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Cudrania tricuspidata: an updated review on ethnomedicine, phytochemistry and pharmacology

Lan-Ting Xin ab, Shi-Jun Yueab, Ya-Chu Fanab, Jing-Shuai Wuab, Dan Yanc, Hua-Shi Guan*ab and Chang-Yun Wang*ab
aKey Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China. E-mail: changyun@ouc.edu.cn; hsguan@ouc.edu.cn; Fax: +86 532 82031536; Tel: +86 532 82031536 Tel: +86 532 82031667
bLaboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, P. R. China
cBeijing Shijitan Hospital, Capital Medical University, Beijing 100038, P. R. China

Received 17th April 2017 , Accepted 3rd June 2017

First published on 22nd June 2017


Abstract

Cudrania tricuspidata is a perennial plant of the family Moraceae with numerous medicinal and nutritional applications. It has been widely used in East Asia as an important traditional folk medicine for the treatment of many ailments such as eczema, mumps, tuberculosis, contusions, insomnia and acute arthritis. The whole plant of C. tricuspidata, including the roots, leaves, bark, stems and fruits, has been found to contain diverse phytochemicals, including xanthones, flavonoids, organic acids, and polysaccharides, with various bioactivities. In particular, xanthones and flavonoids, as the main active constituents, isolated from C. tricuspidata have been proven to possess notable anti-inflammatory, antioxidative, antitumor, hepatoprotective, neuroprotective and anti-obesity effects. This review summarizes the botany, traditional uses, phytochemistry and pharmacology of C. tricuspidata, and the limitations of studies on this species have also been discussed such that to serve as the basis for further research and development on this medicinal plant.


1 Introduction

Cudrania tricuspidata (Carr.) Bur. ex Lavallee, which is a deciduous thorny tree belonging to the family Moraceae, is widespread throughout East Asia1 and is known as cudrang, mandarin melon berry, silkworm thorn, storehouse bush, hariguwa (in Japanese) and che (in Chinese).2–4 In China, C. tricuspidata roots have been used as ‘Chuan-po-shi’ in traditional Chinese medicine (TCM) in the treatment of gonorrhea, rheumatism, jaundice, boils, scabies, bruising, and dysmenorrhea;5,6 its root bark has been widely used in the treatment of lumbago, hemoptysis, and contusions;7 and its roots and stems have also been applied in the forms of syrups, granules and injections to cure tumors of the digestive tract.8 In Korea, C. tricuspidata has become one of the most ubiquitous folk remedies against cancer during the last few decades.9 In addition to the above medical uses, in China the stems and roots of C. tricuspidata have been used to prepare herbal teas or functional beverages for a long period;10 the stems, which contain a reddish-yellow dye, have been noted for their use in coloring imperial garments;3 and the tender leaves of C. tricuspidata have been used as a perfect food for breeding silkworms since the Han dynasty, and the natural silk has been praised under the name of Zhe Si.11 Its edible fruits have been made into juices, jams, alcoholic beverages, dietary supplements and other health products in Korea.12 Moreover, its bark fibers have been utilized to make paper and its trunks have been used as valuable timber for furniture manufacture.13

The immense medicinal and economic value of C. tricuspidata has encouraged numerous studies of its phytochemicals and pharmacological activities. C. tricuspidata extracts have been demonstrated to possess good therapeutic effects against various ailments including inflammation,14,15 tumors,16,17 obesity,18,19 and diabetes.20,21 Xanthones and flavonoids have been considered to be the two major classes of phytochemicals in C. tricuspidata. For example, prenylated xanthones and flavonoids were found to be the most important and abundant constituents in its leaves and root bark with regard to their notable anti-inflammatory,22,23 antitumor,16,24 hepatoprotective,25,26 neuroprotective,27,28 and anticoagulant29 activities; hydroxybenzyl flavonoid glycosides from the stem bark were reported to be promising natural antioxidant and antitumor agents;30 and prenylated isoflavonoids and benzylated flavonoids from the fruits displayed potential anti-inflammatory31 and antioxidant32 activities. Besides, a glycoprotein (75 kDa) from C. tricuspidata, which consisted of carbohydrate (72.5%) and protein moieties (27.5%), exhibited distinctive characteristics with anti-inflammatory,33 antioxidant,34 hepatoprotective,35 and immunomodulatory36 effects.

To date, to the best of our knowledge, no comprehensive review concerning C. tricuspidata has been available. A literature survey was conducted via an electronic search using PubMed, Scopus, ACS, Web of Science, ScienceDirect, China Knowledge Resource Integrated Database (CNKI), Google Scholar, SciFinder and a library search for ethnobotanical textbooks. The Plant List (www.theplantlist.org), the Missouri Botanical Garden's Tropicos nomenclature database (www.tropicos.org) and the Chinese Field Herbarium (www.cfh.ac.cn) were used to validate the taxonomy and also obtain information regarding subspecies and cultivars. On the basis of the literature search, we reviewed the achievements of research on the botanical characteristics, traditional uses, phytochemicals and pharmacological activities of C. tricuspidata so as to provide a systematic summary of the literature for further research on, and development of, this medicinal plant.

2 Botany and traditional uses of C. tricuspidata

2.1. Botany of C. tricuspidata

C. tricuspidata is one of six species in the genus Cudrania, which is endemic to Asia and Oceania, of the family Moraceae in the order Urticales.37 Five species, namely, C. tricuspidata, C. cochinchinensis (Lour.) Kudo et Masam, C. fruticosa (Roxb.) Wight ex Kurz, C. amboinensis (Bl.) Miq., and C. pubescens Trec., as well as C. cochinchinensis var. gerontogea (Nakai) Kudo et Masam, have been widely cultivated in Southern China, including Yunnan, Fujian and Jiangsu provinces, as well as in Hebei province, as profitable plants for producing valuable fruits and timber.38,39 In Europe C. tricuspidata was introduced into cultivation in 1870, and in the USA in 1909.40 In contrast, wild populations of this species are now under threat of extinction.

As a hardy deciduous plant, C. tricuspidata is widely distributed in lowlands, foothills, forests, or dense scrub at altitudes of between 500 and 2000 m. It can eventually grow to a height of approximately 1.0–7.0 m (Fig. 1), but often exists as a broad spreading bush or small tree. Its leaves have single alternate ovate to rhombic-ovate blades with a size of 5.0–14.0 cm long and 3.0–6.0 cm wide; its flowers have a dioecious capitulum with an inflorescence length of 0.5 (male) or 1.0–1.5 cm (female); the color of its syncarpous fruits is orange-red when mature; and its roots, which are up to 50 cm long, are yellow and irregularly cylindrical.37


image file: c7ra04322h-f1.tif
Fig. 1 Whole plant (∼200 years) (A), fruits (B) and roots (C) of C. tricuspidata.

2.2. Traditional uses

Since ancient times, C. tricuspidata has been used as a folk medicine in oriental countries.41 The medicinal material, which is known as Zhemu in TCM, is sweet in taste, slightly warm in nature and acts on the liver and spleen meridians in TCM theory.42 Its medicinal usage was first documented in Ben Cao Shi Yi (700–800 A.D., Tang Dynasty), which is a famous masterpiece of TCM,42 followed by other Chinese medical classics such as Ben Cao Yan Yi (1116 A.D., Song Dynasty),43 Ben Cao Hui Yan (1624 A.D., Ming Dynasty),44 and the Dictionary of Chinese Herbal Medicine (2006 Edition).6 Notably, C. tricuspidata roots, together with the roots of C. cochinchinensis (Lour.) Kudo et Masam, have been recorded as ‘Chuan-po-shi’ in the Chinese Pharmacopoeia (1977 Edition).5 According to traditional applications and empirical practice, the bark of C. tricuspidata has mainly been used to strengthen the body and improve health conditions, and the trunk to invigorate the circulation of the blood and cure impaludism.42 An aqueous decoction of its fruits and leaves (15–30 g) could be taken orally to relieve rheumatoid arthritis. Scabies and eczema could be alleviated using a decoction of its roots mixed with the roots of C. cochinchinensis and glutinous rice.45 An aqueous decoction of its roots combined with Acanthus ilicifolius L. and Desmodium pulchellum (L.) Benth. was documented to treat hepatitis, in particular viral hepatitis.46,47 Currently, the bark of C. tricuspidata, together with Zhemu syrup (a traditional Chinese patent medicine), is widely employed in TCM clinics for the treatment of cancer of the alimentary system, in particular gastric carcinoma.8,24 Specifically, C. tricuspidata has been widely used with a long folkloric medicinal history by Chinese nationalities including Yi, Wa, Tong, Bai and Yao.

In the Korean classic Donguibogam (1613 A.D., Joseon Dynasty), C. tricuspidata was recorded as treating eczema, mumps, tuberculosis, contusions, and acute arthritis.48 Its fruits are commonly consumed in the Korean daily diet owing to its diverse biological effects, e.g., antioxidant, anti-inflammatory and immunomodulatory activities.12 In addition, during the last few decades, the whole plant of C. tricuspidata has been exploited as an important folk remedy for cancer in Korea.49

3 Phytochemistry

Over recent decades, a large number of chemical constituents have been isolated from C. tricuspidata. Xanthones and flavonoids have been recognized to be the main active and structurally diverse constituents responsible for the various activities of this species, followed by organic acids, polysaccharides, phenylpropanoids, and other constituents (Table 1).
Table 1 Chemical constituents of C. tricuspidata
No. Compound name(s) Tissue(s) Ref.
Xanthones
1 Cudratricusxanthone A Whole plant 49
2 Cudratricusxanthone B Roots 17
3 Cudratricusxanthone C Roots 17
4 Cudratricusxanthone D Roots 17
5 Cudratricusxanthone E Roots 17
6 Cudratricusxanthone F Roots 17
7 Cudratricusxanthone G Roots 17
8 Cudratricusxanthone H Roots 17
9 Cudratricusxanthone I Roots 55
10 Cudratricusxanthone J Roots 50
11 Cudratricusxanthone K Roots 50
12 Cudratricusxanthone L Roots 50
13 Cudratricusxanthone M Roots 50
14 Cudratricusxanthone N Roots 143
15 Cudratricusxanthone O Roots 143
16 Cudratricusxanthone P/cudracuspixanthone A Roots 116 and 143
17 Cudraxanthone A Root bark 144
18 Cudraxanthone B Root bark 144
19 Cudraxanthone C Root bark 144
20 Cudraxanthone D Root bark 4
21 Cudraxanthone E Root bark 146
22 Cudraxanthone F Root bark 146
23 Cudraxanthone G Root bark 146
24 Cudraxanthone H Root bark 147
25 Cudraxanthone I Root bark 147
26 Cudraxanthone J Root bark 147
27 Cudraxanthone K Root bark 147
28 Cudraxanthone L Root bark 148
29 Cudraxanthone M Root bark 148
30 Cudraxanthone N Root bark 148
31 Cudraxanthone O Root bark 148
32 Cudracuspixanthone B/cudratrixanthone B Roots 27 and 116
33 Cudracuspixanthone C Roots 116
34 Cudracuspixanthone D Roots 116
35 Cudracuspixanthone E Roots 88
36 Cudracuspixanthone F Roots 88
37 Cudracuspixanthone G Roots 88
38 Cudratrixanthone A Root bark 27
39 Cudratrixanthone C Root bark 27
40 Cudratrixanthone D Root bark 27
41 Cudratrixanthone E Root bark 27
42 Cudratrixanthone F Root bark 27
43 Cudratrixanthone G Root bark 27
44 Cudratrixanthone H Root bark 27
45 Cudratrixanthone I Root bark 27
46 Cudratrixanthone J Root bark 27
47 Cudratrixanthone K Root bark 27
48 Cudratrixanthone L Root bark 27
49 Cudratrixanthone M Root bark 27
50 Cudratrixanthone N Root bark 27
51 Cudratrixanthone O Root bark 27
52 Cudratrixanthone P Root bark 145
53 Cudratrixanthone Q Root bark 145
54 Cudratrixanthone R Root bark 145
55 Cudratrixanthone S Root bark 145
56 Cudratrixanthone T Root bark 145
57 Cudratrixanthone U Root bark 145
58 Cudratrixanthone V Root bark 145
59 Cudratrixanthone W Root bark 145
60 Alvaxanthone Roots 88
61 Alloathyriol Roots 88
62 Dulxanthone B Twigs 75
63 Gerontoxanthone A Root bark 25
64 Gerontoxanthone C Root bark 27
65 Gerontoxanthone I Roots 88
66 Isocudraniaxanthone A Roots 116
67 Isocudraniaxanthone B Root bark 56
68 Isocudraxanthone K Root bark 25
69 Isogentisin Roots 88
70 Isoalvaxanthone Roots 88
71 Laxanthone I Root bark 116
72 Macluraxanthone B Whole plant 49
73 Macluraxanthone C Roots 55
74 Nigrolineaxanthone F Root bark 27
75 Neriifolone A Root bark 27
76 Toxyloxanthone B Root bark 145
77 Toxyloxanthone C Roots 17
78 Xanthone V1a Roots 17
79 1-Trihydroxy-3,6,7-trimethoxyxanthone Roots 55
80 1,3,5-Trihydroxy-4-prenylxanthone Roots 116
81 1,3,5-Trihydroxy-2-(3-methylbut-2-enyl)xanthone Root bark 27
82 1,3,5,6-Tetrahydroxyxanthone Bark 149
83 1,3,6,7-Tetrahydroxy-2-(3-methylbut-2-enyl)-8-(2-methylbut-3-en-2-yl)-9H-xanthen-9-one Roots 52
84 1,3,7-Trihydroxy-4-(1,1-dimethyl-2-propenyl)-5,6-(2,2-dimethylchromeno)xanthone Roots 52
85 1,5-Dihydroxy-3,6-dimethoxyxanthen-9-one Twigs 75
86 1,7-Dihydroxy-3,6-dimethoxyxanthone Roots 55
87 1,6,7-Trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone Roots 119
88 1,6,7-Trihydroxy-3-methyl-4-(1,1,3-trimethyl-2-buten-1-yl)-9H-xanthen-9-one Root bark 23
89 2-Deprenylrheediaxanthone B Root bark 116
90 2,6-Dihydroxyxanthone Roots 116
91 3-O-Methylcudratrixanthone G Root bark 27
92 5-O-Methylformoxanthone C Root bark 27
93 6-Deoxyisojacareubin Root bark 27
94 6-Deoxy-γ-mangostin Root bark 27
95 7-O-Demethylcudratrixanthone C Root bark 145
96 8-Prenylxanthone Roots 88
97 16-Hydroxycudratrixanthone Q Root bark 145
98 16-Hydroxycudratrixanthone M Root bark 145
99 16-Methoxycudratrixanthone M Root bark 145
[thin space (1/6-em)]
Flavonoids
Flavones
100 Artocarpesin Roots and stems 17
101 Apigenin Fruits 168
102 Apigenin-7-O-β-D-glucopyranoside Fruits 168
103 Cudraflavone A Root bark 150
104 Cudraflavone B Root bark 150
105 Cudraflavone C Root bark 151
106 Cudraflavone D Root bark 151
107 Cudraflavone F Roots 58
108 Cudraflavone G Roots 58
109 Cudraflavone H Root bark 145
110 Cycloartocarpesin B Roots 17
111 Cyclomorusin Twigs 75
112 Cycloartocarpin Whole plant 152
113 Hirsutrin/quercetin-3-O-β-D-glucopyranoside Fruits 66
114 Kuwanon C Roots 125
115 Licoflavone C Leaves 153
116 5,7,2′,4′-Tetrahydroxyflavone/norarthocarpetin Stems 154
117 6-Prenylapigenin Roots 58
118 Kaempferol Root bark 134
119 Kaempferol-3-O-β-D-glucopyranoside/astragalin Fruits 168
120 Kaempferol-7-O-β-D-glucopyranoside/populnin Whole plant 155
121 6-p-Hydroxybenzyl kaempferol-7-O-β-D-glucopyranoside Root bark 156
122 Morin Root bark 124
123 Myricetin Roots 117
124 Nicotiflorine Fruits 168
125 Quercetin Twigs, root bark and stems 75, 106 and 157
126 Quercetin-7-O-β-D-glucopyranoside/quercimeritrin Root bark 158
127 6-p-Hydroxybenzyl quercetin-7-O-β-D-glucopyranoside Root bark 156
128 Rutin Fruits 66
Flavanones
129 Cudraflavanone A Root bark 158
130 Cudraflavanone B Roots 125
131 Cudraflavanone C Roots 55
132 Cudraflavanone D Roots 55
133 Cudraflavanone E Roots 58
134 Cudraflavanone F Roots 58
135 Cudraflavanone G Root bark 145
136 (2R)-Cudraflavanone H Root bark 145
137 (2S)-Cudraflavanone H Root bark 145
138 Cycloaltilisin 7 Twigs 75
139 Cudracuspiflavanone A Root bark 124
140 Carthamidin Leaves 153
141 Dalenin Root bark 145
142 Dicycloeuchrestaflavanone B Root bark 145
143 Euchrestaflavanone B Root bark 157
144 Euchrestaflavanone C Root bark 157
145 Eriodictyol Stem bark 30
146 Naringenin Twigs and root bark 75 and 157
147 Pinocembrin Root bark 145
148 Prunin Fruits 168
149 Steppogenin Twigs, roots and stems 75, 159 and 160
150 Tomentosanol D Root barks 145
151 (2S)-2′,5,7-Trihydroxy-6-(3-hydroxy-3-methylbutyl)-6′′,6′′-dimethylpyrano[2′′,3′′:4′,5′]flavanone Roots 58
152 2′,5,7-Trihydroxy-4′,5′-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl)flavanone Root bark 157
153 4′-Hydroxyisolonchocarpin Root bark 145
154 5-Dehydroxybavachinone A Root bark 145
155 5,7,3′,5′-Tetrahydroxyflavanone Root bark 124
156 6-Prenylnaringenin Roots 161
157 8-Prenylnaringenin Root bark 124
158 Aromadendrin/dihydrokaempferol Root bark and twigs 75 and 156
159 Dihydrokaempferol-7-O-β-D-glucoside Twigs 75
160 trans-Dihydromorin Twigs and whole plant 133 and 152
161 Gericudranin A Stem bark 16
162 Gericudranin B Stem bark 16
163 Gericudranin C Stem bark 16
164 Gericudranin D Stem bark 58
165 Gericudranin E Stem bark 58
166 Taxifolin/dihydroquercetin Twigs and stems 75 and 160
167 Taxifolin-7-methyl ether Twigs 75
168 Taxifolin-7-O-β-D-glucopyranoside Twigs 75
169 Tricusposide Bark 149
170 (2S,3S)-2,3-trans-Dihydromorin-7-O-β-D-glucoside Twigs 75
171 (2R,3R)-2,3-Dihydro-3,5,6,7-tetrahydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one Root bark 124
172 3,5,7,2′,4′-Pentahydroxydihydroflavonol Whole plant 152
173 5,7,4′-Trihydroxy-8-p-hydroxybenzyldihydroflavonol Root bark 124
Isoflavones
174 Cudraisoflavone B Fruits 28
175 Cudraisoflavone C Fruits 28
176 Cudraisoflavone D Fruits 28
177 Cudraisoflavone E Fruits 28
178 Cudraisoflavone F Fruits 28
179 Cudraisoflavone G Fruits 28
180 Cudraisoflavone H Fruits 28
181 Cudraisoflavone I Fruits 28
182 Cudraisoflavone J Fruits 28
183 Cudraisoflavone K Fruits 28
184 Cudraisoflavone L (1) Leaves 87
185 Cudraisoflavone L (2) Fruits 168
186 Cudraisoflavone M Fruits 168
187 Cudraisoflavone N Fruits 168
188 Cudraisoflavone O Fruits 168
189 Cudraisoflavone P Fruits 168
190 Cudraisoflavone Q Fruits 168
191 Cudraisoflavone R Fruits 168
192 Cudraisoflavone S Fruits 168
193 Cudraisoflavone T Fruits 168
194 Cudracusisoflavone A Fruits 66
195 Cudracusisoflavone B Fruits 66
196 Auriculasin Fruits 28
197 Anagyroidisoflavone A Fruits 28
198 Alpinumisoflavone Fruits 32
199 Biochanin A Root bark 124
200 Erysenegalensein E Fruits 31
201 Isoerysenegalensein E Fruits 31
202 Erythrinin B/wighteone/6-isopentenylgenistein Twigs and fruits 28 and 102
203 Erythrinin C Fruits 28
204 Eryvarin B Fruits 28
205 Erysubin A Leaves 87
206 Euchrenone b8 Fruits 28
207 Euchrenone b9 Fruits 28
208 Euchrenone b10 Fruits 28
209 Erythrivarone A Leaves 153
210 Derrone Fruits 28
211 Derrone-4′-O-methyl ether Fruits 66
212 Flaniostatin Leaves 162
213 Flemiphilippinin B Whole plants 163
214 Flemiphilippinin G Fruits 28
215 Furowanin B Leaves 86
216 Gancaonin A Fruits 116
217 Gancaonin B Fruits 28
218 Genistein Twigs and bark 75 and 149
219 Genistein-4′-O-β-glucopyranoside/sophorobioside Fruits 168
220 Genistin Bark 149
221 Glycyrrhisoflavone Twigs 75
222 Isolupalbigenin Leaves 86
223 Isochandalone Fruits 66
224 Lupiwighteone Fruits 28
225 Lupalbigenin Leaves 87
226 Laburnetin Root bark 145
227 Millewanin H Leaves 87
228 Millewanin G Leaves 153
229 Osajin Fruits 32
230 Orobol Fruits 31
231 Oroboside Fruits 66
232 Orobol-8-C-glucoside Twigs 75
233 Pomiferin Fruits 32
234 Parvisoflavone A Root bark 145
235 Senegalensin Fruits 31
236 Santal Twigs 75
237 Sphaerobioside Twigs 75
238 Ulexin B Fruits 66
239 Ulexone B Fruits 66
240 Warangalon Fruits 28
241 3′-O-Methylorobol Root bark 124
242 4′-O-Methylalpinumisoflavone Fruits and stem bark 105 and 116
243 4′-O-Methylcudraisoflavone O Fruits 168
244 4′-O-Methylcudraisoflavone P Fruits 168
245 4′-O-Methylerythrinin C Fruits 168
246 4′,7-Dihydroxy-5-methoxyisoflavone/5-O-methylgenistein Stems 154
247 5,3′-Dihydroxy-4′-methoxy-2′′,2′′-dimethylpyrano[5′′,6′′;6,7]isoflavone Fruits 31
248 5,3′,4′-Trihydroxy-6′′,6′′-dimethylpyrano[2′′,3′′;7,6]isoflavone Fruits 66
249 5,4′-Dihydroxy-8-(3′′-methylbut-2′′-enyl)-2′′′-(4′′′-hydroxy-4′′′-methylethyl)furano[4′′′,5′′′;6,7]isoflavone Fruits 31
250 5,4′-Dihydroxy-6-(3′′-methylbut-2′′-enyl)-2′′′-(4′′′-hydroxy-4′′′-methylethyl)-3′′′-methoxydihydrofurano[4′′′,5′′′;7,8]isoflavone Fruits 31
251 5,7-Dihydroxy-6-(2′′-hydroxy-3′′-methylbut-3′′-enyl)-4′-methoxyisoflavone Fruits 31
252 5,7,4′-Trihydroxy-6,8-diprenylisoflavone/6,8-diprenylgenistein/8-(γ,γ-dimethylallyl)wighteone Fruits 32 and 75
253 5,7,4′-Trihydroxydihydroisoflavone Whole plant 152
254 6,8-Diprenylorobol/5,7,3′,4′-tetrahydroxy-6,8-diprenylisoflavone Twigs and fruits 28 and 75
255 6-Prenylorobol Leaves 153
256 7,4′-Dimethoxy-5-hydroxyisoflavone Fruits 66
257 8-Hydroxygenistein Root bark 145
[thin space (1/6-em)]
Organic acids
258 Butyl citrate Trunk 15
259 Benzoic acid Fruits 76
260 Boric acid Fruits 76
261 Citric acid Fruits 70
262 Mandelic acid Fruits 76
263 Methyl linoleate Trunk 15
264 Malic acid Fruits 70
265 Oxalic acid Fruits 70
266 Palmitic acid Trunk 15
267 Palmitic acid methyl ester Trunk 15
268 Palmitic acid β-monoglyceride Trunk 15
269 Protocatechuic acid Twigs 75
270 Succinic acid Fruits 70
271 Stearic acid Trunk 15
272 Syringic acid Trunk 15
273 Tartaric acid Fruits 70
274 threo-9,10-O-Isopropylidene-13-hydroxy-(11E)-octadecenoic acid Roots 164
275 n-Decanoic acid Roots and stems 10
276 n-Nonanoic acid Roots 10
277 n-Pentanoic acid Roots and stems 10
278 n-Hexanoic acid Roots and stems 10
279 n-Heptanoic acid Roots 10
280 n-Octanoic acid Roots 10
281 (E)-2-Decenoic acid Roots 10
282 (E)-2-Octenoic acid Roots and stems 10
283 2′,3′-Dihydroxypropyl pentadecanoate Roots 165
284 4-Hydroxybenzoic acid Fruits 168
285 9,12-Octadecadienoic acid Trunk 15
286 9,12,15-Octadecatrienoic acid methyl ester Trunk 15
287 9,12,15-Octadecatrien-1-ol Trunk 15
288 9,17-Octadecadienal Trunk 15
289 γ-Hexadecalactone Root bark 145
[thin space (1/6-em)]
Polysaccharides
290 CTP-B1 Roots 73
291 CTPS-01 Roots 72
292 CPS-0 Roots 71
293 CTPS-1A Roots 71
294 CTPS-2B Roots 71
295 CTPS-3A Roots 71
[thin space (1/6-em)]
Phenylpropanoids
296 Bergapten Root bark 145
297 Cudrastilbene Roots 159
298 cis-3′,4′-Diisovalerylkhellactone Root bark 145
299 Demethylsuberosin Whole plant 163
300 Decursinol angelate Root bark 145
301 Gomisin A Roots 166
302 Gomisin H Roots 166
303 Hyuganin C Root bark 145
304 Imperatorin Whole plant 163
305 Isoimperatorin Whole plant 163
306 Oxyresveratrol Twigs 75
307 Scopoletin Trunk 15
308 Schizandrin Whole plant 166
309 Syringaresinol Whole plant 166
310 Umbelliferone Root bark 151
311 Xanthyletin Root bark 145
312 7-Hydroxy-2H-1-benzopyran-2-one Trunk 15
313 5-Methoxy-4,5-diphenyl-2(5H)-furanone Twigs 75
314 3-Methyl-2(5H)-furanone Roots 10
315 5-Ethyl-2(5H)-furanone Roots 10
316 5,5-Dimethyl-2(5H)-furanone Roots 10
[thin space (1/6-em)]
Other ingredients
317 Betulin Roots 165
318 Butyrospermol Fruits 168
319 Camphene Roots 10
320 Drimenol Roots 10
321 Dihydroctinidiolide Stems 10
322 Glutinol Root bark 145
323 Lupeol Roots 165
324 Lanosta-8-24-dien-3β-ol-acetate Trunk 15
325 Lanosta-8-en-3-one Trunk 15
326 Lanosta-7,24-diene-3β-ol Whole plant 152
327 Lanosta-7,24-diene-3β-O-acetate Whole plant 152
328 Olean-12-ene Trunk 15
329 Taraxerone Stems 160
330 Terpin hydrate Roots 10
331 Ursolic acid Roots 165
332 (E)-Geranylacetone Roots 10
333 (E)-β-Ionone Roots and stems 10
334 (E)-Linalool oxide Roots 10
335 (Z)-Linalool oxide Roots 10
336 (E)-α-Terpineol Roots and stems 10
337 α-Amyrin Root bark 145
338 Campesterol Trunk 15
339 Daucosterol Roots 165
340 Itesmol Roots 165
341 β-Sitosterol Roots 165
342 γ-Sitosterol Trunk 15
343 Achilleol A Whole plant 163
344 Antiarol Fruits 76
345 Anisaldehyde Roots 10
346 Aristolone Trunk 15
347 Adacene 12 Fruits 76
348 Brosimine B Root bark 145
349 Benzophenone Stems 10
350 Benzylhydrazine Fruits 76
351 Bis(2-azabicyclo[2.2.1]hept-5-en-2-yl)diazene Fruits 76
352 Butylated hydroxytoluene Fruits 76
353 Cudracuspiphenone A Roots 116
354 Cudracuspiphenone B Roots 116
355 Cudrachromone A Root bark 145
356 Cudraphenol A Root bark 145
357 Cudraphenol B Root bark 145
358 Cudraphenol C Root bark 145
359 Cudraphenone E Root bark 145
360 Cudradihydrochalcone A Fruits 168
361 Cudrabibenzyl A Fruits 168
362 (E)-Cinnamic aldehyde Roots and stems 10
363 Dopamine Fruits 76
364 Demeton-O-methyl Fruits 76
365 Diethyl phthalate Fruits 76
366 Ethyl-N-methylcarbamate Fruits 76
367 Eriosematin A Root bark 145
368 Ethyl p-tert-butylbenzoic acid Fruits 76
369 Eugenol Roots and stems 10
370 Isoeugenol Roots 10
371 Isoencecalin Root bark 145
372 Indene Fruits 76
373 Lavender lactone Roots 10
374 Lycopene Fruits 77
375 Lutein Fruits 77
376 Palustrol Fruits 76
377 Peonoside Bark 149
378 Phenol Fruits, roots and stems 10 and 76
379 Phytofluene Fruits 77
380 Phenylethyl alcohol Roots and stems 10
381 Pyridine Roots 10
382 Pyrrole-2-carboxaldehyde Stems 10
383 Ruboxanthin Fruits 77
384 Salicylamide Fruits 76
385 Scyllitol Fruits 76
386 Sucrose Bark 149
387 Stachydrine Roots 167
388 Tridecanol Fruits 76
389 Undecane Fruits 76
390 Vanillin Root bark 145
391 Zeaxanthin Fruits 77
392 p-Vinylguaiacol Roots and stems 10
393 n-Hexanal Roots 10
394 n-Hexanol Roots 10
395 n-Butanol Roots 10
396 n-Nonanal Roots and stems 10
397 N-Acetylnorephedrine Fruits 76
398 1-Phenyl-1-cyclohexylethane Fruits 76
399 1-Methyl-2-pyrrolidone Roots and stems 10
400 1-[(2,4,6-Trimethylphenyl)methyl]imidazole Fruits 76
401 (4S)-1,1-Difluoro-4 vinylspiropentane Fruits 76
402 2-Deuteriophenylalanine Fruits 76
403 2-Furanmethanol Trunk 15
404 2-Ethyl-1-hexanol Roots and stems 10
405 2-Acetylpyrrole Stems 10
406 2,3-Dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one Trunk 15
407 2,4-Bis(4-hydroxybenzyl)phenol Root bark and stems 10 and 145
408 2,5-Furandione Trunk 15
409 3-Methoxycarbonylindole Root bark 145
410 3-Methyl-2,5-furandione Trunk 15
411 4-Acetylpyrazole Roots 10
412 4-Ethylguaiacol Roots and stems 10
413 4-Hydroxybenzalacetone Root bark 145
414 4-Hydroxymethylbenzoate Root bark 145
415 4-(Methoxymethyl)phenol Whole plant 163
416 4-Methyltridecane Fruits 76
417 4-Methylguaiacol Roots 10
418 4-Hydroxybenzaldehyde/p-hydroxybenzaldehyde Trunk 15
429 4-Valerolactone Roots and stems 10
420 4,4-Diphenyl-5-methyl-2-cyclohexenone Fruits 76
421 p-Hydroxybenzyl alcohol Trunk 15
422 5-(Hydroxymethyl)-2-furancarboxaldehyde Trunk 15
423 5-Hydroxy-2,2-dimethyl-2H,6H-benzodipyran-6-one Root bark 124
424 5-Methyl-1H-pyrrole-2-carboxaldehyde Stems 10
425 5,7-Dihydroxychromone Root bark 124
426 6-Pentyl-5,6-dihydro-2H-pyran-2-one Roots and stems 10
427 8-Chloro-6-(2-fluorophenyl)imidazole[1,2-a][1,4]benzodiazepine Fruits 76
428 α-Carotene Fruits 77
429 β-Carotene Fruits 77
430 Neo-β-carotene Fruits 77
431 γ-Amylbutyrolactone Roots and stems 10
432 γ-Butylbutyrolactone Roots and stems 10
433 γ-Butyrolactone Roots 10
434 γ-Caprolactone Roots 10
435 γ-Crotonolactone Roots 10
436 γ-Dodecalactone Roots and stems 10
437 γ-Palmitolactone Roots 10
438 Arginine Roots 167
439 Alanine Roots 167
440 Aspartate Roots 167
441 Glutamic acid Roots 167
442 Proline Roots 167
443 Polycopene Fruits 77


3.1. Xanthones (1–99)

The presence of abundant xanthones substituted by a variety of isoprenoid, phenolic and methoxy groups has been considered to be a taxonomic feature of C. tricuspidata (Fig. 2).17,49,50 Among these, from the perspective of the structure–activity relationship (SAR), xanthones substituted by isoprenoid groups display better biological activities. For instance, cudratricusxanthone A (CTXA, 1), cudraxanthones L (28) and M (29), and macluraxanthone B (72) are notable isoprenylated xanthones with anti-inflammatory,22 antitumor,17 neuroprotective,51 hepatoprotective,26 monoamine oxidase (MAO)-inhibiting,50 anticoagulant,29 antidiabetic,52 and neuraminidase-inhibiting effects.53 Cudratricusxanthones B–E (2–5) and G (7), cudraxanthones D (20), L and M, and macluraxanthones B and C (73), which are classed as catecholic xanthones, could be converted into quinone methide intermediates in an enzymatic or a non-enzymatic manner54 and were reported to have significant antitumor activity.17,49,55,56 In addition, catecholic xanthones, specifically cudraxanthone C (19) and 1,3,7-trihydroxy-4-(1,1-dimethyl-2-propenyl)-5,6-(2,2-dimethylchromeno)xanthone (84), exhibited both potent superoxide- and hydroxyl radical-scavenging activities, which could be rationalized by their chelating effect with Fe2+ ions.56
image file: c7ra04322h-f2.tif
Fig. 2 Chemical structures of xanthones and flavonoids isolated from C. tricuspidata.

It should be noted that investigations into quantitative analysis of the characteristic xanthones in C. tricuspidata are scarce. On the basis of HPLC analysis, cudratricusxanthones B, D and F (6) and macluraxanthone B in C. tricuspidata root bark were found to account for 0.017%, 0.026%, 0.025% and 0.071%, respectively.57 The quantitative analysis of other xanthones in C. tricuspidata is worth investigating in the future.

3.2. Flavonoids (100–257)

Flavonoids account for the largest proportion of C. tricuspidata and have attracted particular interest because of their well-defined pharmacological activities. To date, more than 120 flavonoids (Fig. 2) have been isolated from C. tricuspidata and can be classified into flavones (100–128), flavanones (129–173), and isoflavones (174–257). Structurally, the majority of them possess prenylated, benzylated, and methoxy groups substituted on their aromatic rings. Cudraflavanone E (133), which is isolated from C. tricuspidata roots, features a rare flavanone skeleton with the B-ring fused to a furan ring.58 Lee et al.16,59 isolated a series of rare benzyl-substituted flavonoids, i.e., gericudranins A–E (161–165), from C. tricuspidata. Notably, prenylated flavonoids have been regarded as attractive specialized metabolites with diverse biological activities. Specifically, cudraflavone B (104), which is a prominent prenylated flavonoid from the roots of C. tricuspidata, exhibited MAO-inhibiting,50 antiatherosclerotic,9 anti-inflammatory,60 hepatoprotective,25 antitumor,61 and neuroprotective62 effects. Euchrestaflavanones B (143) and C (144) displayed antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, Bacillus subtilis and Bacillus cereus.63

The investigation of the biosynthesis of the prenylflavonoids in C. tricuspidata has been attempted. Dai et al.64 established a cell suspension culture of C. tricuspidata for the enzymatic preparation of prenylflavonoids. A flavonoid prenyltransferase was identified as C. tricuspidata isoliquiritigenin 3′-dimethylallyltransferase.64 This enzyme was found to be able to regioselectively introduce dimethylallyl diphosphate at the ortho-position of the phenolic moiety in the common 2,4-dihydroxyacetophenone substructure shared by the three types of flavonoids, i.e., chalcones, isoflavones, and flavones.64,65 These studies could improve our knowledge of the mechanism of the biosynthesis and accumulation of prenylated flavonoids in C. tricuspidata.

The constituents and quantities of the flavonoids in C. tricuspidata fruits have been demonstrated to change in accordance with their maturation stage. Unripe fruits of C. tricuspidata were found to have a higher content of total flavonoids in comparison with ripe fruits. An analysis of the chemical constituents revealed that flavonoids with a side chain of cyclized prenyl 2,2-dimethylpyran rings were predominant in the unripe fruits, whereas flavonoids with a linear prenyl side chain were the main constituents in ripe fruits.66

Only a few studies have been reported concerning the quantitative analysis of representative flavonoids in C. tricuspidata. By UV-vis spectrophotometry, the concentration of total flavonoid glycosides in C. tricuspidata roots was measured to be up to 3.96 mg g−1 (as rutin equivalents).67 By HPLC analysis, the flavonoids kaempferol (118), quercetin (125), naringenin (146) and taxifolin (166) in C. tricuspidata were found to occur at 0.30, 0.09, 1.94 and 0.63 mg g−1 in the roots and 0.08, 0.04, 0.90 and 0.62 mg g−1 in the stems, respectively.68 Jeon et al.69 reported the isolation of prenylated isoflavonoids from an n-hexane extract of C. tricuspidata fruits using centrifugal partition chromatography and found that the main flavonoids 4′-O-methylalpinumisoflavone (242), 6,8-diprenylgenistein (252) and 6,8-diprenylorobol (254) amounted to 2.7%, 7.6% and 6.4%, respectively.

3.3. Organic acids (258–289)

To date, thirty-one organic acids and their esters have been isolated from C. tricuspidata. The stem extract was reported to contain n-hexanoic acid (278) in the greatest concentration (9.89 μg g−1) followed by 2-acetylpyrrole (405, 1.86 μg g−1), whereas the root extract was found to have n-hexanoic acid (13.13 μg g−1) in the greatest concentration followed by n-heptanoic acid (279, 2.05 μg g−1).10 Jung et al.70 reported that the levels of organic acids such as citric acid (261), malic acid (264), oxalic acid (265), succinic acid (270) and tartaric acid (273) in C. tricuspidata fruits varied with the maturation stage, and malic acid was the most abundant.

3.4. Polysaccharides (290–295)

The yield of total polysaccharides (CTPS) amounted to 1.0% in the roots of C. tricuspidata.71 Six polysaccharides with strong immunomodulatory activities, namely, CTP-B1 (290), CTPS-01 (291), CPS-0 (292), CTPS-1A (293), CTPS-2B (294) and CTPS-3A (295), were obtained from the roots of C. tricuspidata.72–74 Their backbones were revealed to be commonly substituted with α-D-glucuronic acid, 4-O-methyl-α-D-glucuronic acid, and neutral sugar units such as α-L-arabinose, α-D-xylose and α-D-galactose.74

3.5. Phenylpropanoids (296–316)

Twenty-one phenylpropanoids have been reported in C. tricuspidata, such as oxyresveratrol (306),75 scopoletin (307),15 3-methyl-2(5H)-furanone (314),10 and 5-ethyl-2(5H)-furanone (315).10 Oxyresveratrol, as a representative phenylpropanoid, was isolated from the twigs of C. tricuspidata, exhibited potent inhibitory activity against mushroom tyrosinase and might serve as an anti-browning agent for food.75

3.6. Others (317–443)

In addition to the aforementioned components, a large number of other components have also been identified in C. tricuspidata. Twenty-nine compounds were identified in the essential oil of C. tricuspidata fruits, which accounted for 94.46% of the essential oil, such as demeton-O-methyl (364), diethyl phthalate (365), ethyl-N-methylcarbamate (366), indene (372), scyllitol (385), tridecanol (388) and 1-phenyl-1-cyclohexylethane (398).76 It should be mentioned that a series of carotenoids were identified in C. tricuspidata fruits, including lycopene (374), lutein (375), phytofluene (379), ruboxanthin (383), zeaxanthin (391), α-carotene (428), β-carotene (429), neo-β-carotene (430) and polycopene (443).77

4 Pharmacological properties

Accumulated studies have revealed that the extracts and components of C. tricuspidata exhibited a broad spectrum of pharmacological activities, including anti-inflammatory,22,23 antioxidant,78,79 antitumor,16,24 hepatoprotective,25,26 neuroprotective,27,28 antiobesity,18,19 immunomodulatory,70,71 antiatherosclerotic,80,81 antimicrobial,11,76 skin-protecting,79,82 and antidiabetic21,52 effects. The presence of a variety of bioactive compounds may be synergistically or individually responsible for the various activities of this species (Fig. 3). Among these, xanthones and flavonoids are representative ingredients that mainly possess anti-inflammatory, antioxidant and antitumor activities.
image file: c7ra04322h-f3.tif
Fig. 3 Pharmacological activities of 124 active components from C. tricuspidata. The active compounds (circles) map ten pharmacological properties (yellow ovals). The pink circles represent multiple pharmacological properties. The green circles represent only one pharmacological property.

4.1. Anti-inflammatory activity

There has been strong evidence that diseases associated with inflammation may be ameliorated by C. tricuspidata. The anti-inflammatory molecular mechanisms could be elucidated on the basis of the effects of the extracts and compounds from C. tricuspidata (Fig. 4). It has been reported that a methanolic extract of C. tricuspidata could decrease the production of the pro-inflammatory cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ) by selectively inhibiting the proliferation of anti-CD3/CD28-mediated CD4+CD25 T-cells.15 The chloroform (CHCl3) fraction of C. tricuspidata was observed to inhibit the overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) by decreasing the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and reducing the levels of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 in RAW 264.7 mouse macrophage cells stimulated with lipopolysaccharide (LPS).83 The ethyl acetate (EtOAc) fraction of the stem bark could suppress the production of NO and expression of iNOS in RAW 264.7 cells stimulated with IFN-γ/LPS via the inactivation of nuclear factor-κB (NF-κB).84 The EtOAc fraction of C. tricuspidata stem bark could inhibit the differentiation of osteoclasts stimulated by IL-1β and mediated by receptor activator of NF-κB ligand, the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK), and the expression of c-Fos and nuclear factor of activated T-cells c1 (NFATc1).85 The EtOAc fraction of the whole plant was also found to reduce the expression of IL-1β, matrix metalloproteinases (MMPs), COX-2 and PGE2 by inhibiting the phosphorylation of MAPK and the activation of NF-κB signalling pathways in rheumatoid synovial fibroblasts.86 The above research suggested that C. tricuspidata may be useful for managing bone destruction in inflammatory diseases, such as rheumatoid arthritis (RA).
image file: c7ra04322h-f4.tif
Fig. 4 Molecular mechanisms of anti-inflammatory extracts and compounds from C. tricuspidata.

Numerous compounds from C. tricuspidata possess noticeable anti-inflammatory properties. Prenylated isoflavones from the leaves of C. tricuspidata, including cudraisoflavone L (184), wighteone (202) and furowanin B (215) exhibited potential anti-inflammatory activity by inhibiting the production of NO in LPS-stimulated RAW 264.7 cells, with inhibition values of 72.5 ± 2.4%, 66.9 ± 1.8%, and 55.4 ± 2.7% at a concentration of 10 μM, respectively.87 It was found that the position of hydroxyl groups in the xanthone moiety was important for the NO-inhibiting activity, and the catechol moiety was partially responsible for the inhibitory activity (Table 2).88 A C. tricuspidata glycoprotein suppressed the expression of iNOS and COX-2 via the regulation of NF-κB in LPS-stimulated RAW 264.7 cells.34 The xanthone CTXA, as an effective inducer of heme oxygenase-1 (HO-1), significantly inhibited the production of PGE2, NO, TNF-α, and IL-1β and increased the activity of HO in LPS-stimulated RAW 264.7 macrophages.22 Moreover, CTXA could exert anti-soluble endothelial cell protein C receptor (anti-sEPCR) shedding activity against vascular inflammation via inhibiting the expression of TNF-α-converting enzyme induced by phorbol-12-myristate-13-acetate in endothelial cells.89 Cudraflavone B was not only a potent inhibitor of TNF-α by blocking the translocation of NF-κB from the cytoplasm to the nucleus in macrophages derived from a THP-1 human monocytic leukemia cell line, but was also an inhibitor of COX-1 and COX-2 with higher selectivity toward COX-2, which suggested that it could be used as a lead for the development of non-steroidal anti-inflammatory drugs.60

Table 2 Anti-inflammatory activities of prenylated xanthones and flavonoids against LPS-induced RAW 264.7 cells
Compd IC50 (μM) Ref. Compd IC50 (μM) Ref.
16 21.4 88 96 19.8 88
18 20.1 88 200 18.4 31
28 17.8 88 201 12.7 31
32 20.0 88 230 18.7 31
34 23.5 88 235 13.1 31
66 18.0 88 249 12.1 31
67 24.8 88 250 11.8 31
69 18.7 88 252 19.2 31
89 16.1 88      


Allergic inflammation affects roughly one-quarter of people in the world.90 5,7,3′,4′-Tetrahydroxy-6,8-diprenylisoflavone (254) not only interfered with the interaction between IgE and high-affinity IgE receptor (FcεRI) and the expression of FcεRIβ mRNA but also inhibited the redistribution of F-actin and downstream signalling by suppressing the activation of FcεRI-mediated spleen tyrosine kinase in mast cells, which was suggestive of therapeutic potential for controlling mast cell activation in allergic processes.91 Treatment with the C. tricuspidata glycoprotein resulted in degranulation for allergic response (β-hexosaminidase) and the activation of MAPK/activator protein-1 (AP-1) and NF-κB, as well as the expression of cytokines related to allergic inflammation (IL-4, IL-6, TNF-α, IFN-γ, and IL-1β), which are indirectly activated by bisphenol A or di(2-ethylhexyl) phthalate in HMC-1 and RBL-2H3 cells.33,92–96

4.2. Antioxidant activity

Evidence has mounted that C. tricuspidata could act as an efficient free-radical scavenger and thus help the antioxidant defense system (Table 3). C. tricuspidata leaves, in comparison with other parts, exhibited the highest scavenging activities against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and the highest ferric reducing/antioxidant power (FRAP), which was correlated with their high level of polyphenols (73.60 ± 0.28 mg g−1), in particular quercetin.97,98 It has been reported that C. tricuspidata leaves could produce more quercetin and kaempferol aglycones via Lactobacillus-mediated fermentation, which would increase antioxidant activities (DPPH and ABTS assays), and thereby could be developed as high-value-added food materials and functional foods.99–102 An aqueous extract of C. tricuspidata (2 mg mL−1) exhibited significant scavenging activities of 50.2% (ABTS) and 40.5% (FRAP), respectively.103 The antioxidant activity of C. tricuspidata fruits was revealed to change depending on the maturation stage and was positively associated with the contents of prenylflavonoids such as artocarpesin (100), alpinumisoflavone (198), 6-isopentenylgenistein (202), 4′-O-methylalpinumisoflavone and 6,8-diprenylgenistein.104 The prenyl group on the A-ring of isoflavone was a potent contributor against the ABTS radical system.105 The C. tricuspidata glycoprotein (100 μg mL−1) exhibited strong scavenging activities against DPPH, superoxide anions and hydroxyl radicals, with no pro-oxidant activity in vitro.34 It should be interesting to investigate the in vivo antioxidant potentials of these compounds for preventing various radical-mediated injuries in pathological situations.
Table 3 Antioxidant activities of extracts and compounds of C. tricuspidataa
Sample IC50 Ref.
DPPH ABTS TBARS
a N.A = not available.
The MeOH extract of leaves 13.29 μg mL−1 N.A N.A 78
The MeOH extract of root bark 54.48 mg mL−1 N.A 15.13 mg mL−1 156
The ethyl ether fraction of MeOH extract of root bark 30.78 mg mL−1 N.A 7.72 mg mL−1 156
The EtOAc fraction of MeOH extract of root bark 20.32 mg mL−1 N.A 7.46 mg mL−1 156
The n-BuOH fraction of MeOH extract of root bark 93.37 mg mL−1 N.A >20 mg mL−1 156
Compd 20 N.A N.A 6.2 μM 23
Compd 28 N.A N.A 3.8 μM 23
Compd 29 N.A N.A 2.2 μM 23
Compd 67 N.A N.A 0.8 μM 23
Compd 72 N.A N.A 4.5 μM 23
Compd 84 N.A N.A 12.6 μM 23
Compd 88 N.A N.A 2.6 μM 23
Compd 104 >300 μM 4.2 μM N.A 157
Compd 110 >300 μM 8.2 μM N.A 157
Compd 120 4.14 μg mL−1 N.A 3.65 μg mL−1 156
Compd 121 5.94 μg mL−1 N.A 3.24 μg mL−1 156
Compd 126 4.04 μg mL−1 N.A 3.72 μg mL−1 156
Compd 127 5.50 μg mL−1 N.A 3.71 μg mL−1 156
Compd 143 >300 μM 5.4 μM N.A 157
Compd 144 >300 μM 6.0 μM N.A 157
Compd 145 N.A N.A 3 μg mL−1 30
Compd 149 N.A N.A 10 μg mL−1 30
Compd 152 >300 μM 8.3 μM N.A 157
Compd 166 N.A N.A 6 μg mL−1 30
Compd 230 N.A N.A 3 μg mL−1 30
Compd 254 >200 μM 16.3 μM N.A 105


4.3. Antitumor activity

During recent decades, C. tricuspidata has been demonstrated to possess promising antitumor and cytotoxic activities, and its cortices and root bark have been widely employed in TCM clinics for the treatment of cancer of the alimentary system, in particular gastric carcinoma.7,55 An EtOAc extract of C. tricuspidata stem bark displayed significant cytotoxicity against HL-60 cells, and the mechanism underlying its cytotoxicity may be due to apoptosis.106 A CHCl3 extract of C. tricuspidata roots exhibited significant cytotoxicity against human gastric carcinoma cell lines (SGC-7901 and BGC-823).17 An MeOH extract of C. tricuspidata stems could induce the apoptosis of cervical cancer cells via the extrinsic pathway, as well as via the repression of human papillomavirus type-16 oncoproteins E6 and E7 and the alteration of p53 and p-pRb protein levels, instead of cytotoxicity.107 In nude mouse models of B16 melanoma and human SK-OV3 xenografted tumors, the tumor-inhibiting rates of the total flavonoids (250 mg kg−1) from C. tricuspidata were 50.54% and 46.38%, respectively.108

Several compounds isolated from C. tricuspidata displayed considerable inhibitory activity against various tumor cells in an MTT assay (Table 4). The isoprenylated xanthones 20, 28, and 29 exhibited potent cytotoxic activity against HL-60 cells owing to apoptosis in a DNA fragmentation assay.56 Gericudranins A–E isolated from the stem bark of C. tricuspidata exhibited cytotoxicity against human tumor cell lines such as CRL1579 (skin), LOX-IMVI (skin), MOLT-4F (leukemia), KM12 (colon) and UO-31 (renal).16,58 The p-hydroxybenzyl moiety at C-6 was revealed to be essential for the cytotoxic activity.16,58 2′,5,7-Trihydroxy-4′,5′-(2,2-dimethylchromeno)-8-(3-hydroxy-3-methylbutyl)flavanone (152) could inhibit the activity of topoisomerase I (IC50 = 1.0 mM) and induce apoptotic cell death of U937 human leukemia cells, at least in part, via the inhibition of DNA topoisomerase I activity.109 Cudraflavanone A (129) inhibited mammalian topoisomerase I with an IC50 of 0.4 mM and inhibited the activity of protein kinase C with an IC50 of 150 μM.110 Euchrestaflavanone B could inhibit the activity of protein kinase CKII with an IC50 of 78 μM.111 Cudraflavone B was demonstrated to be a lead for the development of a potential candidate for treating human oral squamous cell carcinoma cells via the activation of MAPK and NF-κB, as well as the silent information regulator 1 (SIRT1) pathway.61 Cudraxanthone H (24) and isocudraxanthone K (62) exerted significant antiproliferative and apoptosis-inducing effects in oral squamous cell carcinoma cells (IC50 values of 14.31 and 17.91 μM for HNSCC4 and 14.91 and 20.01 μM for HNSCC12 after treatment for 72 h) via the NF-κB and NIMA-interacting 1 pathways and mitochondrial death receptor, MAPK, NF-κB, and HIF-1α signalling pathways, respectively.112,113 Likewise, the cytotoxic effect of cudraflavone B was also documented against HNSCC4 cells (IC50 of 18.3, 12.6, and 10.9 μM after treatment for 24, 48, and 72 h) and HNSCC12 cells (IC50 of 19.5, 12.0, and 10.7 μM after treatment for 24, 48, and 72 h).61 CTXA could suppress the migration and invasion of MCF-7 and MDA-MB-231 breast cancer cells by downregulating MMP-9 and induce apoptosis by activating the mitochondrial-associated apoptotic signalling pathway, which suggests that it may be a novel antitumor agent for breast cancer therapy.114 Cudratricusxanthone G could inhibit the proliferation, migration and invasion of SW620 human colorectal carcinoma cells instead of displaying cytotoxicity by targeting MMP-2, thereby regulating the activation of Rac1, Cdc42 and their downstream target AP-1.24 Notably, the chemical and biogenic synthesis and molecular modification of unique compounds isolated from C. tricuspidata have attracted attention. For example, from gericudranin A a series of derivatives were synthesized by structural modification, some of which exhibited strong cytotoxicity against several cancer cell lines such as SNB19, MOLT-4F, and K562 cells in a sulforhodamine B assay.115 It is suggested that more attention should be paid to the SAR and in vivo antitumor mechanisms of the antitumor constituents of C. tricuspidata.

Table 4 Cytotoxic activities of extracts, xanthones and flavonoids against tumor cells
Sample Model Active concentration Ref. Sample Model Active concentration Ref.
a HL-60 = promyelocytic leukemia cell line.b U937 = human leukemia cell line.c HeLa = human carcinoma cell line.d MCF-7 = human breast cancer cell line.e HepG2 = human hepatoma cell line.f MDA-MB-231 = human breast cancer cell line.g BGC-823 = stomach cancer cell line.h A549 = lung carcinoma cell line.i L1210 = mouse leukemia cell line.j SK-OV3 = human ovarian cancer cell line.k HT-29 = human colon carcinoma cell line.l AGS = human lung cancer cell line.m HCT-116 = human colon carcinoma cell line.n SMMC-7721 = human hepatocellular carcinoma cell line.o SGC-7901 = human gastric cancer cell line.p P388 = mouse leukemia cell line.q CRL1579 = human skin cancer cell line.r LOX-IMVI = human melanoma cell line.s MOLT-4F = human leukemia cell line.t KM12 = human colon carcinoma cell line.u UO-31 = human renal cell line.
The EtOAc extract of stem bark HL-60a 30 μg mL−1 (IC50) 106 The EtOAc fraction of fruits MCF-7 66.8 μg mL−1 (IC50) 142
U937b 40 μg mL−1 (IC50) 106 MDA-MB-231f 75.4 μg mL−1 (IC50) 142
HeLac 58 μg mL−1 (IC50) 106 Total flavonoids BGC-823g 6.11 μg mL−1 (IC50) 107
MCF-7d 44 μg mL−1 (IC50) 106 A549h 12.20 μg mL−1 (IC50) 107
HepG2e 69 μg mL−1 (IC50) 106 L1210i 12.73 μg mL−1 (IC50) 107
Compd 1 BGC-823 15.2 μg mL−1 (IC50) 17 Compd 72 A549 2.8 μM (IC50) 49
A549 5.93 μM (IC50) 49 25.8 μM (LD50) 56
45.8 μM (LD50) 56 SK-OV3 4.24 μM (IC50) 49
SK-OV3j 7.09 μM (IC50) 49 23.1 μM (LD50) 56
43.2 μM (LD50) 56 HT-29 28.0 μM (LD50) 56
HT-29k 41.4 μM (LD50) 56 HL-60 29.5 μM (LD50) 56
HL-60 32.8 μM (LD50) 56 AGS 15.2 μM (LD50) 56
AGSl 32.8 μM (LD50) 56 Compd 73 HCT-116 6.66 μM (IC50) 55
Compd 2 HCT-116m 3.9 μg mL−1 (IC50) 17 SMMC-7721 5.13 μM (IC50) 55
SMMC-7721n 6.9 μg mL−1 (IC50) 17 SGC-7901 3.63 μM (IC50) 55
SGC-7901o 4.3 μg mL−1 (IC50) 17 BGC-823 3.11 μM (IC50) 55
Compd 3 HCT-116 12.2 μg mL−1 (IC50) 17 Compd 77 HCT-116 2.8 μg mL−1 (IC50) 17
SMMC-7721 8.9 μg mL−1 (IC50) 17 SMMC-7721 8.8 μg mL−1 (IC50) 17
Compd 4 HCT-116 4.1 μg mL−1 (IC50) 17 SGC-7901 11.8 μg mL−1 (IC50) 17
SMMC-7721 4.2 μg mL−1 (IC50) 17 BGC-823 5.2 μg mL−1 (IC50) 17
SGC-7901 9.8 μg mL−1 (IC50) 17 Compd 78 HCT-116 1.3 μg mL−1 (IC50) 17
Compd 5 HCT-116 4.7 μg mL−1 (IC50) 17 SMMC-7721 6.2 μg mL−1 (IC50) 17
SMMC-7721 4.2 μg mL−1 (IC50) 17 SGC-7901 3.4 μg mL−1 (IC50) 17
SGC-7901 5.4 μg mL−1 (IC50) 17 Compd 84 A549 61.9 μM (LD50) 56
BGC-823 1.6 μg mL−1 (IC50) 17 SK-OV3 70.4 μM (LD50) 56
Compd 6 HCT-116 21.31 μM (IC50) 55 HT-29 46.3 μM (LD50) 56
SMMC-7721 50.7 μM (IC50) 55 HL-60 35.9 μM (LD50) 56
SGC-7901 26.34 μM (IC50) 55 AGS 44.7 μM (LD50) 56
BGC-823 17.62 μM (IC50) 55 Compd 129 SMMC-7721 32.04 μM (IC50) 55
Compd 7 HCT-116 1.8 μg mL−1 (IC50) 17 SGC-7901 28.68 μM (IC50) 55
SMMC-7721 2.7 μg mL−1 (IC50) 17 BGC-823 26.90 μM (IC50) 55
SGC-7901 3.4 μg mL−1 (IC50) 17 U937 6.0 μM (IC50) 110
BGC-823 1.6 μg mL−1 (IC50) 17 Compd 130 HCT-116 24.37 μM (IC50) 55
Compd 9 SMMC-7721 11.7 μg mL−1 (IC50) 17 SMMC-7721 28.94 μM (IC50) 55
SGC-7901 1.8 μg mL−1 (IC50) 17 SGC-7901 65.86 μM(IC50) 55
BGC-823 9.2 μg mL−1 (IC50) 17 BGC-823 28.68 μM (IC50) 55
Compd 19 A549 61.7 μM (LD50) 56 Compd 143 U937 0.8 μM (IC50) 111
SK-OV3 74.5 μM (LD50) 56 HeLa 0.8 μM (IC50) 111
HT-29 50.7 μM (LD50) 56 Compd 145 P388p 3.3 μg mL−1 (IC50) 30
HL-60 40.8 μM (LD50) 56 Compd 149 P388 6.2 μg mL−1 (IC50) 30
AGS 49.5 μM (LD50) 56 Compd 152 U937 10.0 μM (IC50) 109
Compd 20 A549 16.3 μM (LD50) 56 Compd 158 P388 15.0 μg mL−1 (IC50) 30
SK-OV3 23.8 μM (LD50) 56 Compd 161 CRL1579q 3.65 μM (EC50) 16
HT-29 20.7 μM (LD50) 56 LOX-IMVIr 11.99 μM (EC50) 16
HL-60 6.2 μM (LD50) 56 MOLT-4Fs 2.65 μM (EC50) 16
AGS 4.7 μM (LD50) 56 KM12t 13.70 μM (EC50) 16
Compd 21 HCT-116 26.05 μM (IC50) 55 UO-31u 6.99 μM (EC50) 16
SMMC-7721 38.32 μM (IC50) 55 Compd 162 CRL1579 13.12 μM (EC50) 16
SGC-7901 32.04 μM (IC50) 55 LOX-IMVI 31.26 μM (EC50) 16
BGC-823 40.24 μM (IC50) 55 MOLT-4F 23.07 μM (EC50) 16
Compd 24 HCT-116 5.50 μM (IC50) 55 KM12 28.05 μM (EC50) 16
SMMC-7721 5.67 μM (IC50) 55 UO-31 9.78 μM (EC50) 16
SGC-7901 3.07 μM (IC50) 55 Compd 163 CRL1579 3.34 μM (EC50) 16
BGC-823 2.82 μM (IC50) 55 LOX-IMVI 13.46 μM (EC50) 16
Compd 28 A549 3.15 μM (IC50) 49 MOLT-4F 7.62 μM (EC50) 16
33.5 μM (LD50) 56 KM12 13.84 μM (EC50) 16
SK-OV3 4.72 μM (IC50) 49 UO-31 16.82 μM (EC50) 16
38.0 μM (LD50) 56 Compd 164 CRL1579 9.50 μM (EC50) 59
HT-29 11.4 μM (LD50) 56 LOX-IMVI 16.60 μM (EC50) 59
HL-60 8.6 μM (LD50) 56 MOLT-4F 8.90 μM (EC50) 59
AGS 3.9 μM (LD50) 56 KM12 5.00 μM (EC50) 59
Compd 29 HCT-116 3.4 μg mL−1 (IC50) 17 UO-31 5.20 μM (EC50) 59
SMMC-7721 5.1 μg mL−1 (IC50) 17 Compd 165 CRL1579 2.90 μM (EC50) 59
SGC-7901 9.5 μg mL−1 (IC50) 17 LOX-IMVI 12.50 μM (EC50) 59
BGC-823 2.6 μg mL−1 (IC50) 17 MOLT-4F 10.7 μM (EC50) 59
A549 11.8 μM (LD50) 56 KM12 11.9 μM (EC50) 59
SK-OV3 14.6 μM (LD50) 56 UO-31 7.60 μM (EC50) 59
HT-29 12.1 μM (LD50) 56 Compd 202 HL-60 18.0 μM (IC50) 87
HL-60 8.2 μM (LD50) 56 Compd 205 HL-60 4.3 μM (IC50) 87
AGS 4.1 μM (LD50) 56 Compd 215 HL-60 6.7 μM (IC50) 87
Compd 67 A549 57.8 μM (LD50) 56 Compd 222 HL-60 5.1 μM (IC50) 87
SK-OV3 71.3 μM (LD50) 56 Compd 225 HL-60 8.8 μM (IC50) 87
HT-29 65.0 μM (LD50) 56 Compd 226 HL-60 10.1 μM (IC50) 87
HL-60 45.2 μM (LD50) 56 Compd 227 HL-60 5.2 μM (IC50) 87
AGS 43.9 μM (LD50) 56 Compd 246 P388 0.18 μg mL−1 (IC50) 30
Compd 184 HL-60 9.5 μM (IC50) 87 Compd 254 HL-60 4.3 μM (IC50) 87


4.4. Hepatoprotective activity

Liver disease remains one of the most serious health problems without satisfactory drugs. The CHCl3 fraction of an MeOH extract of C. tricuspidata root bark exhibited a significant hepatoprotective effect on tacrine-induced cytotoxicity in HepG2 cells.26 CTXA, cudratricusxanthone E, cudraxanthone L and macluraxanthone B, which were isolated from the CHCl3 fraction, displayed the strongest hepatoprotective effects on tacrine-induced cytotoxicity in HepG2 cells at 10 μg mL−1.26 Cudraflavone B and gericudranin E were further isolated from this MeOH extract and displayed significant protective effects against tacrine-induced cytotoxicity in HepG2 cells, with EC50 values of 37.39 and 39.87 μM, respectively.25 Cudracuspixanthone A (16) and cudracuspiphenones A (353) and B (354) exhibited moderate antiproliferative activity against HSC-T6 cells, with IC50 values of 9.7, 3.3, and 7.1 μM, respectively.116 It was demonstrated that 1,1-dimethylallyl or 2,3,3-trimethyl-2,3-dihydrofuran moieties in the xanthones played important roles for the inhibitory activity.116 The glycoprotein (75 kDa) isolated from C. tricuspidata fruits was effective in preventing CCl4-induced liver damage in A/J mice by significantly increasing the activities of superoxide dismutase, catalase, and glutathione peroxidase, as well as decreasing the production of TBARS, lactate dehydrogenase (LDH) and NO.35 These constituents might be preferred alternatives for liver disease, and in vivo assays are essential to ascertain their hepatoprotective role fully.

4.5. Neuroprotective activity

An aqueous extract of C. tricuspidata roots exhibited a stronger protective effect against neurotoxicity induced by oxidative stress than those of leaves, stems, and fruits, which was correlated with its high level of phenolic compounds, in particular kaempferol, myricetin (123) and quercetin.117 CTXA and cudraflavone B displayed significant neuroprotective activity against glutamate-induced neurotoxicity via the induction of HO-1 in HT22 mouse hippocampal cells.51,62 The neuroprotective effect of cudraflavone B was probably regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathways.62

MAOs are responsible for the degradation of neurotransmitters including noradrenaline, dopamine, and 5-hydroxytryptamine in the central nervous system.118 The dichloromethane (CH2Cl2) fraction of C. tricuspidata fruits was active in inhibiting mouse brain MAO, and gancaonin A (216), 4′-O-methylalpinumisoflavone, and alpinumisoflavone inhibited MAO in a concentration-dependent manner, with IC50 values of 19.4, 23.9, and 25.8 μM, respectively. Of these, gancaonin A exhibited a selective inhibitory effect against MAO-B (IC50 = 0.8 μM) in comparison with MAO-A (IC50 > 800 μM).118 CTXA, cudraflavanone A and cudraflavone B exhibited moderate inhibitory effects against mouse brain MAO, with IC50 values of 88.3, 89.7, and 80.0 μM, respectively.50

The neuroprotective potential of the flavonoids orobol (230), 6-prenylorobol (255) and 6,8-diprenylorobol was evaluated via enhancing the ubiquitin/proteasome-dependent degradation of α-synuclein and synphilin-1 in SH-SY5Y human neuroblastoma cells induced by 6-hydroxydopamine (6-OHDA) (Table 5), which signified that they might be possible candidates for the treatment of neurodegenerative diseases.119 5,7-Dihydroxychromone (426) could prevent 6-OHDA-induced oxidative stress and apoptosis in SH-SY5Y cells via the activation of the Nrf2/ARE signalling pathway and the overexpression of antioxidant enzymes, including HO-1, NAD(P)H: quinone oxidoreductase and the glutamate-cysteine ligase catalytic subunit.120 In LPS-stimulated BV2 mouse microglia, CTXA (IC50 = 0.98 μM) decreased the production of TNF-α, IL-1β, and IL-12, inhibited the phosphorylation and degradation of IκB-α, and blocked the nuclear translocation of p50 and p65 by inhibiting the NF-κB and MAPK pathways.121 Cudraflavanone D (132) could suppress the production of NO in LPS-induced BV2 microglial cells with an IC50 value of 6.28 μM and exert anti-neuroinflammatory activity by targeting iNOS and COX-2 via the MAPK and NF-κB pathways.1 Demethylsuberosin (299), as a potent proteasome activator, attenuated the 1-methyl-4-phenylpyridinium-induced dysfunction of the chymotrypsin-like and caspase-like activities of proteasomes in SH-SY5Y cells with EC50 values of 0.76 μM and 0.82 μM, respectively, and protected SH-SY5Y cells against 1-methyl-4-phenylpyridinium-induced cell death, with an EC50 value of 0.17 μM.122 4′-O-Methylalpinumisoflavone isolated from C. tricuspidata fruits exerted anti-neuroinflammatory effects against LPS-induced microglial activation in BV2 cells by decreasing NF-κB signalling and the phosphorylation of MAPKs.123 The above results demonstrated that those compounds with neuroprotective activities could be considered as candidates for further research for therapeutic purposes into neurodegenerative diseases such as Parkinson's disease.

Table 5 Neuroprotective activity of compounds against 6-OHDA-induced SH-SY5Y cells
Compd EC50 (μM) Ref. Compd EC50 (μM) Ref.
17 4.5 27 142 9.1 145
28 8.2 27 227 15.2 119
39 7.2 27 228 18.5 119
43 16.6 27 230 6.4 119
44 2.4 27 254 10.1 119
45 2.2 27 255 4.5 119
51 0.8 27 305 9.2 145
64 3.0 27 311 8.0 145
74 15.5 27 322 12.9 145
75 0.7 27 343 6.2 145
91 2.3 27 416 11.2 168
97 5.1 27 419 30.2 145
103 15.5 145 426 1.9 145


4.6. Antiobesity activity

Excess body weight and obesity are severe threats to public health worldwide. The leaves of C. tricuspidata, in comparison with other parts, exhibited the most pronounced inhibitory effect against pancreatic lipase (PL), which is a key enzyme for lipid absorption, with an IC50 value of 9.91 μg mL−1 in vitro, and were able to reduce plasma triacylglycerol levels and delay dietary fat absorption in vivo.18 The optimal conditions for the maximum PL-inhibiting activity and extraction yield of C. tricuspidata fruits were determined using response surface methodology to be an ethanol concentration of 74.5%, a temperature of 61.9 °C, and an extraction time of 13.5 h.12 Flavonoids isolated from C. tricuspidata, namely, cudraflavanones A and D and 5,7,4′-trihydroxy-6,8-diprenylisoflavone, inhibited PL, with IC50 values of 9.0, 6.5, and 65.0 μM, respectively.12,124 Further SAR studies highlighted that the prenyl moiety and number and position of hydroxyl groups of the flavonoids seemed to affect the PL-inhibiting activity, which needs to be clarified using more derivatives. The PL-inhibiting activity of C. tricuspidata fruits has been proven to vary with their maturation stage.66 Unripe fruits of C. tricuspidata, in accordance with their higher content of total phenolic compounds and flavonoids, exhibited stronger PL-inhibiting activity in comparison to ripe fruits.66 In addition, an isoflavone, namely, cudracusisoflavone B (195), from unripe fruits exhibited strong PL-inhibiting activity, with an IC50 value of 16.8 μM, in a non-competitive manner.66 Therefore, the maturation stage is an important factor for the efficacy, and unripe fruits appeared to be a good source of agents for the regulation of obesity. Protein-tyrosine phosphatases (PTP1B) are also important risk factors for obesity-related metabolic diseases. The leaves of C. tricuspidata displayed a strong inhibitory effect against PTP1B and substantially inhibited fat accumulation in 3T3-L1 cells in a dose-dependent manner.19 Xanthones and flavonoids isolated from the roots of C. tricuspidata, including CTXA, cudratricusxanthones L (12) and N (14), cudracuspixanthone A, cudraxanthones D, L, and M, macluraxanthone B, 1,6,7-trihydroxy-2-(1,1-dimethyl-2-propenyl)-3-methoxyxanthone (87), cudraflavone C (105), kuwanon C (114), cudraflavanone D and euchrestaflavanone C, displayed a significant inhibitory activity against PTP1B in a dose-dependent manner, with IC50 values ranging from 1.9 to 13.6 μM.125 In comparison with flavonoids, prenylated xanthones displayed stronger PTP1B-inhibiting effects, which suggested that they may be promising agents for the future discovery of novel PTP1B inhibitors.

An aqueous extract of C. tricuspidata leaves that underwent fermentation mediated by lactic acid bacteria was proven to be beneficial for promoting osteogenic differentiation of osteoblastic cells and inhibiting fat accumulation in adipocytes.99 In diet-induced obesity (DIO) mice, this extract could decrease levels of aspartate aminotransferase, alanine aminotransferase, total fat mass, triglycerides, and blood glucose and was also found to promote the phosphorylation of IRS-1 and Akt in liver tissues and improve insulin secretion.19 Correspondingly, the leaves of C. tricuspidata could be used as materials to produce a functional food product with antiobesity effects.126 6,8-Diprenylgenistein, which is a flavonoid isolated from C. tricuspidata, was proven to decrease body weight, epididymal fat and serum triglyceride levels in DIO mice.127 The underlying mechanism of this compound has been demonstrated, namely, that it could inhibit lipogenic genes by the regulation of transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) and hormones such as leptin and adiponectin.127 6,8-Diprenylgenistein was also found to regulate acetyl-CoA carboxylase (ACC) and hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) by the activation of AMP-activated protein kinase (AMPK).127 Further investigation is warranted to determine whether their beneficial effects are associated with gut microbiota, which is a topic of recent and growing interest.

4.7. Immunomodulatory effects

Emerging evidence has suggested that C. tricuspidata is a potent immunomodulator. An aqueous extract of C. tricuspidata displayed potent adjuvant activity to enhance antigen-specific antibody responses and cellular immune responses against keyhole limpet hemocyanin.128 In recent years, plant polysaccharides have emerged as an important class of bioactive natural products that are ideal therapeutic candidates for immunomodulatory functions with low toxicity. The in vitro immunomodulatory activities of the polysaccharides from C. tricuspidata roots were investigated in relation to the activation of mouse peritoneal macrophages.71,74 The results showed that the four water-soluble polysaccharides, namely, CTPS-1A, CTPS-2B, CTPS-3A, and CTP-B1, could directly stimulate the proliferation of mouse splenocytes alone or in combination with concanavalin A or LPS within the concentration range of 6.25 to 100 μg mL−1, in a comparable way to the immunomodulator lentinan.71,74 T-helper type 1 (Th1) and Th2 cytokines have been demonstrated to interact reciprocally to maintain a balanced immune network. The C. tricuspidata glycoprotein could prevent the development of immune diseases related to Th2 cell responses, such as autoimmune diseases, viral infections, and allergies.36,129 The precise mechanism of the differentiation of Th cells into Th1 or Th2 cells as induced by the C. tricuspidata glycoprotein remains to be elucidated.

4.8. Antiatherosclerotic activity

CTXA from C. tricuspidata was found to exert inhibitory effects on the synthesis and proliferation of DNA in vascular smooth muscle cells stimulated by platelet-derived growth factor (PDGF)-BB by suppressing the PDGF receptor β-chain and downregulating the Ras-Raf-MEK-ERK1/2 signalling pathways, and may serve as an antiatherosclerotic lead compound.80 Likewise, cudraflavanone A was useful in the prevention of atherosclerosis or restenosis after angioplasty, and the molecular mechanism was found to be that it inhibited the PDGF-BB-induced growth of rat aortic smooth muscle cells via an Akt-dependent pathway.81 In addition, cudraflavone B was observed to inhibit the proliferation of rat aortic smooth muscle cells by inducing the expression of p21cip1 and p27kip1 and subsequent cell cycle arrest with a reduction in the phosphorylation of pRb at the G1-S phase, which suggests its therapeutic potential for treating cardiovascular disease.9 Low-density lipoprotein (LDL) has been known to play a crucial role in the development of atherosclerosis and hypercholesterolemia.130 Many compounds isolated from C. tricuspidata have been confirmed to be effective in preventing the oxidation of LDL in a TBARS assay (Table 3).

4.9. Antimicrobial activity

The essential oil of C. tricuspidata fruits was proven to be able to disrupt the membrane functions of both Gram-positive and Gram-negative bacteria, which led to its effective use as a natural antimicrobial agent to control food-borne pathogens in the food industry. The antibacterial activity of the essential oil was investigated against Bacillus cereus ATCC 13061, Staphylococcus aureus ATCC 12600, Listeria monocytogenes ATCC 7644, Salmonella typhimurium ATCC 43174 and Escherichia coli O157:H7 ATCC 43889.76 The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the essential oil were in the range of 250–500 μg mL−1 and 500–1000 μg mL−1, respectively.76 In addition, a methanolic extract of C. tricuspidata roots exhibited high antifungal activity against Gymnosporangium haraeanum Syd., Pyricularia oryzae Cav., Rhizoctonia solani Kühn, and Colletotrichum graminicola (Ces.) Wilson, with EC50 values of 803, 997, 981 and 930 μg mL−1, respectively.11

4.10. Skin protection

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by elevated immunoglobulin E (IgE) levels, mast cell infiltration and skin lesions including pruritus, erythema and eczema.131 An ethanolic extract of C. tricuspidata stems could be applied topically to decrease serum IgE levels and mast cell counts in the dermis of the skin in an AD-like NC/Nga mouse model induced by Dermatophagoides farinae extract.131 Similarly, an aqueous extract of C. tricuspidata fruits was also found to inhibit the development of AD-like skin lesions induced by repeated applications of D. farinae in sensitized NC/Nga mice by reducing plasma concentrations of mouse thymus and activation-regulated chemokine (mTARC), histamine and IgE.132 Nevertheless, the definite active compounds responsible for the anti-atopic dermatitis activity remain to be identified.

A methanolic extract of C. tricuspidata stems was demonstrated to prevent skin inflammation and skin aging via suppressing the solar ultraviolet-induced expression of COX-2.82 The EtOAc fraction (IC50 = 24.4 ppm) and the n-BuOH fraction (IC50 = 88.3 ppm) of the C. tricuspidata stem extract could reduce the activity of tyrosinase and the melanin content in a concentration-dependent manner.79 It was found that the flavonoids steppogenin (149, IC50 = 2.52 μM) and trans-dihydromorin (160, IC50 = 21.54 μM) and the phenylpropanoid oxyresveratrol (IC50 = 2.85 μM) from the twigs of C. tricuspidata displayed potent inhibitory activities against mushroom tyrosinase and the melanogenesis process in melanocytes, which suggested their potential to be developed as skin-whitening agents in cosmetics and anti-browning agents in food.75 The tyrosinase-inhibiting activity of the flavonoids could be affected by the hydroxyl groups substituted at the 2- and 4-positions of the aromatic ring.75 Oxyresveratrol and trans-dihydromorin, as hypopigmenting agents, could induce post-transcriptional degradation of microphthalmia-associated transcription factor (MITF), leading to significant decreases in the production of tyrosinase-related protein 1 (TRP-1) and tyrosinase-related protein 2 (TRP-2) in b16 and melan-a cells.133 Besides, 6,8-diprenylorobol and pomiferin (233) could inhibit the photooxidation of A2E, which is an important constituent of lipofuscin in the retinal pigment epithelium, in a dose-dependent manner.32 Collectively, these studies clearly showed that C. tricuspidata and the isolated bioactive compounds could be used as cosmeceutical materials and food constituents for the promotion of skin health.

4.11. Antidiabetic activity

Lee et al.20 reported that the aqueous extract of C. tricuspidata leaves could significantly improve hepatic insulin resistance and hyperglycemia by controlling obesity-induced stress in the hepatic endoplasmic reticulum and inflammation in the liver of db/db mice. Furthermore, an in vitro study demonstrated that both C. tricuspidata leaves and the isolated compound kaempferol could reduce hepatic insulin resistance by suppressing insulin receptor substrate signalling and the inflammatory response in HepG2 cells induced by endoplasmic reticulum stress.134 In addition, the α-glucosidase-inhibiting activities of aqueous extracts of C. tricuspidata stems and roots depended on the harvesting time and climate.21 A root extract exerted potent inhibitory effects on α-glucosidase activity, with 77% inhibition at a concentration of 300 μg mL−1, which signified that the root could serve as an antidiabetic biomaterial.21 Xanthones, including CTXA, cudratricusxanthone F, cudraxanthones D and L, macluraxanthone B, 1,3,6,7-tetrahydroxy-2-(3-methylbut-2-enyl)-8-(2-methylbut-3-en-2-yl)-9H-xanthen-9-one (83) and 1,3,7-trihydroxy-4-(1,1-dimethyl-2-propenyl)-5,6-(2,2-dimethylchromeno)xanthone (84), displayed inhibitory activities against α-glucosidase, with IC50 values of 16.2–52.9 μM.52 CTXA was also proven to prevent the production of NO, the expression of iNOS, and the activation of JAK/STAT and NF-κB in RINm5F cells induced by IL-1β and IFN-γ and to inhibit the glucose-stimulated secretion of insulin in pancreatic islets.135 The above results suggested that C. tricuspidata may be a promising therapeutic material in the treatment of diabetes.

4.12. Others

Besides the above pharmacological properties, other biological activities of C. tricuspidata have also been reported. An aqueous extract of C. tricuspidata stems could decrease systolic blood pressure in hypertension induced by NG-nitro-L-arginine methyl ester, in part by enhancing the generation of vascular NO/cGMP and the amelioration of renal functions.136 The anticoagulant activity of CTXA was investigated by Yoo et al.,29 who revealed that CTXA could inhibit the generation of cell-based thrombin, activated factor X (FXa) and thrombin and exhibited thrombolytic activity by decreasing the ratio of plasminogen activator inhibitor type 1 (PAI-1) to tissue-type plasminogen activator (t-PA).

Park et al.53 revealed that xanthones bearing 6,7 vicinal dihydroxy groups on the A ring, including CTXA, cudratricusxanthone F, cudraxanthones D, L and M, macluraxanthone B, and 1,3,6,7-tetrahydroxy-2-(3-methylbut-2-enyl)-8-(2-methylbut-3-en-2-yl)-9H-xanthen-9-one, displayed nanomolar inhibitory activity (IC50: 80–270 nM) against neuraminidase. Cudraflavanone A, which bears a C-8 hydrated prenyl group, also displayed high neuraminidase-inhibiting activity, with an IC50 of 380 nM.137 This implied that these xanthones and flavonoids may be potential antiviral agents in the future.

The above descriptions indicated that many compounds have a variety of activities, in particular CTXA, which is a major and important component with a wide range of activities. Recently, pharmacokinetic studies of representative constituents of C. tricuspidata have also attracted attention. The in vitro metabolic profiling of CTXA in human liver microsomes has been recently investigated, which revealed that eight identified metabolites of CTXA were involved with cytochrome P450 enzymes (CYPs) and uridine 5′-diphospho-glucuronosyltransferase enzymes (UGTs).138 In a follow-up study, CTXA has been demonstrated to exhibit reversible competitive inhibition of CYP1A2 and CYP2C9 and non-competitive inhibition of CYP2C8 in human liver microsomes, which has begun to shed light on the in vivo metabolism of CTXA.139 Cudratricusxanthone B, as another example, has also been investigated for its pharmacokinetics by a fast and sensitive HPLC-MS/MS method, but its oral bioavailability (OB) remains unclear and merits future investigation.140 Therefore, it is suggested that the pharmacokinetics of this plant should be studied systematically.

5 Conclusions

This review provides an up-to-date and comprehensive summary concerning the botany, traditional uses, phytochemistry and pharmacology of the traditional folk medicine C. tricuspidata. As a medicinal plant, C. tricuspidata has been used to treat rheumatism, bruising, scabies, hepatitis, jaundice, gonorrhea, dysmenorrhea and amenorrhea in East Asia for thousands of years. During the last few decades, C. tricuspidata-derived extracts and compounds have attracted much attention for their promising biological activities, including anti-inflammatory, antioxidant, antitumor, hepatoprotective, immunomodulatory, neuroprotective, antiobesity, antimicrobial, antiatherosclerotic, skin-protecting, and antidiabetic activities. Obviously, some pharmacological activities are not related to the traditional uses of this species but provide valuable hints for new areas of application. Xanthones and flavonoids are the two major classes of constituent that contribute either directly or indirectly to the biological effects of C. tricuspidata, followed by minor classes, including organic acids, polysaccharides, phenylpropanoids, and others. Findings and knowledge regarding the phytochemistry and pharmacology of C. tricuspidata have established a basis for further research on, and development of, this medicinal plant and its active components. Notably, the unique structures isolated from C. tricuspidata have aroused interest in research on the chemical and biogenic synthesis of these bioactive compounds that is suitable for large-scale preparation and molecular modification. This should be beneficial for the development and application of natural compounds from C. tricuspidata and their synthetic analogues. As a rich source of medicines and functional foods, quality control of C. tricuspidata is crucial to ensure both safety and efficacy. It is suggested that current advances, including mass spectrometry-based chemical profiling and DNA barcoding, should be used to authenticate, differentiate, and evaluate the quality of C. tricuspidata. Importantly, a common international criterion should be established with the ultimate goal of ensuring the effectiveness and safety and maximizing the medicinal benefits of C. tricuspidata.

As recent insights into the pharmacological mechanisms of C. tricuspidata are limited to in vitro bioassays of a limited number of molecules, it is essential and urgent to investigate the mechanisms of the bioactive extracts/isolates in appropriate animal models. To the best of our knowledge, few relevant data from clinical trials of C. tricuspidata (only in Chinese clinics) have been reported, and most clinical trials used a relatively small sample size and insufficient information. It is suggested that the efficacy of C. tricuspidata should be assessed in the future by combining its pharmacological effects, mechanisms of action and clinical applications. Detailed studies of the pharmacokinetics and toxicological properties and preclinical and clinical trials of C. tricuspidata are also eagerly awaited. More knowledge should be accumulated concerning the bioavailability, metabolism and toxicity of C. tricuspidata, which will be valuable for understanding its dosage efficacy and in vivo effects. It should be noted that the interaction between the bioactive constituents of C. tricuspidata and the human microbiota is an underappreciated aspect, as the gut microbiota plays a vital role in the pathogenesis and progression of obesity, diabetes and related metabolic disorders.141 Current findings have demonstrated that C. tricuspidata may serve as a good source of prebiotics that promote the growth of probiotic bacteria and improve the antioxidant activity of dairy products, which is of great interest for the development of functional foods.

Acknowledgements

We would like to thank Drs Xue-qing Zhang (Ocean University of China), Cheng Qu (Nanjing University of Chinese Medicine) and master Miao-yin Zhang (The Johns Hopkins University) for critically reading a previous version of this manuscript. We apologize to authors whose relevant work was not included in this review owing to space constraints. This work was supported by the National High Technology Research and Development Program of China (863 Program) (No. 2013AA093001), The Scientific and Technological Innovation Project Financially Supported by Qingdao National Laboratory for Marine Science and Technology (No. 2015ASKJ02), and the Taishan Scholars Program, China.

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Footnote

These authors have contributed equally to this work.

This journal is © The Royal Society of Chemistry 2017