medicine; The Ministry of Education Key
Laboratory of Standardization of Chinese Herbal Medicine; State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, China b
Graduate School of Environmental Science, Hokkaido University, Sapporo 0010024, Japan
* Corresponding author. Pharmacy College，Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China. #
Co-first author.
E-mail
addresses:
[email protected]
(Maoyuan
Jiang),
[email protected]
(Shengjia
Zhao),
[email protected] (Shasha Yang), [email protected] (Xia Lin), [email protected] (Xiguo He), [email protected] (Xinyi Wei), [email protected] (Qin Song), [email protected] (Rui Li), [email protected] (Chaomei Fu), [email protected] (Jinming Zhang), [email protected] (Zhen Zhang)
1
1
Abstract
2
Ethnopharmacological relevance: Licorice (Gancao in Chinese, GC), the dried root
3
and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza
4
glabra L., is an “essential herbal medicine” in traditional Chinese medicine (TCM).
5
There is a classic traditional Chinese medicine theory says that “nine out of ten
6
formulas contain licorice” and licorice is considered as one of the most important
7
herbal medicine which can reduce toxicity and increase efficacy of certain herbal
8
medicine while it is combined application. In addition, it is a “medicine food
9
homology” herbal medicine and also be widely used as a health food product and
10
natural sweetener. However, no systematic literature review has been compiled to
11
reveal its superiority. Herein, the aim of this work is to develop an overview of the
12
state on phytochemicals, as well as effects of licorice in combination preparations,
13
which can provide better understand the superiority of licorice and the special position
14
in the application of TCM. Besides, ethnobotany, ethnopharmacological uses, quality
15
control and toxicology of licorice have also been researched, which would provide
16
reference for future clinical and basic research needs.
17
Materials and methods: The information about licorice was collected from various
18
sources including classic books about Chinese herbal medicine, and scientific
19
databases including scientific journals, books, and pharmacopeia. A total of 124
20
bibliographies, which are published from 1976 to 2019, have been searched and
21
researched.
22
Results: In this study, the interaction of chemical compounds between licorice and
23
toxic herbal medicine, pharmacological effect of licorice, and the effect of licorice on
24
pharmacokinetics of toxic compounds are considered as the main mechanisms
25
underlying the effects of licorice in combination preparations. Besides, ethnobotany, 2
26
ethnopharmacological uses and chemical constituents have been summarized.
27
Conclusion: This work comprehensively reviews the state on ethnobotany,
28
ethnopharmacological uses, phytochemicals, combined applications, quality control
29
and toxicology of licorice. It will provide systematic insights into this ancient drug for
30
further development and clinical use.
31
Keywords: Licorice, Ethnobotany, Phytochemicals, pharmacological activities,
32
Effects of licorice in combination preparations, Toxicology
33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
3
48 49
1.Introduction
50
Licorice is native to southern Europe and parts of Asia. It is widely used as an
51
herbal medicine and natural sweetener. As a traditional Chinese medicine used for
52
1000 years, licorice is recorded in the list declared by the Ministry of Health of China
53
which contains 101 traditional edible-medicinal herbs (NationalHealthCommission,
54
2018). Besides, many classic formulas containing licorice have been developed into
55
Chinese patented drugs and commonly used in clinics (Tian et al., 2009).
56
Licorice is an “essential herbal medicine” in China. Since 25 A.D., licorice has
57
been extensively used by the Chinese to tonify qi (life energy) of the heart and spleen.
58
It is also useful to relieve cough, phlegm, dyspnea, spasms, and pain (Li, 2013). In
59
TCM formulas, it is the most frequently used herbal medicine which can harmonize
60
the characteristics of other herbal medicine. For example, there are 283 formulas
61
recorded in the oldest clinical classic in China (Han Dynasty, 220 A.D.), “Shang Han
62
Za Bing Lun”, and licorice has been frequently used 140 times. Therefore, a classic
63
says “nine out of ten formulas contain licorice”(Shifang Jiucao 十方九草) (Wang et
64
al., 2002). Furthermore, due to its effect (the harmonize character in TCM), licorice is
65
usually combined application with herbal medicine such as Aconitum carmichaelii
66
Debx., Paeonia lactiflora Pall. and Zingiber of ficinale Rose. (Wang, 2015).
67
Since the 1960s, a number of studies on licorice have been conducted. To date,
68
more than 200 chemical constituents have been isolated from licorice.
69
Pharmacological studies verified that it has the efficacy of liver protection, digestive
70
system and nervous system protection, anticancer, anti-inflammatory, anti-allergy,
71
anti-AIDS and so on (Liu, 2013). Besides, the underlying mechanism that effects of 4
72
licorice in combination preparations is also one of the hot spots. However, there are
73
not yet any comprehensive studies compiling all these research advances and
74
explaining its superiority. This work comprehensively reviews will provide systematic
75
insights into this ancient drug for further development and clinical use, especially on
76
its effects in combination preparations.
77
2. Ethnobotany
78
Licorice (Glycyrrhizae Radix et Rhizoma) is the root of Glycyrrhiza uralensis
79
Fisch., Glycyrrhiza glabra L. or Glycyrrhiza inflata Bat. These three species, which
80
are recorded in the latest edition (2015 Edition) of Chinese Pharmacopoeia, all belong
81
to the genus Glycyrrhiza. However, there are some different morphological
82
characteristics of the root, rhizome, seed, fruit, and inflorescence as well as the leaf
83
and stem height of these three plants. The morphological characteristics of the three
84
Glycyrrhiza species are described in Table 1 (Fig. 1) (Gao et al., 2017; Zhou, 2010).
85 86 87 88 89 90
Fig. 1 (a-1) Hand painted whole-plant of G. uralensis Fisch, (a-2) aerial part of G. uralensis Fisch, (a-3) flower of G. uralensis Fisch, (a-4) root of G. uralensis Fisch, (b-1) hand painted whole-plant of G. glabra L, (b-2) aerial part of G. glabra L, (b-3) flower of G. glabra L, (b-4) root of G. glabra L, (c-1) hand painted whole-plant of G. inflata Bat, (c-2) aerial part of G. inflata Bat, (c-3) flower of G. inflata Bat, (c-4) root of G. inflata Bat. 5
91 92
93 94 95 96 97
Table 1 The morphological characteristics of three Glycyrrhiza Species Category G. uralensis Fisch.
Root The surface is yellowish brown and rough. With obvious longitudinal wrinkles and round holes
Rhizome The surface is yellowish brown and rough. The longitudinal furrow is deep and wide, and the bulging axillary buds are visible.
Seed Dark brown green, about 2.3~4.6 mm in diameter
Fruit Pod, sickle shaped, 3.1~4.6 cm long, with wrinkles, densely stigma glandular hairs, spiny after abscission.
Inflorescence Racemes, densely capitate, shorter than leaves, 4~12 cm long.
Leaf Odd pinnate Leaf, lobule 2~8 pairs
Stem height
G. glabra L.
The surface is yellowish brown and rough. A hole with fine longitudinal wrinkles and length
The surface is yellow and rough. The longitudinal furrow is deep and wide, and the bulging axillary buds are visible.
Light brown green with a diameter of about 1.5~3.0 mm
Pod, cylindrical, 2.0~3.6 cm long, smooth and glabrous
Racemes, densely spikes, slightly longer or longer than leaves, 10~19 cm long.
Odd pinnate Leaf, lobule 3~10 pairs
45～180 cm
G. inflata Bat.
The surface is dark brown, brown and rufous, and very rough. A hole with a prominent protruding longitudinal wrinkle and length.
The surface is dark brown and rough. Axillary buds with obvious longitudinal grooves and visible eminence
Yellowish green 0.8~2.5 mm
Pod, long ellipse Form, about 0.8~2.5cm long, swollen, slightly adenoma.
Racemes, sparsely spikes, equal to leaves, 5~16 cm long.
Odd pinnate Leaf, lobule 1~4 pairs
50～150 cm
6
35～120 cm
98
Licorice can be propagated by seeds and underground roots or rhizomes. The
99
suitable temperature and light are the key to ensuring the normal development of
100
licorice seedlings. Ma Haige found that the suitable germination conditions of wild
101
licorice seeds are 20~30
102
while 30
103
semi-arid sandy soil, desert edges and loess hilly areas 150~1400 meters above sea
104
level. It is fond of abundant light, minimal rainfall, intense summer heat, severe cold
105
in the winter, and large temperature difference between day and night (Ma et al.,
106
2014). Based on ancient records, licorice was mostly concentrated in Gansu, Ningxia,
107
Shaanxi, Shanxi, Inner Mongolia, and with sporadic distribution throughout Qinghai,
108
Hebei and Shandong. So far, there has been no noticeable change in its origin (Xie
109
and Wang, 2009). In addition, G. uralensis Fisch. is widely distributed throughout
110
Inner Mongolia, Gansu, Xinjiang, Qinghai, Shaanxi, Ningxia, Shanxi, and
111
Heilongjiang. G. glabra L. is mainly distributed in Xinjiang. In addition, G. inflata
112
Bat. is mainly distributed in Xinjiang and in the northwest region of Gansu (Fig. 2)
113
(Wang et al., 2011).
and light for 10 h/d; 20
was suitable for seedling radicles,
was favorable for the hypocotyl. Generally, licorice grows in arid to
114 115
Fig. 2 Climatic and ecological adaptability distribution in China 7
116
3. Ethnopharmacological uses
117
3.1. Application in China
118
Licorice is widely used in China for long times. The first documented medical
119
use of licorice in China can be traced back to Shennong bencao jing (simplified
120
Chinese:神农本草经), which was written in 200 B.C. In this classic, licorice is
121
classified into the first-class herbal medicine, which means non-toxic and edible.
122
Furthermore, licorice is often used as “herb pairs” to harmonize the charecristics of
123
the herbal medicine. Wang analyzed the frequency of licorice use in Shanghan zabing
124
lun (simplified Chinese: 伤 寒 杂 病 论 ), and found it was used in 63% of the
125
prescriptions. Therefore, licorice is honored as “nine out of ten formulas contain
126
licorice” (Wang et al., 2002). Besides, the top ten herbs which are most frequently
127
combined with licorice are as follows: Fructus Jujubae (Da Zao, 63 times), Ramulus
128
Cinnamomi (Gui Zhi, 63 times), Rhizoma Zingiberis Recens (Sheng Jiang, 60 times),
129
Radix Paeoniae Alba (Shao Yao, 43 times), Herba Ephedrae (Ma Huang, 28 times),
130
Radix Ginseng (Ren Shen, 27 times), Rhizoma Pinelliae (Ban Xia, 26 times),
131
Rhizoma Zingiberis (Gan Jiang, 26 times), Radix Aconiti Lateralis Praeparata (Fu Zi,
132
20 times), Poria (Fu Ling, 17 times), and Gypsum Fibrosum (Shi Gao, 17 times)
133
(Wang et al., 2013).
134
Nowadays, many classic formulas containing licorice have been developed into
135
Chinese patented drugs. For example, licorice oral solution is used to treat upper
136
respiratory infection, bronchitis, colds and cough. Sijunzi Granule is used to treat
137
spleen and stomach qi deficiency, poor appetite and loose stools. Yinqiao Powder is
138
used to treat external cold, fever, headache, dry mouth, cough, sore throat and short
139
red urine. Fuzi lizhong pill is used in treating spleen and stomach deficiency, 8
140
epigastric crymodynia, vomiting, diarrhea, as well as hands and feet coldness (Fig. 3).
141 142 143 144
Fig. 3 (a) Compound Glycyrrhiza Oral Solution, (b) Sijunzi Granule, (c) Yinqiao Powder, (d) Fuzi lizhong pills
145
industry in China. Glycyrrhizin has been widely used in food and beverage industries
146
as a sweetener because of the sweet-tasting. For example, in gum, chocolate, sucrose,
147
beer and drinks. Besides, licorice is an important plant for improving soil, maintaining
148
soil and water as well as blocking wind for its character of resistance to cold, hot,
149
drought and saline-alkali conditions. Moreover, licorice can be processed into a
150
popular feed for all kinds of livestock. Licorice is a kind of leguminous pasture crop
151
and has excellent quality in arid and semi-arid areas (Feng et al., 1995).
152
3.2. Application in other countries
In addition, licorice also plays an important role in animal husbandry and
153
In Iran, Licorice is an indigenous medicinal plant and has been used for
154
centuries. Some drugs containing licorice have been produced, such as “Gastrin”,
155
“Licophar”, “Reglisidin” and “Shirinnoush”. These drugs have health efficacy
156
including anti-inflammatory and anti-microbial properties. Licorice still has a good
157
potential capacity to produce more pharmaceutical products, not only limited to local
158
use but also for exportation and introduction as a valuable therapeutic remedy
159
(Bahmani et al., 2015).
160
In
Japan,
the
cosmetics
manufacturing
industry makes
use
of
the
161
anti-inflammatory effect and solubilizing properties of licorice to produce cosmetics
162
with high transparency and good adhesiveness. To neutralize or relieve toxic 9
163
substances in cosmetics and prevent allergic reaction, licorice extracts are widely used
164
in cosmetics such as cream, water, dew, skin milk, and honey (Zhang et al., 2000). A
165
tobacco substitutes made from licorice tissue culture medium has also successfully
166
developed in Japan. The flavor of this cigarette is soft and it contains no-nicotine as
167
well as low-tar (Wang et al., 2002).
168
In IV–III century B.C., Greek provided the first use of licorice as a drug in
169
Europe. The name of the plant itself is derived from two Greek terms, γλυκυ’ζ “sweet”,
170
and ρίζη “root”. Greeks probably learnt about the pharmacological uses of licorice
171
from the Scythians, an ethnic group who lived to the north and east of Greece in the
172
area of the Ukraine between the Black and Caspian Seas. Licorice is used to remedy
173
asthma, diseases affecting voice, lung diseases, cough (Cristina et al., 2005).
174
In the first century A.D., Italians placed licorice among the 650 medicinal
175
substances of plant origin listed in their De Materia Medica. At the beginning of the
176
Imperial Age (I–V century A.D.), Roman gave a detailed description of the licorice
177
plant in the monumental work Naturalis Historia of Plinius. The author suggested
178
licorice as a remedy for asthma, malaises of the throat, ulcerations of the mouth
179
(Cristina et al., 2005).
180
In Germany, the first attempt at creating a botanical nomenclature came from
181
Leonhard Fuchs, who concerning licorice, accurately described and characterized the
182
plant, and reported its scientific name to be the German term Süeβholz “sweet root”,
183
which is still in use today. Licorice is considered an herbal medicine that could
184
alleviate artery diseases, heart palpitations, and angina from the Middle Ages.
185
(Cristina et al., 2005).
186
4. Phytochemicals
187
G. uralensis Fisch. is the most popular species among the three kind of 10
188
Glycyrrhiza plants because of its widespread cultivation, productivity and good
189
quality. Compared with two other plants, G. uralensis Fisch has been the most
190
extensively studied. Since the 1960s, researchers at home and abroad have been
191
thoroughly studying the chemical components of G. uralensis Fisch., G. inflata Bat.
192
and G. glabra L.. These chemical compounds include flavonoids, triterpenoid
193
saponins, coumarins, phenols and polysaccharides.
194
4.1 Flavonoids
195
Flavonoids are the main constituent of licorice. The C6-C3-C6 basic structure are
196
listed in Fig. 4. Flavonoids are mainly divided into five types: flavanones, flavones,
197
flavonols, chalcones, and isoflavones.
198
Flavonoids in licorice have been discovered and isolated continuously from 1992
199
to 2017. In 1992, Glyasperin A, Glyasperin B, Glyasperin C and Glyasperin D (Zeng
200
et al., 1992), belonging to the flavanones, were first isolated by Japanese scientists
201
and their structures were identified by NMR technology. In 1993, Isao K. found a
202
chalcone
203
7-O-apioglucosyl-7,4'-dihydroxyflavone, dehydroglyasperin C, asperopterocaepin,
204
and 1-methoxyphaseollidin (Isao et al., 1993). The structures of above four flavones
205
and glucoisoliquiritin apioside have been verified (Isao et al., 1998). In 1997, Tsutomu
206
H.’s
207
glycyrrhiza-isoflavones
208
tetrahydroxy-methoxychalcone (Tsutomu et al., 1997). In recent years, researchers
209
have conducted a great deal of studies on the compounds of licorice flavones and
210
some constituents have been isolated, such as licorice ning and kanzonol
211
2014; Zhao et al., 2017a; Zhao et al., 2016). Peking University scientists found two
212
flavone
team
component,
first
isoliquiritin
found
apioside.
glycyrrhiza B,
and
flavonol
And
he
also
glycyrrhiza-isoflavones
glycyrrhiza-isoflavones
component,
glycyuralin 11
found
A
C
A and
(He et al.,
and
213
5,7,3′,4′-tetrahydroxy-6-(3-hydroxy-3-methylbutyl)-isoflavone in 2016. The former
214
belongs to the flavones, the latter belongs to the isoflavone group (Ji et al., 2016).
215
Besides, 28 flavonoids were isolated and identified by HPLC-Q-TOF-MS in 2016
216
(Zhao et al., 2016).
217
Liquiritin is main compound in G. uralensis Fisch.. In 2004, a HPLC method has
218
been established to measure the content of liquiritin in G. uralensis Fisch. from
219
different habitats. With the mobile phase of 0.5% acetic acid water (v/v, A) and
220
acetonitrile (B) as well as the 276 nm UV detection wavelength, the content of
221
liquiritin was detected from 0.23% to 2.46% (Wu et al., 2004). In 2008, Peng studied
222
the distribution of liquiritin in different part of licorice. The result shows that liquiritin
223
mostly accumulates in the underground portions of licorice, and the content variation
224
is related to the age of the underground portion and the aboveground growing parts
225
(Peng et al., 2008).
226 227 228
Fig. 4 The basic structure of flavonoids
4.2 Triterpene saponins
229
Triterpene saponins are another main bioactive constituent in licorice. (Liang et
230
al., 2006). The aglycone of triterpenoids in licorice is mainly 3β-hydroxy oleanolic 12
231
acid (The structure is listed in Fig. 5). Glycyrrhizin is recognized to be the most active
232
ingredient in triterpene saponins (Hao, 2001).
233
Scholars at home and abroad focused on the content of glycyrrhizin in licorice,
234
because it is the main active component of licorice. In 1976, Kiliacky J. measured
235
glycyrrhizic acid by HPLC (Kiliacky et al., 1976). Since 1980, Chinese researchers
236
have begun to study the content of glycyrrhizin in licorice. Li measured the
237
glycyrrhizin in G. uralensis Fisch. by the volumetric method (Li and Xie, 1980). Then,
238
in 1987, Liu first measured the content of glycyrrhetinic acid which has been
239
hydrolyzed from glycyrrhizin, and the result has been used to indirectly calculate the
240
content of glycyrrhizin (Liu et al., 1987). In 1989, an HPLC method to measure
241
glycyrrhizin has been established (Fu et al., 1989). Then, Sun used HPCE method to
242
measure the glycyrrhizin and glycyrrhetinic acid in Compound Liquorice Tablets at
243
the same time(Sun et al., 2011). In addition, He found 8 triterpene saponins by
244
UPLC-MS/MS in 2014 (He et al., 2014). And 16 triterpene saponins have been
245
discovered and identified by LC-MS in 2016 (Zhao et al., 2016). To sum up,
246
researchers have established a quick and accurate method of identifying triterpene
247
saponins in licorice (Ma et al., 2018).
248
In addition, researchers have improved the extraction and separation method.
249
Sun
250
used a nonionic surfactant micellar extraction system to replace the organic reagent.
251
The extraction rate increased to 90.3% (Sun et al., 2007). Shabkhiz reported that they
252
extracted glycyrrhizin from licorice roots by superheated water extraction (SWE)
253
method: 100℃ (temperature), 15 ml/min (flow velocity), and 120 min (time). The
254
results showed that this improved method can increase the GA yield (54.760 mg/g)
13
255
compared with the yield conducted by the Soxhlet method (28.760 mg/g) and
256
ultrasonic extraction (18.240 mg/g) (Shabkhiz et al., 2016).
257 258 259
Fig. 5 the structure of 3β-hydroxy oleanolic acid 4.3 Coumarins and phenols
260
In 1978, Takeshi K. found 3-arylcoumarin--glycyrin. The structure is
261
2',4'-dihydroxy-5,7-dimethoxy-6-γ,γ-dimethyally1-3-arylcoumarin (Takeshi et al.,
262
1978). In 1997, researchers from Okayama University found an active compound
263
named isolicopyranocoumarin, and the compound showed the most potent radical
264
scavenged activity effect on 1,1-diphenyl-2-picrylhydrazyl (Tsutomu et al., 1997).
265
Chinese researchers first isolated three coumarins from G. uralensis Fisch., including
266
7,2',4'-
267
hedysarimcoumestan E. Furthermore, some phenols were discovered in G. uralensis
268
Fisch. by scholars locally and abroad
269
4.4 Polysaccharides
trihydroxy-5-methoxy-3-arylcoumarin,
hedysarimcoumestan
B,
and
(Liu et al., 2011).
270
Glycyrrhiza polysaccharides (GP), as natural plant polysaccharides, are also the
271
bioactive substances in licorice (Hiroaki et al., 1996). In 1990, glycyrrhizans UA and
272
glycyrrhizans UB were isolated and identified from the roots of G. uralensis Fisch. in
273
Masashi T.’s study. The results show that glycyrrhizan UA is composed of
274
L-arabinose, D-galactose, L-rhamnose, and D-galacturonic acid in a molar ratio of
275
20:14:1:3. Glycyrrhizan UB is composed of L-arabinose, D-galactose, D-glucose, 14
276
L-rhamnose, and D-galacturonic acid in a molar ratio of 12:10:1:10:20. Additionally,
277
the two polysaccharides exert activities in the reticuloendothelial system (Masashi et
278
al., 1990). Then, Noriko discovered a novel neutral polysaccharide, glycyrrhizans UC.
279
Using methylation analysis, carbon-13 nuclear magnetic resonance and periodate
280
oxidation
281
arabino-3,6-galacto-glucan-type-polysaccharide. This polysaccharide showed the
282
same biological activities as glycyrrhizan UA and glycyrrhizan UB (Noriko et al.,
283
1990). So far, more and more polysaccharide fractions have been isolated from G.
284
uralensis Fisch.. Zhao found two anticomplementary polysaccharide fractions from it
285
(Zhao et al., 1991). Chinese scholars isolated a water-soluble polysaccharide and
286
found that these polysaccharide fractions have macrophage immunomodulatory
287
activity. Currently, the research of glycyrrhiza polysaccharides is a hot topic (Cheng
288
et al., 2008a; Cheng et al., 2008b).
289
4.5 Essential oil
studies,
its
structure
was
indicated
as
290
Subtle and characteristic smell is an important property of licorice, and the odour
291
is related to its volatile components (essential oil) (Liang et al., 2005). In 2012, 13
292
volatile components were isolated in G. inflata Bat. by using steam distillation and
293
solid-phase microextraction (A.Farag and A.Wessjohann, 2012). In 2016, researchers
294
from China found numerous volatile components in G. uralensis Fisch. by using gas
295
chromatography-mass spectrometry (GC–MS) (He et al., 2016). Then, some volatile
296
components were reported (Zhou et al., 2017).
297
4.6. Others
298
In 1990, Han isolated two alkaloids from the roots of G. uralensis Fisch.. These
299
alkaloids
300
5,6,7,8-tetrahydro-4-methylquinoline by spectral data (Han et al., 1990). Then, they
were
identified
as
5,6,7,8-tetrahydro-2,4-dimethylquinoline
15
and
301
isolated
302
3-methyl-6,7,8-trihydro-pyrrolo [1,2-a] pyrimidin-2-one in G. uralensis Fisch.. It was
303
the first reported that alkaloids were isolated and identified from licorice (Han and
304
Chung, 1990). In 2001, content of alkaloids that were quinoline and isoquinoline in
305
licorice was measured by Chinese researchers (Zhang et al., 2001). Besides,
306
glycyrrhiza alkaloids extraction process was optimize by using genetic algorithm (Li
307
et al., 2018). Whether these components are bioactive compounds also needs further
308
research. In addition, there are other components in G. uralensis Fisch., such as
309
yunganoside, liconeolignan, β-sitosterol, and tetrahydropalmatine. All of these
310
components make up a large and complex material basis of licorice.
another
pyrrolo-pyrimidine
alkaloid
and
identified
as
311
As an important part of medication study, chemical composition has been
312
attracting much attention. The discovery and research of new chemical components
313
depend on advanced instruments and research methods. Besides, the discovery of new
314
active ingredients should be conducted under the guidance of TCM theory. For
315
example, TCM theory claims that licorice has the effect of “Huanji zhitong and qutan
316
zhike”(缓急止痛,祛痰止咳), moreover, modern research (Liu et al., 2007a; Wang and
317
Su, 2002) found that isoliquiritigenin, one of the major flavonoids in licorice, can
318
relieve the smooth muscle spasm of gastrointestinal and bronchial tract. The effect of
319
this component is associated with the traditional Chinese medicine efficacy of licorice.
320
Comprehensively analyzing the traditional theories and modern research conclusions
321
above, it reminds us that some other active ingredients with the effect of "Huanji
322
zhitong, qutan zhike" may been found in flavonoids of licorice. It is more targeted and
323
efficient to combine TCM theory and existing researches in exploring new active
324
constituents. 16
325
5. The effects of licorice in combination preparations
326
Herbal medicine combined application in prescription is the characteristic of
327
TCM. A TCM formula are usually classified as monarch (main) drugs, minister drugs,
328
assistant drugs, and guide drugs. Besides, in TCM theory, every herbal medicine in
329
formula is ascribed a property, “cold”, “cool”, “neutral”, “warm”, or “hot”. “Cool”
330
and “cold” herbal medicine treat heat diseases such as high fever, strong sweating,
331
and strong thirsty. “Warm” and “hot” herbal medicine treat cold diseases such as cold
332
limbs, aversion to cold, and watery diarrhea (Ergil and Ergil, 2010; Wang et al., 2013)
333
As a first-class herbal medicine, licorice is tonic, nontoxic and slightly “cold” in
334
property. Additionally, it has the ability to harmonize the characteristics of other
335
herbal medicine. That means, on the one hand, licorice can mitigate “hot” or “cold” in
336
property of certain herbal medicine while it is combining used in preparations. On the
337
other hand, it can improve the efficacy of herbal medicine in a formula simultaneously.
338
In addition, it also can modulate the taste of herbs due to its sweet flavor.
339
We believe that the interaction of chemical compounds between licorice and
340
toxic herbal medicine, pharmacological effect of licorice, and the effect of licorice on
341
pharmacokinetics of toxic compounds are main mechanisms underlying effects of
342
licorice in combination preparations. The variation of chemical component while
343
licorice is in combined application are widely studied. The research results are
344
showed in Table 2. And the mechanism of bioactivity enhancing/toxicity reducing
345
efficacy of licorice is helpful for understanding its “essential herbal medicine”
346
superiority.
347
5.1 Chemical composition variation while combining application with licorice
348
5.1.1 G. uralensis Fisch. and Paeonia lactiflora Pall. (GanCao-Baishao, GC-BS)
349
GC and BS are firstly recorded in shen nong ben cao jing. They compose a 17
350
classic traditional Chinese formula: Shaoyao Gancao Decoction (simplified Chinese:
351
芍药甘草汤). Researchers found that the content of paeoniflorin in the BS decoction
352
was less than that in the GC-BS co-decoction (Wang et al., 2014). In
353
subsequent studies, Zhu measured oxidized paeoniflorin, paeoniflorin, albiflorin and
354
benzoyl paeoniflorin in the BS decoction and the co-decoction. The result suggested
355
that the four compounds increased in the co-decoction (Zhu et al., 2016).
356
5.1.2 G. uralensis Fisch. and Zingiber officinale Rose. (GanCao-Ganjiang, GC-GJ)
357
GJ is the root of Zingiber officinale Rosc. Jiang found that 6-gingerol, 8-gingerol,
358
and 6-shogaol increased in the GC-GJ co-decoction compared to GJ single decoction.
359
(Jiang et al., 2015). The results show that the dissolution of the active ingredient in GJ
360
have been increased in combining usage with GC. Two key points are illustrated. On
361
the one hand, the experimental data provide scientific basis for the theory of Mutual
362
compatibility of GC-GJ. On the other hand, it confirmed that GC plays a harmonizer
363
role in TCM.
364
5.1.3 G. uralensis Fisch. and Ephedra sinica Stapf (GanCao-Mahuang, GC-MH)
365
MH is the stem of Ephedra sinica Stapf. It contains ephedrine, pseudoephedrine,
366
methyl
367
pseudoephedrine and volatile oil. Using LC-MS, Meng found that the ephedrine
368
increased by 14.52% and the methylephedrine increased by 64% in the GC-MH
369
co-decoction (Meng et al., 2009). Besides, Xu discovered that the dissolution rates of
370
demethylpseudoephedrine hydrochloride, demethylmethylephedrine hydrochloride,
371
ephedrine hydrochloride, pseudoephedrine hydrochloride and methylephedrine
372
hydrochloride were reduced in the GC-MH co-decoction (Xu et al., 2012).
373
5.1.4 G. uralensis Fisch. and Aconitum carmichaelii Debx. (GanCao-Fuzi, GC-FZ)
ephedrine,
methyl
pseudoephedrine,
18
methamphetamine,
methylene
374
FZ, the root of Aconitum carmichaelii Debx., is a toxic herbal medicne because
375
of the toxic ester alkaloids. The GC-FZ is the most notable TCM herb pair showing
376
bioactivity enhancing and toxicity reducing efficacy. Currently, Chinese scholars have
377
studied the bioactivity enhancing and toxicity reducing mechanism of this herb pair.
378
In 2013, Zhang researched the difference of the content of chemical components (6
379
ester alkaloids) between sediment in the FZ decoction and sediment in the FZ-GC
380
co-decoction.
381
benzoylmesaconitine 49.46 µg/g, benzoylaconitine 31.45 µg/g, benzoylhypaconitine
382
24.63 µg/g, mesaconitine 8.29 µg/g, and hypaconitine 28.49 µg/g; while the
383
co-decoction sediment included benzoylmesaconitine 119.12 µg/g, benzoylaconitine
384
61.63 µg/g, benzoylhypaconitine 101.23 µg/g, mesaconitine 32.15 µg/g, hypaconitine
385
64.42 µg/g, aconitine 45.76 µg/g (JM Zhang et al., 2013). Moreover, Wang found that
386
the contents of alkaloids in the FZ-GC co-decoction were significantly lower than the
387
contents in the FZ decoction (Wang, 2014). It is indicated that the FZ-GC
388
co-decoction is less toxic because the ester-series alkaloids and constituents in licorice
389
formed chelate precipitates (JM Zhang et al., 2013).
390
5.1.5 G. uralensis Fisch. and Rheum palmatum L. (GanCao-Dahuang, GC-DH)
The
results
showed
that
FZ
decoction sediment
included
391
Dahuang Gancao Decoction(simplified Chinese:大黄甘草汤), recorded in Jingui
392
Yaolue (simplified Chinese: 金 匮 要 略 ), consists of DH and GC. Han and Jin
393
determined the content of free and combined anthraquinones by UV in the DH
394
decoction and the GC-DH co-decoction (the ratio of DH-GC is 2:1). The content of
395
free anthraquinone was 6.84 ±0.64 mg/g and the content of combined anthraquinone
396
was 9.41±0.54 mg/g in the DH decoction. The content of free anthraquinone was
397
11.96±0.60 mg/g and the content of combined anthraquinone was 3.61±0.19 mg/g in
398
the GC-DH co-decoction. The result showed that the free anthraquinone increased and 19
399
the combined anthraquinone was reduced in the co-decoction. Glycyrrhizin and
400
combined anthraquinone formed precipitates and combined anthraquinone was
401
reduced in the co-decoction, which is considered to be the main toxic component
402
(Han et al., 2009). Besides, the GC combined application with DH can promote the
403
dissolution of total anthraquinone in co-decoction, which may be the main bioactivity
404
enhancing efficacy mechanism (Luo, 2017).
405
5.1.6 G. uralensis Fisch. and Strychnos nux-vomica L. (GanCao-Maqianzi, GC-MQZ)
406
Strychnine and brucine are the main effective as well as toxic compounds in
407
MQZ. Zhao examined the GC-MQZ co-decoction and the MQZ decoction. He found
408
that the co-decoction has the low contents of strychnine and brucine compared with
409
the contents in the MQZ decoction. Moreover, researchers detected the contents of
410
semen strychni in different co-decoctions which made of different proportions of
411
licorice. The result showed that strychnine was reduced by 95.7% and brucine was
412
reduced by 93.3% when the ratio of GC-MQZ is 16:1. It suggested that the contents of
413
the strychnine and brucine would change as the dose of licorice changes and the
414
chemical composition of licorice reacted with strychnine and brucine to form
415
precipitates (Zhao et al., 2014).
416
5.1.7 G. uralensis Fisch. and Zingiber officinale Rose. (GanCao-Ganjiang, GC-GJ)
417
Volatile oils are regarded slightly toxic and as the material basis of “acrid & dry”
418
(xin & zao) in TCM. Li found that 6-gingerol and glycyrrhizic acid were reduced in
419
the GC-GJ co-decoction compared with the content of 6-gingerol and glycyrrhizic
420
acid in the GJ decoction. With an increasing proportion of GC, 6-gingerol is reduced
421
even more (Li et al., 2016). The results suggest that the increased use of GC may limit
422
the “acrid & dry” property of GJ. And it provides a material basis of the detoxification
423
mechanism of GC. 20
424
In conclusion, it can be found that the change of content of the active component
425
in the compound Chinese medicine may be one of the main reasons of effect of
426
licorice in combination preparations. Firstly, glycyrrhiza saponins are excellent
427
surfactants which can significantly reduce the interfacial tension between the two
428
phases, improve the solubility and thereby enhance the bioavailability of active
429
substances (Cai et al., 2012). Secondly, Licorice compounds react with other toxic
430
compounds to produce precipitation in decoction, and it reduces the solubility of toxic
431
compounds (Wang et al., 2008). Thus, the toxic compounds administrated into the
432
body become less because most of precipitation was leave outside rather than being
433
taken into body.
434 435
21
436
Table 2 Compounds variation and possible mechanisms while herbal medicine is combined with licorice NO.
GC-herbal medicine B
Extraction solvent
Extraction method
Analytical method
1
GC-BS (Paeonia lactiflora Pall.) GC-BS (Paeonia lactiflora Pall.)
Water
Decoct
HPLC A phase: 0.01% phosphoric acid B phase: acetonitrile
Water
Decoct
HPLC A phase: 0.1% phosphate aqueous solution B phase: acetonitrile
2
Compounds variation “↑”: increase “↓”:reduce “↑” “↓”
Mechanism
Ref.
Paeoniflorin ↑
The interaction of the constituents in GC and BS increased the dissolution of the paeoniflorin
(Wang et al., 2014)
Oxypaeoniflorin ↑ Albiflorin ↑ Paeoniflorin ↑ Benzoylpaeoniflorin ↑ Gallic acid ↓ Oxypaeoniflorin ↓ (+)-catechin ↓ Paeoniflorin ↓ Benzoylpaeoniflorin ↓ Albiflorin ↑ Benzoic acid ↑ 6-Gingerol ↓
The interaction of the constituents in GC and BS increased the dissolution of these constituents
(Zhu et al., 2016)
Unknown
(Kim et al., 2014)
Unknown
(Li et al., 2009)
3
GC-BS (Paeonia lactiflora Pall.)
Water
Reflux
HPLC-PDA A phase: 0.1% formic acid B phase: acetonitrile
4
GC-GJ (Zingiber of ficinale Rose.) GC-GJ (Zingiber of ficinale Rose.) GC-MH (Ephedra sinica Stapf) GC-MH (Ephedra sinica Stapf)
Water
Reflux
HPLC A phase: 0.05% phosphate B phase: Acetonitrile
Water
Reflux
HPLC: A phase: 0.1% glacial acetic acid B phase: Acetonitrile
6-Gingerol ↓ 8-Gingerol ↓ 6-Shogaol reduced ↓
Unknown
(Jiang et al., 2015)
Water
Reflux
GC-MS
Ephedrine↑ Methylephedrine ↑
Glycyrrhizin promotes the dissolution of ephedrine alkaloids
(Meng et al., 2009)
Water
Decoct
GC-MS
Demethylpseudoephedrine↓ Demethylephedrine↓ Ephedrine↓ Pseudoephedrine ↓ Methyl ephedrine↓
Organic acids in GC reacts with alkaloids in MH to form non-soluble alkaloid-organic acid complex salt.
(Xu et al., 2012)
5
6
7
22
8
GC-FZ (Aconitum carmichaelii Debx.)
Water
Reflux
9
GC-FZ (Aconitum carmichaelii Debx.) GC-FZ (Aconitum carmichaelii Debx.)
Water
Decoct
Water
10
11
12
13
GC-DH (Rheum palmatum L.) GC-DH (Rheum palmatum L.） GC-MQZ (Strychnose nux-vomica L.)
HPLC-Q-TOF/MS A phase: 5 mmol/L ammonium acetate solution (0.1% acetic acid) B phase: acetonitrile (0.1% formic acid) HPLC Methanol: water: chloroform: trichloroethylamine = 70:30:2:0.1
Hypaconitine ↓ Aconitine ↓
Molecular interactions between the alkaloids in FZ and the flavones of GC
(Lin et al., 2014)
Aconitine ↓ Total toxic alkaloids ↓
Unknown
(Wang, 2014)
Decoct
HPLC-TOF-MS A phase: 5 mmol/L ammonium acetate (0.1% acetic acid) B phase: acetonitrile (0.1% formic acid)
The association between tertiary amine N in alkaloids and glycyrrhizin C=O
(Zhang et al., 2013)
Water
Decoct/ Reflux
Unknown
(Luo et al., 2016)
Water
Decoct
HPLC A phase: 1% glacial acetic acid B phase: methanol spectrophotometry
Benzoylmesaconine ↑ Benzoylaconitine ↑ Benzoylhypaconitine ↑ Mesaconitine ↑ Hypaconitine ↑ Aconitine↑ (in sediments) Total anthraquinones ↑ Combined anthraquinones ↑ Free anthraquinones ↑ Combined anthraquinones ↓
(Han et al., 2009)
Water chloroform
Reflux
Glycyrrhizin and combined anthraquinone formed precipitation, while had a solubilizing effect on free anthraquinones Components in liquorice combined with brucine and strychnine to form water-insoluble deposits
14
GC-MQZ (Strychnose nux-vomica L.)
Water
Reflux
15
GC-HB (Phellodendr on chinense Schneid. )
Water
Reflux
HPLC A phase: 0.01mol /L sodium heptane sulfonate mixed with 0.02mol /L potassium dihydrogen phosphate (pH adjusted by 10% phosphoric acid 2.8) (21-79) B phase: acetonitrile HPLC A phase: 0.1% formic acid solution B phase: 0.1% acetonitrile formate solution HPLC
Brucine ↓ Strychnine ↓
23
(Zhao et al., 2009)
Brucine ↓ Strychnine decreased ↓
Components in liquorice combined with brucine and strychnine to form deposits, which is released slowly in vivo.
(Guo et al., 2017)
Berberine hydrochloride ↑
Glycyrrhizin and berberine hydrochloride form sediments
(Zou et al., 2009)
437
5.2 Pharmacological changes while combining application with licorice
438
Based on pharmacological studied, we hold that the pharmacological effect of
439
certain herbal medicine can be enhanced by conjunction with licorice. For example,
440
the pain relief and anti-inflammatory effects of Baishao were strengthened while
441
combining with licorice (Liang et al., 2016; Liu et al., 2007b; Wang et al., 2016b).
442
Besides, the toxic and side effects of certain herbal medicien can be attenuated by
443
conjunction with licorice. For instance, Melia toosendan Sieb.et Zucc. is a TCM with
444
hepatotoxicity. After application with licorice, it was found that the toxicity was
445
reduced. The mechanism probably is that licorice can inhibit the increase of AST、
446
ALT and ALP in rat serum and reduce the level of MDA、TNF-α and IL-6 in liver
447
homogenate (Zhuo et al., 2018). More studies of licorice cooperating with other
448
herbal medicine are summarized in Table 3.
449
So far, most of the research on the physiological efficacy of licorice remains at
450
the compound level. In the future, it can be analyzed from a more microscopic
451
perspective through modern genomics technology and proteomics technology, which
452
also provides a new method to solve the problem of unclear combination mechanism
453
of licorice.
24
454 455
Table 3 The combination effect of licorice and possible mechanisms while licorice is combined application with certain herbal medicine No .
GC-herbal medicine( B)
Experimen tal model
Dose range tested (crude drug)
Minimal active concentration
Duration
1
GC-BS (Paeonia lactiflora Pall.) GC-BS (Paeonia lactiflora Pall.) GC-BS (Paeonia lactiflora Pall.)
Mice
0.2 g/10g
0.2 g/10g
3d
Mice
150 ~ 600 mg/kg
150 mg/kg
Mice
43 g/kg
GC-CLZ (Melia toosendan Sieb, et Zucc.) GC-ZSM (Daphne giraldii Nitsche)
Mice
180 g/kg
Rats
540, 1620, 2700 mg/kg
540 mg/kg
31 d
Anti-adjuvant-induce d arthritis
Bioactivity enhancing efficacy
GC-DH (Rheum palmatum L.) GC-HYZ (Dioscorea bulbifera L.) GC-HYZ (Dioscorea bulbifera
Rats
40 mg/kg
40 mg/kg
7d
Anti-inflammatory
Bioactivity enhancing efficacy
Rats
27 g/kg
27 g/kg
35 d
Renal toxicity
Toxicity reducing efficacy
Unknown
(Fan et al., 2014; Zhao et al., 2018)
Rats
9 g/kg
9 g/kg
35 d
Liver damage
Toxicity reducing efficacy
GC Inhibited the expression of mRNA in CYP1A2 ， and slightly
(Hua et al., 2014)
2
3
4
5
6
7
8
Effect of Herbal medicine B/toxicity of herbal medicine B Abirritation
Bioactivity enhancing /Toxicity reducing efficacy Bioactivity enhancing efficacy
Mechanism
Ref
Unknown
(Jiang et al., 2011; Wang et al., 2016b)
5d
Abirritation and anti-inflammatory
Bioactivity enhancing efficacy
Liquorice glycosides and paeony glucosides are both have analgesic and anti-inflammatory efficacy
(Kong et al., 2018; Liu et al., 2007b)
43 g/kg
7d
Reduce capillary permeability, abirritation and anti-inflammatory
Bioactivity enhancing efficacy
Liquorice total glycosides and paeony glucosides are both have analgesic and anti-inflammatory efficacy
(Liang et al., 2016)
180 g/kg
14 d
Hepatotoxicity
Toxicity reducing efficacy
GC inhibited the increase of AST、 ALT and ALP in rat serum and reduce
(Zhuo et al., 2018)
25
the level of MDA、TNF-α and IL-6 in liver homogenate. Regulating TNF-α、IL-1β、VEGF and MIF to inhibit inflammatory cells infiltration, making synovial tissues hyperplasia and alleviating the damage of cartilage and bone Strengthening the effect of reducing the expression of TNF-α、IL-6、IL-8 in rat serum
(Zhang et al., 2014)
(Kong et al., 2014; Xu et al., 2016)
L.) 9
10
11
12
13
14
15
16
GC-HYZ (Dioscorea bulbifera L.) GC-SDG (Sophora tonkinensis Gapnep.) GC-LGT (Tripterygi um wilfordii Hook. f.) GC-GZ (Cinnamom um cassia Presl) GC-KS (Sophora flavescens Ait.) GC-HH (Carthamus tinctorius L.) GC-HH (Carthamus tinctorius L.)
GC-WM (Prunus mume (Sieb. )Sieb . et. Zucc.)
down-regulated the expression of CYP2C19. GC restrained the increase of the liver index, ALT, AST of rat which are induced by HYZ
Mice
0.075 g/g
0.075 g/g
30 d
Hepatotoxicity
Toxicity reducing efficacy
Mice
18, 24, 36 g /kg
18 g/kg
21 d
Hepatotoxicity
Toxicity reducing efficacy
GC restrained the increase of ALT, AST in rat serum
(Pan and Hua, 2016)
Rats
15 g/kg
15 g/kg
14 d
Hepatotoxicity
Toxicity reducing efficacy
GC has efficacy of protecting liver and antagonizing HMGB1
(Li et al., 2015; Zhao et al., 2017b)
Rats
1.62 g/kg
1.62 g/kg
30 d
Energy metabolism
Bioactivity enhancing efficacy
GC-GZ regulated the content of GLU, GC and T3 in rat serum
(Sun et al., 2016b; Yao et al., 2014)
Rats
10, 20, 30 g/kg
10 g/kg
7d
Acute toxicity
Toxicity reducing efficacy
Unknown
(Shi et al., 2015b; Wang et al., 2015)
Rats
20 g/kg
20 g/kg
15 d
Resist blood stasis
Bioactivity enhancing efficacy
GC-HH decreased viscosity of the blood, and increased ATP, ADP and AMP content
(Dong et al., 2017; Han et al., 2013)
Rats
20 g/kg
20 g/kg
30 d
Resist blood stasis
Bioactivity enhancing efficacy
(Wang et al., 2018)
Rats
1.8 g/kg
1.8 g/kg
7d
Anti-radiation salivary gland injury
Bioactivity enhancing efficacy
The compatibility of GC with HH promotes the absorption of safflower active ingredients, which act on epinephrine receptors, thereby improving the systolic function of mesenteric blood vessels in rats with blood stasis unknown
26
(Hua et al., 2011)
(Ye et 2018)
al.,
17
18
19
GC-FZ (Aconitum carmichaeli i Debx.) GC-FZ (Aconitum carmichaeli i Debx.) GC-SFJ (Silybum marianum (L. )Gaertn. )
Rats
3.77, 17.79 mg/kg
23.77, 17.79 mg/kg
28 d
Anti-adjuvant-induce d arthritis
Bioactivity enhancing efficacy
GC enhanced the effect of FZ on decreasing the serum level of cytokines IL-1β, TNF-α and PGE2.
(Tong et al., 2014; Yang et al., 2010)
Rats
11.4, 12.9, 15 g/kg
11.4 g/kg
/
Cardiotoxicity
Toxicity reducing efficacy
GC inhibited the increase of cardiac rhythm, and protected cardiac cell
(Sun et al., 2016a; Xie et al., 2012)
Rats
125, 250 mg/kg
125 mg/kg
42 d
Hepatoprotective efficacy
Bioactivity enhancing efficacy
Silymarin in SFJ and glycyrrhizin in GC can significantly reduce ALT, AST, ALP, and TBARS levels and increase GSH, SOD, and CAT levels.
(Rasool et al., 2014)
27
456
5.3 Pharmacokinetic changes while combining application with licorice
457
The possibility is well-known in phyto-pharmacology that particular concomitant
458
compounds in an extract, e.g. polyphenols or saponins (in licorice) that often do not
459
possess specific pharmacological effects themselves may increase the solubility
460
and/or the resorption rate of other major constituents in the extract and thereby
461
enhance its bioavailability virtually in a kind of pharmacokinetic effect (Wagner and
462
Ulrich-Merzenich, 2009). Therefore, pharmacokinetic studies are helpful in
463
understanding the action mechanism underlying effects of licorice in combination
464
preparations. Changes of pharmacokinetic parameters of components in the
465
combination of GC licorice with other herbal medicine are summarized in Table 4.
466
These studies focused on the absorption and distribution of active/toxic components in
467
vivo and provided some modern evidences for dynamic change of components in the
468
blood.
469
Licorice could influence the pharmacokinetic profiles of aconitine in Aconitum
470
carmichaelii Debx. (FuZi, FZ). Cmax and ACU of aconitine in rats orally administrated
471
FZ-GC co-decoction significantly reduced compared to that in rats treated with FZ
472
single decoction (Wang et al., 2012). We believe that the absorption and distribution
473
of aconitine were slowed down, which may be the main toxicity reducing efficacy
474
mechanism. Most of the results show that peak time (Tmax) and clearance (CL) of toxic
475
components in certain herbal medicine were increased and peak plasma concentration
476
(Cmax), area under the curves (ACU), and half-life (T1/2) of toxic components in certain
477
herbal medicine were reduced in combining application with licorice.
478
Besides, Cmax and ACU of active components in certain herbal medicine were
479
increased after combining application with licorice. For instance, licorice could
480
influence the pharmacokinetic profiles of platycodin D and deapio-platycodin D in 28
481
Platycodon grandiflorum (Jacq.) A. DC. (JieGeng, JG). Cmax and ACU of Platycodin
482
D and Deapio-platycodin D in rats orally administrated JG-GC co-decoction
483
significantly increased compared to that in rats treated with JG single decoction (Shan
484
et al., 2015).
29
485
Table 4 The changes of pharmacokinetic parameters of toxic/active components when licorice is in combined application with certain herbs N o. 1
2
3
4
5
6
7
8
GC-herbal medicine (B) GC-LGT LGT (Tripterygium wilfordii Hook. f.) GC-LGT LGT (Tripterygium wilfordii Hook. f.) GC-FZ FZ (Aconitum carmichaelii Debx.) GC-FZ FZ (Aconitum carmichaelii Debx.) GC-MQZ MQZ (Strychnose nux-vomica L.) GC-MQZ MQZ (Strychnose nux-vomica L.) GC-KS KS (Sophora flavescens Ait.) GC-KS KS (Sophora
Experimental model Rat
components
Tmax/h
Cmax/µg·L-1
T1/2/h
CL/
ACU/µg·h-1·L-1
Ref
Triptonide (toxic component)
1.00 1.00
708.06 ± 66.98 647.62 ± 61.76
0.52 ± 0.10 0.92 ± 0.16
0.14 ± 0.08 0.11 ± 0.018
9331. 61 ± 1203. 97 11172. 23 ± 1858. 56
(Zhang et al., 2010)
Rat
Triptolide (toxic component)
0.03 0.03
147.48 ± 17.48 249.12 ± 32.97
0.35 ± 0.01 0.31 ± 0.02
11.11 ± 2.37 4.94 ± 1.08
63.04± 9.97 141.65±20.38
(Liu et al., 2010)
Rat
Hypaconitine (toxic component)
5.91 ± 0.78 2.40 ± 0.53
132.98 ± 16.21 160.90 ± 125.74
/ /
0.02 ± 0.01 0.06 ± 0.01
1773.85 ± 256.43 1310.45 ± 186.94
(Zhang et al., 2011)
Rat
Aconitine (toxic component)
7.25 ± 1.00 1.00 ± 0.00
0.04 ± 0.01 0.09 ± 0.02
7.81 ± 3.88 14.69 ± 3.30
/ /
0.54 ± 0.11 0.73 ± 0.15
(Wang et al., 2012)
Rat
Strychnine (toxic component)
0.8 ± 0.2 0.5 ± 0.1
302.8 ± 7.5 241.4 ± 12.9
2.3 ± 0.7 3.9 ± 0.9
/ /
516.40 ± 79.50 547.50 ± 69.00
(Gu et al., 2014)
Rat
Brucine (toxic component)
0.6 ± 0.2 0.8 ± 0.1
54.8 ± 0.9 63.1 ± 2.2
3.5 ± 1.2 3.2 ± 1.5
/ /
142.50 ± 21.90 94.00 ± 12.10
(Gu et al., 2014)
Rat
Oxymatrine (toxic component)
3.00 3.00
64.70 ± 5.80 74.20 ± 6.90
5.12 ± 0.23 8.09 ± 0.21
32.6 ± 3.3 24.13 ± 2.1
475.21 ± 35.23 585.95 ± 48.67
(Shi et al., 2015a)
Rat
Matrine (toxic component)
3.00 3.00
2115.4 ± 156.4 3148.7 ± 212.2
5.95 ± 0.26 5.37 ± 0.23
0.67 ± 0.17 0.42 ± 0.12
18969 ± 1554 29142 ± 2313
(Shi et al., 2015)
30
flavescens Ait.) 9
10
11
12
13
14
GC-DH DH (Rheum palmatum L.) GC-GZ GZ (Cinnamomum cassia Presl) GC-JG JG (Platycodon grandiflorum (Jacq.) A. DC.) GC-JG JG (Platycodon grandiflorum (Jacq.) A. DC.) GC-BS BS (Paeonia lactiflora Pall.) GC-BS BS (Paeonia lactiflora Pall.)
Rat
Rhein (toxic component)
0.57 ± 0.08 0.53 ± 0.08
1980 ± 160 7380 ± 670
0.55 ± 0.092 0.73 ± 0.089
6.93 ± 0.65 3.12 ± 0.28
5350 ± 480 24040 ± 2370
(Han et al., 2010)
Rat
Cinnamic acid (active component)
0.15 ± 0.04 0.18 ± 0.07
6497 ± 724 4258 ± 675
2.56 ± 0.59 2.27 ± 0.29
8649 ± 1527 7031 ± 1970
8252.00 ± 1536.00 4636.00 ± 820.00
(Wang et al., 2016a)
Rat
Platycodin D (active component)
3.94 ± 1.16 2.86 ± 1.07
69.66 ± 36.83 17.94 ± 9.33
2.11 ± 0.58 1.22 ± 0.62
/ /
540.21 ± 222.15 88.97 ± 45.42
(Shan et al., 2015)
Rat
Deapio-platycodin D (active component)
4.22 ± 1.55 1.22 ± 0.89
24.11 ± 11.25 13.46 ± 6.43
2.22 ± 1.52 0.78 ± 0.27
/ /
181.31 ± 73.50 81.31 ± 27.75
(Shan et al., 2015)
Rat
Paeoniflorin (active component)
0.34 ± 0.17 0.50 ± 0.12
2770 ± 1200 1720 ± 7300
1.01 ± 0.75 2.35 ± 0.52
/ /
5288.67 ± 1127.17 4639.83 ±127.17
(Li, 2016)
Rat
Paeoniflorin (active component)
0.50 ±0.17 0.33 ±0.17
1.14 ± 0.39 0.39± 0.12
2.17± 0.84 5.94 ± 2.10
/ /
/ /
(Wang, 2010)
31
486
6. Quality control
487
As recorded in the Chinese Pharmacopoeia 2015 edition, the content of
488
glycyrrhizin and liquiritin in licorice should be more than 2.0% and 0.50%,
489
respectively. The quality of traditional Chinese medicine is the guarantee of clinical
490
efficacy and the key of the development of traditional Chinese medicine industry.
491
Quality control of traditional Chinese medicine (TCM) is one of the national strategic
492
issue related to the development of TCM science and industry and it always been the
493
focus by the field.
494
6.1 Application of Quality marker in QC
495
While a mass of chemical components have been isolated and identified form
496
licorice, it remains a gap that which components are relevant for QC or safety
497
assessment of licorice. Chinese scholars have done a lot of work for the quality
498
control of Chinese traditional medicine and the research level has also made great
499
progress, but there are some deficiencies. For example, the research on
500
pharmacodynamic material basis of traditional Chinese medicine is weak, which leads
501
to the index ingredient of quality control is not closely related to the efficacies of
502
traditional Chinese medicine. Hence, Chinese Medicine Quality Markers is introduced
503
into quality control of Chinese medicine by professor Liu Changxiao. The core theory
504
of TCM Q-Markers is “effective, unique, transmission and traceability, measurable
505
and prescription compatibility”. Firstly, Quality markers (Q-markers) are unique
506
chemical substances and inherent secondary metabolites in traditional Chinese
507
medicine or chemical substances formed in the process of processing and preparation.
508
Besides, Q-markers should have a definite chemical structure and bioactivity.
509
Secondly, the thinking mode and research method of TCM Q-markers focus on the
510
dynamic change and the transmissibility and traceability of Q-markers in the whole 32
511
production
512
processing-Preparation-Pharmaceutical process-Delivery and metabolism in vivo),
513
which fits the essential characteristics of TCM and is helpful to establish quality
514
control and traceability system in the entire production state. Thirdly, the
515
identification of Q-markers should be related to the clinical use of traditional Chinese
516
medicine. To be specific, Q-markers should be considered and confirmed based on the
517
final active constituents in the traditional clinical application, and clinical expression
518
form of efficacy of traditional Chinese medicine. (Liu et al., 2016; Zhang et al., 2019).
519
Chinese Medicine Quality Markers should be used for further quality control of
520
licorice.
521
6.2 The property of multi-layer and multi-targets of traditional Chinese medicine
522
As a widely used and cultivated traditional Chinese herbal medicine, licorice
523
hold the property of multi-component, multi-layer and multi-target same as other
524
herbal medicine. The main and effective components in licorice are complex,
525
including flavonoids, triterpenoid saponins, and coumarins, which result in
526
pharmacological efficacy diverse (Chen, 2008; Chen et al., 2013). Because of this,
527
one single component cannot on behalf of the quality and the complex
528
pharmacological actions of licorice itself, so do the content of glycyrrhizin and
529
liquiritin. The quality control system of licorice needs to be improved and completed.
530
Liquiritigenin, isoliquiritigenin and glycyrrhiza polysaccharides, all of which have
531
been reported that having certain pharmaceutical efficacy but still out of the list of
532
quality control constituents. Therefore, the comprehensive consideration of symbolic
533
components above should be considered to carry out in quality control, in order to
534
reflect the substantial quality of licorice as far as possible. The essential point to carry
535
out the pharmacological study is controlling the quality of licorice. Making multiple
process
(Original
33
plant-Harvesting
and
536
active components the dominant position rather than individual effective ingredient is
537
of vital importance.
538
6.3 The adulterant of licorice
539
Glycyrrhiza pallidiflora Maxim., which belongs to the genus Glycyrrhiza, is a
540
major adulterant of licorice. But it has barely pharmacological activities as licorice
541
(Han, 2013). Supported by Fourier transform infrared spectroscopy, Tashi established
542
a method of identification of standard and false licorice (Glycyrrhiza pallidiflora
543
Maxim.). The result showed there are some certain differences in their chemical
544
components that are reflected in the IR spectra. Farther, they are quite different from
545
each other in second derivative spectra and 2D spectra. Based on the differences
546
reflected in the IR, IR second derivative spectrum and 2D IR, the standard licorice can
547
be identified from the false easily and clearly (Tashi et al., 2006). Yang collected 240
548
licorice plants from 21 populations of 7 provinces, and amplified their ITS and
549
psbA-trnH sequences. ITS sequences with a full length of 616 bp and psbA-trnH
550
sequences with a full length of 389 bp were obtained separately. With the combination
551
analysis of ITS and psbA-trnH sequences, the molecular identification method of
552
original licorice was established (Yang et al., 2017).
553
7. Toxicology
554
Licorice is widely used as a “medicine food homology” herbal medicine, so it is
555
very important to systematically evaluate the safety of licorice. Based on TCM theory,
556
as the saying that “all drugs are slightly toxicity”(是药三分毒), although licorice is
557
regarded as a kind of natural, safe and effective edible-medicine, but its dosage and
558
duration should also be paid attention. Some studies on the toxicity and dosage and
559
duration of licorice are as follows: 34
560
500, 1000, and 2000 mg/kg licorice extract was orally administered to male rats,
561
none significant harm to reproductive function has been found, and the upper-limit
562
dose (2000mg/kg) and long-term exposure to licorice might not cause serious adverse
563
effects (Shin et al., 2008). Another study on the application of glycyrrhizin in the
564
treatment of acute autoimmune hepatitis showed that the adverse reactions of
565
glycyrrhizin are depend on the dosage and duration of usage. It is safe that
566
glycyrrhizin is used in normal dose (below 100 mg/d)(Yasui et al., 2011).
567
Glycocorticosteroid-like action of licorice could stimulate the central nervous system,
568
therefore, mental and cardiovascular patients who treat diseased with licorice should
569
take care about the dosage and duration (Decio et al., 2003; Shen, 2002). There are
570
reports indicated that licorice and its preparations could induce gastrointestinal
571
reactions, while most patients can recover without special treatment after the herbal
572
medicine administration is stopped (Zheng and Yan, 1998).
573
8. Conclusions
574
Abundant chemical components have been isolated and identified from licorice,
575
but whether the components are suitable as quality control ingredients and their
576
pharmacological activity are still need further researched and analyzed. Firstly, index
577
components (Q-markers) which is relevant for QC or safety assessment should be
578
screened out from a mass of components mentioned above for the quality control of
579
licorice. Meanwhile, some key constituents maybe react with other compounds of
580
certain herbal medicine to produce precipitation, so the change of Q-markers should
581
be considered when licorice is used in combination preparations. Besides, a uniform
582
and specific quality standard of licorice should be developed in the future for species
583
in different region all over the world. Secondly, although amounts of isolated
584
compounds of licorice have been revealed, further research is needed to evaluate 35
585
which components are the basis for certain pharmacological effects of licorice.
586
Furthermore, the role (reduce toxicity/increase efficacy) of the numerous constituents
587
in combination preparations need to be assessed.
588
The research that combination application mechanism of licorice and other
589
herbal medicine mainly focus on interaction of chemical compounds between licorice
590
and toxic herbal medicine, pharmacological effect of licorice, and the effect of licorice
591
on pharmacokinetics of toxic compounds. But the research is preliminary, there are
592
still many problems to be solved. First of all, some current research suggested that
593
licorice compounds reacted with other toxic compounds to produce precipitation in
594
vitro. Thus, the solubility of toxic compounds is reduced in decoction that is taken
595
into body, and most of precipitation was leave outside rather than being taken into
596
body. The process maybe reduces the absorption of toxic compounds in vivo. But it is
597
not clear how a small part of precipitation taken into body is absorbed and distributed
598
in vivo, and whether licorice actually slow down the absorption of toxic ingredients in
599
vivo. Caco-2, MDCK-MKRI, TC-7 cell model and everted intestinal sac model could
600
be used to illustrate the absorption of toxic components for understanding the
601
mechanism. Also, according to the measured apparent permeability coefficient and the
602
efflux rate of two-way transport, the corresponding absorption mechanism can be
603
inferred. Secondly, the most studies on pharmacological effects while combining
604
application with licorice merely focus on the macroscopic model (eg. rat and mice
605
model) rather than micromodel. All results provided some macroscopic references for
606
understanding the underlying mechanism of combination effect of licorice. However,
607
more researches for understanding this mechanism exactly need to be revealed by
608
cellular level and molecular level experiments. More importantly, the current clinical
609
research of detoxification effect of licorice is still scanty, there are a gap between 36
610
scientific evidence and a long-term practice. Also, it could be of considerable
611
therapeutic risk lack of the sound (clinical) evidence. Therefore, clinical research on
612
detoxification effect should be a key point in future research. At last, modern
613
pharmaceutics point out that whether drugs work or not is associated to its effectively
614
delivered to its target. And physiological studies have shown that the intestinal barrier
615
is the major barrier for oral absorption of substances. Therefore, the studies on
616
intestinal absorption, transporters and biological targets is helpful to reveal the
617
mechanism of the combination effect.
37
618
Acknowledgements
619
This work was supported by the National Natural Science Foundation of China
620
(No.81803742, No.81703718), Key Project of Natural Science Fund of Sichuan
621
Province (No.18ZA0187), Pre-research National Natural Science Foundation of
622
Chengdu University of Traditional Chinese Medicine (No. ZRYY1718), Key Project
623
of Xinglin Scholars’ Foundation of Chengdu University of Traditional Chinese
624
Medicine (QNXZ2019031).
625
ABBREVIATIONS
626
ALT, alanine aminotransferase; AST, aspartate aminotransferase; Akt, protein kinase
627
B; CCR5, chemokine receptor CYP1A2, cytochrome P450 1A2; CYP2C19,
628
cytochrome P450 2C19; GLU, glucose; GSH, glutathione; HMGB1, high-mobility
629
group box1 protein; HPLC-Q-TOF/MS, high performance liquid chromatography
630
coupled with quadrupole time-of-flight mass spectrometry; IL-1, interleukin-1; IFN-γ,
631
interferon gamma; IL-17, interleukin 17; IL-1β, interleukin-1β; IL-6, interleukin-6;
632
IL-8, interleukin-8; MDA, malondialdehyde; MIF, macrophage migration inhibitors;
633
SWE, superheated water extraction; SOD, superoxide dismutase; TCM, traditional
634
Chinese medicine; TNF-α, tumour necrosis factor-alpha; TBARS, thiobarbituric acid
635
reactive substances; VEGF, vascular endothelial growth factor.
636
Conflict of interest the authors declared
637
We declare that we have no financial and personal relationships with other
638
people or organizations that can inappropriately influence our work, there is no
639
professional or other personal interest of any nature or kind in any product, service
640
and/or company that could be construed as influencing the position presented in or the
641
review of the manuscript entitled.
642 38
643
Reference
644
A.Farag, M., A.Wessjohann, L., 2012. Volatiles profiling in medicinal licorice roots using steam
645
distillation and solid-phase microextraction (SPME) coupled to chemometrics. Journal of Food
646
Science 77, 1179-1184.
647
Bahmani, M., RafieianKopaei, M., Jeloudari, M., Eftekhari, Z., Delfan, B., Zargaran, A.,
648
Forouzan, S., 2015. A review of the health effects and uses of drugs of plant licorice
649
(Glycyrrhiza glabra L.) in Iran. Asian Pacific Journal of Tropical Disease 5, 127-129.
650
Cai, S., Lv, S., Wang, Y., Li, Y., 2012. Solubility and Apparent Oil / Water Partition Coefficient
651
of Glycyrrhizin and Pachymic Acid. Information on Traditional Chinese Medicine 29, 118-121.
652
Chen, Y.H., 2008. Studies on the chemical constituents and related pharmacodynamics of
653
liquorice from different sources, college of pharmacy. BeiJiing University of Chinese medicine,
654
China, p. 133.
655
Chen, Y.H., Huang, M.J., Wang, W.Q., Sun, J.N., 2013. Comparative Study on Major
656
Ingredient Contents and Effect of Depressing Transaminase of Licorice from Different Sources.
657
Chinese Journal of Experimental Traditional Medical Formulae 19, 113-116.
658
Cheng, A., Wan, F., Jin, Z., Wang, J., Xu, X., 2008a. Nitrite oxide and inducible nitric oxide
659
synthase were regulated by polysaccharides isolated from Glycyrrhiza uralensis Fisch. Journal
660
of ethnopharmacology 118, 59-64.
661
Cheng, A., Wan, F., Wang, J., Jin, Z., Xu, X., 2008b. Macrophage immunomodulatory activity
662
of
663
immunopharmacology 8, 43-50.
664
Cristina, F., Michael, E., Eugenio, R., Giorgio, Z., Armanini., D., 2005. A history of the
665
therapeutic use of liquorice in Europe. Journal of ethnopharmacology 99, 317-324.
666
Decio, A., Lorenzo, C., Andrea, S., 2003. Pseudohyperal dosteronism: pathogenetic
667
mechanisms. Critical Reviews in Clinical Laboratory Scienses 40, 295-335.
668
Dong, J.N., Ma, C.C., Jia, P., Chen, L., Long, L.H., Wang, S.X., Zheng, X.H., 2017. Effect of
669
Carthami Flos-Glycyrrhizae Radix et Rhizoma compatibility on energy metabolism in the tissue
670
of rats with cold coagulation blood stasis. Chinese Journal of Pharmaceutical Analysis 37,
671
1389-1397.
672
Ergil, M.C., Ergil, K.V., 2010. Pocket atlas of Chinese medicine. Deutsche Zeitschrift Für
673
Akupunktur 53, 75-76.
674
Fan, J.J., Bi, C.H., Liu, J., Huang, Z.F., 2014. Experimental Study of Rhizoma Dioscoreae
675
Bulbiferae Concerted Radix Glycyrrhiza Reducing Renal Toxicity in Rats．. Journal of Medical
676
Research | J Med Res 43, 31-33.
677
Feng, J.Z., Lu, X.Z., Lu, J.M., Zhang, X.H., 1995. A study on development of animal husbandry
678
by using Glycyrrhiza. Journal of Arid Land Resource and Environment 9, 84-89.
679
Fu, M.N., Dai, F.B., Zheng, H.C., Fu, K.Z., 1989. The determination of the content of
680
Glycyrrhizic acid in liquorice
polysaccharides
isolated
from
Glycyrrhiza
uralensis
Fish.
International
by HPLC. Academic Journal of Second Military Medical 39
681
University 10, 257-260.
682
Gao, X., Zhao, D., Zhao, J.J., Zhang, X., Wang, Y.H., Wang, H.Q., 2017. Herbal textural
683
research on Glycyrrhizae Radix et Rhizoma. Chinese Journal of Experimental Traditional
684
Medical Formulae 23, 193-198.
685
Gu, L.Q., Wang, X.F., Liu, Z.Z., Ju, P., Zhang, L.H., Zhang, Y.Y., Ma, B.J., Bi, K.S., Chen, X.H.,
686
2014. A study of Semen Strychni-induced renal injury and herb-herb interaction of Radix
687
Glycyrrhizae extract and/or Rhizoma Ligustici extract on the comparative toxicokinetics of
688
strychnine and brucine in rats. Food and Chemical Toxicology 68, 226-233.
689
Guo, Y.Y., Ma, W.B., Xiao, H.B., Yan, J., Li, G.Y., Sun, S., Yang, D.Y., Lu, S.W., 2017.
690
Changes of toxic substance in different phase of compatibility decoction Strychni
691
Glycyrrhizae Radix et Rhizoma based on UPLC-MS technique Chinese Traditional and Herbal
692
Drugs 23, 4880-4884.
693
Han, D.C., 2013. Identification of licorice, China News of Traditional Chinese Medicine. State
694
Administration of Traditional Chinese Medicine of the People's Republic of China China, pp.
695
1-2.
696
Han, G., Jin, G.C., Ye, X.Z., Bi, R., Dong, Y., 2009. Effect of glycyrrhetinic acid on extraction
697
rate of anthraquinoids in dahuanggancao decoction. Lishizhen Medicine and Materia Medica
698
Research 20, 704-705.
699
Han, G., Kang, X., Zhe, G.Y., Fan, Y., Wang, L.X., Liu, L., la, W.Y., 2010. Effect of
700
Compatibility Using Glycyrrhiza and Rhubarb on Pharmacokinetics of Rhein in Rats. Chinese
701
Journal of Experimental Traditional Medical Formulae 16, 72-74.
702
Han, S.Y., Li, H.X., Ma, X., Zhang, K., Ma, Z.Z., Jiang, Y., Tu, P.F., 2013. Evaluation of the
703
anti-myocardial ischemia effect of individual and combined extracts of Panax notoginseng and
704
Carthamus tinctorius in rats. Journal of ethnopharmacology 45, 722-727.
705
Han, Y.N., Chung, M., 1990. A Pyrrolo-pyrimidine Alkaloid from Glycyrrhiza uralensis Archives
706
of Pharmacal Research 13, 103-104.
707
Han, Y.N., Chung, M., Kim, T., Han, B., 1990. Two
708
Glycyrrhiza
709
Hao, F., 2001. Advances in Glycyrrhizin research abroad. China Pharmacy 12, 500-501.
710
He, M., Lv, H.Y., Liao, Y.C., 2014. A multiplex approach for the UPLC-PDA-MS/MS data：
711
analysis of licorice. National symposium on Chinese medicine in 2014, 106-114.
712
He, M., Yang, Z.Y., Guan, W.N., Goncalves, C.M.V., Nie, J., Wu, H., 2016. GC-MS analysis
713
and volatile profile comparison for the characteristic smell from Liang-wai Gan Cao
714
(glycyrrhiza uralensis) and honry-roasting product. journal of Chromatographic Science 54,
715
879-887.
716
Hiroaki, K., Norito, T., Zhao, J., Hideki, K., Haruki, Y., 1996. Pectic Polysaccharides from
717
Roots of Glycyrrhiza uralensis: Possible Contribution of Neutral Oligosaccharides in the
718
Galacturonase-Resistant Region to Anti-Complementary and Mitogenic Activities. Planta
719
Medica 62, 14-19.
Semen and
Tetrahydroquinoline Alkaloids
from
uralensis Archives of Pharmacal Research 13, 101-102.
40
720
Hua, B.C., Hu, J., Wang, R.G., Li, Y.C., Lin, J.M., Zheng, L.P., Lin, R.H., Chen, X.F., 2011.
721
Experimental research of Radix Glycyrrhiza on Reducing Hepatic Toxicity induced by Rhizoma
722
Dioscoreae bulbiferae. World Journal of Intergrated Traditional and Westem Medicine 6,
723
24-27.
724
Hua, B.C., Huang, Z.F., Liu, J., Chen, X.L., Chen, X.F., Wang, Y.H., Zhuo, S., 2014. Effects of
725
the compatibility of Huangyaozi and Gancao on the CYP450 mRNA expression in rat liver.
726
Pharmacy and Clinics of Chinese Materia Medica 5, 12-14.
727
Isao, K., Chen, W., Kazuyuki, H., Motomasa, K., Ren, J., 1998. Chemical studies of chinese
728
Licorice-root.II. Five new flavonoid constituents from the root of Glycyrrhiza aspera Pall.
729
collected in XingJiang. Chemical & Pharmaceutical Bulletin 46, 1511-1517.
730
Isao, K., Kazuyuki, H., Emiko, U., Chen, W., Masayuki, Y., Ren, J., 1993. Saponin and
731
Sapogenol.L. on the constituents of root of Glycyrrhiza uralensis Fischer from Xinjiang,China.
732
Chemical structures of licorice-Saponin L3 and Isoliquiritin Apioside. Chemical &
733
Pharmaceutical Bulletin 41, 1567-1572.
734
Ji, S., Li, Z., Song, W., Wang, Y., Liang, W., Li, K., Tang, S., Wang, Q., Qiao, X., Zhou, D., Yu,
735
S., Ye, M., 2016. Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the
736
Effective Components of a Traditional Herbal Medicine. Journal of natural products 79,
737
281-292.
738
Jiang, D.X., Chena, Y.S., Hou, X.T., Xu, J.F., Mu, X., Chen, W., 2011. Influence of Paeonia
739
lactiflora roots extract on cAMP-phosphodiesterase activity and
740
action. Journal
741
Jiang, Y.P., Peng, W., Cao, L.M., You, Y., Gao, F., Fu, C.M., 2015. Change law of gingerols
742
from zingiberis Rhizoma in sini tang before and After Compatibility with Other Herbs. Chinese
743
Journal of Experimental Traditional Medical Formulae 21, 1-4.
744
JM Zhang, Fu, C.M., He, Y.X., Lu, J.R., Gao, F., Wang, J.S., Liao, W., 2013. Comparison on
745
chemical components in sediments of Aconiti Lateralis Radix Preparata-Glycyrrhizae Radix et
746
Rhizoma before and after their compatibility Chinese Traditional and Herbal Drugs 44,
747
165-169.
748
Kiliacky, J., Ross, M., Turner, T., 1976. The determination of β-Glycyrrhetinic acid in liquorice
749
by high pressure liquid chromatography. Planta Medica 30, 311-316.
750
Kim, J.H., Shin, H.K., Seo, C.S., 2014. Chemical interaction between Paeonia lactiflora and
751
Glycyrrhiza
752
high-performance liquid chromatography method: herbal combination and chemical interaction
753
in a decoction. Journal of separation science 37, 2704-2715.
754
Kong, M., Liu, H.-H., Wu, J., Shen, M.Q., Wang, Z.G., Duan, S.M., Zhang, Y.B., Zhu, H., Li,
755
S.-L., 2018. Effects of sulfur-fumigation on the pharmacokinetics, metabolites and
756
analgesic activity of Radix Paeoniae Alba. Journal of ethnopharmacology 212, 95-105.
757
Kong, X.y., Wan, H.y., Su, X.h., Zhang, C., Yang, Y., Li, X.m., Yao, L., Lin, N., 2014. Rheum
758
palmatum L. and Coptis chinensis Franch., exert antipyretic effect on yeast-induced pyrexia
of
related
anti-inflammatory
Ethnopharmacology 137, 914-920.
uralensis,
the
components
of
41
Jakyakgamcho-tang,
using
a
validated
759
rats involving regulation of TRPV1 and TRPM8 expression. Journal of ethnopharmacology 153,
760
160-168.
761
Li, H.Y., 2016. The effect of Sini powder on pharmacokinetics of active components of Paeonia
762
lactiflora Pall, Clinical college of Chinese medicine. Liaoning University of Traditional Chinese
763
Medicine, China.
764
Li, J., 2013. The effects and coupling of Radix Glycyrrhizae in Treatise on Cold Damage
765
Diseases, College of Basic Medicine. Guangzhou University of Chinese Medicine, China, p.
766
58.
767
Li, J., Li, B., Xu, B., Guo, S.X., 2018. Study on the optimal extraction process of glycyrrhiza
768
alkaloids. China Food Additives, 128.
769
Li, J., Ren, A.N., Zhao, Y., 2016. HPLC determination of 6-gingerol, glycyrrhizic acid and
770
liquiritin contents after Zingiberis Rhizoma compatibility with Glycyrrhizae Radix et Rhizoma.
771
Central South Pharmacy 14, 994-997.
772
Li, S.D., Xie, J., 1980. The determination of content of Glycyrrhizin in liquorice by volumetric
773
method. Special Wild Economic Animal and Plant Research 1, 35-36.
774
Li, X.X., Du, F.Y., Liu, H.X., Jian Bo Ji, Xing, J., 2015. Investigation of the active components in
775
Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity. Journal of
776
ethnopharmacology 162, 238-243.
777
Liang, B., Yang, A.F., Huang, F.L., Hu, B.Z., 2006. Research advances on chemical
778
constituents and pharmacological activities in Glycyrrhiza. Journal of Northeast Agricultural
779
University 37, 115-119.
780
Liang, W.N., Su, M.X., Chen, M.Y., 2016. Experimental study on analgesic and
781
anti-inflammatory effects of combination of peony and liquorice. Journal of North Pharmacy 13,
782
123-124.
783
Liang, Y., Qu, L.H., Fang, Y.K., Guo, B.J., Song, Y.P., 2005. GC-MS analysis of volatile
784
constituents of Glycyrrhiza uralensis Fisch. Northwest Pharmaceutical Journal 20, 3-5.
785
Lin, Y.J., You, Y., Ji, N.P., Zhang, J.M., Chen, Q.W., Fu, C.M., 2014. Changes of chemical
786
ingredients before and after compatibility of Aconiti Lateralis Radix Praeparata and
787
Glycyrrhizae Radix et Rhizoma Praeparata
788
fingerprint technology. hinese Traditional and Herbal Drugs
789
Liu, B., Wen, Q., Zhang, J., Yang, J., 2007a. Antiasthmatic effect of isoliquiritigenin and its
790
mechanism. chinese journal of clinical pharmacy 16, 348-352.
791
Liu, C., Chen, S., Xiao, X., Zhang, T., Hou, W., Liao, M., 2016. A new concept on quality
792
marker of Chinese materia medica: Quality control for Chinese medicinal products. Chinese
793
Traditional and Herbal Drugs 47, 1443-1455.
794
Liu, G., Kuang, J., Fang, X.J., 1987. The determination of Glycyrrhizic acid in extractum
795
Glycyrrhizae with a colorimetric method. Journal of Ningxia University 2, 2-5.
796
Liu, H., 2013. Systems approaches and polypharmacology for drug discovery from licorice,
797
School of bioinformatics. Northwest A & F University, China, p. 46. 42
cum Melle analyzed by HPLC-Q-TOF/MS 45, 1556-1560.
798
Liu, J.Q., Li, Q., Zhang, R., Liu, F., Zhang, W., He, Z.H., Hong, Q., Kou, X.L., Wu, J.M., 2010.
799
LC-MS/MS studies on effect of Glycyrrhiza uralensis on metabolism distrbution and excretion
800
of triptolide in rat. Chin J Pharm Anal 30, 1665-1671.
801
Liu, T.S., Zhao, X.H., Duan, J.N., Di, L.Q., Huang, Y.Z., 2007b. Study on anti-inflammatory and
802
analgesic action of total Glucosides from shaoyao gancao Decoction and its compound
803
mechanism. Traditional Chinese Drug Research and Clinical Pharmacology 18, 427-430.
804
Liu, Y.C., Chen, Y.G., Wang, D., Gao, X.Y., Guo, H.Z., Fu, X.T., Wang, W.Q., 2011. Studies
805
on chemical constituents on roots of Glycyrrhiza uralensis. Chinese Journal of Pharmaceutical
806
Analysis 31, 1251-1255.
807
Luo, X.J., 2017. Effect of rhubarb glycyrrhiza on the dissolution of contents of anthraquinones
808
in rhubarb. Journal of Sichuan of Traditional Chinese Medicine 35, 47-49.
809
Ma, H.G., Jiang, Q., Wang, Z.J., Liu, H., He, J.L., 2014. Effect of light and temperature on seed
810
germination of glycyrrhiza uralensis under different pretreatment. Research of Soiland Water
811
Conservation 21, 225-235.
812
Ma, H.J., Gao, J., Zhang, Y.L., Zhang, X., Miao, X.Z., Tan, P., 2018. Study on identification of
813
compounds and their fragmentation pathways in licorice by HPLC-MSn. China Journal of
814
Traditional Chinese Medicine and Pharmacy 33, 1120-1123.
815
Masashi, T., Noriko, S., Mieko, K., Ryoko, G., Sumiko, A., Yuko, O., 1990. Characterization of
816
two polysaccharides having activity on the reticuloendothelial system from the root of
817
Glycyrrhiza uralensis. Chemical & Pharmaceutical Bulletin 38, 1667-1671.
818
Meng, X.Y., Pi, Z.F., Song, F.R., Liu, Z.Q., Liu, S.Y., 2009. Changes in the effect compounds
819
and the anti-inflammatory activity before and after the decoction of ephedra and liquorite.
820
chinese journal of applied chemistry 7, 801-806.
821
NationalHealthCommission, 2018. Both Food and Chinese Medicinal Materials Catalogue
822
Management Method, in: China, M.o.H.o. (Ed.). Ministry of Health of China, China, pp. 1-16.
823
Noriko, S., Masashi, T., Mieko, K., Ryoko, G., Akemi, S., Noriko, S., 1990. A novel neutral
824
polysaccharide having activity on the reticuloendothelial system from the root of glycyrrhiza
825
uralensis. Chemical & Pharmaceutical Bulletin 38, 3069-3071.
826
Pan, S.F., Hua, B.C., 2016. Study of Radix Glycyrrhiza on reducing hepatic toxicity induced by
827
Radix et Rhizoma sophorae tonkinensis in mice. . journal of jiangxi university of TCM 28,
828
90-92.
829
Peng, L., Hu, Z.H., Li, J.T., Zhang, Q., 2008. Distribution and dynamic variation of liquiritin in
830
Glycyrrhiza uralensis Fisch. Chinese Journal of Pharmaceutical Analysis 28, 1230-1233.
831
Rasool, M., Iqbal, J., Malik, A., Ramzan, H.S., Qureshi, M.S., Asif, M., Qazi, M.H., Kamal, M.A.,
832
Chaudhary, A.G., Al-Qahtani, M.H., Gan, S.H., Karim, S., 2014. Hepatoprotective Effects of
833
Silybum marianum (Silymarin) and Glycyrrhiza glabra (Glycyrrhizin) in Combination: A
834
Possible Synergy. Evidence-based complementary and alternative medicine : eCAM 2014,
835
641597.
836
Shabkhiz, M.A., Eikani, M.H., Bashiri, S.Z., Golmohammad, F., 2016. Superheated water 43
837
extraction of glycyrrhizic acid from licorice root. Food chemistry 210, 396-401.
838
Shan, J.J., Zou, J.S., Xie, T., Kang, A., Zhou, W., Xu, J.Y., Shen, C.S., Du, L.i.N., Wang, S.C.,
839
Di, L.Q., 2015. Effects of Gancao on pharmacokinetic profiles of platycodin D and
840
deapio-platycodin D in Jiegeng. Journal of
841
Shen, M.Y., 2002. Clinical application and notice of liquorice. Zhejiang Journal of Integrated
842
Traditional Chinese and Western Medicine 12, 784-785.
843
Shi, L., Tang, X.L., Dang, X.L., Wang, Q.H., Wang, X., He, P., Wang, Q.W., Liu, L.N., You, L.X.,
844
Yan, Z., 2015a. Investigating herb–herb interactions: The potential attenuated toxicity
845
mechanism of the combined use of Glycyrrhizae radix et rhizoma (Gancao) and Sophorae
846
flavescentis radix (Kushen). Journal of ethnopharmacology 165, 243-250.
847
Shi, L., Tang, X.l., Dang, X.l., Wang, Q.h., Wang, X.r., He, P., Wang, Q.w., Liu, L.n., Liu, X.Y.,
848
Zhang, Y., 2015b. Investigating herb–herb interactions: The potential attenuated toxicity
849
mechanism of the combined use of Glycyrrhizae radix et rhizoma (Gancao) and Sophorae fl
850
avescentis radix (Kushen). Journal of ethnopharmacology 165, 243-250.
851
Shin, S., Jang, J.Y., Choi, B.I., Baek, I.J., Yon, J.M., Hwang, B.Y., Park, D., Jeon, J.H., Nam,
852
S.Y., Yun, Y.W., 2008. Licorice extract does not impair the male reproductive function of rats.
853
Exp Anim 57, 11-17.
854
Sun, B., Wanga, X.b., Cao, R.l., Zhang, Q., Liu, Q., Xu, M.f., Zhang, M., Du, X.b., Dong, F.t.,
855
Yan, X.z., 2016a. NMR-based metabonomics study on the effect of Gancao in the attenuation
856
of toxicity in rats induced by Fuzi. Journal of ethnopharmacology 193, 617-626.
857
Sun, C., Xie, Y.C., Tian, Q.L., Liu, H.Z., 2007. Separation of glycyrrhizic acid and liquiritin from
858
licorice root by aqueous nonionic surfactant mediated extraction. Colloids and Surfaces A:
859
Physicochemical and Engineering Aspects 305, 42-47.
860
Sun, G.X., Wang, Y., Sun, Y.q., 2011. The Quantitative Determinations of Glycyrrhizic Acid,
861
Glycyrrhetinic Acid, Morphine, and Sodium Benzoate in Compound Liquorice Tablets by
862
HPCE. Journal of Liquid Chromatography & Related Technologies 26, 43-51.
863
Sun, L., Zong, S.B., Li, J.C., Lv, Y.Z., Li Na
864
J.P., Xiao, W., 2016b. The essential oil from the twigs of Cinnamomum cassia Presl alleviates
865
pain and inflammation in mice. Journal of ethnopharmacology 194, 904-912.
866
Takeshi, K., Tamotsu, S., Shoji, S., 1978. A new 3-Arylcoumarin from Licorice root. Chemical
867
& Pharmaceutical Bulletin 26, 135-140.
868
Tashi, A., Zhou, Q., Dong, X.O., Sun, S.Q., 2006. Study on the identification of standard and
869
false Gancao by Fourier transform infrared spectroscopy. Spectroscopy and Spectral Analysis
870
26, 1238-1241.
871
Tian, S.Z., Yang, Y.T., Yang, X., Chang, L., 2009. Analysis of licorice preparation in the
872
Edition of Chinese Pharmacopoeia. Chinese Traditional Patent Medicine 31, 1434-1435.
873
Tong, P.j., Xu, S.b., Cao, G., Jin, W.d., Guo, Y.w., Cheng, Y., Jin, H.t., Shan, L.t., Xiao, L.w.,
874
2014. Chondroprotective activity of a detoxicated traditional Chinese medicine (Fuzi)of
875
Aconitum
carmichaeli Debx
against
Ethnopharmacology 170, 50-56.
Liu, Zheng Zhong
Wang, Zhou, J., Cao, L., Kou,
severe-stage osteoarthritis 44
model
2005
induced
by
876
monoiodoacetate. Journal of ethnopharmacology 151, 740-744.
877
Tsutomu, H., Miyuki, T., Hideyuki, I., Takashi, Y., 1997. Phenolic constituents of liquorice VII.A
878
new Chalcone with a potent radical scavenging activity and accompanying phenolics from
879
Liquorice. Chemical & Pharmaceutical Bulletin 45, 1485-1492.
880
Wagner, H., Ulrich-Merzenich, G., 2009. Synergy research: Approaching a new generation of
881
phytopharmaceuticals.
882
phytopharmacology 16, 97-110.
883
Wang, F., 2014. Clinical research on the change of aconitine in compatible application of Fuzi
884
and Ganjiang, Fuzi and Gancao Clinical Journal of Chinese Medicine 6, 22-25.
885
Wang, F., Su, Y., 2002. Pharmacological action and clinical application of licorice. LiShizhen
886
Medicine and Materia Medica Research 13, 303-304.
887
Wang, J., Dai, L., Li, P.Y., Huo, H.R., Sui, F., Zhang, C.F., Li, L.F., Guo, S.Y., Li, C.H., Jiang,
888
Y.L., 2014. Study on active ingredients for increased efficacy of compatibility of penoy and
889
licorice. Chinese Journal of Experimental Traditional Medical Formulae 20, 83-86.
890
Wang, M., Liu, B., Qi, Y., Song, Y., Xie, S., Luo, X., Cai, R., 2008. Effect of Glycyrrhiza
891
Uralensis Saponins on Acute Toxicity of Platycodins. Chinese Journal of Experimental
892
Traditional Medical Formulae 14, 59-61.
893
Wang, Q.E., Ren, H., Cao, X.L., 2011. Research and utilization statue of licorice. Chinese
894
Agricultural Science Bulletin 27, 290-295.
895
Wang, S., 2015. The efficacy and taboo of licorice research in "Treatise on Febrile Diseases",
896
College of Basic Medicine. Liaoning University of Traditional Chinese Medicine, China, p. 53.
897
Wang, S.J., 2010. Study on pharmacokinetic of shaoyao-licorice decoction in rats, Clinical
898
college of Chinese medicine. Liaoning University of Chinese Medicine, China.
899
Wang, S.N., Sun, L.J., Gu, L.Q., Zhang, Y.Y., Zhao, S.M., Zhao, L.S., Bi, K.S., Chen, X.H.,
900
2016a. The comparative pharmacokinetics of four bioactive ingredients after administration of
901
Ramulus Cinnamomi-Radix Glycyrrhizae herb pair extract, Ramulus Cinnamomi extract and
902
Radix Glycyrrhizae extract. Biomed Chromatography 30, 1270-1277.
903
Wang, S.X., Wang, J., Ma, C.C., Jia, P., Yang, Y., Zheng, X.H., 2018. Effect of
904
safflower-liquorice on vasomotion of mesanteric artery in rats with cold coagulation and blood
905
stasis. Chin Hosp Pharm J 38, 387-392.
906
Wang, X., Zhang, H., Chen, L.L., Shan, L.H., Fan, G.W., Gao, X.M., 2013. Liquorice, a unique
907
"guide drug" of traditional Chinese medicine: a review of its role in drug interactions. Journal of
908
Ethnopharmacol 150, 781-790.
909
Wang, X.P., Huang, X.W., Wang, N.N., Wu, R.J., Li, H.Y., Yu, Z.M., Shou, D., 2015. Toxicity of
910
the water extraction of Radix sophorae flavescentis formulated with Ｒadix Glycyrrhizae on
911
mice. CHINESE ACHIVES OF TＲADITIONAL CHINESE MEDICINE 33, 1653-1655.
912
Wang, Z.L., Du, J.C., Yu, L.Q., Ba, D.L., Shi, Z., 2002. The utilization value , current research
913
and problems of Glycyrrhiza. Grassland of China 24, 73-76.
914
Wang, Z.Q., Zeng, R., Tan, Z.R., Chen, Y., Tian, Y.W., Wang, B., li, J., Chen, L.F., 2012.
Phytomedicine
:
international
45
journal
of
phytotherapy
and
915
Pharmacokinetics of aconitine and glycyrrhetic acid in separation and combination with Aconiti
916
lateralis Radix praeparata and Glycyrrhizae Radix et Rhizoma in rats. Chinese Traditional
917
Patent Medicine 34, 2305-2309.
918
Wang, Z.Y., Cui, S.L., Li, L.F., Li, H., Zhang, J., 2016b. Synergistic study of peony and
919
liquorice decoction. Science & Technology Vision 5, 274-275.
920
Wu, W.P., Yan, H.T., Sun, W.J., 2004. HPLC determination of Liquiritin in Licorice. Chinese
921
Journal of Pharmaceutical Analysis 24, 425-427.
922
Xie, J.B., Wang, W.Q., 2009. Study on evolution and history of liquorice production area.
923
Research and Practice of Chinese Medicines 23, 35-36.
924
Xie, S.H., Zhang, G.P., Sun, G.B., Chen, R.C., Zhang, S.Y., He, L., Ye, Z.G., 2012.
925
Detoxication experimental study on different compatibility proportion of Aconiti Lateralis Radix
926
Praeparata and Glycyrrhizae Radix et Rhizoma. China journal of chinese meteria medica 37,
927
2210-2214.
928
Xu, W.J., Zhao, J., Zhou, H.F., Luo, J.B., 2012. Effects of different compatibility on content of
929
active ingredients and anti - inflammatory activity of liquorice ephedrae. Journal of Sichuan of
930
Traditional Chinese Medicine 30, 50-54.
931
Xu, X., Meng, N., Yu, Y.J., Hu, M.R., 2016. Effect of the Combined Use of Ｒheum and
932
Liquorice on Inflammatory Factors in Ｒats With Intestinal Function Failure. Chinese General
933
Practice 19, 1824-1827.
934
Yang, J.H., Zhang, Y.Y., Wan, H.T., Zhu, Z.H., Li, J.H., 2010. Experimental study on the
935
combination of aconite alkaloid and glycyrrhizin active substances against adjuvant arthritis in
936
rats. Chinese Traditional and Herbal Drugs 41, 439-444.
937
Yang, R., Li, W.D., Ma, Y.S., Zhou, S., Xue, Y.T., Lin, R.C., Liu, Y., 2017. The molecular
938
identification of licorice species and the quality evaluation of licorice slices Acta Pharmaceutica
939
Sinica 52, 318-326.
940
Yao, F.Y., Wang, B.Z., Peng, S.H., Wang, X., Zheng Yun Zuo, 2014. Effects of glycyrrhiza
941
osmanthus decoction on energy metabolism in low temperature rats. TCM Research 27,
942
67-70.
943
Yasui, S., Fujiwara, K., Tawada, A., Fukuda, Y., Nakano, M., Yokosuka, O., 2011. Efficacy of
944
Intravenous Glycyrrhizin in the Early Stage of Acute Onset Autoimmune Hepatitis. Digestive
945
Diseases and Sciences 56, 3638-3647.
946
Ye, J.Y., Chen, P.Y., Zhang, J.P., Ye, Q.Q., Chen, G.L., 2018. The Influence of Combination of
947
Wumei and Gancao and Single Use of Wumei or Gancao on rats with radiation-induced
948
salivary gland injury. Henan Traditional Chinese Medicine 38, 360-362.
949
Zeng, L., Toshio, F., Taro, N., Zhang, R.Y., Lou, Z.C., 1992. Four new prenylated flavonoids,
950
glyasperins A, B, C, and D from the roots of Glycyrrhiza aspera. Heterocycles 34, 575-587.
951
Zhang, J., Yao, J., Ding, L., Guo, S.J., Yong Li Yang, 2000. Advancement of research on the
952
utilization of glycyrrhiza. Grassland and Turf 89.
953
Zhang, J., Yao, J., Yang, Y.L., Wang, Y.F., Peng, G.L., Wang, Y.J., 2001. Analysis and 46
954
contents mensurate of alkaloid in l iquorice. Acta Botanica Boreali-Occidentalia Sinica 21,
955
1259-1262.
956
Zhang, J.M., Fu, C.M., Su, S.H., Li, Y., Zhang, Z., 2011. Compatibility Effect between Radix
957
Aconiti Lateralis and Radix Glycyrrhizae on Pharmacokinetics of Hypaconitine in Rat Plasma
958
by LC-MS/MS. World Science and Technology 13, 1048-1053.
959
Zhang, R., Li, Q., Liu, F., Liu, J.Q., Zhang, W., He, Z.H., Hong, Q., Kou, X.L., Wu, J.M., 2010.
960
Effect of Glycyrrhiza uralensis on Metabolism and Distribution and Excretion of Triptonide in
961
vivo by LC-MS-MS. Chinese Journal of Experimental Traditional Medical Formulae 16,
962
152-156.
963
Zhang, T., Bai, G., Liu, C., 2019. The concept, core theory and research methods of Chinese
964
medicine quality markers. Acta Pharmaceutica Sinica 54, 187-195.
965
Zhang, W., Gong, L., Zhou, L.L., Shan, J.J., Chen, L.T., Xu, H.Q., Di, L.Q., 2014. Effect of
966
different compatibility of Daphnes Giraldii Cortex and Glycyrrhizae Radix et Rhizoma on
967
adjuvant-induced arthritis in rats
968
Zhao, D.S., Wu, Z.T., Li, Z.Q., Wang, L.L., Jiang, L.L., Shi, W., Li, P., Li, H.J., 2018.
969
Liver-specific metabolomics characterizes the hepatotoxicity of Dioscorea bulbifera rhizome in
970
rats by integration of GC-MS and 1H-NMR. Journal of ethnopharmacology 226, 111-119.
971
Zhao, J.F., Hiroaki, K., Haruki, Y., 1991. Heterogeneity and characterisation of mitogenic and
972
anti-complementary pectic polysaccharides from the roots of Glycyrrhiza
973
et D.C. Carbohydr Res 219, 149-172.
974
Zhao, L., Ma, G.H., Yu, J., Fu, L.Y., 2014. Effect on Alkaloid components in strychnos
975
Nux-vomical L. by different decocting time and compatibility dosages of Radix Glycyrrhizae.
976
LIAONING JOURNAL OF TRADITIONAL CHINESE MEDICINE 41, 1937-1939.
977
Zhao, P.Y., Jiao, L.W., Zhang, Z.M., Yang, X.Y., Xu, J.Z., Lian, Y.H., Bayaer, E., 2017a. Study
978
of the differences of flavonoids compounds in Glycyrrhiza residues from different countries by
979
UPLC-QTOF-MS. China Food Additives, 111-116.
980
Zhao, X.M., Gong, M., Dong, J.M., Wang, J.B., Xiao, X.H., Zhao, K.J., Ma, Z.J., 2017b.
981
Preliminary research on effect of licorice-processed Tripterygium wilfordii on reducing liver
982
toxicity. China journal of chinese meteria medica 42, 119-124.
983
Zhao, Y.M., Liu, S.X., Zhang, C.X., Liu, D.L., Zhang, T.J., 2016. Analysis on chemical
984
constituents from
985
Traditional and Herbal Drugs 47, 2061-2068.
986
Zheng, P., Yan, Y., 1998. Adverse reactions of Licorice and its preparations. ACTA CHINESE
987
MEDICINE AND PHARMACOLOGY, 29-30.
988
Zhou, C., 2010. Licorice. Agricultural press, BeiJing.
989
Zhou, Q., Wang, L., Dai, Y.P., Zhou, H.L., 2017. Influence of Mix-fring with Honry Technics on
990
Volatile Components of Glycyrrhi Radix et Rhizoma Based on GC-MS. Chinese Journal of
991
Experimental Traditional Medical Formulae 23, 87-90.
992
Zhu, G.W., Zhang, G.J., Sun, Y., Wang, M., Qu, L., Xiang, L., Lu, L.N., Wu, Y.L., Yang, Y.F.,
Chinese Traditional and Herbal Drugs
Glycyrrhizae Radix et Rhizoma
47
45, 1418-1426.
uralensis
Fisch
by HOLC-Q-TOF-MS. Chinese
993
Zheng, J., 2016. Analysis of different active components in Radix Paeoniae Alba,Glyycrrhizae
994
Radix Et Rhzoma and their drug pair. World Chinese Medicine | World Chin Med 11, 143-150.
995
Zhuo, S., Hua, B., He, K., Cai, W., Liu, T., Huang, X., Xu, W., 2018. The study on the
996
detoxication
997 998
Rational Drug Use 11, 93-95.
of liquorice on hepatotoxicity of Melia toosendan Sieb.et Zucc. Chin J of Clinical
48
S0378-8741(19)30411-8
DOI:
https://doi.org/10.1016/j.jep.2019.112439
Reference:
JEP 112439
To appear in:
Journal of Ethnopharmacology
Received Date: 30 January 2019 Revised Date:
26 November 2019
Accepted Date: 26 November 2019
Please cite this article as: Jiang, M., Zhao, S., Yang, S., Lin, X., He, X., Wei, X., Song, Q., Li, R., Fu, C., Zhang, J., Zhang, Z., An “essential herbal medicine”—licorice: A review of phytochemicals and its effects in combination preparations, Journal of Ethnopharmacology (2020), doi: https://doi.org/10.1016/ j.jep.2019.112439. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.
An “essential herbal medicine”—licorice: a review of phytochemicals and its effects in combination preparations Maoyuan Jianga, #, Shengjia Zhaoa, #, Shasha Yanga, XiaLina, Xiguo Hea, Xinyi Weia, Qin Songb, RuiLia, Chaomei Fua, Jinming Zhanga, Zhen Zhanga, * a
Pharmacy College，Chengdu University of Traditional Chinese Medicine; The Ministry of Education Key
Laboratory of Standardization of Chinese Herbal Medicine; State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu 611137, China b
Graduate School of Environmental Science, Hokkaido University, Sapporo 0010024, Japan
* Corresponding author. Pharmacy College，Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China. #
Co-first author.
addresses:
[email protected]
(Maoyuan
Jiang),
[email protected]
(Shengjia
Zhao),
[email protected] (Shasha Yang), [email protected] (Xia Lin), [email protected] (Xiguo He), [email protected] (Xinyi Wei), [email protected] (Qin Song), [email protected] (Rui Li), [email protected] (Chaomei Fu), [email protected] (Jinming Zhang), [email protected] (Zhen Zhang)
1
1
Abstract
2
Ethnopharmacological relevance: Licorice (Gancao in Chinese, GC), the dried root
3
and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat. or Glycyrrhiza
4
glabra L., is an “essential herbal medicine” in traditional Chinese medicine (TCM).
5
There is a classic traditional Chinese medicine theory says that “nine out of ten
6
formulas contain licorice” and licorice is considered as one of the most important
7
herbal medicine which can reduce toxicity and increase efficacy of certain herbal
8
medicine while it is combined application. In addition, it is a “medicine food
9
homology” herbal medicine and also be widely used as a health food product and
10
natural sweetener. However, no systematic literature review has been compiled to
11
reveal its superiority. Herein, the aim of this work is to develop an overview of the
12
state on phytochemicals, as well as effects of licorice in combination preparations,
13
which can provide better understand the superiority of licorice and the special position
14
in the application of TCM. Besides, ethnobotany, ethnopharmacological uses, quality
15
control and toxicology of licorice have also been researched, which would provide
16
reference for future clinical and basic research needs.
17
Materials and methods: The information about licorice was collected from various
18
sources including classic books about Chinese herbal medicine, and scientific
19
databases including scientific journals, books, and pharmacopeia. A total of 124
20
bibliographies, which are published from 1976 to 2019, have been searched and
21
researched.
22
Results: In this study, the interaction of chemical compounds between licorice and
23
toxic herbal medicine, pharmacological effect of licorice, and the effect of licorice on
24
pharmacokinetics of toxic compounds are considered as the main mechanisms
25
underlying the effects of licorice in combination preparations. Besides, ethnobotany, 2
26
ethnopharmacological uses and chemical constituents have been summarized.
27
Conclusion: This work comprehensively reviews the state on ethnobotany,
28
ethnopharmacological uses, phytochemicals, combined applications, quality control
29
and toxicology of licorice. It will provide systematic insights into this ancient drug for
30
further development and clinical use.
31
Keywords: Licorice, Ethnobotany, Phytochemicals, pharmacological activities,
32
Effects of licorice in combination preparations, Toxicology
33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
3
48 49
1.Introduction
50
Licorice is native to southern Europe and parts of Asia. It is widely used as an
51
herbal medicine and natural sweetener. As a traditional Chinese medicine used for
52
1000 years, licorice is recorded in the list declared by the Ministry of Health of China
53
which contains 101 traditional edible-medicinal herbs (NationalHealthCommission,
54
2018). Besides, many classic formulas containing licorice have been developed into
55
Chinese patented drugs and commonly used in clinics (Tian et al., 2009).
56
Licorice is an “essential herbal medicine” in China. Since 25 A.D., licorice has
57
been extensively used by the Chinese to tonify qi (life energy) of the heart and spleen.
58
It is also useful to relieve cough, phlegm, dyspnea, spasms, and pain (Li, 2013). In
59
TCM formulas, it is the most frequently used herbal medicine which can harmonize
60
the characteristics of other herbal medicine. For example, there are 283 formulas
61
recorded in the oldest clinical classic in China (Han Dynasty, 220 A.D.), “Shang Han
62
Za Bing Lun”, and licorice has been frequently used 140 times. Therefore, a classic
63
says “nine out of ten formulas contain licorice”(Shifang Jiucao 十方九草) (Wang et
64
al., 2002). Furthermore, due to its effect (the harmonize character in TCM), licorice is
65
usually combined application with herbal medicine such as Aconitum carmichaelii
66
Debx., Paeonia lactiflora Pall. and Zingiber of ficinale Rose. (Wang, 2015).
67
Since the 1960s, a number of studies on licorice have been conducted. To date,
68
more than 200 chemical constituents have been isolated from licorice.
69
Pharmacological studies verified that it has the efficacy of liver protection, digestive
70
system and nervous system protection, anticancer, anti-inflammatory, anti-allergy,
71
anti-AIDS and so on (Liu, 2013). Besides, the underlying mechanism that effects of 4
72
licorice in combination preparations is also one of the hot spots. However, there are
73
not yet any comprehensive studies compiling all these research advances and
74
explaining its superiority. This work comprehensively reviews will provide systematic
75
insights into this ancient drug for further development and clinical use, especially on
76
its effects in combination preparations.
77
2. Ethnobotany
78
Licorice (Glycyrrhizae Radix et Rhizoma) is the root of Glycyrrhiza uralensis
79
Fisch., Glycyrrhiza glabra L. or Glycyrrhiza inflata Bat. These three species, which
80
are recorded in the latest edition (2015 Edition) of Chinese Pharmacopoeia, all belong
81
to the genus Glycyrrhiza. However, there are some different morphological
82
characteristics of the root, rhizome, seed, fruit, and inflorescence as well as the leaf
83
and stem height of these three plants. The morphological characteristics of the three
84
Glycyrrhiza species are described in Table 1 (Fig. 1) (Gao et al., 2017; Zhou, 2010).
85 86 87 88 89 90
Fig. 1 (a-1) Hand painted whole-plant of G. uralensis Fisch, (a-2) aerial part of G. uralensis Fisch, (a-3) flower of G. uralensis Fisch, (a-4) root of G. uralensis Fisch, (b-1) hand painted whole-plant of G. glabra L, (b-2) aerial part of G. glabra L, (b-3) flower of G. glabra L, (b-4) root of G. glabra L, (c-1) hand painted whole-plant of G. inflata Bat, (c-2) aerial part of G. inflata Bat, (c-3) flower of G. inflata Bat, (c-4) root of G. inflata Bat. 5
91 92
93 94 95 96 97
Table 1 The morphological characteristics of three Glycyrrhiza Species Category G. uralensis Fisch.
Root The surface is yellowish brown and rough. With obvious longitudinal wrinkles and round holes
Rhizome The surface is yellowish brown and rough. The longitudinal furrow is deep and wide, and the bulging axillary buds are visible.
Seed Dark brown green, about 2.3~4.6 mm in diameter
Fruit Pod, sickle shaped, 3.1~4.6 cm long, with wrinkles, densely stigma glandular hairs, spiny after abscission.
Inflorescence Racemes, densely capitate, shorter than leaves, 4~12 cm long.
Leaf Odd pinnate Leaf, lobule 2~8 pairs
Stem height
G. glabra L.
The surface is yellowish brown and rough. A hole with fine longitudinal wrinkles and length
The surface is yellow and rough. The longitudinal furrow is deep and wide, and the bulging axillary buds are visible.
Light brown green with a diameter of about 1.5~3.0 mm
Pod, cylindrical, 2.0~3.6 cm long, smooth and glabrous
Racemes, densely spikes, slightly longer or longer than leaves, 10~19 cm long.
Odd pinnate Leaf, lobule 3~10 pairs
45～180 cm
G. inflata Bat.
The surface is dark brown, brown and rufous, and very rough. A hole with a prominent protruding longitudinal wrinkle and length.
The surface is dark brown and rough. Axillary buds with obvious longitudinal grooves and visible eminence
Yellowish green 0.8~2.5 mm
Pod, long ellipse Form, about 0.8~2.5cm long, swollen, slightly adenoma.
Racemes, sparsely spikes, equal to leaves, 5~16 cm long.
Odd pinnate Leaf, lobule 1~4 pairs
50～150 cm
6
35～120 cm
98
Licorice can be propagated by seeds and underground roots or rhizomes. The
99
suitable temperature and light are the key to ensuring the normal development of
100
licorice seedlings. Ma Haige found that the suitable germination conditions of wild
101
licorice seeds are 20~30
102
while 30
103
semi-arid sandy soil, desert edges and loess hilly areas 150~1400 meters above sea
104
level. It is fond of abundant light, minimal rainfall, intense summer heat, severe cold
105
in the winter, and large temperature difference between day and night (Ma et al.,
106
2014). Based on ancient records, licorice was mostly concentrated in Gansu, Ningxia,
107
Shaanxi, Shanxi, Inner Mongolia, and with sporadic distribution throughout Qinghai,
108
Hebei and Shandong. So far, there has been no noticeable change in its origin (Xie
109
and Wang, 2009). In addition, G. uralensis Fisch. is widely distributed throughout
110
Inner Mongolia, Gansu, Xinjiang, Qinghai, Shaanxi, Ningxia, Shanxi, and
111
Heilongjiang. G. glabra L. is mainly distributed in Xinjiang. In addition, G. inflata
112
Bat. is mainly distributed in Xinjiang and in the northwest region of Gansu (Fig. 2)
113
(Wang et al., 2011).
and light for 10 h/d; 20
was suitable for seedling radicles,
was favorable for the hypocotyl. Generally, licorice grows in arid to
114 115
Fig. 2 Climatic and ecological adaptability distribution in China 7
116
3. Ethnopharmacological uses
117
3.1. Application in China
118
Licorice is widely used in China for long times. The first documented medical
119
use of licorice in China can be traced back to Shennong bencao jing (simplified
120
Chinese:神农本草经), which was written in 200 B.C. In this classic, licorice is
121
classified into the first-class herbal medicine, which means non-toxic and edible.
122
Furthermore, licorice is often used as “herb pairs” to harmonize the charecristics of
123
the herbal medicine. Wang analyzed the frequency of licorice use in Shanghan zabing
124
lun (simplified Chinese: 伤 寒 杂 病 论 ), and found it was used in 63% of the
125
prescriptions. Therefore, licorice is honored as “nine out of ten formulas contain
126
licorice” (Wang et al., 2002). Besides, the top ten herbs which are most frequently
127
combined with licorice are as follows: Fructus Jujubae (Da Zao, 63 times), Ramulus
128
Cinnamomi (Gui Zhi, 63 times), Rhizoma Zingiberis Recens (Sheng Jiang, 60 times),
129
Radix Paeoniae Alba (Shao Yao, 43 times), Herba Ephedrae (Ma Huang, 28 times),
130
Radix Ginseng (Ren Shen, 27 times), Rhizoma Pinelliae (Ban Xia, 26 times),
131
Rhizoma Zingiberis (Gan Jiang, 26 times), Radix Aconiti Lateralis Praeparata (Fu Zi,
132
20 times), Poria (Fu Ling, 17 times), and Gypsum Fibrosum (Shi Gao, 17 times)
133
(Wang et al., 2013).
134
Nowadays, many classic formulas containing licorice have been developed into
135
Chinese patented drugs. For example, licorice oral solution is used to treat upper
136
respiratory infection, bronchitis, colds and cough. Sijunzi Granule is used to treat
137
spleen and stomach qi deficiency, poor appetite and loose stools. Yinqiao Powder is
138
used to treat external cold, fever, headache, dry mouth, cough, sore throat and short
139
red urine. Fuzi lizhong pill is used in treating spleen and stomach deficiency, 8
140
epigastric crymodynia, vomiting, diarrhea, as well as hands and feet coldness (Fig. 3).
141 142 143 144
Fig. 3 (a) Compound Glycyrrhiza Oral Solution, (b) Sijunzi Granule, (c) Yinqiao Powder, (d) Fuzi lizhong pills
145
industry in China. Glycyrrhizin has been widely used in food and beverage industries
146
as a sweetener because of the sweet-tasting. For example, in gum, chocolate, sucrose,
147
beer and drinks. Besides, licorice is an important plant for improving soil, maintaining
148
soil and water as well as blocking wind for its character of resistance to cold, hot,
149
drought and saline-alkali conditions. Moreover, licorice can be processed into a
150
popular feed for all kinds of livestock. Licorice is a kind of leguminous pasture crop
151
and has excellent quality in arid and semi-arid areas (Feng et al., 1995).
152
3.2. Application in other countries
In addition, licorice also plays an important role in animal husbandry and
153
In Iran, Licorice is an indigenous medicinal plant and has been used for
154
centuries. Some drugs containing licorice have been produced, such as “Gastrin”,
155
“Licophar”, “Reglisidin” and “Shirinnoush”. These drugs have health efficacy
156
including anti-inflammatory and anti-microbial properties. Licorice still has a good
157
potential capacity to produce more pharmaceutical products, not only limited to local
158
use but also for exportation and introduction as a valuable therapeutic remedy
159
(Bahmani et al., 2015).
160
In
Japan,
the
cosmetics
manufacturing
industry makes
use
of
the
161
anti-inflammatory effect and solubilizing properties of licorice to produce cosmetics
162
with high transparency and good adhesiveness. To neutralize or relieve toxic 9
163
substances in cosmetics and prevent allergic reaction, licorice extracts are widely used
164
in cosmetics such as cream, water, dew, skin milk, and honey (Zhang et al., 2000). A
165
tobacco substitutes made from licorice tissue culture medium has also successfully
166
developed in Japan. The flavor of this cigarette is soft and it contains no-nicotine as
167
well as low-tar (Wang et al., 2002).
168
In IV–III century B.C., Greek provided the first use of licorice as a drug in
169
Europe. The name of the plant itself is derived from two Greek terms, γλυκυ’ζ “sweet”,
170
and ρίζη “root”. Greeks probably learnt about the pharmacological uses of licorice
171
from the Scythians, an ethnic group who lived to the north and east of Greece in the
172
area of the Ukraine between the Black and Caspian Seas. Licorice is used to remedy
173
asthma, diseases affecting voice, lung diseases, cough (Cristina et al., 2005).
174
In the first century A.D., Italians placed licorice among the 650 medicinal
175
substances of plant origin listed in their De Materia Medica. At the beginning of the
176
Imperial Age (I–V century A.D.), Roman gave a detailed description of the licorice
177
plant in the monumental work Naturalis Historia of Plinius. The author suggested
178
licorice as a remedy for asthma, malaises of the throat, ulcerations of the mouth
179
(Cristina et al., 2005).
180
In Germany, the first attempt at creating a botanical nomenclature came from
181
Leonhard Fuchs, who concerning licorice, accurately described and characterized the
182
plant, and reported its scientific name to be the German term Süeβholz “sweet root”,
183
which is still in use today. Licorice is considered an herbal medicine that could
184
alleviate artery diseases, heart palpitations, and angina from the Middle Ages.
185
(Cristina et al., 2005).
186
4. Phytochemicals
187
G. uralensis Fisch. is the most popular species among the three kind of 10
188
Glycyrrhiza plants because of its widespread cultivation, productivity and good
189
quality. Compared with two other plants, G. uralensis Fisch has been the most
190
extensively studied. Since the 1960s, researchers at home and abroad have been
191
thoroughly studying the chemical components of G. uralensis Fisch., G. inflata Bat.
192
and G. glabra L.. These chemical compounds include flavonoids, triterpenoid
193
saponins, coumarins, phenols and polysaccharides.
194
4.1 Flavonoids
195
Flavonoids are the main constituent of licorice. The C6-C3-C6 basic structure are
196
listed in Fig. 4. Flavonoids are mainly divided into five types: flavanones, flavones,
197
flavonols, chalcones, and isoflavones.
198
Flavonoids in licorice have been discovered and isolated continuously from 1992
199
to 2017. In 1992, Glyasperin A, Glyasperin B, Glyasperin C and Glyasperin D (Zeng
200
et al., 1992), belonging to the flavanones, were first isolated by Japanese scientists
201
and their structures were identified by NMR technology. In 1993, Isao K. found a
202
chalcone
203
7-O-apioglucosyl-7,4'-dihydroxyflavone, dehydroglyasperin C, asperopterocaepin,
204
and 1-methoxyphaseollidin (Isao et al., 1993). The structures of above four flavones
205
and glucoisoliquiritin apioside have been verified (Isao et al., 1998). In 1997, Tsutomu
206
H.’s
207
glycyrrhiza-isoflavones
208
tetrahydroxy-methoxychalcone (Tsutomu et al., 1997). In recent years, researchers
209
have conducted a great deal of studies on the compounds of licorice flavones and
210
some constituents have been isolated, such as licorice ning and kanzonol
211
2014; Zhao et al., 2017a; Zhao et al., 2016). Peking University scientists found two
212
flavone
team
component,
first
isoliquiritin
found
apioside.
glycyrrhiza B,
and
flavonol
And
he
also
glycyrrhiza-isoflavones
glycyrrhiza-isoflavones
component,
glycyuralin 11
found
A
C
A and
(He et al.,
and
213
5,7,3′,4′-tetrahydroxy-6-(3-hydroxy-3-methylbutyl)-isoflavone in 2016. The former
214
belongs to the flavones, the latter belongs to the isoflavone group (Ji et al., 2016).
215
Besides, 28 flavonoids were isolated and identified by HPLC-Q-TOF-MS in 2016
216
(Zhao et al., 2016).
217
Liquiritin is main compound in G. uralensis Fisch.. In 2004, a HPLC method has
218
been established to measure the content of liquiritin in G. uralensis Fisch. from
219
different habitats. With the mobile phase of 0.5% acetic acid water (v/v, A) and
220
acetonitrile (B) as well as the 276 nm UV detection wavelength, the content of
221
liquiritin was detected from 0.23% to 2.46% (Wu et al., 2004). In 2008, Peng studied
222
the distribution of liquiritin in different part of licorice. The result shows that liquiritin
223
mostly accumulates in the underground portions of licorice, and the content variation
224
is related to the age of the underground portion and the aboveground growing parts
225
(Peng et al., 2008).
226 227 228
Fig. 4 The basic structure of flavonoids
4.2 Triterpene saponins
229
Triterpene saponins are another main bioactive constituent in licorice. (Liang et
230
al., 2006). The aglycone of triterpenoids in licorice is mainly 3β-hydroxy oleanolic 12
231
acid (The structure is listed in Fig. 5). Glycyrrhizin is recognized to be the most active
232
ingredient in triterpene saponins (Hao, 2001).
233
Scholars at home and abroad focused on the content of glycyrrhizin in licorice,
234
because it is the main active component of licorice. In 1976, Kiliacky J. measured
235
glycyrrhizic acid by HPLC (Kiliacky et al., 1976). Since 1980, Chinese researchers
236
have begun to study the content of glycyrrhizin in licorice. Li measured the
237
glycyrrhizin in G. uralensis Fisch. by the volumetric method (Li and Xie, 1980). Then,
238
in 1987, Liu first measured the content of glycyrrhetinic acid which has been
239
hydrolyzed from glycyrrhizin, and the result has been used to indirectly calculate the
240
content of glycyrrhizin (Liu et al., 1987). In 1989, an HPLC method to measure
241
glycyrrhizin has been established (Fu et al., 1989). Then, Sun used HPCE method to
242
measure the glycyrrhizin and glycyrrhetinic acid in Compound Liquorice Tablets at
243
the same time(Sun et al., 2011). In addition, He found 8 triterpene saponins by
244
UPLC-MS/MS in 2014 (He et al., 2014). And 16 triterpene saponins have been
245
discovered and identified by LC-MS in 2016 (Zhao et al., 2016). To sum up,
246
researchers have established a quick and accurate method of identifying triterpene
247
saponins in licorice (Ma et al., 2018).
248
In addition, researchers have improved the extraction and separation method.
249
Sun
250
used a nonionic surfactant micellar extraction system to replace the organic reagent.
251
The extraction rate increased to 90.3% (Sun et al., 2007). Shabkhiz reported that they
252
extracted glycyrrhizin from licorice roots by superheated water extraction (SWE)
253
method: 100℃ (temperature), 15 ml/min (flow velocity), and 120 min (time). The
254
results showed that this improved method can increase the GA yield (54.760 mg/g)
13
255
compared with the yield conducted by the Soxhlet method (28.760 mg/g) and
256
ultrasonic extraction (18.240 mg/g) (Shabkhiz et al., 2016).
257 258 259
Fig. 5 the structure of 3β-hydroxy oleanolic acid 4.3 Coumarins and phenols
260
In 1978, Takeshi K. found 3-arylcoumarin--glycyrin. The structure is
261
2',4'-dihydroxy-5,7-dimethoxy-6-γ,γ-dimethyally1-3-arylcoumarin (Takeshi et al.,
262
1978). In 1997, researchers from Okayama University found an active compound
263
named isolicopyranocoumarin, and the compound showed the most potent radical
264
scavenged activity effect on 1,1-diphenyl-2-picrylhydrazyl (Tsutomu et al., 1997).
265
Chinese researchers first isolated three coumarins from G. uralensis Fisch., including
266
7,2',4'-
267
hedysarimcoumestan E. Furthermore, some phenols were discovered in G. uralensis
268
Fisch. by scholars locally and abroad
269
4.4 Polysaccharides
trihydroxy-5-methoxy-3-arylcoumarin,
hedysarimcoumestan
B,
and
(Liu et al., 2011).
270
Glycyrrhiza polysaccharides (GP), as natural plant polysaccharides, are also the
271
bioactive substances in licorice (Hiroaki et al., 1996). In 1990, glycyrrhizans UA and
272
glycyrrhizans UB were isolated and identified from the roots of G. uralensis Fisch. in
273
Masashi T.’s study. The results show that glycyrrhizan UA is composed of
274
L-arabinose, D-galactose, L-rhamnose, and D-galacturonic acid in a molar ratio of
275
20:14:1:3. Glycyrrhizan UB is composed of L-arabinose, D-galactose, D-glucose, 14
276
L-rhamnose, and D-galacturonic acid in a molar ratio of 12:10:1:10:20. Additionally,
277
the two polysaccharides exert activities in the reticuloendothelial system (Masashi et
278
al., 1990). Then, Noriko discovered a novel neutral polysaccharide, glycyrrhizans UC.
279
Using methylation analysis, carbon-13 nuclear magnetic resonance and periodate
280
oxidation
281
arabino-3,6-galacto-glucan-type-polysaccharide. This polysaccharide showed the
282
same biological activities as glycyrrhizan UA and glycyrrhizan UB (Noriko et al.,
283
1990). So far, more and more polysaccharide fractions have been isolated from G.
284
uralensis Fisch.. Zhao found two anticomplementary polysaccharide fractions from it
285
(Zhao et al., 1991). Chinese scholars isolated a water-soluble polysaccharide and
286
found that these polysaccharide fractions have macrophage immunomodulatory
287
activity. Currently, the research of glycyrrhiza polysaccharides is a hot topic (Cheng
288
et al., 2008a; Cheng et al., 2008b).
289
4.5 Essential oil
studies,
its
structure
was
indicated
as
290
Subtle and characteristic smell is an important property of licorice, and the odour
291
is related to its volatile components (essential oil) (Liang et al., 2005). In 2012, 13
292
volatile components were isolated in G. inflata Bat. by using steam distillation and
293
solid-phase microextraction (A.Farag and A.Wessjohann, 2012). In 2016, researchers
294
from China found numerous volatile components in G. uralensis Fisch. by using gas
295
chromatography-mass spectrometry (GC–MS) (He et al., 2016). Then, some volatile
296
components were reported (Zhou et al., 2017).
297
4.6. Others
298
In 1990, Han isolated two alkaloids from the roots of G. uralensis Fisch.. These
299
alkaloids
300
5,6,7,8-tetrahydro-4-methylquinoline by spectral data (Han et al., 1990). Then, they
were
identified
as
5,6,7,8-tetrahydro-2,4-dimethylquinoline
15
and
301
isolated
302
3-methyl-6,7,8-trihydro-pyrrolo [1,2-a] pyrimidin-2-one in G. uralensis Fisch.. It was
303
the first reported that alkaloids were isolated and identified from licorice (Han and
304
Chung, 1990). In 2001, content of alkaloids that were quinoline and isoquinoline in
305
licorice was measured by Chinese researchers (Zhang et al., 2001). Besides,
306
glycyrrhiza alkaloids extraction process was optimize by using genetic algorithm (Li
307
et al., 2018). Whether these components are bioactive compounds also needs further
308
research. In addition, there are other components in G. uralensis Fisch., such as
309
yunganoside, liconeolignan, β-sitosterol, and tetrahydropalmatine. All of these
310
components make up a large and complex material basis of licorice.
another
pyrrolo-pyrimidine
alkaloid
and
identified
as
311
As an important part of medication study, chemical composition has been
312
attracting much attention. The discovery and research of new chemical components
313
depend on advanced instruments and research methods. Besides, the discovery of new
314
active ingredients should be conducted under the guidance of TCM theory. For
315
example, TCM theory claims that licorice has the effect of “Huanji zhitong and qutan
316
zhike”(缓急止痛,祛痰止咳), moreover, modern research (Liu et al., 2007a; Wang and
317
Su, 2002) found that isoliquiritigenin, one of the major flavonoids in licorice, can
318
relieve the smooth muscle spasm of gastrointestinal and bronchial tract. The effect of
319
this component is associated with the traditional Chinese medicine efficacy of licorice.
320
Comprehensively analyzing the traditional theories and modern research conclusions
321
above, it reminds us that some other active ingredients with the effect of "Huanji
322
zhitong, qutan zhike" may been found in flavonoids of licorice. It is more targeted and
323
efficient to combine TCM theory and existing researches in exploring new active
324
constituents. 16
325
5. The effects of licorice in combination preparations
326
Herbal medicine combined application in prescription is the characteristic of
327
TCM. A TCM formula are usually classified as monarch (main) drugs, minister drugs,
328
assistant drugs, and guide drugs. Besides, in TCM theory, every herbal medicine in
329
formula is ascribed a property, “cold”, “cool”, “neutral”, “warm”, or “hot”. “Cool”
330
and “cold” herbal medicine treat heat diseases such as high fever, strong sweating,
331
and strong thirsty. “Warm” and “hot” herbal medicine treat cold diseases such as cold
332
limbs, aversion to cold, and watery diarrhea (Ergil and Ergil, 2010; Wang et al., 2013)
333
As a first-class herbal medicine, licorice is tonic, nontoxic and slightly “cold” in
334
property. Additionally, it has the ability to harmonize the characteristics of other
335
herbal medicine. That means, on the one hand, licorice can mitigate “hot” or “cold” in
336
property of certain herbal medicine while it is combining used in preparations. On the
337
other hand, it can improve the efficacy of herbal medicine in a formula simultaneously.
338
In addition, it also can modulate the taste of herbs due to its sweet flavor.
339
We believe that the interaction of chemical compounds between licorice and
340
toxic herbal medicine, pharmacological effect of licorice, and the effect of licorice on
341
pharmacokinetics of toxic compounds are main mechanisms underlying effects of
342
licorice in combination preparations. The variation of chemical component while
343
licorice is in combined application are widely studied. The research results are
344
showed in Table 2. And the mechanism of bioactivity enhancing/toxicity reducing
345
efficacy of licorice is helpful for understanding its “essential herbal medicine”
346
superiority.
347
5.1 Chemical composition variation while combining application with licorice
348
5.1.1 G. uralensis Fisch. and Paeonia lactiflora Pall. (GanCao-Baishao, GC-BS)
349
GC and BS are firstly recorded in shen nong ben cao jing. They compose a 17
350
classic traditional Chinese formula: Shaoyao Gancao Decoction (simplified Chinese:
351
芍药甘草汤). Researchers found that the content of paeoniflorin in the BS decoction
352
was less than that in the GC-BS co-decoction (Wang et al., 2014). In
353
subsequent studies, Zhu measured oxidized paeoniflorin, paeoniflorin, albiflorin and
354
benzoyl paeoniflorin in the BS decoction and the co-decoction. The result suggested
355
that the four compounds increased in the co-decoction (Zhu et al., 2016).
356
5.1.2 G. uralensis Fisch. and Zingiber officinale Rose. (GanCao-Ganjiang, GC-GJ)
357
GJ is the root of Zingiber officinale Rosc. Jiang found that 6-gingerol, 8-gingerol,
358
and 6-shogaol increased in the GC-GJ co-decoction compared to GJ single decoction.
359
(Jiang et al., 2015). The results show that the dissolution of the active ingredient in GJ
360
have been increased in combining usage with GC. Two key points are illustrated. On
361
the one hand, the experimental data provide scientific basis for the theory of Mutual
362
compatibility of GC-GJ. On the other hand, it confirmed that GC plays a harmonizer
363
role in TCM.
364
5.1.3 G. uralensis Fisch. and Ephedra sinica Stapf (GanCao-Mahuang, GC-MH)
365
MH is the stem of Ephedra sinica Stapf. It contains ephedrine, pseudoephedrine,
366
methyl
367
pseudoephedrine and volatile oil. Using LC-MS, Meng found that the ephedrine
368
increased by 14.52% and the methylephedrine increased by 64% in the GC-MH
369
co-decoction (Meng et al., 2009). Besides, Xu discovered that the dissolution rates of
370
demethylpseudoephedrine hydrochloride, demethylmethylephedrine hydrochloride,
371
ephedrine hydrochloride, pseudoephedrine hydrochloride and methylephedrine
372
hydrochloride were reduced in the GC-MH co-decoction (Xu et al., 2012).
373
5.1.4 G. uralensis Fisch. and Aconitum carmichaelii Debx. (GanCao-Fuzi, GC-FZ)
ephedrine,
methyl
pseudoephedrine,
18
methamphetamine,
methylene
374
FZ, the root of Aconitum carmichaelii Debx., is a toxic herbal medicne because
375
of the toxic ester alkaloids. The GC-FZ is the most notable TCM herb pair showing
376
bioactivity enhancing and toxicity reducing efficacy. Currently, Chinese scholars have
377
studied the bioactivity enhancing and toxicity reducing mechanism of this herb pair.
378
In 2013, Zhang researched the difference of the content of chemical components (6
379
ester alkaloids) between sediment in the FZ decoction and sediment in the FZ-GC
380
co-decoction.
381
benzoylmesaconitine 49.46 µg/g, benzoylaconitine 31.45 µg/g, benzoylhypaconitine
382
24.63 µg/g, mesaconitine 8.29 µg/g, and hypaconitine 28.49 µg/g; while the
383
co-decoction sediment included benzoylmesaconitine 119.12 µg/g, benzoylaconitine
384
61.63 µg/g, benzoylhypaconitine 101.23 µg/g, mesaconitine 32.15 µg/g, hypaconitine
385
64.42 µg/g, aconitine 45.76 µg/g (JM Zhang et al., 2013). Moreover, Wang found that
386
the contents of alkaloids in the FZ-GC co-decoction were significantly lower than the
387
contents in the FZ decoction (Wang, 2014). It is indicated that the FZ-GC
388
co-decoction is less toxic because the ester-series alkaloids and constituents in licorice
389
formed chelate precipitates (JM Zhang et al., 2013).
390
5.1.5 G. uralensis Fisch. and Rheum palmatum L. (GanCao-Dahuang, GC-DH)
The
results
showed
that
FZ
decoction sediment
included
391
Dahuang Gancao Decoction(simplified Chinese:大黄甘草汤), recorded in Jingui
392
Yaolue (simplified Chinese: 金 匮 要 略 ), consists of DH and GC. Han and Jin
393
determined the content of free and combined anthraquinones by UV in the DH
394
decoction and the GC-DH co-decoction (the ratio of DH-GC is 2:1). The content of
395
free anthraquinone was 6.84 ±0.64 mg/g and the content of combined anthraquinone
396
was 9.41±0.54 mg/g in the DH decoction. The content of free anthraquinone was
397
11.96±0.60 mg/g and the content of combined anthraquinone was 3.61±0.19 mg/g in
398
the GC-DH co-decoction. The result showed that the free anthraquinone increased and 19
399
the combined anthraquinone was reduced in the co-decoction. Glycyrrhizin and
400
combined anthraquinone formed precipitates and combined anthraquinone was
401
reduced in the co-decoction, which is considered to be the main toxic component
402
(Han et al., 2009). Besides, the GC combined application with DH can promote the
403
dissolution of total anthraquinone in co-decoction, which may be the main bioactivity
404
enhancing efficacy mechanism (Luo, 2017).
405
5.1.6 G. uralensis Fisch. and Strychnos nux-vomica L. (GanCao-Maqianzi, GC-MQZ)
406
Strychnine and brucine are the main effective as well as toxic compounds in
407
MQZ. Zhao examined the GC-MQZ co-decoction and the MQZ decoction. He found
408
that the co-decoction has the low contents of strychnine and brucine compared with
409
the contents in the MQZ decoction. Moreover, researchers detected the contents of
410
semen strychni in different co-decoctions which made of different proportions of
411
licorice. The result showed that strychnine was reduced by 95.7% and brucine was
412
reduced by 93.3% when the ratio of GC-MQZ is 16:1. It suggested that the contents of
413
the strychnine and brucine would change as the dose of licorice changes and the
414
chemical composition of licorice reacted with strychnine and brucine to form
415
precipitates (Zhao et al., 2014).
416
5.1.7 G. uralensis Fisch. and Zingiber officinale Rose. (GanCao-Ganjiang, GC-GJ)
417
Volatile oils are regarded slightly toxic and as the material basis of “acrid & dry”
418
(xin & zao) in TCM. Li found that 6-gingerol and glycyrrhizic acid were reduced in
419
the GC-GJ co-decoction compared with the content of 6-gingerol and glycyrrhizic
420
acid in the GJ decoction. With an increasing proportion of GC, 6-gingerol is reduced
421
even more (Li et al., 2016). The results suggest that the increased use of GC may limit
422
the “acrid & dry” property of GJ. And it provides a material basis of the detoxification
423
mechanism of GC. 20
424
In conclusion, it can be found that the change of content of the active component
425
in the compound Chinese medicine may be one of the main reasons of effect of
426
licorice in combination preparations. Firstly, glycyrrhiza saponins are excellent
427
surfactants which can significantly reduce the interfacial tension between the two
428
phases, improve the solubility and thereby enhance the bioavailability of active
429
substances (Cai et al., 2012). Secondly, Licorice compounds react with other toxic
430
compounds to produce precipitation in decoction, and it reduces the solubility of toxic
431
compounds (Wang et al., 2008). Thus, the toxic compounds administrated into the
432
body become less because most of precipitation was leave outside rather than being
433
taken into body.
434 435
21
436
Table 2 Compounds variation and possible mechanisms while herbal medicine is combined with licorice NO.
GC-herbal medicine B
Extraction solvent
Extraction method
Analytical method
1
GC-BS (Paeonia lactiflora Pall.) GC-BS (Paeonia lactiflora Pall.)
Water
Decoct
HPLC A phase: 0.01% phosphoric acid B phase: acetonitrile
Water
Decoct
HPLC A phase: 0.1% phosphate aqueous solution B phase: acetonitrile
2
Compounds variation “↑”: increase “↓”:reduce “↑” “↓”
Mechanism
Ref.
Paeoniflorin ↑
The interaction of the constituents in GC and BS increased the dissolution of the paeoniflorin
(Wang et al., 2014)
Oxypaeoniflorin ↑ Albiflorin ↑ Paeoniflorin ↑ Benzoylpaeoniflorin ↑ Gallic acid ↓ Oxypaeoniflorin ↓ (+)-catechin ↓ Paeoniflorin ↓ Benzoylpaeoniflorin ↓ Albiflorin ↑ Benzoic acid ↑ 6-Gingerol ↓
The interaction of the constituents in GC and BS increased the dissolution of these constituents
(Zhu et al., 2016)
Unknown
(Kim et al., 2014)
Unknown
(Li et al., 2009)
3
GC-BS (Paeonia lactiflora Pall.)
Water
Reflux
HPLC-PDA A phase: 0.1% formic acid B phase: acetonitrile
4
GC-GJ (Zingiber of ficinale Rose.) GC-GJ (Zingiber of ficinale Rose.) GC-MH (Ephedra sinica Stapf) GC-MH (Ephedra sinica Stapf)
Water
Reflux
HPLC A phase: 0.05% phosphate B phase: Acetonitrile
Water
Reflux
HPLC: A phase: 0.1% glacial acetic acid B phase: Acetonitrile
6-Gingerol ↓ 8-Gingerol ↓ 6-Shogaol reduced ↓
Unknown
(Jiang et al., 2015)
Water
Reflux
GC-MS
Ephedrine↑ Methylephedrine ↑
Glycyrrhizin promotes the dissolution of ephedrine alkaloids
(Meng et al., 2009)
Water
Decoct
GC-MS
Demethylpseudoephedrine↓ Demethylephedrine↓ Ephedrine↓ Pseudoephedrine ↓ Methyl ephedrine↓
Organic acids in GC reacts with alkaloids in MH to form non-soluble alkaloid-organic acid complex salt.
(Xu et al., 2012)
5
6
7
22
8
GC-FZ (Aconitum carmichaelii Debx.)
Water
Reflux
9
GC-FZ (Aconitum carmichaelii Debx.) GC-FZ (Aconitum carmichaelii Debx.)
Water
Decoct
Water
10
11
12
13
GC-DH (Rheum palmatum L.) GC-DH (Rheum palmatum L.） GC-MQZ (Strychnose nux-vomica L.)
HPLC-Q-TOF/MS A phase: 5 mmol/L ammonium acetate solution (0.1% acetic acid) B phase: acetonitrile (0.1% formic acid) HPLC Methanol: water: chloroform: trichloroethylamine = 70:30:2:0.1
Hypaconitine ↓ Aconitine ↓
Molecular interactions between the alkaloids in FZ and the flavones of GC
(Lin et al., 2014)
Aconitine ↓ Total toxic alkaloids ↓
Unknown
(Wang, 2014)
Decoct
HPLC-TOF-MS A phase: 5 mmol/L ammonium acetate (0.1% acetic acid) B phase: acetonitrile (0.1% formic acid)
The association between tertiary amine N in alkaloids and glycyrrhizin C=O
(Zhang et al., 2013)
Water
Decoct/ Reflux
Unknown
(Luo et al., 2016)
Water
Decoct
HPLC A phase: 1% glacial acetic acid B phase: methanol spectrophotometry
Benzoylmesaconine ↑ Benzoylaconitine ↑ Benzoylhypaconitine ↑ Mesaconitine ↑ Hypaconitine ↑ Aconitine↑ (in sediments) Total anthraquinones ↑ Combined anthraquinones ↑ Free anthraquinones ↑ Combined anthraquinones ↓
(Han et al., 2009)
Water chloroform
Reflux
Glycyrrhizin and combined anthraquinone formed precipitation, while had a solubilizing effect on free anthraquinones Components in liquorice combined with brucine and strychnine to form water-insoluble deposits
14
GC-MQZ (Strychnose nux-vomica L.)
Water
Reflux
15
GC-HB (Phellodendr on chinense Schneid. )
Water
Reflux
HPLC A phase: 0.01mol /L sodium heptane sulfonate mixed with 0.02mol /L potassium dihydrogen phosphate (pH adjusted by 10% phosphoric acid 2.8) (21-79) B phase: acetonitrile HPLC A phase: 0.1% formic acid solution B phase: 0.1% acetonitrile formate solution HPLC
Brucine ↓ Strychnine ↓
23
(Zhao et al., 2009)
Brucine ↓ Strychnine decreased ↓
Components in liquorice combined with brucine and strychnine to form deposits, which is released slowly in vivo.
(Guo et al., 2017)
Berberine hydrochloride ↑
Glycyrrhizin and berberine hydrochloride form sediments
(Zou et al., 2009)
437
5.2 Pharmacological changes while combining application with licorice
438
Based on pharmacological studied, we hold that the pharmacological effect of
439
certain herbal medicine can be enhanced by conjunction with licorice. For example,
440
the pain relief and anti-inflammatory effects of Baishao were strengthened while
441
combining with licorice (Liang et al., 2016; Liu et al., 2007b; Wang et al., 2016b).
442
Besides, the toxic and side effects of certain herbal medicien can be attenuated by
443
conjunction with licorice. For instance, Melia toosendan Sieb.et Zucc. is a TCM with
444
hepatotoxicity. After application with licorice, it was found that the toxicity was
445
reduced. The mechanism probably is that licorice can inhibit the increase of AST、
446
ALT and ALP in rat serum and reduce the level of MDA、TNF-α and IL-6 in liver
447
homogenate (Zhuo et al., 2018). More studies of licorice cooperating with other
448
herbal medicine are summarized in Table 3.
449
So far, most of the research on the physiological efficacy of licorice remains at
450
the compound level. In the future, it can be analyzed from a more microscopic
451
perspective through modern genomics technology and proteomics technology, which
452
also provides a new method to solve the problem of unclear combination mechanism
453
of licorice.
24
454 455
Table 3 The combination effect of licorice and possible mechanisms while licorice is combined application with certain herbal medicine No .
GC-herbal medicine( B)
Experimen tal model
Dose range tested (crude drug)
Minimal active concentration
Duration
1
GC-BS (Paeonia lactiflora Pall.) GC-BS (Paeonia lactiflora Pall.) GC-BS (Paeonia lactiflora Pall.)
Mice
0.2 g/10g
0.2 g/10g
3d
Mice
150 ~ 600 mg/kg
150 mg/kg
Mice
43 g/kg
GC-CLZ (Melia toosendan Sieb, et Zucc.) GC-ZSM (Daphne giraldii Nitsche)
Mice
180 g/kg
Rats
540, 1620, 2700 mg/kg
540 mg/kg
31 d
Anti-adjuvant-induce d arthritis
Bioactivity enhancing efficacy
GC-DH (Rheum palmatum L.) GC-HYZ (Dioscorea bulbifera L.) GC-HYZ (Dioscorea bulbifera
Rats
40 mg/kg
40 mg/kg
7d
Anti-inflammatory
Bioactivity enhancing efficacy
Rats
27 g/kg
27 g/kg
35 d
Renal toxicity
Toxicity reducing efficacy
Unknown
(Fan et al., 2014; Zhao et al., 2018)
Rats
9 g/kg
9 g/kg
35 d
Liver damage
Toxicity reducing efficacy
GC Inhibited the expression of mRNA in CYP1A2 ， and slightly
(Hua et al., 2014)
2
3
4
5
6
7
8
Effect of Herbal medicine B/toxicity of herbal medicine B Abirritation
Bioactivity enhancing /Toxicity reducing efficacy Bioactivity enhancing efficacy
Mechanism
Ref
Unknown
(Jiang et al., 2011; Wang et al., 2016b)
5d
Abirritation and anti-inflammatory
Bioactivity enhancing efficacy
Liquorice glycosides and paeony glucosides are both have analgesic and anti-inflammatory efficacy
(Kong et al., 2018; Liu et al., 2007b)
43 g/kg
7d
Reduce capillary permeability, abirritation and anti-inflammatory
Bioactivity enhancing efficacy
Liquorice total glycosides and paeony glucosides are both have analgesic and anti-inflammatory efficacy
(Liang et al., 2016)
180 g/kg
14 d
Hepatotoxicity
Toxicity reducing efficacy
GC inhibited the increase of AST、 ALT and ALP in rat serum and reduce
(Zhuo et al., 2018)
25
the level of MDA、TNF-α and IL-6 in liver homogenate. Regulating TNF-α、IL-1β、VEGF and MIF to inhibit inflammatory cells infiltration, making synovial tissues hyperplasia and alleviating the damage of cartilage and bone Strengthening the effect of reducing the expression of TNF-α、IL-6、IL-8 in rat serum
(Zhang et al., 2014)
(Kong et al., 2014; Xu et al., 2016)
L.) 9
10
11
12
13
14
15
16
GC-HYZ (Dioscorea bulbifera L.) GC-SDG (Sophora tonkinensis Gapnep.) GC-LGT (Tripterygi um wilfordii Hook. f.) GC-GZ (Cinnamom um cassia Presl) GC-KS (Sophora flavescens Ait.) GC-HH (Carthamus tinctorius L.) GC-HH (Carthamus tinctorius L.)
GC-WM (Prunus mume (Sieb. )Sieb . et. Zucc.)
down-regulated the expression of CYP2C19. GC restrained the increase of the liver index, ALT, AST of rat which are induced by HYZ
Mice
0.075 g/g
0.075 g/g
30 d
Hepatotoxicity
Toxicity reducing efficacy
Mice
18, 24, 36 g /kg
18 g/kg
21 d
Hepatotoxicity
Toxicity reducing efficacy
GC restrained the increase of ALT, AST in rat serum
(Pan and Hua, 2016)
Rats
15 g/kg
15 g/kg
14 d
Hepatotoxicity
Toxicity reducing efficacy
GC has efficacy of protecting liver and antagonizing HMGB1
(Li et al., 2015; Zhao et al., 2017b)
Rats
1.62 g/kg
1.62 g/kg
30 d
Energy metabolism
Bioactivity enhancing efficacy
GC-GZ regulated the content of GLU, GC and T3 in rat serum
(Sun et al., 2016b; Yao et al., 2014)
Rats
10, 20, 30 g/kg
10 g/kg
7d
Acute toxicity
Toxicity reducing efficacy
Unknown
(Shi et al., 2015b; Wang et al., 2015)
Rats
20 g/kg
20 g/kg
15 d
Resist blood stasis
Bioactivity enhancing efficacy
GC-HH decreased viscosity of the blood, and increased ATP, ADP and AMP content
(Dong et al., 2017; Han et al., 2013)
Rats
20 g/kg
20 g/kg
30 d
Resist blood stasis
Bioactivity enhancing efficacy
(Wang et al., 2018)
Rats
1.8 g/kg
1.8 g/kg
7d
Anti-radiation salivary gland injury
Bioactivity enhancing efficacy
The compatibility of GC with HH promotes the absorption of safflower active ingredients, which act on epinephrine receptors, thereby improving the systolic function of mesenteric blood vessels in rats with blood stasis unknown
26
(Hua et al., 2011)
(Ye et 2018)
al.,
17
18
19
GC-FZ (Aconitum carmichaeli i Debx.) GC-FZ (Aconitum carmichaeli i Debx.) GC-SFJ (Silybum marianum (L. )Gaertn. )
Rats
3.77, 17.79 mg/kg
23.77, 17.79 mg/kg
28 d
Anti-adjuvant-induce d arthritis
Bioactivity enhancing efficacy
GC enhanced the effect of FZ on decreasing the serum level of cytokines IL-1β, TNF-α and PGE2.
(Tong et al., 2014; Yang et al., 2010)
Rats
11.4, 12.9, 15 g/kg
11.4 g/kg
/
Cardiotoxicity
Toxicity reducing efficacy
GC inhibited the increase of cardiac rhythm, and protected cardiac cell
(Sun et al., 2016a; Xie et al., 2012)
Rats
125, 250 mg/kg
125 mg/kg
42 d
Hepatoprotective efficacy
Bioactivity enhancing efficacy
Silymarin in SFJ and glycyrrhizin in GC can significantly reduce ALT, AST, ALP, and TBARS levels and increase GSH, SOD, and CAT levels.
(Rasool et al., 2014)
27
456
5.3 Pharmacokinetic changes while combining application with licorice
457
The possibility is well-known in phyto-pharmacology that particular concomitant
458
compounds in an extract, e.g. polyphenols or saponins (in licorice) that often do not
459
possess specific pharmacological effects themselves may increase the solubility
460
and/or the resorption rate of other major constituents in the extract and thereby
461
enhance its bioavailability virtually in a kind of pharmacokinetic effect (Wagner and
462
Ulrich-Merzenich, 2009). Therefore, pharmacokinetic studies are helpful in
463
understanding the action mechanism underlying effects of licorice in combination
464
preparations. Changes of pharmacokinetic parameters of components in the
465
combination of GC licorice with other herbal medicine are summarized in Table 4.
466
These studies focused on the absorption and distribution of active/toxic components in
467
vivo and provided some modern evidences for dynamic change of components in the
468
blood.
469
Licorice could influence the pharmacokinetic profiles of aconitine in Aconitum
470
carmichaelii Debx. (FuZi, FZ). Cmax and ACU of aconitine in rats orally administrated
471
FZ-GC co-decoction significantly reduced compared to that in rats treated with FZ
472
single decoction (Wang et al., 2012). We believe that the absorption and distribution
473
of aconitine were slowed down, which may be the main toxicity reducing efficacy
474
mechanism. Most of the results show that peak time (Tmax) and clearance (CL) of toxic
475
components in certain herbal medicine were increased and peak plasma concentration
476
(Cmax), area under the curves (ACU), and half-life (T1/2) of toxic components in certain
477
herbal medicine were reduced in combining application with licorice.
478
Besides, Cmax and ACU of active components in certain herbal medicine were
479
increased after combining application with licorice. For instance, licorice could
480
influence the pharmacokinetic profiles of platycodin D and deapio-platycodin D in 28
481
Platycodon grandiflorum (Jacq.) A. DC. (JieGeng, JG). Cmax and ACU of Platycodin
482
D and Deapio-platycodin D in rats orally administrated JG-GC co-decoction
483
significantly increased compared to that in rats treated with JG single decoction (Shan
484
et al., 2015).
29
485
Table 4 The changes of pharmacokinetic parameters of toxic/active components when licorice is in combined application with certain herbs N o. 1
2
3
4
5
6
7
8
GC-herbal medicine (B) GC-LGT LGT (Tripterygium wilfordii Hook. f.) GC-LGT LGT (Tripterygium wilfordii Hook. f.) GC-FZ FZ (Aconitum carmichaelii Debx.) GC-FZ FZ (Aconitum carmichaelii Debx.) GC-MQZ MQZ (Strychnose nux-vomica L.) GC-MQZ MQZ (Strychnose nux-vomica L.) GC-KS KS (Sophora flavescens Ait.) GC-KS KS (Sophora
Experimental model Rat
components
Tmax/h
Cmax/µg·L-1
T1/2/h
CL/
ACU/µg·h-1·L-1
Ref
Triptonide (toxic component)
1.00 1.00
708.06 ± 66.98 647.62 ± 61.76
0.52 ± 0.10 0.92 ± 0.16
0.14 ± 0.08 0.11 ± 0.018
9331. 61 ± 1203. 97 11172. 23 ± 1858. 56
(Zhang et al., 2010)
Rat
Triptolide (toxic component)
0.03 0.03
147.48 ± 17.48 249.12 ± 32.97
0.35 ± 0.01 0.31 ± 0.02
11.11 ± 2.37 4.94 ± 1.08
63.04± 9.97 141.65±20.38
(Liu et al., 2010)
Rat
Hypaconitine (toxic component)
5.91 ± 0.78 2.40 ± 0.53
132.98 ± 16.21 160.90 ± 125.74
/ /
0.02 ± 0.01 0.06 ± 0.01
1773.85 ± 256.43 1310.45 ± 186.94
(Zhang et al., 2011)
Rat
Aconitine (toxic component)
7.25 ± 1.00 1.00 ± 0.00
0.04 ± 0.01 0.09 ± 0.02
7.81 ± 3.88 14.69 ± 3.30
/ /
0.54 ± 0.11 0.73 ± 0.15
(Wang et al., 2012)
Rat
Strychnine (toxic component)
0.8 ± 0.2 0.5 ± 0.1
302.8 ± 7.5 241.4 ± 12.9
2.3 ± 0.7 3.9 ± 0.9
/ /
516.40 ± 79.50 547.50 ± 69.00
(Gu et al., 2014)
Rat
Brucine (toxic component)
0.6 ± 0.2 0.8 ± 0.1
54.8 ± 0.9 63.1 ± 2.2
3.5 ± 1.2 3.2 ± 1.5
/ /
142.50 ± 21.90 94.00 ± 12.10
(Gu et al., 2014)
Rat
Oxymatrine (toxic component)
3.00 3.00
64.70 ± 5.80 74.20 ± 6.90
5.12 ± 0.23 8.09 ± 0.21
32.6 ± 3.3 24.13 ± 2.1
475.21 ± 35.23 585.95 ± 48.67
(Shi et al., 2015a)
Rat
Matrine (toxic component)
3.00 3.00
2115.4 ± 156.4 3148.7 ± 212.2
5.95 ± 0.26 5.37 ± 0.23
0.67 ± 0.17 0.42 ± 0.12
18969 ± 1554 29142 ± 2313
(Shi et al., 2015)
30
flavescens Ait.) 9
10
11
12
13
14
GC-DH DH (Rheum palmatum L.) GC-GZ GZ (Cinnamomum cassia Presl) GC-JG JG (Platycodon grandiflorum (Jacq.) A. DC.) GC-JG JG (Platycodon grandiflorum (Jacq.) A. DC.) GC-BS BS (Paeonia lactiflora Pall.) GC-BS BS (Paeonia lactiflora Pall.)
Rat
Rhein (toxic component)
0.57 ± 0.08 0.53 ± 0.08
1980 ± 160 7380 ± 670
0.55 ± 0.092 0.73 ± 0.089
6.93 ± 0.65 3.12 ± 0.28
5350 ± 480 24040 ± 2370
(Han et al., 2010)
Rat
Cinnamic acid (active component)
0.15 ± 0.04 0.18 ± 0.07
6497 ± 724 4258 ± 675
2.56 ± 0.59 2.27 ± 0.29
8649 ± 1527 7031 ± 1970
8252.00 ± 1536.00 4636.00 ± 820.00
(Wang et al., 2016a)
Rat
Platycodin D (active component)
3.94 ± 1.16 2.86 ± 1.07
69.66 ± 36.83 17.94 ± 9.33
2.11 ± 0.58 1.22 ± 0.62
/ /
540.21 ± 222.15 88.97 ± 45.42
(Shan et al., 2015)
Rat
Deapio-platycodin D (active component)
4.22 ± 1.55 1.22 ± 0.89
24.11 ± 11.25 13.46 ± 6.43
2.22 ± 1.52 0.78 ± 0.27
/ /
181.31 ± 73.50 81.31 ± 27.75
(Shan et al., 2015)
Rat
Paeoniflorin (active component)
0.34 ± 0.17 0.50 ± 0.12
2770 ± 1200 1720 ± 7300
1.01 ± 0.75 2.35 ± 0.52
/ /
5288.67 ± 1127.17 4639.83 ±127.17
(Li, 2016)
Rat
Paeoniflorin (active component)
0.50 ±0.17 0.33 ±0.17
1.14 ± 0.39 0.39± 0.12
2.17± 0.84 5.94 ± 2.10
/ /
/ /
(Wang, 2010)
31
486
6. Quality control
487
As recorded in the Chinese Pharmacopoeia 2015 edition, the content of
488
glycyrrhizin and liquiritin in licorice should be more than 2.0% and 0.50%,
489
respectively. The quality of traditional Chinese medicine is the guarantee of clinical
490
efficacy and the key of the development of traditional Chinese medicine industry.
491
Quality control of traditional Chinese medicine (TCM) is one of the national strategic
492
issue related to the development of TCM science and industry and it always been the
493
focus by the field.
494
6.1 Application of Quality marker in QC
495
While a mass of chemical components have been isolated and identified form
496
licorice, it remains a gap that which components are relevant for QC or safety
497
assessment of licorice. Chinese scholars have done a lot of work for the quality
498
control of Chinese traditional medicine and the research level has also made great
499
progress, but there are some deficiencies. For example, the research on
500
pharmacodynamic material basis of traditional Chinese medicine is weak, which leads
501
to the index ingredient of quality control is not closely related to the efficacies of
502
traditional Chinese medicine. Hence, Chinese Medicine Quality Markers is introduced
503
into quality control of Chinese medicine by professor Liu Changxiao. The core theory
504
of TCM Q-Markers is “effective, unique, transmission and traceability, measurable
505
and prescription compatibility”. Firstly, Quality markers (Q-markers) are unique
506
chemical substances and inherent secondary metabolites in traditional Chinese
507
medicine or chemical substances formed in the process of processing and preparation.
508
Besides, Q-markers should have a definite chemical structure and bioactivity.
509
Secondly, the thinking mode and research method of TCM Q-markers focus on the
510
dynamic change and the transmissibility and traceability of Q-markers in the whole 32
511
production
512
processing-Preparation-Pharmaceutical process-Delivery and metabolism in vivo),
513
which fits the essential characteristics of TCM and is helpful to establish quality
514
control and traceability system in the entire production state. Thirdly, the
515
identification of Q-markers should be related to the clinical use of traditional Chinese
516
medicine. To be specific, Q-markers should be considered and confirmed based on the
517
final active constituents in the traditional clinical application, and clinical expression
518
form of efficacy of traditional Chinese medicine. (Liu et al., 2016; Zhang et al., 2019).
519
Chinese Medicine Quality Markers should be used for further quality control of
520
licorice.
521
6.2 The property of multi-layer and multi-targets of traditional Chinese medicine
522
As a widely used and cultivated traditional Chinese herbal medicine, licorice
523
hold the property of multi-component, multi-layer and multi-target same as other
524
herbal medicine. The main and effective components in licorice are complex,
525
including flavonoids, triterpenoid saponins, and coumarins, which result in
526
pharmacological efficacy diverse (Chen, 2008; Chen et al., 2013). Because of this,
527
one single component cannot on behalf of the quality and the complex
528
pharmacological actions of licorice itself, so do the content of glycyrrhizin and
529
liquiritin. The quality control system of licorice needs to be improved and completed.
530
Liquiritigenin, isoliquiritigenin and glycyrrhiza polysaccharides, all of which have
531
been reported that having certain pharmaceutical efficacy but still out of the list of
532
quality control constituents. Therefore, the comprehensive consideration of symbolic
533
components above should be considered to carry out in quality control, in order to
534
reflect the substantial quality of licorice as far as possible. The essential point to carry
535
out the pharmacological study is controlling the quality of licorice. Making multiple
process
(Original
33
plant-Harvesting
and
536
active components the dominant position rather than individual effective ingredient is
537
of vital importance.
538
6.3 The adulterant of licorice
539
Glycyrrhiza pallidiflora Maxim., which belongs to the genus Glycyrrhiza, is a
540
major adulterant of licorice. But it has barely pharmacological activities as licorice
541
(Han, 2013). Supported by Fourier transform infrared spectroscopy, Tashi established
542
a method of identification of standard and false licorice (Glycyrrhiza pallidiflora
543
Maxim.). The result showed there are some certain differences in their chemical
544
components that are reflected in the IR spectra. Farther, they are quite different from
545
each other in second derivative spectra and 2D spectra. Based on the differences
546
reflected in the IR, IR second derivative spectrum and 2D IR, the standard licorice can
547
be identified from the false easily and clearly (Tashi et al., 2006). Yang collected 240
548
licorice plants from 21 populations of 7 provinces, and amplified their ITS and
549
psbA-trnH sequences. ITS sequences with a full length of 616 bp and psbA-trnH
550
sequences with a full length of 389 bp were obtained separately. With the combination
551
analysis of ITS and psbA-trnH sequences, the molecular identification method of
552
original licorice was established (Yang et al., 2017).
553
7. Toxicology
554
Licorice is widely used as a “medicine food homology” herbal medicine, so it is
555
very important to systematically evaluate the safety of licorice. Based on TCM theory,
556
as the saying that “all drugs are slightly toxicity”(是药三分毒), although licorice is
557
regarded as a kind of natural, safe and effective edible-medicine, but its dosage and
558
duration should also be paid attention. Some studies on the toxicity and dosage and
559
duration of licorice are as follows: 34
560
500, 1000, and 2000 mg/kg licorice extract was orally administered to male rats,
561
none significant harm to reproductive function has been found, and the upper-limit
562
dose (2000mg/kg) and long-term exposure to licorice might not cause serious adverse
563
effects (Shin et al., 2008). Another study on the application of glycyrrhizin in the
564
treatment of acute autoimmune hepatitis showed that the adverse reactions of
565
glycyrrhizin are depend on the dosage and duration of usage. It is safe that
566
glycyrrhizin is used in normal dose (below 100 mg/d)(Yasui et al., 2011).
567
Glycocorticosteroid-like action of licorice could stimulate the central nervous system,
568
therefore, mental and cardiovascular patients who treat diseased with licorice should
569
take care about the dosage and duration (Decio et al., 2003; Shen, 2002). There are
570
reports indicated that licorice and its preparations could induce gastrointestinal
571
reactions, while most patients can recover without special treatment after the herbal
572
medicine administration is stopped (Zheng and Yan, 1998).
573
8. Conclusions
574
Abundant chemical components have been isolated and identified from licorice,
575
but whether the components are suitable as quality control ingredients and their
576
pharmacological activity are still need further researched and analyzed. Firstly, index
577
components (Q-markers) which is relevant for QC or safety assessment should be
578
screened out from a mass of components mentioned above for the quality control of
579
licorice. Meanwhile, some key constituents maybe react with other compounds of
580
certain herbal medicine to produce precipitation, so the change of Q-markers should
581
be considered when licorice is used in combination preparations. Besides, a uniform
582
and specific quality standard of licorice should be developed in the future for species
583
in different region all over the world. Secondly, although amounts of isolated
584
compounds of licorice have been revealed, further research is needed to evaluate 35
585
which components are the basis for certain pharmacological effects of licorice.
586
Furthermore, the role (reduce toxicity/increase efficacy) of the numerous constituents
587
in combination preparations need to be assessed.
588
The research that combination application mechanism of licorice and other
589
herbal medicine mainly focus on interaction of chemical compounds between licorice
590
and toxic herbal medicine, pharmacological effect of licorice, and the effect of licorice
591
on pharmacokinetics of toxic compounds. But the research is preliminary, there are
592
still many problems to be solved. First of all, some current research suggested that
593
licorice compounds reacted with other toxic compounds to produce precipitation in
594
vitro. Thus, the solubility of toxic compounds is reduced in decoction that is taken
595
into body, and most of precipitation was leave outside rather than being taken into
596
body. The process maybe reduces the absorption of toxic compounds in vivo. But it is
597
not clear how a small part of precipitation taken into body is absorbed and distributed
598
in vivo, and whether licorice actually slow down the absorption of toxic ingredients in
599
vivo. Caco-2, MDCK-MKRI, TC-7 cell model and everted intestinal sac model could
600
be used to illustrate the absorption of toxic components for understanding the
601
mechanism. Also, according to the measured apparent permeability coefficient and the
602
efflux rate of two-way transport, the corresponding absorption mechanism can be
603
inferred. Secondly, the most studies on pharmacological effects while combining
604
application with licorice merely focus on the macroscopic model (eg. rat and mice
605
model) rather than micromodel. All results provided some macroscopic references for
606
understanding the underlying mechanism of combination effect of licorice. However,
607
more researches for understanding this mechanism exactly need to be revealed by
608
cellular level and molecular level experiments. More importantly, the current clinical
609
research of detoxification effect of licorice is still scanty, there are a gap between 36
610
scientific evidence and a long-term practice. Also, it could be of considerable
611
therapeutic risk lack of the sound (clinical) evidence. Therefore, clinical research on
612
detoxification effect should be a key point in future research. At last, modern
613
pharmaceutics point out that whether drugs work or not is associated to its effectively
614
delivered to its target. And physiological studies have shown that the intestinal barrier
615
is the major barrier for oral absorption of substances. Therefore, the studies on
616
intestinal absorption, transporters and biological targets is helpful to reveal the
617
mechanism of the combination effect.
37
618
Acknowledgements
619
This work was supported by the National Natural Science Foundation of China
620
(No.81803742, No.81703718), Key Project of Natural Science Fund of Sichuan
621
Province (No.18ZA0187), Pre-research National Natural Science Foundation of
622
Chengdu University of Traditional Chinese Medicine (No. ZRYY1718), Key Project
623
of Xinglin Scholars’ Foundation of Chengdu University of Traditional Chinese
624
Medicine (QNXZ2019031).
625
ABBREVIATIONS
626
ALT, alanine aminotransferase; AST, aspartate aminotransferase; Akt, protein kinase
627
B; CCR5, chemokine receptor CYP1A2, cytochrome P450 1A2; CYP2C19,
628
cytochrome P450 2C19; GLU, glucose; GSH, glutathione; HMGB1, high-mobility
629
group box1 protein; HPLC-Q-TOF/MS, high performance liquid chromatography
630
coupled with quadrupole time-of-flight mass spectrometry; IL-1, interleukin-1; IFN-γ,
631
interferon gamma; IL-17, interleukin 17; IL-1β, interleukin-1β; IL-6, interleukin-6;
632
IL-8, interleukin-8; MDA, malondialdehyde; MIF, macrophage migration inhibitors;
633
SWE, superheated water extraction; SOD, superoxide dismutase; TCM, traditional
634
Chinese medicine; TNF-α, tumour necrosis factor-alpha; TBARS, thiobarbituric acid
635
reactive substances; VEGF, vascular endothelial growth factor.
636
Conflict of interest the authors declared
637
We declare that we have no financial and personal relationships with other
638
people or organizations that can inappropriately influence our work, there is no
639
professional or other personal interest of any nature or kind in any product, service
640
and/or company that could be construed as influencing the position presented in or the
641
review of the manuscript entitled.
642 38
643
Reference
644
A.Farag, M., A.Wessjohann, L., 2012. Volatiles profiling in medicinal licorice roots using steam
645
distillation and solid-phase microextraction (SPME) coupled to chemometrics. Journal of Food
646
Science 77, 1179-1184.
647
Bahmani, M., RafieianKopaei, M., Jeloudari, M., Eftekhari, Z., Delfan, B., Zargaran, A.,
648
Forouzan, S., 2015. A review of the health effects and uses of drugs of plant licorice
649
(Glycyrrhiza glabra L.) in Iran. Asian Pacific Journal of Tropical Disease 5, 127-129.
650
Cai, S., Lv, S., Wang, Y., Li, Y., 2012. Solubility and Apparent Oil / Water Partition Coefficient
651
of Glycyrrhizin and Pachymic Acid. Information on Traditional Chinese Medicine 29, 118-121.
652
Chen, Y.H., 2008. Studies on the chemical constituents and related pharmacodynamics of
653
liquorice from different sources, college of pharmacy. BeiJiing University of Chinese medicine,
654
China, p. 133.
655
Chen, Y.H., Huang, M.J., Wang, W.Q., Sun, J.N., 2013. Comparative Study on Major
656
Ingredient Contents and Effect of Depressing Transaminase of Licorice from Different Sources.
657
Chinese Journal of Experimental Traditional Medical Formulae 19, 113-116.
658
Cheng, A., Wan, F., Jin, Z., Wang, J., Xu, X., 2008a. Nitrite oxide and inducible nitric oxide
659
synthase were regulated by polysaccharides isolated from Glycyrrhiza uralensis Fisch. Journal
660
of ethnopharmacology 118, 59-64.
661
Cheng, A., Wan, F., Wang, J., Jin, Z., Xu, X., 2008b. Macrophage immunomodulatory activity
662
of
663
immunopharmacology 8, 43-50.
664
Cristina, F., Michael, E., Eugenio, R., Giorgio, Z., Armanini., D., 2005. A history of the
665
therapeutic use of liquorice in Europe. Journal of ethnopharmacology 99, 317-324.
666
Decio, A., Lorenzo, C., Andrea, S., 2003. Pseudohyperal dosteronism: pathogenetic
667
mechanisms. Critical Reviews in Clinical Laboratory Scienses 40, 295-335.
668
Dong, J.N., Ma, C.C., Jia, P., Chen, L., Long, L.H., Wang, S.X., Zheng, X.H., 2017. Effect of
669
Carthami Flos-Glycyrrhizae Radix et Rhizoma compatibility on energy metabolism in the tissue
670
of rats with cold coagulation blood stasis. Chinese Journal of Pharmaceutical Analysis 37,
671
1389-1397.
672
Ergil, M.C., Ergil, K.V., 2010. Pocket atlas of Chinese medicine. Deutsche Zeitschrift Für
673
Akupunktur 53, 75-76.
674
Fan, J.J., Bi, C.H., Liu, J., Huang, Z.F., 2014. Experimental Study of Rhizoma Dioscoreae
675
Bulbiferae Concerted Radix Glycyrrhiza Reducing Renal Toxicity in Rats．. Journal of Medical
676
Research | J Med Res 43, 31-33.
677
Feng, J.Z., Lu, X.Z., Lu, J.M., Zhang, X.H., 1995. A study on development of animal husbandry
678
by using Glycyrrhiza. Journal of Arid Land Resource and Environment 9, 84-89.
679
Fu, M.N., Dai, F.B., Zheng, H.C., Fu, K.Z., 1989. The determination of the content of
680
Glycyrrhizic acid in liquorice
polysaccharides
isolated
from
Glycyrrhiza
uralensis
Fish.
International
by HPLC. Academic Journal of Second Military Medical 39
681
University 10, 257-260.
682
Gao, X., Zhao, D., Zhao, J.J., Zhang, X., Wang, Y.H., Wang, H.Q., 2017. Herbal textural
683
research on Glycyrrhizae Radix et Rhizoma. Chinese Journal of Experimental Traditional
684
Medical Formulae 23, 193-198.
685
Gu, L.Q., Wang, X.F., Liu, Z.Z., Ju, P., Zhang, L.H., Zhang, Y.Y., Ma, B.J., Bi, K.S., Chen, X.H.,
686
2014. A study of Semen Strychni-induced renal injury and herb-herb interaction of Radix
687
Glycyrrhizae extract and/or Rhizoma Ligustici extract on the comparative toxicokinetics of
688
strychnine and brucine in rats. Food and Chemical Toxicology 68, 226-233.
689
Guo, Y.Y., Ma, W.B., Xiao, H.B., Yan, J., Li, G.Y., Sun, S., Yang, D.Y., Lu, S.W., 2017.
690
Changes of toxic substance in different phase of compatibility decoction Strychni
691
Glycyrrhizae Radix et Rhizoma based on UPLC-MS technique Chinese Traditional and Herbal
692
Drugs 23, 4880-4884.
693
Han, D.C., 2013. Identification of licorice, China News of Traditional Chinese Medicine. State
694
Administration of Traditional Chinese Medicine of the People's Republic of China China, pp.
695
1-2.
696
Han, G., Jin, G.C., Ye, X.Z., Bi, R., Dong, Y., 2009. Effect of glycyrrhetinic acid on extraction
697
rate of anthraquinoids in dahuanggancao decoction. Lishizhen Medicine and Materia Medica
698
Research 20, 704-705.
699
Han, G., Kang, X., Zhe, G.Y., Fan, Y., Wang, L.X., Liu, L., la, W.Y., 2010. Effect of
700
Compatibility Using Glycyrrhiza and Rhubarb on Pharmacokinetics of Rhein in Rats. Chinese
701
Journal of Experimental Traditional Medical Formulae 16, 72-74.
702
Han, S.Y., Li, H.X., Ma, X., Zhang, K., Ma, Z.Z., Jiang, Y., Tu, P.F., 2013. Evaluation of the
703
anti-myocardial ischemia effect of individual and combined extracts of Panax notoginseng and
704
Carthamus tinctorius in rats. Journal of ethnopharmacology 45, 722-727.
705
Han, Y.N., Chung, M., 1990. A Pyrrolo-pyrimidine Alkaloid from Glycyrrhiza uralensis Archives
706
of Pharmacal Research 13, 103-104.
707
Han, Y.N., Chung, M., Kim, T., Han, B., 1990. Two
708
Glycyrrhiza
709
Hao, F., 2001. Advances in Glycyrrhizin research abroad. China Pharmacy 12, 500-501.
710
He, M., Lv, H.Y., Liao, Y.C., 2014. A multiplex approach for the UPLC-PDA-MS/MS data：
711
analysis of licorice. National symposium on Chinese medicine in 2014, 106-114.
712
He, M., Yang, Z.Y., Guan, W.N., Goncalves, C.M.V., Nie, J., Wu, H., 2016. GC-MS analysis
713
and volatile profile comparison for the characteristic smell from Liang-wai Gan Cao
714
(glycyrrhiza uralensis) and honry-roasting product. journal of Chromatographic Science 54,
715
879-887.
716
Hiroaki, K., Norito, T., Zhao, J., Hideki, K., Haruki, Y., 1996. Pectic Polysaccharides from
717
Roots of Glycyrrhiza uralensis: Possible Contribution of Neutral Oligosaccharides in the
718
Galacturonase-Resistant Region to Anti-Complementary and Mitogenic Activities. Planta
719
Medica 62, 14-19.
Semen and
Tetrahydroquinoline Alkaloids
from
uralensis Archives of Pharmacal Research 13, 101-102.
40
720
Hua, B.C., Hu, J., Wang, R.G., Li, Y.C., Lin, J.M., Zheng, L.P., Lin, R.H., Chen, X.F., 2011.
721
Experimental research of Radix Glycyrrhiza on Reducing Hepatic Toxicity induced by Rhizoma
722
Dioscoreae bulbiferae. World Journal of Intergrated Traditional and Westem Medicine 6,
723
24-27.
724
Hua, B.C., Huang, Z.F., Liu, J., Chen, X.L., Chen, X.F., Wang, Y.H., Zhuo, S., 2014. Effects of
725
the compatibility of Huangyaozi and Gancao on the CYP450 mRNA expression in rat liver.
726
Pharmacy and Clinics of Chinese Materia Medica 5, 12-14.
727
Isao, K., Chen, W., Kazuyuki, H., Motomasa, K., Ren, J., 1998. Chemical studies of chinese
728
Licorice-root.II. Five new flavonoid constituents from the root of Glycyrrhiza aspera Pall.
729
collected in XingJiang. Chemical & Pharmaceutical Bulletin 46, 1511-1517.
730
Isao, K., Kazuyuki, H., Emiko, U., Chen, W., Masayuki, Y., Ren, J., 1993. Saponin and
731
Sapogenol.L. on the constituents of root of Glycyrrhiza uralensis Fischer from Xinjiang,China.
732
Chemical structures of licorice-Saponin L3 and Isoliquiritin Apioside. Chemical &
733
Pharmaceutical Bulletin 41, 1567-1572.
734
Ji, S., Li, Z., Song, W., Wang, Y., Liang, W., Li, K., Tang, S., Wang, Q., Qiao, X., Zhou, D., Yu,
735
S., Ye, M., 2016. Bioactive Constituents of Glycyrrhiza uralensis (Licorice): Discovery of the
736
Effective Components of a Traditional Herbal Medicine. Journal of natural products 79,
737
281-292.
738
Jiang, D.X., Chena, Y.S., Hou, X.T., Xu, J.F., Mu, X., Chen, W., 2011. Influence of Paeonia
739
lactiflora roots extract on cAMP-phosphodiesterase activity and
740
action. Journal
741
Jiang, Y.P., Peng, W., Cao, L.M., You, Y., Gao, F., Fu, C.M., 2015. Change law of gingerols
742
from zingiberis Rhizoma in sini tang before and After Compatibility with Other Herbs. Chinese
743
Journal of Experimental Traditional Medical Formulae 21, 1-4.
744
JM Zhang, Fu, C.M., He, Y.X., Lu, J.R., Gao, F., Wang, J.S., Liao, W., 2013. Comparison on
745
chemical components in sediments of Aconiti Lateralis Radix Preparata-Glycyrrhizae Radix et
746
Rhizoma before and after their compatibility Chinese Traditional and Herbal Drugs 44,
747
165-169.
748
Kiliacky, J., Ross, M., Turner, T., 1976. The determination of β-Glycyrrhetinic acid in liquorice
749
by high pressure liquid chromatography. Planta Medica 30, 311-316.
750
Kim, J.H., Shin, H.K., Seo, C.S., 2014. Chemical interaction between Paeonia lactiflora and
751
Glycyrrhiza
752
high-performance liquid chromatography method: herbal combination and chemical interaction
753
in a decoction. Journal of separation science 37, 2704-2715.
754
Kong, M., Liu, H.-H., Wu, J., Shen, M.Q., Wang, Z.G., Duan, S.M., Zhang, Y.B., Zhu, H., Li,
755
S.-L., 2018. Effects of sulfur-fumigation on the pharmacokinetics, metabolites and
756
analgesic activity of Radix Paeoniae Alba. Journal of ethnopharmacology 212, 95-105.
757
Kong, X.y., Wan, H.y., Su, X.h., Zhang, C., Yang, Y., Li, X.m., Yao, L., Lin, N., 2014. Rheum
758
palmatum L. and Coptis chinensis Franch., exert antipyretic effect on yeast-induced pyrexia
of
related
anti-inflammatory
Ethnopharmacology 137, 914-920.
uralensis,
the
components
of
41
Jakyakgamcho-tang,
using
a
validated
759
rats involving regulation of TRPV1 and TRPM8 expression. Journal of ethnopharmacology 153,
760
160-168.
761
Li, H.Y., 2016. The effect of Sini powder on pharmacokinetics of active components of Paeonia
762
lactiflora Pall, Clinical college of Chinese medicine. Liaoning University of Traditional Chinese
763
Medicine, China.
764
Li, J., 2013. The effects and coupling of Radix Glycyrrhizae in Treatise on Cold Damage
765
Diseases, College of Basic Medicine. Guangzhou University of Chinese Medicine, China, p.
766
58.
767
Li, J., Li, B., Xu, B., Guo, S.X., 2018. Study on the optimal extraction process of glycyrrhiza
768
alkaloids. China Food Additives, 128.
769
Li, J., Ren, A.N., Zhao, Y., 2016. HPLC determination of 6-gingerol, glycyrrhizic acid and
770
liquiritin contents after Zingiberis Rhizoma compatibility with Glycyrrhizae Radix et Rhizoma.
771
Central South Pharmacy 14, 994-997.
772
Li, S.D., Xie, J., 1980. The determination of content of Glycyrrhizin in liquorice by volumetric
773
method. Special Wild Economic Animal and Plant Research 1, 35-36.
774
Li, X.X., Du, F.Y., Liu, H.X., Jian Bo Ji, Xing, J., 2015. Investigation of the active components in
775
Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity. Journal of
776
ethnopharmacology 162, 238-243.
777
Liang, B., Yang, A.F., Huang, F.L., Hu, B.Z., 2006. Research advances on chemical
778
constituents and pharmacological activities in Glycyrrhiza. Journal of Northeast Agricultural
779
University 37, 115-119.
780
Liang, W.N., Su, M.X., Chen, M.Y., 2016. Experimental study on analgesic and
781
anti-inflammatory effects of combination of peony and liquorice. Journal of North Pharmacy 13,
782
123-124.
783
Liang, Y., Qu, L.H., Fang, Y.K., Guo, B.J., Song, Y.P., 2005. GC-MS analysis of volatile
784
constituents of Glycyrrhiza uralensis Fisch. Northwest Pharmaceutical Journal 20, 3-5.
785
Lin, Y.J., You, Y., Ji, N.P., Zhang, J.M., Chen, Q.W., Fu, C.M., 2014. Changes of chemical
786
ingredients before and after compatibility of Aconiti Lateralis Radix Praeparata and
787
Glycyrrhizae Radix et Rhizoma Praeparata
788
fingerprint technology. hinese Traditional and Herbal Drugs
789
Liu, B., Wen, Q., Zhang, J., Yang, J., 2007a. Antiasthmatic effect of isoliquiritigenin and its
790
mechanism. chinese journal of clinical pharmacy 16, 348-352.
791
Liu, C., Chen, S., Xiao, X., Zhang, T., Hou, W., Liao, M., 2016. A new concept on quality
792
marker of Chinese materia medica: Quality control for Chinese medicinal products. Chinese
793
Traditional and Herbal Drugs 47, 1443-1455.
794
Liu, G., Kuang, J., Fang, X.J., 1987. The determination of Glycyrrhizic acid in extractum
795
Glycyrrhizae with a colorimetric method. Journal of Ningxia University 2, 2-5.
796
Liu, H., 2013. Systems approaches and polypharmacology for drug discovery from licorice,
797
School of bioinformatics. Northwest A & F University, China, p. 46. 42
cum Melle analyzed by HPLC-Q-TOF/MS 45, 1556-1560.
798
Liu, J.Q., Li, Q., Zhang, R., Liu, F., Zhang, W., He, Z.H., Hong, Q., Kou, X.L., Wu, J.M., 2010.
799
LC-MS/MS studies on effect of Glycyrrhiza uralensis on metabolism distrbution and excretion
800
of triptolide in rat. Chin J Pharm Anal 30, 1665-1671.
801
Liu, T.S., Zhao, X.H., Duan, J.N., Di, L.Q., Huang, Y.Z., 2007b. Study on anti-inflammatory and
802
analgesic action of total Glucosides from shaoyao gancao Decoction and its compound
803
mechanism. Traditional Chinese Drug Research and Clinical Pharmacology 18, 427-430.
804
Liu, Y.C., Chen, Y.G., Wang, D., Gao, X.Y., Guo, H.Z., Fu, X.T., Wang, W.Q., 2011. Studies
805
on chemical constituents on roots of Glycyrrhiza uralensis. Chinese Journal of Pharmaceutical
806
Analysis 31, 1251-1255.
807
Luo, X.J., 2017. Effect of rhubarb glycyrrhiza on the dissolution of contents of anthraquinones
808
in rhubarb. Journal of Sichuan of Traditional Chinese Medicine 35, 47-49.
809
Ma, H.G., Jiang, Q., Wang, Z.J., Liu, H., He, J.L., 2014. Effect of light and temperature on seed
810
germination of glycyrrhiza uralensis under different pretreatment. Research of Soiland Water
811
Conservation 21, 225-235.
812
Ma, H.J., Gao, J., Zhang, Y.L., Zhang, X., Miao, X.Z., Tan, P., 2018. Study on identification of
813
compounds and their fragmentation pathways in licorice by HPLC-MSn. China Journal of
814
Traditional Chinese Medicine and Pharmacy 33, 1120-1123.
815
Masashi, T., Noriko, S., Mieko, K., Ryoko, G., Sumiko, A., Yuko, O., 1990. Characterization of
816
two polysaccharides having activity on the reticuloendothelial system from the root of
817
Glycyrrhiza uralensis. Chemical & Pharmaceutical Bulletin 38, 1667-1671.
818
Meng, X.Y., Pi, Z.F., Song, F.R., Liu, Z.Q., Liu, S.Y., 2009. Changes in the effect compounds
819
and the anti-inflammatory activity before and after the decoction of ephedra and liquorite.
820
chinese journal of applied chemistry 7, 801-806.
821
NationalHealthCommission, 2018. Both Food and Chinese Medicinal Materials Catalogue
822
Management Method, in: China, M.o.H.o. (Ed.). Ministry of Health of China, China, pp. 1-16.
823
Noriko, S., Masashi, T., Mieko, K., Ryoko, G., Akemi, S., Noriko, S., 1990. A novel neutral
824
polysaccharide having activity on the reticuloendothelial system from the root of glycyrrhiza
825
uralensis. Chemical & Pharmaceutical Bulletin 38, 3069-3071.
826
Pan, S.F., Hua, B.C., 2016. Study of Radix Glycyrrhiza on reducing hepatic toxicity induced by
827
Radix et Rhizoma sophorae tonkinensis in mice. . journal of jiangxi university of TCM 28,
828
90-92.
829
Peng, L., Hu, Z.H., Li, J.T., Zhang, Q., 2008. Distribution and dynamic variation of liquiritin in
830
Glycyrrhiza uralensis Fisch. Chinese Journal of Pharmaceutical Analysis 28, 1230-1233.
831
Rasool, M., Iqbal, J., Malik, A., Ramzan, H.S., Qureshi, M.S., Asif, M., Qazi, M.H., Kamal, M.A.,
832
Chaudhary, A.G., Al-Qahtani, M.H., Gan, S.H., Karim, S., 2014. Hepatoprotective Effects of
833
Silybum marianum (Silymarin) and Glycyrrhiza glabra (Glycyrrhizin) in Combination: A
834
Possible Synergy. Evidence-based complementary and alternative medicine : eCAM 2014,
835
641597.
836
Shabkhiz, M.A., Eikani, M.H., Bashiri, S.Z., Golmohammad, F., 2016. Superheated water 43
837
extraction of glycyrrhizic acid from licorice root. Food chemistry 210, 396-401.
838
Shan, J.J., Zou, J.S., Xie, T., Kang, A., Zhou, W., Xu, J.Y., Shen, C.S., Du, L.i.N., Wang, S.C.,
839
Di, L.Q., 2015. Effects of Gancao on pharmacokinetic profiles of platycodin D and
840
deapio-platycodin D in Jiegeng. Journal of
841
Shen, M.Y., 2002. Clinical application and notice of liquorice. Zhejiang Journal of Integrated
842
Traditional Chinese and Western Medicine 12, 784-785.
843
Shi, L., Tang, X.L., Dang, X.L., Wang, Q.H., Wang, X., He, P., Wang, Q.W., Liu, L.N., You, L.X.,
844
Yan, Z., 2015a. Investigating herb–herb interactions: The potential attenuated toxicity
845
mechanism of the combined use of Glycyrrhizae radix et rhizoma (Gancao) and Sophorae
846
flavescentis radix (Kushen). Journal of ethnopharmacology 165, 243-250.
847
Shi, L., Tang, X.l., Dang, X.l., Wang, Q.h., Wang, X.r., He, P., Wang, Q.w., Liu, L.n., Liu, X.Y.,
848
Zhang, Y., 2015b. Investigating herb–herb interactions: The potential attenuated toxicity
849
mechanism of the combined use of Glycyrrhizae radix et rhizoma (Gancao) and Sophorae fl
850
avescentis radix (Kushen). Journal of ethnopharmacology 165, 243-250.
851
Shin, S., Jang, J.Y., Choi, B.I., Baek, I.J., Yon, J.M., Hwang, B.Y., Park, D., Jeon, J.H., Nam,
852
S.Y., Yun, Y.W., 2008. Licorice extract does not impair the male reproductive function of rats.
853
Exp Anim 57, 11-17.
854
Sun, B., Wanga, X.b., Cao, R.l., Zhang, Q., Liu, Q., Xu, M.f., Zhang, M., Du, X.b., Dong, F.t.,
855
Yan, X.z., 2016a. NMR-based metabonomics study on the effect of Gancao in the attenuation
856
of toxicity in rats induced by Fuzi. Journal of ethnopharmacology 193, 617-626.
857
Sun, C., Xie, Y.C., Tian, Q.L., Liu, H.Z., 2007. Separation of glycyrrhizic acid and liquiritin from
858
licorice root by aqueous nonionic surfactant mediated extraction. Colloids and Surfaces A:
859
Physicochemical and Engineering Aspects 305, 42-47.
860
Sun, G.X., Wang, Y., Sun, Y.q., 2011. The Quantitative Determinations of Glycyrrhizic Acid,
861
Glycyrrhetinic Acid, Morphine, and Sodium Benzoate in Compound Liquorice Tablets by
862
HPCE. Journal of Liquid Chromatography & Related Technologies 26, 43-51.
863
Sun, L., Zong, S.B., Li, J.C., Lv, Y.Z., Li Na
864
J.P., Xiao, W., 2016b. The essential oil from the twigs of Cinnamomum cassia Presl alleviates
865
pain and inflammation in mice. Journal of ethnopharmacology 194, 904-912.
866
Takeshi, K., Tamotsu, S., Shoji, S., 1978. A new 3-Arylcoumarin from Licorice root. Chemical
867
& Pharmaceutical Bulletin 26, 135-140.
868
Tashi, A., Zhou, Q., Dong, X.O., Sun, S.Q., 2006. Study on the identification of standard and
869
false Gancao by Fourier transform infrared spectroscopy. Spectroscopy and Spectral Analysis
870
26, 1238-1241.
871
Tian, S.Z., Yang, Y.T., Yang, X., Chang, L., 2009. Analysis of licorice preparation in the
872
Edition of Chinese Pharmacopoeia. Chinese Traditional Patent Medicine 31, 1434-1435.
873
Tong, P.j., Xu, S.b., Cao, G., Jin, W.d., Guo, Y.w., Cheng, Y., Jin, H.t., Shan, L.t., Xiao, L.w.,
874
2014. Chondroprotective activity of a detoxicated traditional Chinese medicine (Fuzi)of
875
Aconitum
carmichaeli Debx
against
Ethnopharmacology 170, 50-56.
Liu, Zheng Zhong
Wang, Zhou, J., Cao, L., Kou,
severe-stage osteoarthritis 44
model
2005
induced
by
876
monoiodoacetate. Journal of ethnopharmacology 151, 740-744.
877
Tsutomu, H., Miyuki, T., Hideyuki, I., Takashi, Y., 1997. Phenolic constituents of liquorice VII.A
878
new Chalcone with a potent radical scavenging activity and accompanying phenolics from
879
Liquorice. Chemical & Pharmaceutical Bulletin 45, 1485-1492.
880
Wagner, H., Ulrich-Merzenich, G., 2009. Synergy research: Approaching a new generation of
881
phytopharmaceuticals.
882
phytopharmacology 16, 97-110.
883
Wang, F., 2014. Clinical research on the change of aconitine in compatible application of Fuzi
884
and Ganjiang, Fuzi and Gancao Clinical Journal of Chinese Medicine 6, 22-25.
885
Wang, F., Su, Y., 2002. Pharmacological action and clinical application of licorice. LiShizhen
886
Medicine and Materia Medica Research 13, 303-304.
887
Wang, J., Dai, L., Li, P.Y., Huo, H.R., Sui, F., Zhang, C.F., Li, L.F., Guo, S.Y., Li, C.H., Jiang,
888
Y.L., 2014. Study on active ingredients for increased efficacy of compatibility of penoy and
889
licorice. Chinese Journal of Experimental Traditional Medical Formulae 20, 83-86.
890
Wang, M., Liu, B., Qi, Y., Song, Y., Xie, S., Luo, X., Cai, R., 2008. Effect of Glycyrrhiza
891
Uralensis Saponins on Acute Toxicity of Platycodins. Chinese Journal of Experimental
892
Traditional Medical Formulae 14, 59-61.
893
Wang, Q.E., Ren, H., Cao, X.L., 2011. Research and utilization statue of licorice. Chinese
894
Agricultural Science Bulletin 27, 290-295.
895
Wang, S., 2015. The efficacy and taboo of licorice research in "Treatise on Febrile Diseases",
896
College of Basic Medicine. Liaoning University of Traditional Chinese Medicine, China, p. 53.
897
Wang, S.J., 2010. Study on pharmacokinetic of shaoyao-licorice decoction in rats, Clinical
898
college of Chinese medicine. Liaoning University of Chinese Medicine, China.
899
Wang, S.N., Sun, L.J., Gu, L.Q., Zhang, Y.Y., Zhao, S.M., Zhao, L.S., Bi, K.S., Chen, X.H.,
900
2016a. The comparative pharmacokinetics of four bioactive ingredients after administration of
901
Ramulus Cinnamomi-Radix Glycyrrhizae herb pair extract, Ramulus Cinnamomi extract and
902
Radix Glycyrrhizae extract. Biomed Chromatography 30, 1270-1277.
903
Wang, S.X., Wang, J., Ma, C.C., Jia, P., Yang, Y., Zheng, X.H., 2018. Effect of
904
safflower-liquorice on vasomotion of mesanteric artery in rats with cold coagulation and blood
905
stasis. Chin Hosp Pharm J 38, 387-392.
906
Wang, X., Zhang, H., Chen, L.L., Shan, L.H., Fan, G.W., Gao, X.M., 2013. Liquorice, a unique
907
"guide drug" of traditional Chinese medicine: a review of its role in drug interactions. Journal of
908
Ethnopharmacol 150, 781-790.
909
Wang, X.P., Huang, X.W., Wang, N.N., Wu, R.J., Li, H.Y., Yu, Z.M., Shou, D., 2015. Toxicity of
910
the water extraction of Radix sophorae flavescentis formulated with Ｒadix Glycyrrhizae on
911
mice. CHINESE ACHIVES OF TＲADITIONAL CHINESE MEDICINE 33, 1653-1655.
912
Wang, Z.L., Du, J.C., Yu, L.Q., Ba, D.L., Shi, Z., 2002. The utilization value , current research
913
and problems of Glycyrrhiza. Grassland of China 24, 73-76.
914
Wang, Z.Q., Zeng, R., Tan, Z.R., Chen, Y., Tian, Y.W., Wang, B., li, J., Chen, L.F., 2012.
Phytomedicine
:
international
45
journal
of
phytotherapy
and
915
Pharmacokinetics of aconitine and glycyrrhetic acid in separation and combination with Aconiti
916
lateralis Radix praeparata and Glycyrrhizae Radix et Rhizoma in rats. Chinese Traditional
917
Patent Medicine 34, 2305-2309.
918
Wang, Z.Y., Cui, S.L., Li, L.F., Li, H., Zhang, J., 2016b. Synergistic study of peony and
919
liquorice decoction. Science & Technology Vision 5, 274-275.
920
Wu, W.P., Yan, H.T., Sun, W.J., 2004. HPLC determination of Liquiritin in Licorice. Chinese
921
Journal of Pharmaceutical Analysis 24, 425-427.
922
Xie, J.B., Wang, W.Q., 2009. Study on evolution and history of liquorice production area.
923
Research and Practice of Chinese Medicines 23, 35-36.
924
Xie, S.H., Zhang, G.P., Sun, G.B., Chen, R.C., Zhang, S.Y., He, L., Ye, Z.G., 2012.
925
Detoxication experimental study on different compatibility proportion of Aconiti Lateralis Radix
926
Praeparata and Glycyrrhizae Radix et Rhizoma. China journal of chinese meteria medica 37,
927
2210-2214.
928
Xu, W.J., Zhao, J., Zhou, H.F., Luo, J.B., 2012. Effects of different compatibility on content of
929
active ingredients and anti - inflammatory activity of liquorice ephedrae. Journal of Sichuan of
930
Traditional Chinese Medicine 30, 50-54.
931
Xu, X., Meng, N., Yu, Y.J., Hu, M.R., 2016. Effect of the Combined Use of Ｒheum and
932
Liquorice on Inflammatory Factors in Ｒats With Intestinal Function Failure. Chinese General
933
Practice 19, 1824-1827.
934
Yang, J.H., Zhang, Y.Y., Wan, H.T., Zhu, Z.H., Li, J.H., 2010. Experimental study on the
935
combination of aconite alkaloid and glycyrrhizin active substances against adjuvant arthritis in
936
rats. Chinese Traditional and Herbal Drugs 41, 439-444.
937
Yang, R., Li, W.D., Ma, Y.S., Zhou, S., Xue, Y.T., Lin, R.C., Liu, Y., 2017. The molecular
938
identification of licorice species and the quality evaluation of licorice slices Acta Pharmaceutica
939
Sinica 52, 318-326.
940
Yao, F.Y., Wang, B.Z., Peng, S.H., Wang, X., Zheng Yun Zuo, 2014. Effects of glycyrrhiza
941
osmanthus decoction on energy metabolism in low temperature rats. TCM Research 27,
942
67-70.
943
Yasui, S., Fujiwara, K., Tawada, A., Fukuda, Y., Nakano, M., Yokosuka, O., 2011. Efficacy of
944
Intravenous Glycyrrhizin in the Early Stage of Acute Onset Autoimmune Hepatitis. Digestive
945
Diseases and Sciences 56, 3638-3647.
946
Ye, J.Y., Chen, P.Y., Zhang, J.P., Ye, Q.Q., Chen, G.L., 2018. The Influence of Combination of
947
Wumei and Gancao and Single Use of Wumei or Gancao on rats with radiation-induced
948
salivary gland injury. Henan Traditional Chinese Medicine 38, 360-362.
949
Zeng, L., Toshio, F., Taro, N., Zhang, R.Y., Lou, Z.C., 1992. Four new prenylated flavonoids,
950
glyasperins A, B, C, and D from the roots of Glycyrrhiza aspera. Heterocycles 34, 575-587.
951
Zhang, J., Yao, J., Ding, L., Guo, S.J., Yong Li Yang, 2000. Advancement of research on the
952
utilization of glycyrrhiza. Grassland and Turf 89.
953
Zhang, J., Yao, J., Yang, Y.L., Wang, Y.F., Peng, G.L., Wang, Y.J., 2001. Analysis and 46
954
contents mensurate of alkaloid in l iquorice. Acta Botanica Boreali-Occidentalia Sinica 21,
955
1259-1262.
956
Zhang, J.M., Fu, C.M., Su, S.H., Li, Y., Zhang, Z., 2011. Compatibility Effect between Radix
957
Aconiti Lateralis and Radix Glycyrrhizae on Pharmacokinetics of Hypaconitine in Rat Plasma
958
by LC-MS/MS. World Science and Technology 13, 1048-1053.
959
Zhang, R., Li, Q., Liu, F., Liu, J.Q., Zhang, W., He, Z.H., Hong, Q., Kou, X.L., Wu, J.M., 2010.
960
Effect of Glycyrrhiza uralensis on Metabolism and Distribution and Excretion of Triptonide in
961
vivo by LC-MS-MS. Chinese Journal of Experimental Traditional Medical Formulae 16,
962
152-156.
963
Zhang, T., Bai, G., Liu, C., 2019. The concept, core theory and research methods of Chinese
964
medicine quality markers. Acta Pharmaceutica Sinica 54, 187-195.
965
Zhang, W., Gong, L., Zhou, L.L., Shan, J.J., Chen, L.T., Xu, H.Q., Di, L.Q., 2014. Effect of
966
different compatibility of Daphnes Giraldii Cortex and Glycyrrhizae Radix et Rhizoma on
967
adjuvant-induced arthritis in rats
968
Zhao, D.S., Wu, Z.T., Li, Z.Q., Wang, L.L., Jiang, L.L., Shi, W., Li, P., Li, H.J., 2018.
969
Liver-specific metabolomics characterizes the hepatotoxicity of Dioscorea bulbifera rhizome in
970
rats by integration of GC-MS and 1H-NMR. Journal of ethnopharmacology 226, 111-119.
971
Zhao, J.F., Hiroaki, K., Haruki, Y., 1991. Heterogeneity and characterisation of mitogenic and
972
anti-complementary pectic polysaccharides from the roots of Glycyrrhiza
973
et D.C. Carbohydr Res 219, 149-172.
974
Zhao, L., Ma, G.H., Yu, J., Fu, L.Y., 2014. Effect on Alkaloid components in strychnos
975
Nux-vomical L. by different decocting time and compatibility dosages of Radix Glycyrrhizae.
976
LIAONING JOURNAL OF TRADITIONAL CHINESE MEDICINE 41, 1937-1939.
977
Zhao, P.Y., Jiao, L.W., Zhang, Z.M., Yang, X.Y., Xu, J.Z., Lian, Y.H., Bayaer, E., 2017a. Study
978
of the differences of flavonoids compounds in Glycyrrhiza residues from different countries by
979
UPLC-QTOF-MS. China Food Additives, 111-116.
980
Zhao, X.M., Gong, M., Dong, J.M., Wang, J.B., Xiao, X.H., Zhao, K.J., Ma, Z.J., 2017b.
981
Preliminary research on effect of licorice-processed Tripterygium wilfordii on reducing liver
982
toxicity. China journal of chinese meteria medica 42, 119-124.
983
Zhao, Y.M., Liu, S.X., Zhang, C.X., Liu, D.L., Zhang, T.J., 2016. Analysis on chemical
984
constituents from
985
Traditional and Herbal Drugs 47, 2061-2068.
986
Zheng, P., Yan, Y., 1998. Adverse reactions of Licorice and its preparations. ACTA CHINESE
987
MEDICINE AND PHARMACOLOGY, 29-30.
988
Zhou, C., 2010. Licorice. Agricultural press, BeiJing.
989
Zhou, Q., Wang, L., Dai, Y.P., Zhou, H.L., 2017. Influence of Mix-fring with Honry Technics on
990
Volatile Components of Glycyrrhi Radix et Rhizoma Based on GC-MS. Chinese Journal of
991
Experimental Traditional Medical Formulae 23, 87-90.
992
Zhu, G.W., Zhang, G.J., Sun, Y., Wang, M., Qu, L., Xiang, L., Lu, L.N., Wu, Y.L., Yang, Y.F.,
Chinese Traditional and Herbal Drugs
Glycyrrhizae Radix et Rhizoma
47
45, 1418-1426.
uralensis
Fisch
by HOLC-Q-TOF-MS. Chinese
993
Zheng, J., 2016. Analysis of different active components in Radix Paeoniae Alba,Glyycrrhizae
994
Radix Et Rhzoma and their drug pair. World Chinese Medicine | World Chin Med 11, 143-150.
995
Zhuo, S., Hua, B., He, K., Cai, W., Liu, T., Huang, X., Xu, W., 2018. The study on the
996
detoxication
997 998
Rational Drug Use 11, 93-95.
of liquorice on hepatotoxicity of Melia toosendan Sieb.et Zucc. Chin J of Clinical
48