Traditional Uses, Chemical Constituents and Pharmacological Activities of the Toona sinensis Plant

Abstract

Toona sinensis (A. Juss.) Roem., which is widely distributed in China, is a homologous plant resource of medicine and food. The leaves, seeds, barks, buds and pericarps of T. sinensis can be used as medicine with traditional efficacy. Due to its extensive use in traditional medicine in the ancient world, the T. sinensis plant has significant development potential. In this review, 206 compounds, including triterpenoids (1–133), sesquiterpenoids (134–135), diterpenoids (136–142), sterols (143–147), phenols (148–167), flavonoids (168–186), phenylpropanoids (187–192) and others (193–206), are isolated from the T. sinensis plant. The mass spectrum cracking laws of representative compounds (64, 128, 129, 154–156, 175, 177, 179 and 183) are reviewed, which are conducive to the discovery of novel active substances. Modern pharmacological studies have shown that T. sinensis extracts and their compounds have antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor, hepatoprotective, antiviral, antibacterial, immunopotentiation and other biological activities. The traditional uses, chemical constituents, compound cracking laws and pharmacological activities of different parts of T. sinensis are reviewed, laying the foundation for improving the development and utilization of its medicinal value.

Full text

Citation: Zhao, M.; Li, H.; Wang, R.;
Lan, S.; Wang, Y.; Zhang, Y.; Sui, H.;
Li, W. Traditional Uses, Chemical
Constituents and Pharmacological
Activities of the Toona sinensis Plant.
Molecules 2024,29, 718. https://
doi.org/10.3390/molecules29030718
Academic Editor: Satyajit D Sarker
Received: 2 January 2024
Revised: 21 January 2024
Accepted: 21 January 2024
Published: 4 February 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
molecules
Review
Traditional Uses, Chemical Constituents and Pharmacological
Activities of the Toona sinensis Plant
Mengyao Zhao 1, †, Huiting Li 1 ,† , Rongshen Wang 1, Shuying Lan 1, Yuxin Wang 1, Yuhua Zhang 1, Haishan Sui 2, *
and Wanzhong Li 1,*
1School of Pharmacy, Shandong Second Medical University, Weifang 261053, China;
wfmc20221028@126.com (M.Z.); wnmclht@126.com (H.L.); wangrs199012@163.com (R.W.);
18878630861@163.com (S.L.); 18363412971@163.com (Y.W.); zhangyh@wfmc.edu.cn (Y.Z.)
2Weifang City Inspection and Testing Center, Weifang 261100, China
*Correspondence: shs751527082@126.com (H.S.); liwz@wfmc.edu.cn (W.L.)
†These authors contributed equally to this work.
Abstract: Toona sinensis (A. Juss.) Roem., which is widely distributed in China, is a homologous plant
resource of medicine and food. The leaves, seeds, barks, buds and pericarps of T. sinensis can be
used as medicine with traditional efficacy. Due to its extensive use in traditional medicine in the
ancient world, the T. sinensis plant has significant development potential. In this review, 206 com-
pounds, including triterpenoids (1–133), sesquiterpenoids (134–135), diterpenoids (136–142), sterols
(143–147), phenols (148–167), flavonoids (168–186), phenylpropanoids (187–192) and others (193–206),
are isolated from the T. sinensis plant. The mass spectrum cracking laws of representative compounds
(64,128,129,154–156,175,177,179 and 183) are reviewed, which are conducive to the discovery of
novel active substances. Modern pharmacological studies have shown that T. sinensis extracts and
their compounds have antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitu-
mor, hepatoprotective, antiviral, antibacterial, immunopotentiation and other biological activities.
The traditional uses, chemical constituents, compound cracking laws and pharmacological activities
of different parts of T. sinensis are reviewed, laying the foundation for improving the development
and utilization of its medicinal value.
Keywords: Toona sinensis; traditional uses; chemical constituent; pharmacological activity
1. Introduction
The Toona genus (Meliaceae) comprises about 15 species, which are distributed from
Asia to Oceania. Approximately four species, including Toona sinensis (A. Juss.) Roem,
Toona ciliata M. Roem., Toona microcarpa (C. DC.) Harms and Toona rubriflora C. J. Tseng, are
found in China with distribution in the south, southwest and north [
1
]. In addition to the
characteristics of the species, T. sinensis seeds have membranous wings, which facilitate
flying and spreading. More than 2000 years of cultivation history has resulted in the
species’ strong cold resistance. Of course, it already had this genetic advantage, which
made it widely cultivated on the lands of China [
2
,
3
]. T. sinensis has a long history of
cultivation, wide distribution, strong adaptability and easy reproduction. It is a valuable
multifunctional tree species that integrates food, medicine and materials, beautifies the
environment and has significant potential for development and utilization [4,5].
T. sinensis was first published in Tang Materia Medica, describing its efficacy in trans-
forming food and medicine, which were widely used in traditional medicine in the ancient
world [
6
]. The traditional efficacy of T. sinensis is closely associated with a variety of
phytochemical constituents. Previous phytochemical investigations on this plant have
revealed that the secondary metabolites include triterpenoids, sesquiterpenoids, diter-
penoids, sterols, phenols, flavonoids and phenylpropanoids [
7
,
8
]. Among the phytochem-
ical constituents, triterpenoids are known to be the main constituents, such as limonoid,
Molecules 2024,29, 718. https://doi.org/10.3390/molecules29030718 https://www.mdpi.com/journal/molecules

Molecules 2024,29, 718 2 of 31
apo-tirucallane and tirucallane [
9
]. It is important to quickly characterize the natural prod-
ucts in these complex plant extracts. Mass spectrometry is a powerful tool for analyzing
chemical compositions. Understanding the cracking laws of compounds from T. sinensis
is important for the discovery of active substances with novel structures [
10
]. Modern
studies have also reported that T. sinensis possesses various pharmacological activities,
including antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor,
hepatoprotective, antiviral, antibacterial and other biological activities [
11
–
13
] (Figure 1).
Together, these findings have provided many new insights and a strong scientific basis for
supporting its practical use in medical situations.
Molecules 2024, 29, x FOR PEER REVIEW 2 of 32
constituents, triterpenoids are known to be the main constituents, such as limonoid, apo-
tirucallane and tirucallane [9]. It is important to quickly characterize the natural products
in these complex plant extracts. Mass spectrometry is a powerful tool for analyzing chem-
ical compositions. Understanding the cracking laws of compounds from T. sinensis is im-
portant for the discovery of active substances with novel structures [10]. Modern studies
have also reported that T. sinensis possesses various pharmacological activities, including
antidiabetic, antidiabetic nephropathy, antioxidant, anti-inflammatory, antitumor, hepa-
toprotective, antiviral, antibacterial and other biological activities [11–13] (Figure 1). To-
gether, these findings have provided many new insights and a strong scientific basis for
supporting its practical use in medical situations.
In this review, we compile the progress on phytochemical studies over the past few
decades, with all the elucidated compounds listed. The biological characterizations of the
extracts and compounds isolated from T. sinensis plant are also discussed. Therefore, this
review will provide a guide for the full utilization of these plants for new drug develop-
ment and pharmaceutical applications through a comprehensive understanding of the de-
velopment status of T. sinensis.
Figure 1. Different parts of the T. sinensis plant and its chemical constituents and pharmacological
activities.
2. Traditional Uses
T. sinensis, a deciduous woody plant native to Eastern and Southeastern Asia, is used
as a vegetable source in China and Malaysia and as animal fodder in India [14,15]. The T.
sinensis plant, a unique tree species in China, is popularly known as “Xiang Chun”,
Figure 1. Different parts of the T. sinensis plant and its chemical constituents and pharmacolo-
gical activities.
In this review, we compile the progress on phytochemical studies over the past few
decades, with all the elucidated compounds listed. The biological characterizations of
the extracts and compounds isolated from T. sinensis plant are also discussed. Therefore,
this review will provide a guide for the full utilization of these plants for new drug
development and pharmaceutical applications through a comprehensive understanding of
the development status of T. sinensis.
2. Traditional Uses
T. sinensis, a deciduous woody plant native to Eastern and Southeastern Asia, is used
as a vegetable source in China and Malaysia and as animal fodder in India [
14
,
15
]. The

Molecules 2024,29, 718 3 of 31
T. sinensis plant, a unique tree species in China, is popularly known as “Xiang Chun”,
“Chinese toon” or “Chinese mahogany” and has a long history in medicine, with wide uses
and rich sources [16,17].
T. sinensis has been widely used in traditional Chinese medicine (TCM), the effects of
which, including heat-clearing, diuresis and detoxification, were known in ancient times.
All parts of this plant, including the leaves, seeds, barks, buds and pericarps, have been
traditionally used in folk medicine to treat various diseases. T. sinensis leaves taste bitter
and flat. Their summer dampness-dispelling, detoxification and insecticidal effects are used
to treat the spleen and stomach channel for summer-dampness injury, nausea, vomiting,
loss of appetite and other symptoms [
18
]. The barks of T. sinensis are bitter, astringent and
slightly cold and are used to clear heat and dispel dampness to treat an astringent intestine
by stopping bleeding, treating band disease and killing insects. The barks are used for
diarrhea, dysentery, intestinal wind, blood stools, disc leakage and other symptoms [
19
].
T. sinensis seeds taste bitter and warm. Their wind-dispelling, cold and analgesic effects are
used to treat the lung, liver and large intestine meridian for external wind cold, rheumatism,
stomach pain and other diseases [20,21].
T. sinensis is used as a medicinal plant in traditional medicine. Appropriate amounts
of T. sinensis buds and vinegar are weighed. T. sinensis buds are soaked in vinegar and then
brewed in boiling water into T. sinensis soups to treat colds, which are administered as one
dose daily divided into three. T. sinensis leaves (50 g) are weighed, washed and mashed
and then mixed with rice vinegar or yellow rice wine to treat oral and tongue sores, which
are administered as one dose daily divided into two. T. sinensis leaves, garlic and a small
amount of salt are weighed and mashed together to form a mud, which is applied to an
affected area to treat sores and swelling twice a day for 1–2 h each time. T. sinensis leaves
(20 g), “Jiao Sanxian” (20 g), Agastache rugosa (10 g) and Nelumbo nucifera seeds (15 g) are
weighed, boiled in water to remove the residue and extract the juice and used to treat spleen
and stomach weaknesses and abdominal distention. This is administered as one dose daily
divided into two. T. sinensis root barks (60 g) are weighed, boiled in water to remove the
residue and extract the juice, with an appropriate amount of brown sugar added to the
juice. This is administered as one dose daily divided into three for the treatment of white
band disease. T. sinensis seeds (30 g) are cooked with pork or mutton and used once a week
to treat rheumatic joint pain [22].
3. Phytochemical Constituents
A phytochemical investigation is a critical step in understanding the therapeutic po-
tential of medicinal plants. As a botanical source of bioactive compounds, T. sinensis has
been the subject of extensive research. To date, 206 compounds have been isolated and
characterized from T. sinensis, including triterpenoids (1–133), sesquiterpenoids (134–135),
diterpenoids (136–142), sterols (143–147), phenols (148–167), flavonoids (168–186), phenyl-
propanoids (187–192) and others (193–206). The chemical structures of these compounds
are illustrated in Table 1.
Table 1. Chemical compounds isolated from the T. sinensis plant.
Comp. Name Type Sources Ref.
triterpenoids
1methyl shoreate dammarane stem barks [23]
2shoreic acid dammarane stem barks [23]
3ocotillone dammarane stem barks [23]
4(20S, 24R)-epoxydammarane-12, 25-diol-3-one dammarane stem barks [23]
5(20S, 24R)-epoxydammarane-3β, 25-diol-marane-3β, 25-diol dammarane stem barks [23]
6richenone dammarane stem barks [23]
7cabralealactone dammarane stem barks [23]
8hollongdione dammarane stem barks [23]
920-hydroxy-24-dammaren-3-one dammarane stem barks [23]

Molecules 2024,29, 718 4 of 31
Table 1. Cont.
Comp. Name Type Sources Ref.
10 (20S, 24S)-dihydroxydammar-25-en-3-one dammarane stem barks [23]
11 cylindrictone D dammarane stem barks [23]
12 hispidol B tirucallane barks [24]
13 3β, 25-dihydroxy-tirucalla-7, 23-diene tirucallane seeds [25]
14 3β, 23-dihydroxy-tirucalla-7, 24-diene tirucallane seeds [25]
15 24, 25-epoxy-3β, 23-dihydroxy-7-tirucallene tirucallane seeds [25]
16 piscidinol tirucallane barks [24]
17 bourjotinolone B tirucallane barks [26]
18 (20S)-3-oxo-tirucalla-25-nor-7-en-24-oic acid tirucallane stem barks [23]
19 4, 4, 14-trimethyl-3-oxo-24-nor-5α,13α,14β,17α, 20S-chol-7-en-23-oic
acid tirucallane stem barks [23]
20 (20S)-5α, 8α-epidioxy-3-oxo-24-nor-6,9 (11)-dien-23-oic acid tirucallane stem barks [23]
21 Comp. 1of [24]apo-tirucallane barks [24]
22 Comp. 2of [24]apo-tirucallane barks [24]
23 Comp. 7of [24]apo-tirucallane barks [24]
24 Comp. 8of [24]apo-tirucallane barks [24]
25 21α-O-methylmelianodiol apo-tirucallane pericarps [1,15,27]
26 21β-O-methylmelianodiol apo-tirucallane pericarps [1,15,27]
27 Comp. 9of [24]apo-tirucallane barks [24]
28 sapelin E acetate apo-tirucallane barks [24]
29 grandifoliolenone apo-tirucallane barks [24]
30 bourjotinolone A apo-tirucallane barks [24]
31 Comp. 4of [28]apo-tirucallane seeds, stems [28]
32 Comp. 5of [28]apo-tirucallane stems [28]
33 Comp. 6of [28]apo-tirucallane stems [28]
34 toonasinensin E apo-tirucallane seeds, pericarps [1,15,18,
27]
35 Comp. 13 of [28]apo-tirucallane stems [28]
36 Comp. 17 of [28]apo-tirucallane stems [28]
37 toonasinensin A apo-tirucallane pericarps [1,15,27]
38 Comp. 6of [24]apo-tirucallane barks [24]
39 toonasinensin B apo-tirucallane pericarps [1,15,27]
40 Comp. 18 of [28]apo-tirucallane leaves, stems [28]
41 toonasinensin D apo-tirucallane seeds, pericarps [1,15,27,
28]
42 Comp. 22 of [28]apo-tirucallane leaves [28]
43 toonasinensin C apo-tirucallane leaves, barks,
pericarps
[1,15,24,
27,28]
44 Comp. 21 of [28]apo-tirucallane leaves [28]
45 Comp. 1a of [28]apo-tirucallane seeds [28]
46 Comp. 7a of [28]apo-tirucallane stems [28]
47 Comp. 10a of [28]apo-tirucallane leaves [28]
48 Comp. 5of [24]apo-tirucallane barks [24]
49 Comp. 3of [24]apo-tirucallane barks [24]
50 Comp. 4of [24]apo-tirucallane barks [24]
51 Comp. 1of [28]apo-tirucallane seeds, leaves,
stems [28]
52 Comp. 2of [28]apo-tirucallane leaves, stems [28]
53 Comp. 3of [28]apo-tirucallane leaves, stems [28]
54 Comp. 7of [28]apo-tirucallane leaves, stems [28]
55 Comp. 8of [28]apo-tirucallane leaves [28]
56 Comp. 9of [28]apo-tirucallane stems [28]
57 Comp. 10 of [28]apo-tirucallane leaves [28]
58 Comp. 11 of [28]apo-tirucallane leaves [28]
59 Comp. 12 of [28]apo-tirucallane leaves [28]
60 Comp. 14 of [28]apo-tirucallane leaves [28]
61 Comp. 15 of [28]apo-tirucallane leaves [28]
62 Comp. 16 of [28]apo-tirucallane leaves [28]

Molecules 2024,29, 718 5 of 31
Table 1. Cont.
Comp. Name Type Sources Ref.
63 7-deacetoxy-7α-hydroxygedunin limonoids barks [29]
64 gedunin limonoids barks [29]
65 7-deacetoxy-7α, 11α-dihydroxygedunin limonoids barks [29]
66 7-deacetoxy-7α, 11β-dihydroxygedunin limonoids barks [29]
67 11α-hydroxygedunin limonoids barks [29]
68 11β-hydroxygedunin limonoids barks [29]
69 11-oxogedunin limonoids barks [29]
70 11α-acetoxygedunin limonoids barks [29
71 11β-acetoxygedunin limonoids barks [29]
72 photogedunin limonoids barks [26]
73 toonasinemine I limonoids root barks [30]
74 toonasinemine J limonoids root barks [30]
75 azadirone limonoids barks [24]
76 toonasinemine K limonoids root barks [30]
77 toonasinemine L limonoids root barks [30]
78 toonasinenine F limonoids root barks [30]
79 toonacilianin D limonoids leaves [31]
80 toonasinenine H limonoids leaves [31]
81 toonasinenine G limonoids leaves [31]
82 toonasinenine E limonoids leaves [31]
83 toonasinenoids A limonoids leaves, buds [32]
84 walsurin D limonoids leaves, buds [32]
85 walsurin E limonoids leaves, buds [32]
86 toonaciliatone F limonoids leaves, buds [32]
87 toonayunnanin B limonoids leaves, buds [32]
88 toonasinenoids B limonoids leaves, buds [32]
89 6α-hydroxyazadiradione limonoids leaves, buds [32]
90 trichilenone acetate limonoids leaves, buds [32]
91 toonasinenoid E limonoids leaves, buds [32]
92 14, 15-epoxynimonol limonoids leaves, buds [32]
93 toonasinenoids D limonoids leaves, buds [32]
94 toonaciliatone B limonoids leaves, buds [32]
95 walsunoid H limonoids leaves, buds [32]
96 1α-methoxy-12α-acetoxydihydrocedrelone limonoids leaves, buds [32]
97 dysoxylumosin G limonoids leaves, buds [32]
98 toonasinenoids C limonoids leaves, buds [32]
99 toonasinenine A limonoids leaves [31]
100 toonafolin limonoids leaves [31]
101 toonasinenine B limonoids leaves [31]
102 toonasinenine C limonoids leaves [31]
103 toonasinenine D limonoids leaves [31]
104 proceranone limonoids root barks [33]
105 6-acetoxyobacunol acetate limonoids leaves [34]
106 11β-hydroxy-7α-obacunyl acetate limonoids leaves [35]
107 11-oxo-7α-obacunol limonoids leaves [35]
108 11-oxo-7α-obacunyl acetate limonoids leaves [35]
109 7α-acetoxydihydronomilin limonoids leaves [34]
110 11β-hydroxycneorin G limonoids leaves [35]
111 toonins A limonoids root barks [33]
112 11-oxocneorin G limonoids leaves [35]
113 cedrellin limonoids leaves [34]
114 toonasinenine I limonoids leaves [31]
115 toonasinenine J limonoids leaves [31]
116 surenin limonoids root barks [33]
117 toonins B limonoids root barks [33]
118 carapolide H limonoids root barks [33]
119 carapolide I limonoids root barks [33]
120 toonasinemine A limonoids root barks [30]

Molecules 2024,29, 718 6 of 31
Table 1. Cont.
Comp. Name Type Sources Ref.
121 toonasinemine B limonoids root barks [30]
122 toonasinemine C limonoids root barks [30]
123 toonasinemine F limonoids barks [26]
124 toonasinemine G limonoids root barks [30]
125 toonasinemine D limonoids barks [26]
126 toonasins B limonoids barks [26]
127 toonasinemine E limonoids root barks [30]
128 cycloeucalenol cycloartane pericarps [1,15,27]
129 24-methylenecycloartanol cycloartane pericarps [1,15,27]
130 betulinic acid other barks [26,36]
131 betulin other barks [26]
132 erythrodiol other barks [26]
133 3-oxours-12-en-28-oic acid other roots [36]
134 alismoxide
sesquiterpenoids
pericarps [1,27]
135 oplodiol
sesquiterpenoids
pericarps [1,27]
136 gossweilone diterpenoids barks [26]
137 phytol diterpenoids leaves [34]
138 (9S, 10E, 16R)-9, 16-dihydroxyoctadec-10-ene-12, 14-diyn-1-yl acetate diterpenoids barks [37]
139 2, 6, 10, 15-phytatetraene-14-ol diterpenoids leaves [34]
140 2, 6, 10-phytatriene-1, 14, 15-triol diterpenoids leaves [34]
141 15-tetrahydroxy-3,7, 11, 15, 15-pentamethyl-2, 6, 10-hexadecatriene diterpenoids seeds [25]
142 1-O-acetyl-12, 14, 15-trihydroxy-3, 7, 11, 15, 15-pentamethyl-2, 6,
10-hexadecatriene diterpenoids seeds [25]
143 β-sitosterol sterols
pericarps, barks,
roots
[1,27,33,
38]
144 lawsaritol A sterols pericarps [1,27]
145 (3β, 7α)-7-methoxystigmast-5-en-3-ol sterols pericarps [1,27]
145 stigmast-4-ene-3β, 6β-diol sterols pericarps [1,27]
147 5α, 8α-epidioxy-(22E, 24R)-ergosta-6, 22-dien-3β-ol sterols pericarps [1,27]
148 hydroquinone phenols pericarps [1]
149 4-hydroxybenzylamine phenols pericarps [1,27]
150 protocatechuic acid phenols pericarps [1]
151 3, 4-dihydroxybenzoic acid ethyl ester phenols pericarps [1,27]
152 3-methoxy-4-hydroxy phenylethanol phenols pericarps, roots [1,27,33]
153 coniferyl aldehyde phenols pericarps [1,27]
154 gallic acid phenols pericarps [1]
155 methyl gallate phenols young leaves,
pericarps [1,39]
156 ethyl gallate phenols
young leaves,
leaves, stems,
fruits, pericarps
[25,34,
40,41]
157 syringic acid phenols roots [33]
158 4-methoxy-6-(2′, 4′-dihydroxy-6′-methylphenyl)-pyran-2-one phenols roots [33]
159 aloeemodin phenols roots [33]
160 isoscopoletin phenols roots [33]
161 trigallic acid phenols pericarps [1]
162 7-methoxy trigallic acid phenols pericarps [1]
163 5-O-galloylquinic acid phenols leaves [12]
164 6-O-galloyl-D-glucose phenols leaves, shoots [39]
165 1, 2, 3-tri-O-galloyl-β-D-glucopyranose phenols leaves, shoots [39]
166 1, 2, 3, 6-tetra-O-galloyl-β-D-glucopyranose phenols leaves, shoots [39]
167 1, 2, 3, 4, 6-penta-O-galloyl-β-D-glucose phenols pericarps,
young leaves [1,39]
flavonoids
168 (-)-epicatechin flavan-3-ols stems [40]
169 (-)-epigallocatechin gallate flavan-3-ols leaves [40]
170 (+)-catechin flavan-3-ols leaves, woods [42]

Molecules 2024,29, 718 7 of 31
Table 1. Cont.
Comp. Name Type Sources Ref.
171 procyanidin B3 flavan-3-ols leaves, woods [42]
172 demethoxymatteucinol flavanones stems [40]
173 matteucinol flavanones stems [40]
174 5, 7-dihydroxy-8-methoxy flavone flavones barks [38]
175 kaempferol flavonols young leaves [41]
176 kaempferol-3-O-α-rhamopyranoside flavonols young leaves [41]
177 astragalin flavonols young leaves [41]
178 kaempferitrin flavonols seeds [43]
179 quercetin flavonols young leaves [41]
180 quercetin-3-rhamnoside flavonols pericarps,
young leaves [1,39]
181 quercetin 3-glucoside flavonols pericarps [25]
182 quercetin-3-O-α-L-arabinopyranoside flavonols pericarps [1]
183 rutin flavonols leaves, shoots [39]
184 myricetin flavonols barks [38]
185 myricitrin flavonols barks [38]
186 quercetin 3-O-(2′′-O-galloyl)-β-D-glucopyranoside flavonols leaves [12]
187 cedralins A
phenylpropanoids
leaves [44]
188 toonin C
phenylpropanoids
roots, pericarps [1,27]
189 cedralins B
phenylpropanoids
leaves [44]
190 matairesinol
phenylpropanoids
root barks [33]
191 lyoniresinol
phenylpropanoids
root barks [33]
192 punicatannin C
phenylpropanoids
pericarps [1,27]
193 α-tocopherol others leaves [45]
194 lutein others leaves [45]
195 toonasindiyne A others root barks [46]
196 toonasindiyne B others root barks [46]
197 toonasindiyne C others root barks [46]
198 toonasindiyne D others root barks [46]
199 toonasindiyne E others root barks [46]
200 toonasindiyne F others root barks [46]
201 Comp. 7 of [46] others root barks [46]
202 Comp. 8 of [46] others root barks [46]
203 Comp. 9 of [46] others root barks [46]
204 Comp. 10 of [46] others root barks [46]
205 Comp. 11 of [46] others root barks [46]
206 Comp. 12 of [46] others root barks [46]
3.1. Triterpenoids
Triterpenoids are a class of terpenoids. The basic nucleus of a terpenoid is composed
of 30 carbon atoms. Triterpenoids exist in plants in free form or as glycosides or esters
combined with sugars. Triterpenoids are the main components of T. sinensis. A total of
133 triterpenoids have been isolated from various parts of T. sinensis, including dammarane,
tirucallane, apo-tirucallane, limonoids, cycloartane and other triterpenoids. The most abun-
dant tetracyclic triterpenoids in T. sinensis include dammarane, tirucallane, apo-tirucallane
and limonoid triterpenoids [47]. Their structural correlations are shown in Figure 2.
3.2. Dammarane Triterpenoids
Dammarane triterpenoids derived from the “full chair” conformation of epoxy-squalene
are characterized by a C-8 angular methyl group with a
β
-configuration. In addition, the
C-13 position has a
β
-H configuration. The C-10 position has a
β
-CH
3
configuration.
The C-17 position has
β
-side chains. C-20 has an Ror Sconfiguration. At present, eleven
dammarane triterpenoids (1–11) have been isolated from the stem barks of T. sinensis [
23
], in-
cluding methyl shoreate (1), shoreic acid (2), ocotillone (3), (20S, 24R)-epoxydammarane-12,
25-diol-3-one (4), (20S, 24R)-epoxydammarane-3
β
, 25-diol-marane-3
β
, 25-diol (5), richenone

Molecules 2024,29, 718 8 of 31
(6), cabralealactone (7), hollongdione (8), 20-hydroxy-24-dammaren-3-one (9), (20S, 24S)-
dihydroxydammar-25-en-3-one (10) and cylindrictone D (11) (Figure 3).
Molecules 2024, 29, x FOR PEER REVIEW 8 of 32
197 toonasindiyne C others root barks [46]
198 toonasindiyne D others root barks [46]
199 toonasindiyne E others root barks [46]
200 toonasindiyne F others root barks [46]
201 Comp. 7 of [46] others root barks [46]
202 Comp. 8 of [46] others root barks [46]
203 Comp. 9 of [46] others root barks [46]
204 Comp. 10 of [46] others root barks [46]
205 Comp. 11 of [46] others root barks [46]
206 Comp. 12 of [46] others root barks [46]
3.1. Triterpenoids
Triterpenoids are a class of terpenoids. The basic nucleus of a terpenoid is composed
of 30 carbon atoms. Triterpenoids exist in plants in free form or as glycosides or esters
combined with sugars. Triterpenoids are the main components of T. sinensis. A total of 133
triterpenoids have been isolated from various parts of T. sinensis, including dammarane,
tirucallane, apo-tirucallane, limonoids, cycloartane and other triterpenoids. The most
abundant tetracyclic triterpenoids in T. sinensis include dammarane, tirucallane, apo-tiru-
callane and limonoid triterpenoids [47]. Their structural correlations are shown in Figure
2.
Figure 2. Main skeleton structures of tetracyclic triterpenoids from T. sinensis.
3.2. Dammarane Triterpenoids
Dammarane triterpenoids derived from the “full chair” conformation of epoxy-squa-
lene are characterized by a C-8 angular methyl group with a β-configuration. In addition,
the C-13 position has a β-H configuration. The C-10 position has a β-CH3 configuration.
The C-17 position has β-side chains. C-20 has an R or S configuration. At present, eleven
dammarane triterpenoids (1–11) have been isolated from the stem barks of T. sinensis [23],
including methyl shoreate (1), shoreic acid (2), ocotillone (3), (20S, 24R)-epoxydam-
marane-12, 25-diol-3-one (4), (20S, 24R)-epoxydammarane-3β, 25-diol-marane-3β, 25-diol
(5), richenone (6), cabralealactone (7), hollongdione (8), 20-hydroxy-24-dammaren-3-one
(9), (20S, 24S)-dihydroxydammar-25-en-3-one (10) and cylindrictone D (11) (Figure 3).
Figure 2. Main skeleton structures of tetracyclic triterpenoids from T. sinensis.
3.3. Tirucallane Triterpenoids
Tirucallane triterpenoids have a basic parent nucleus of cyclopentane, the A/B, B/C
and C/D rings of which have a trans configuration. Tirucallane triterpenoids, in general,
have five methyl groups and a side chain composed of eight carbon atoms on the C-17
position of the parent nucleus. That is, the C-4 position has two methyl groups. The
C-10 and C-14 positions have one methyl group each (10
β
and 14
β
, respectively), and
another methyl group is connected to the C-13 position (13
α
). The C-17 side chain is an
α
configuration. At present, nine tirucallane triterpenoids (12–20) have been isolated from
the barks, stem barks and seeds of T. sinensis. Three tirucallane triterpenoids (12,16 and
17) have been isolated from the barks of T. sinensis [
24
,
26
]. Three tirucallane triterpenoids
(13–15) have been isolated from the seeds of T. sinensis [
25
]. Three tirucallane triterpenoids
(18–20) have been isolated from the stem barks of T. sinensis [23] (Figure 3).
3.4. Apo-Tirucallane Triterpenoids
Tirucallane triterpenoids are thought to be the precursors of apo-tirucallane triter-
penoids. Apo-tirucallane triterpenoids are parent-nucleus D rings with the Wagen–Meerwein
rearrangement. This rearrangement results in the formation of double bonds at positions
C-14 and C-15. The
α
side chains connected at positions C-17 may exhibit structural
changes (such as the branched chain, ring formation, hydroxylation, epoxidation and other
structural changes), which are, in general, tetrahydrofuran rings, tetrahydropyran rings
and hepta-membered oxygen-containing rings. Forty-two apo-tirucallane triterpenoids
(21–62) have been isolated from the barks, seeds, leaves, stems and pericarps of T. sinensis.
Thirteen apo-tirucallane triterpenoids (21–24,27–30,38,43 and 48–50) have been isolated
from the barks of T. sinensis [
24
]. Twenty-six apo-tirucallane compounds (31–36,40–47
and 51–62) have been isolated from the seeds, leaves and stems of T. sinensis [
28
]. Seven
apo-tirucallane triterpenoids (25–26,34,37,39,41 and 43) have been isolated from the
pericarps of T. sinensis [1,15,27] (Figure 4).

Molecules 2024,29, 718 9 of 31
Molecules 2024, 29, x FOR PEER REVIEW 9 of 32
Figure 3. Structure of dammarane and tirucallane triterpenoids from T. sinensis.
3.3. Tirucallane Triterpenoids
Tirucallane triterpenoids have a basic parent nucleus of cyclopentane, the A/B, B/C
and C/D rings of which have a trans configuration. Tirucallane triterpenoids, in general,
have five methyl groups and a side chain composed of eight carbon atoms on the C-17
position of the parent nucleus. That is, the C-4 position has two methyl groups. The C-10
and C-14 positions have one methyl group each (10β and 14β, respectively), and another
methyl group is connected to the C-13 position (13α). The C-17 side chain is an α configu-
ration. At present, nine tirucallane triterpenoids (12–20) have been isolated from the barks,
stem barks and seeds of T. sinensis. Three tirucallane triterpenoids (12, 16 and 17) have
been isolated from the barks of T. sinensis [24,26]. Three tirucallane triterpenoids (13–15)
have been isolated from the seeds of T. sinensis [25]. Three tirucallane triterpenoids (18–
20) have been isolated from the stem barks of T. sinensis [23] (Figure 3).
3.4. Apo-Tirucallane Triterpenoids
Tirucallane triterpenoids are thought to be the precursors of apo-tirucallane triterpe-
noids. Apo-tirucallane triterpenoids are parent-nucleus D rings with the Wagen–Meer-
wein rearrangement. This rearrangement results in the formation of double bonds at
Figure 3. Structure of dammarane and tirucallane triterpenoids from T. sinensis.
3.5. Limonoid Triterpenoids
Limonoid triterpenoids are a class of highly oxidized compounds with a skeleton of
4,4,8-trimethyl-17-furanosteroid or one of its derivatives. Biogenetically, limonoids are
derived from the degradation of
∆7
-tinucallol or
∆7
-euphol by the loss of four carbon atoms
at the end of the C-17 side chain. Hence, this class of compounds is also called “tetranormo-
triterpenes”. At present, sixty-five limonoid triterpenoids (63–127) have been isolated
from the barks, root barks, leaves and buds of T. sinensis. Fourteen limonoid triterpenoids
(63–72,75,123,125 and 126) have been isolated from the barks of T. sinensis [
24
,
26
,
29
].
Sixteen limonoid triterpenoids (73–74,76–78,104,111,116–122,124 and 127) have been
isolated from the root barks of T. sinensis [
30
,
33
]. Nineteen limonoid triterpenoids (79–82,

Molecules 2024,29, 718 10 of 31
99–103,105–110 and 112–115) have been isolated from the leaves of T. sinensis [
31
,
34
,
35
].
Sixteen limonoid triterpenoids (83–98) have been isolated from the leaves and buds of T.
sinensis [32] (Figure 5).
Molecules 2024, 29, x FOR PEER REVIEW 10 of 32
positions C-14 and C-15. The α side chains connected at positions C-17 may exhibit struc-
tural changes (such as the branched chain, ring formation, hydroxylation, epoxidation and
other structural changes), which are, in general, tetrahydrofuran rings, tetrahydropyran
rings and hepta-membered oxygen-containing rings. Forty-two apo-tirucallane triterpe-
noids (21–62) have been isolated from the barks, seeds, leaves, stems and pericarps of T.
sinensis. Thirteen apo-tirucallane triterpenoids (21–24, 27–30, 38, 43 and 48–50) have been
isolated from the barks of T. sinensis [24]. Twenty-six apo-tirucallane compounds (31–36,
40–47 and 51–62) have been isolated from the seeds, leaves and stems of T. sinensis [28].
Seven apo-tirucallane triterpenoids (25–26, 34, 37, 39, 41 and 43) have been isolated from
the pericarps of T. sinensis [1,15,27] (Figure 4).
Figure 4. Structure of apo-tirucallane triterpenoids from T. sinensis.
H
O
H
OH
H
O
O
OH
HO
H
H
21 (R)
22 (S)
H
O
H
H
O
O
OH
HO
H
H
23 (R)
24 (S)
H
O
H
OAc
H
O
H
O
O
27
H
O
H
OAc
H
O
H
OH
OH
28
H
O
H
OAc
H
OOH
OH
29
H
H
O
H
H
OOH
OH
H
30
H
H
OH
O
HO
OR
O
O
H
H
O
H
21 24
35
36
(S)
(R)
(S)
ND
R=H
R=CH
3
OH
H
H
OH
O
HO
O
O
H
H
O
H
40
41
-H
-H
H
H
OH
O
HO
O
O
H
H
O
H
34
H
H
OHO
O
H
O
H
OH
OH
44
H
H
OH
O
HO
O
O
H
O
H
H
OH
OH
324
42
43
-H
-H
(S)
ND
H
H
OH
H
OOH
HO
H
H
37
O
O
O
H
H
OH
H
OOH
HO
H
H
O
O
O
39
H
H
H
O
HO
H
H
O
R
25 R = -OCH3
26 R = -O CH3
OH
H
H
OH
H
O
O
O
H
OH
OH
48
H
H
OHO
O
H
O
H
O
OH
45 R1=R
2=H
46 R1=CH
3,R
2=H
47 R1=H,R
2=OH
OR1
R2
H
H
OH
H
O
O
O
H
OH
OH
HO
38
H
H
OH
O
HO
OH
O
O
H
O
H
321 24
31
32
33
-H
-H
-H
(R)
(S)
(S)
(S)
(S)
ND
H
H
H
OH
H
OOH
HO
H
H
49
O
O
O
H
H
OH
O
HO
OR
O
O
H
H
O
H
32124
51
52
53
54
55
56
-H
-H
-H
-H
-H
-H
(R)
(S)
(R)
(R)
(S)
(R)
(S)
(S)
ND
(S)
ND
ND
R=H
R=H
R=H
R=CH
3
R=CH
3
R=CH
3
H
H
OH
H
O
HO
H
H
O
O
O
OH
OH
50
H
H
OH
O
HO
OR
O
O
H
H
O
H
32124
57
58
59
60
61
62
-H
-H
-H
-H
-H
-H
(S)
(R)
(S)
(R)
(S)
(R)
(S)
ND
(S)
ND
ND
ND
R=H
R=H
R=H,(25
R)
R=CH
3
R=CH
3
R=CH
3
OH
3
Figure 4. Structure of apo-tirucallane triterpenoids from T. sinensis.

Molecules 2024,29, 718 11 of 31
Molecules 2024, 29, x FOR PEER REVIEW 11 of 32
3.5. Limonoid Triterpenoids
Limonoid triterpenoids are a class of highly oxidized compounds with a skeleton of
4,4,8-trimethyl-17-furanosteroid or one of its derivatives. Biogenetically, limonoids are de-
rived from the degradation of Δ7-tinucallol or Δ7-euphol by the loss of four carbon atoms
at the end of the C-17 side chain. Hence, this class of compounds is also called
“tetranormo-triterpenes”. At present, sixty-five limonoid triterpenoids (63–127) have been
isolated from the barks, root barks, leaves and buds of T. sinensis. Fourteen limonoid
triterpenoids (63–72, 75, 123, 125 and 126) have been isolated from the barks of T. sinensis
[24,26,29]. Sixteen limonoid triterpenoids (73–74, 76–78, 104, 111, 116–122, 124 and 127)
have been isolated from the root barks of T. sinensis [30,33]. Nineteen limonoid triterpe-
noids (79–82, 99–103, 105–110 and 112–115) have been isolated from the leaves of T. sinen-
sis [31,34,35]. Sixteen limonoid triterpenoids (83–98) have been isolated from the leaves
and buds of T. sinensis [32] (Figure 5).
Figure 5. Structure of limonoid triterpenoids from T. sinensis.
Figure 5. Structure of limonoid triterpenoids from T. sinensis.
3.6. Cycloartane and Other Triterpenoids
Two cycloartane triterpenoids (128 and 129) have been isolated from the pericarps of
T. sinensis [
1
,
15
,
27
]. Two lupinane triterpenoids (130 and 131) and one oleanane triterpenoid
(132) have been isolated from the barks of T. sinensis [
26
]. One ursane triterpenoid (133) has
been isolated from the roots of T. sinensis [36] (Figure 6).

Molecules 2024,29, 718 12 of 31
Molecules 2024, 29, x FOR PEER REVIEW 12 of 32
3.6. Cycloartane and Other Triterpenoids
Two cycloartane triterpenoids (128 and 129) have been isolated from the pericarps of
T. sinensis [1,15,27]. Two lupinane triterpenoids (130 and 131) and one oleanane triterpe-
noid (132) have been isolated from the barks of T. sinensis [26]. One ursane triterpenoid
(133) has been isolated from the roots of T. sinensis [36] (Figure 6).
Figure 6. Structure of cycloartane triterpenoids, other triterpenoids, sesquiterpenoids, diterpenoids
and sterols from T. sinensis.
3.7. Sesquiterpenoids and Diterpenoids
Sesquiterpenoids and diterpenoids are typically synthesized by polymerizing three
to four molecules of isoprene. Sesquiterpenoids are natural terpenoids containing 15 car-
bon atoms. At present, two sesquiterpenoids (134 and 135) have been isolated from the
pericarps of T. sinensis [1,27]. Diterpenoids are terpenoids containing four isoprene units.
They are natural products with complex and diverse structures and important biological
activities. Seven diterpenoids (136–142) have been isolated from T. sinensis. Two diterpe-
noids (136 and 138) have been isolated from the barks of T. sinensis [26,37]. Three diterpe-
noids (137,139 and 140) have been isolated from the leaves of T. sinensis [34]. Two diterpe-
noids (141 and 142) have been isolated from the seeds of T. sinensis [25] (Figure 6).
3.8. Sterols
Sterols are derivatives of a hydrogenated benzene ring system. They are important
active substances that are widely present in organisms. Five sterols (143–147) have been
isolated from the pericarps of T. sinensis [1,27]. Compound 143 has also been isolated from
the barks and roots of T. sinensis [33,38] (Figure 6).
Figure 6. Structure of cycloartane triterpenoids, other triterpenoids, sesquiterpenoids, diterpenoids
and sterols from T. sinensis.
3.7. Sesquiterpenoids and Diterpenoids
Sesquiterpenoids and diterpenoids are typically synthesized by polymerizing three to
four molecules of isoprene. Sesquiterpenoids are natural terpenoids containing 15 carbon
atoms. At present, two sesquiterpenoids (134 and 135) have been isolated from the pericarps
of T. sinensis [
1
,
27
]. Diterpenoids are terpenoids containing four isoprene units. They are
natural products with complex and diverse structures and important biological activities.
Seven diterpenoids (136–142) have been isolated from T. sinensis. Two diterpenoids (136
and 138) have been isolated from the barks of T. sinensis [
26
,
37
]. Three diterpenoids (137,139
and 140) have been isolated from the leaves of T. sinensis [
34
]. Two diterpenoids (141 and
142) have been isolated from the seeds of T. sinensis [25] (Figure 6).
3.8. Sterols
Sterols are derivatives of a hydrogenated benzene ring system. They are important
active substances that are widely present in organisms. Five sterols (143–147) have been
isolated from the pericarps of T. sinensis [
1
,
27
]. Compound 143 has also been isolated from
the barks and roots of T. sinensis [33,38] (Figure 6).

Molecules 2024,29, 718 13 of 31
3.9. Phenols
Phenols are naturally occurring metabolites found widely in plants. They have diverse
pharmacological activities. Various phenolic compounds are distributed in different parts
of T. sinensis. The contents of phenolic acid and its derivatives are relatively high. Twenty
phenols (148–167) have been isolated from various parts of T. sinensis. Twelve compounds
(148–156,161–162 and 167) have been isolated from the pericarps of T. sinensis [
1
,
27
].
Compounds 155 and 167 have also been isolated from the young leaves of T. sinensis [
39
].
Four phenols (157–160) have been isolated from the roots of T. sinensis [
33
]. Compound 163
has been isolated from the leaves of T. sinensis [
12
]. Three compounds (164–166) have been
isolated from leaves and shoots of T. sinensis [39] (Figure 7).
Molecules 2024, 29, x FOR PEER REVIEW 13 of 32
3.9. Phenols
Phenols are naturally occurring metabolites found widely in plants. They have di-
verse pharmacological activities. Various phenolic compounds are distributed in different
parts of T. sinensis. The contents of phenolic acid and its derivatives are relatively high.
Twenty phenols (148–167) have been isolated from various parts of T. sinensis. Twelve
compounds (148–156, 161–162 and 167) have been isolated from the pericarps of T. sinensis
[1,27]. Compounds 155 and 167 have also been isolated from the young leaves of T. sinensis
[39]. Four phenols (157–160) have been isolated from the roots of T. sinensis [33]. Com-
pound 163 has been isolated from the leaves of T. sinensis [12]. Three compounds (164–
166) have been isolated from leaves and shoots of T. sinensis [39] (Figure 7).
Figure 7. Structure of phenols, flavonoids, phenylpropanoids and other compounds from T. sinensis.
HO OH
O O
O
158
OO
O
HO
160
OH O
O
OH
OH
159
O
R1O
R5O
OR2
OR4
OR3G=
OH
OH
OH
O
OO
O
OH
OH
OH
OH
OH
O
HO
OH
ORO
161 R = H
162 R = CH3
R1
R3
R4R2
148 R1= OH, R2= OH, R3=H,R
4=H
149 R1= OH, R2=CH
2NH2,R
3=H,R
4=H
150 R1= OH, R2= COOH, R3= OH, R4=H
151 R1= OH, R2= COOCH2CH3,R
3= OH, R4=H
152 R1= OH, R2=CH
2CH2OH, R3=OCH
3,R
4=H
153 R1= OH, R2= CH=CHCHO, R3=OCH
3,R
4=H
154 R1= OH, R2= COOH, R3= OH, R4=OH
155 R1= OH, R2= COOCH3,R
3= OH, R4=OH
156 R1= OH, R2= COOCH2CH3,R
3= OH, R4=OH
157 R1= OH, R2= COOH, R3=OCH
3,R
4=OCH
3
164 R1=H,R
2=G,R
3=H,R
4=H,R
5=H
165 R1=H,R
2=H,R
3=G,R
4=G,R
5=G
166 R1=H,R
2=G,R
3=G,R
4=G,R
5=G
167 R1=G,R
2=G,R
3=G,R
4=G,R
5=G
HO
OH
OH
O O
OH
OHOH
HOOC
163
OR2O
OH
OR1
OH
O
175 R1=H,R
2=H
176 R1=Rha,R
2=H
177 R1=Glu,R
2=H
178 R1=Rha,R
2=Rha
O
OH
OH
HO
OH R
OH
170 R = H
171 R = (+)-Catechin
OHO
OH
OR
OH
O
179 R = H
180 R = Rha
181 R = Glu
182 R = Ara
183 R = Glu(6-1)Rha
OHO
OH O
O
OHO
OH
OR
OH
OH
O
OH
184 R = H
185 R = Rha
OHO
OH
O
OH
OH
OH
OOH
OH
OH
169
OHO
OH
R
O
172 R = H
173 R = OCH3
O
OH
OH
HO
OH
OH
168
OH
OHO
OH
O
OH
O
OH
O
O
OH
OH
OH
OOH
OH
OH
186
O
O
O
R2O
O
R1
O
187 R1= OH, R2=H
188 R1=OCH
3,R
2=H
189 R1=OCH
3,R
2=-D-Glu
O
O
O
HO
OH
O
190 192
O
HO
HO OH
O
O
O
O
OH
OH
OH
O
OH
OH
O
O
O
HO
O
OH
O
OH
OH
O
191
O
HO
193
HO
OH
194
OH
OH
R
195 R = H
196 R = CH2OH
OH
R1
R2
197 R1==O,R
2=H
198 R1==O,R
2=CH
2OH
199 R1==O,R
2=CH
2OAc
200 R1= OOH, R2=H
201 R1= OOH, R2=CH
2OH
202 R1=-OH, R2=H
203 R1=-OH, R2=CH
2OH
204 R1=-OH, R2=CH
2OAc
OH
R
205 R = H
206 R = CH2OH
Figure 7. Structure of phenols, flavonoids, phenylpropanoids and other compounds from T. sinensis.

Molecules 2024,29, 718 14 of 31
3.10. Flavonoids
In general, a “flavonoid” refers to a compound formed by connecting two phenyl rings
and a heterocyclic ring. That is, the general structure of flavonoids is a 15-carbon skeleton
of C
6
-C
3
-C
6
. Flavonoids exist in almost all green plants (mainly in higher plants) and have
a wide range of biological activities. The subclassification of flavonoids with different
aglycones can be divided into flavan-3-ols, flavanones, flavones and flavonols, all of which
have been isolated from T. sinensis. Nineteen flavonoids (168–186) have been isolated from
various parts of T. sinensis. One flavan-3-ols (168) and two flavanones (172 and 173) have
been isolated from the stems of T. sinensis [
40
]. One flavan-3-ols (169) and one flavonol
(186) have been isolated from the leaves of T. sinensis [
12
,
40
]. Two flavan-3-ols (170 and 171)
have been isolated from the leaves and wood of T. sinensis [
42
]. One flavone (174) and two
flavonols (184 and 185) have been isolated from the barks of T. sinensis [
38
]. Five flavonols
(175–177,179 and 180) have been isolated from the young leaves of T. sinensis [
39
,
41
].
Three flavonols (180–182) have been isolated from the pericarps of T. sinensis [
1
,
25
,
39
]. One
flavonol (183) has been isolated from the leaves and shoots of T. sinensis [39] (Figure 7).
3.11. Phenylpropanoids and Other Compounds
Phenylpropanoids are a group of naturally occurring organic compounds with one or
several C
6
-C
3
units in the basic parent nucleus. They are present widely in higher plants. Six
phenylpropanoid compounds (187–192) have been isolated from the leaves, root barks and
pericarps of T. sinensis. Two phenylpropanoid compounds (187 and 189) have been isolated
from the leaves of T. sinensis [
44
]. Three phenylpropanoid compounds (188,190 and 191)
have been isolated from the root barks of T. sinensis [
33
]. Two phenylpropanoid compounds
(188 and 192) have been isolated from the pericarps of T. sinensis [
1
,
27
] (Figure 7). Two
compounds (193 and 194) have been isolated from the leaves of T. sinensis [
45
]. Twelve
compounds (195–206) have been isolated from the root barks of T. sinensis [46] (Figure 7).
Based on literature findings, we summarized the chemical constituents isolated and
purified from different parts of T. sinensis, which are helpful in identifying the active
constituents of different medicinal parts and provide a reference for subsequent pharmaco-
dynamics research.
4. Compound Cracking Laws
Molecules can undergo a variety of ionizations in ion sources, and the same molecule
can produce a variety of ions. Many ion peaks can also be seen from the mass spectrum,
and most of the ion peaks formed according to the self-cracking laws of the compounds.
Limonoid-type triterpenoids are the main chemical constituents of T. sinensis. Summa-
rizing the cracking laws of these compounds by mass spectrometry (MS) for analyses of the
chemical constituents of T. sinensis is important. The dissociation behaviors of limonoids
upon high-resolution electrospray ionization–tandem mass spectrometry (HR-ESI-MS/MS)
have been proposed [
48
]. In this review article, the possible fragmentation pathways of
gedunin (64) (typical limonoid-type triterpenoid) were deduced. In positive-ion mode,
gedunin was detected as the [M + H]
+
ion at m/z483.2369 (C
28
H
35
O
7
, Cal. 483.2377). In its
MS/MS spectrum, common ions at m/z423.2162 (C
26
H
31
O
5
), 405.2055 (C
26
H
29
O
4
), 395.2211
(C
25
H
31
O
4
), 379.2264 (C
25
H
31
O
3
), 377.2099 (C
25
H
29
O
3
), 327.1951 (C
21
H
27
O
3
) and 161.0594
(C
10
H
9
O
2
), assigned as [M + H
−
C
2
H
4
O
2
]
+
, [M + H
−
C
2
H
6
O
3
]
+
, [M + H
−
C
3
H
4
O
3
]
+
,
[M + H
−
C
3
H
4
O
4
]
+
, [M + H
−
C
3
H
6
O
4
]
+
, [M + H
−
C
7
H
8
O
4
]
+
and [M + H
−
C
18
H
26
O
5
]
+
,
respectively, were observed (Figure 8). Neutral losses of C
2
H
4
O
2
, H
2
O, CO and CO
2
were
the main fragmentation patterns for limonoids in positive-ion mode. In addition, an identi-
cal characteristic ion at m/z161.0594 (C
10
H
9
O
2
) was found in the MS/MS spectra of the
four limonoids, which played an important part in metabolite identification.

Molecules 2024,29, 718 15 of 31
Molecules 2024, 29, x FOR PEER REVIEW 15 of 32
Figure 8. The proposed fragmentation pathway of gedunin (64) [48].
Cycloartane-type triterpenoids are another type of triterpenoid from T. sinensis. The
molecular weight of cycloeucalenol (128) and 24-methylenecycloartanol (129) was con-
firmed by their pseudo-molecular ions: the [M − H2O + H]+ of cycloeucalenol (m/z 409) and
24-methylenecycloartanol (m/z 423), respectively. This confirmation was made using nor-
mal-phase liquid chromatography–mass spectrometry operating in atmospheric pressure
chemical ionization mode. The protonated molecular ions [M + H]+ of cycloeucalenol (m/z
427) and 24-methylenecycloartanol (m/z 441) were very abundant. The spectrum of cy-
cloeucalenol (128) showed fragment ions at m/z 426 [M]+, 411 [M − CH3]+, 408 [M − H2O]+,
393 [M − CH3 − H2O]+, 353 [M − C3H7 − 2CH3 − H2O]+ and 300 [M − C7H13 − CH2 − CH3]+,
which were tentatively identified using gas chromatography–mass spectrometry. The
fragment ions of 24-methylenecycloartanol (129) were at 440 [M]+, 425 [M − CH3]+, 422 [M
− H2O]+, 407 [M − CH3 − H2O]+, 397 [M − C3H7]+, 379 [M − C3H7 − H2O]+, 315 [M − C9H17]+,
300 [M − C9H17 − CH3]+, 285 [M − C9H17 − 2CH3]+ and 203 [M − C9H17 − 5CH3]+ [49].
Phenols and flavonoids are the main secondary metabolites of T. sinensis. In negative-
ion mode, gallic acid (154) was detected as the [M − H]− ion at m/z 169.0137 (C7H6O5). In
its MS/MS spectrum, common ions were at m/z 107.0115, 125.0238 and 140.0717. Methyl
gallate (155) was detected as the [M − H]− ion at m/z 183.0302 (C8H8O5). In its MS/MS spec-
trum, common ions were at m/z 106.0090, 124.016, 125.0211, 151.0040 and 168.0074. Ethyl
gallate (156) was detected as the [M − H]− ion at m/z 197.0457 (C9H10O5). In its MS/MS
spectrum, common ions were at m/z 78.01, 124.0162, 125.0237, 151.0038 and 169.014 [50].
In brief, an identical characteristic ion at m/z 125.02 was found in the MS/MS spectrum,
which played an important part in the metabolite identification of gallic acid and its de-
rivatives.
In negative-ion mode, kaempferol (175, KAE) was detected as the [M − H]− ion at m/z
285.0405 (C15H10O6). In its MS/MS spectrum, common ions were at m/z 107.0136, 159.0488,
O
O
O
OO
O
O
O
O
O
OO
O
O
O
O
O
OO
O
OO
O
O
O
O
O
O
O
O
O
Exact Mass: 422.21Exact Mass: 378.22 Exact Mass: 404.20
Exact Mass: 482.23
Exact Mass: 326.19
Exact Mass: 376.20
Exact Mass: 394.21 Exact Mass: 348.21
H2O
O
O
Exact Mass: 162.07
CO2
C3H4O4C2H4O2CO
C2H6O3
C7H8O4C3H6O4
C3H4O3
C18H26O5
C4H6O4
CO
Figure 8. The proposed fragmentation pathway of gedunin (64) [48].
Cycloartane-type triterpenoids are another type of triterpenoid from T. sinensis. The
molecular weight of cycloeucalenol (128) and 24-methylenecycloartanol (129) was con-
firmed by their pseudo-molecular ions: the [M
−
H
2
O + H]
+
of cycloeucalenol (m/z409)
and 24-methylenecycloartanol (m/z423), respectively. This confirmation was made us-
ing normal-phase liquid chromatography–mass spectrometry operating in atmospheric
pressure chemical ionization mode. The protonated molecular ions [M + H]
+
of cycloeu-
calenol (m/z427) and 24-methylenecycloartanol (m/z441) were very abundant. The
spectrum of cycloeucalenol (128) showed fragment ions at m/z426 [M]
+
, 411 [M
−
CH
3
]
+
,
408 [M
−
H
2
O]
+
, 393 [M
−
CH
3−
H
2
O]
+
, 353 [M
−
C
3
H
7−
2CH
3−
H
2
O]
+
and 300 [M
−
C
7
H
13 −
CH
2−
CH
3
]
+
, which were tentatively identified using gas chromatography–mass
spectrometry. The fragment ions of 24-methylenecycloartanol (129) were at 440 [M]
+
, 425
[M
−
CH
3
]
+
, 422 [M
−
H
2
O]
+
, 407 [M
−
CH
3−
H
2
O]
+
, 397 [M
−
C
3
H
7
]
+
, 379 [M
−
C
3
H
7
−
H
2
O]
+
, 315 [M
−
C
9
H
17
]
+
, 300 [M
−
C
9
H
17 −
CH
3
]
+
, 285 [M
−
C
9
H
17 −
2CH
3
]
+
and
203 [M −C9H17 −5CH3]+[49].
Phenols and flavonoids are the main secondary metabolites of T. sinensis. In negative-
ion mode, gallic acid (154) was detected as the [M
−
H]
−
ion at m/z169.0137 (C
7
H
6
O
5
). In
its MS/MS spectrum, common ions were at m/z107.0115, 125.0238 and 140.0717. Methyl
gallate (155) was detected as the [M
−
H]
−
ion at m/z183.0302 (C
8
H
8
O
5
). In its MS/MS
spectrum, common ions were at m/z106.0090, 124.016, 125.0211, 151.0040 and 168.0074.
Ethyl gallate (156) was detected as the [M
−
H]
−
ion at m/z197.0457 (C
9
H
10
O
5
). In
its MS/MS spectrum, common ions were at m/z78.01, 124.0162, 125.0237, 151.0038 and
169.014 [
50
]. In brief, an identical characteristic ion at m/z125.02 was found in the MS/MS

Molecules 2024,29, 718 16 of 31
spectrum, which played an important part in the metabolite identification of gallic acid
and its derivatives.
In negative-ion mode, kaempferol (175, KAE) was detected as the [M
−
H]
−
ion at m/z
285.0405 (C
15
H
10
O
6
). In its MS/MS spectrum, common ions were at m/z107.0136, 159.0488,
163.0048, 255.0297 and 285.0388 [
51
]. In negative-ion mode, astragalin (177, kaempferol
3-O-
β
-D-glucoside) was detected as the [M
−
H]
−
ion at m/z447.0933 (C
21
H
20
O
11
). In
its MS/MS spectrum, common ions were at m/z125.0271, 163.0381, 283.1305, 285.0368,
295.0438, 357.0590 and 447.0926 [
51
]. In negative-ion mode, quercetin (179) was detected as
the [M
−
H]
−
ion at m/z301.0354 (C
15
H
10
O
7
). In its MS/MS spectrum, common ions were
at m/z83.0210, 93.0366, 107.0121, 109.0269, 121.0300, 149.0260, 151.0027, 163.0004, 178.9969,
193.0103, 273.0378 and 301.0334 [
51
]. In negative-ion mode, rutin (183) was detected as the
[M
−
H]
−
ion at m/z609.1444 (C
27
H
30
O
16
). In its MS/MS spectrum, common ions were at
m/z61.9878, 151.0029, 301.0344, 343.0444, 389.1586, 463.0868 and 571.1987 [
50
]. In summary,
an identical characteristic ion at m/z163 was found in the MS/MS spectrum, which might
have an important role in the metabolite identification of flavonoids and their derivatives.
5. Pharmacological Activities
T. sinensis, a well-known medicinal herb, has been traditionally used for treating
various diseases. Our review of the pharmacological activities of T. sinensis showed that
the bioactive properties included antidiabetic, antidiabetic nephropathy, antioxidant, anti-
inflammatory, antitumor, hepatoprotective, antiviral and antibacterial, and immunopotenti-
ation effects on the male reproductive system and other activities. Detailed information of
T. sinensis is shown in Table 2. These properties of T. sinensis could help us to understand
its pharmacological activities. They also encourage us to use it without hesitation as a
treatment for related diseases.
Table 2. Pharmacological activities of T. sinensis.
Active Constituents Extraction Solvent Experimental Model Regulatory Mechanism aRef.
Antidiabetic activity
leaves extracts supercritical-CO2fluid in vivo: STZ induced
mice triglyceride levels↑, adiponectin levels↓[52]
leaves extracts water
in vivo:
alloxan-induced
diabetic Long-Even rats
GLUT4 mRNA (RT-PCR)↑, GLUT4
protein↑[53]
leaves extracts 50% alcohol/water
in vitro: 3T3-L1
adipocytes treated by
calphostin C
cellular glucose uptake↓[54]
leaves extracts 95% ethanol in vivo and in vitro stimulating glucose uptake, ameliorating
insulin resistance [55]
rutin (183, leaves) water
in vivo:
insulin-resistant type 2
diabetes mouse model
IRK activity↑, glucose uptake↑[56]
quercetin (179, leaves) ethyl acetate
in vivo: diabetic mice
induced by HFD and
alloxan
p65/NF-κB↓, ERK1/2/MAPK↓,
caspase-9↓, caspase-3↓[57]
Antidiabetic
nephropathy activity
seeds extracts petroleum ether in vivo: STZ-induced
DN rats TGF-β1↓, Col IV↓, CTGF↓[58]
seeds extracts n-butanol in vivo: STZ-induced
DN rats
blood glucose
↓
, urinary albumin
↓
, kidney
index↓, oxidative stress index↓, serum
creatinine↓, urea nitrogen levels↓,
oxidative stress↓, TGF-β1↓, Col IV↓,
CTGF↓
[59]

Molecules 2024,29, 718 17 of 31
Table 2. Cont.
Active Constituents Extraction Solvent Experimental Model Regulatory Mechanism aRef.
seeds extracts n-butyl alcohol in vitro: HG-induced
GMCs ROS↓, p47phox↓, Nrf2↑,NQO1↑, HO-1↑[60]
seeds extracts n-butyl alcohol
in vivo: STZ-induced
DN rats
in vitro: HG-induced
human renal
glomerular endothelial
cells
MCP-1↓, ICAM-1↓, p65↓[61]
kaempferitrin (178,
seeds)
in vitro: AGEs-induced
GMCs SOD↑, MDA↓, ROS↓, protecte against OS [43]
kaempferol (175, seeds)
in vitro: HG-induced
GMCs
ROS↓, MDA↓, SOD↑, TGF-β1↓, Col IV↓,
NOX4↓, p22phox↓, Sestrin2↑, AMPK↑[62]
toonasinensin B (39),
toonasinensin D (41),
21α-O-
methylmelianodiol (25),
21β-O-
methylmelianodiol (26)
(pericarps)
in vitro: HG-induced
GMCs NADPH↓, sorbitol↓[27]
two acyclic
diterpenoids (seeds)
in vitro: HG-induced
GMCs Nrf2/HO-1↑, NF-κB↓, TNF-α↓, IL-6↓[25]
Antioxidant activity
leaves, roots, barks
extracts water
in vivo:
senescence-accelerated
mice
in vitro: DPPH·
TBARS
↓
, SOD
↑
, CAT
↑
, GSH-Px
↑
, DPPH
↓
DPPH free-radical activity [63]
leaves extracts acetone in vitro: ORAC, PSC,
HepG2 cells, CAA
anti-proliferative effect, antioxidant
properties [64]
leaves extracts,
gallic acid (154)water
in vitro: AAPH
inducedhuman
umbilical vein
endothelial cells
ROS↓, MDA↓, SOD/CAT↑, reverse
Bax/Bcl-2 dysregulation [65]
leaves extracts,
gallic acid (154)water
in vitro: various
oxidative systems,
AAPH-induced human
erythrocytes
oxidative hemolysis
↓
, lipid peroxidation
↓
,
SOD↓[66]
flavonoids, methyl
gallate (155) (buds) 70% methanol in vitro: ABTS·+,
DPPH·ABTS and DPPH free-radical activity [67]
PGG (167), EG (156)
(young leaves)
liquid-liquid refined
extraction
in vitro: ABTS·+,
DPPH·ABTS and DPPH free-radical activity [68]
five flavonols, three
derivatives of gallic
acid (young leaves)
95% ethanol
in vitro: four
chemical-induced
oxidative models
significant antioxidant properties [41]
toonasinenine D (103),
E (82), G (81), H (80), I
(114) and J (115)
(leaves)
95% ethanol in vitro: ABTS·+,
DPPH·strong scavenging activities [31]
Anti-inflammatory
activity
leaves extracts water in vitro: LPS-induced
macrophage HO-1↑, TNF-α↓[69]
leaves extracts water in vitro: RAW264.7
cells treated with LPS
GSH
↑
, GSH/GSSG
↑
, reverse the effects of
IL-6 and IL-10 [70]
adventitious shoots
extracts
in vitro: LPS treated
RAW 264.7 cells and
propionibacterium
acnes-treated HaCaT
cells
suppress MAPK pathways [71]

Molecules 2024,29, 718 18 of 31
Table 2. Cont.
Active Constituents Extraction Solvent Experimental Model Regulatory Mechanism aRef.
leaves extracts water in vitro: LPS-induced
microglial NO↓, TNF-α↓, iNOS↓[72]
polyphenols (seeds) 50% acetone in vivo: a rat model of
Parkinson’s disease
p38 MAPK↓, protein levels of
infammatory mediators↓[73]
7-DGD (63)
in vivo: LPS-induced
septic shock models
in vitro: macrophages
activate Keap1/Nrf2/HO-1 signaling [74]
7-DGD (63)
in vitro: human
rheumatoid arthritis
synovial fibroblast
activate Nrf2/ARE signaling [75]
DAG (63)in vitro:LPS treated
RAW 264.7 cells K+efflux↓, ROS↓[76]
toonasinenine A (99), B
(101), C (102), D (103),
toonafolin (100)
(leaves)
ethanol in vitro COX-1↓, COX-2↓[31]
toonasinemine A (120),
B (121), F (123), I (73)
(root barks)
CH2Cl2
in vitro: LPS-activated
RAW 264.7
macrophages
NO↓[30]
two acyclic
diterpenoids (141,142)
(seeds)
in vivo: HG- induced
GMCs Nrf-2/HO-1↑, NF-κB↓, TNF-α↓, IL-6↓[25]
quercitrin (180, leaves) 95% ethanol in vitro:APAP-treated
HepG2 cell iNOS↓, COX-2↓, IL-1β↓[77]
polyacetylenes CH2Cl2in vitro: LPS treated
RAW 264.7 cells NO↓[46]
Antitumor activity
leaves extracts water in vitro: osteosarcoma
cells
inhibit the activity of MG-63, Saos-2 and
U2OS osteosarcoma cells. [78]
leaves extracts water in vitro: WEHI-3 cells WEHI-3 cells viability↓, cytochrome C↑,
caspase-3↑, Bax↑, Bcl-2↓[79]
leaves extracts water in vitro: HL-60 cells
induce cytochrome C translocation,
caspase 3 activation, degradation of PARP,
dysregulation of Bcl-2 and Bax
[80]
leaves extracts water in vitro: A549 lung
cancer cells cyclin D1 and cyclin E↓[81]
leaves extracts in vitro: H441 and
H661 cells
cyclin D1 and CDK4↓, block the cell cycle
in G1 phase, Bcl2↓, Bax↑
[82,
83]
leaves extracts water in vitro: ccRCC cells cyclin D1↓, CDK2↓, CDK4↓, p53 ↑,
FOXO3a ↑[84]
leaves extracts in vitro: ovarian cancer
cells
arrest SKOV3 ovarian cancer cells at the
G2/M phase [85]
leaves extracts water
in vitro:
DMBA-induced
hamster cheek pouch
squamous cells
survivin, XIAP, PCNA, iNOS, and COX-2
proteins↓[86]
the total phenolic
(leaves) 60% ethanol in vitro: Caco-2,
HepG2, MCF-7 inhibit proliferation [87]
gallic acid (154, leaves) in vitro: DU145 cells ROS↑, cytotoxic to DU145cells [88]
gallic acid (154, leaves) in vitro: HOSCC cells TNF-α↑, TP53BP2↑, GADD45A↑,
Survivin↓, cIAP1↓, induces cell death [89]
betulinic acid (130),
3-oxours-12-en-28-oic
acid (133) (roots)
in vitro: MGC-803 and
PC3 cells inhibite proliferation, led to apoptosis [36]
toonasinenine A (99), B
(101), C (102), D (103),
toonafolin (100)
(leaves)
95% ethanol in vitro: tumor cell
lines
significant effects on all tumor cell lines
except glioma cell lines [31]

Molecules 2024,29, 718 19 of 31
Table 2. Cont.
Active Constituents Extraction Solvent Experimental Model Regulatory Mechanism aRef.
Hepatoprotective
activity
leaves extracts water in vivo: TAA treated
liver injury rats collagen formation↓, TGF-β1↓[90]
polysaccharide (leaves) water
in vivo: the liver injury
induced by CCl4in
mice
ALT↓, AST↓, MDA↓, SOD↑, GSH-Px↑,
CAT↑, GSH↑, TNF-α↓, IL-6↓[91]
polyphenols (barks and
fruits) water in vitro: FFA-treated
HepG2 cells
lipoprotein↓, activating AMPK pathway,
lipid metabolism↑, lipid accumulation↓[92]
quercetin (179, leaves) 70% ethanol
in vivo: diabetic mice
induced by HFD and
alloxouracil
ameliorating oxidative stress in the liver,
protects hepatocytes [57]
quercitrin (180, leaves) 95% ethanol
in vivo:APAP-treated
HepG2 cell
in vitro: APAP-treated
animal models
activation of defensive genes and the
inhibition of pro-inflammatory genes via
the suppressions of JNK and p38 signaling
[77]
Antiviral and
antibacterial activity
tender leaves extracts in vitro anti-SARS coronavirus [93]
tender leaves extracts water in vitro anti-influenza A virus (H1N1) [94]
sesquiterpene from
essential oil (leaves) n-hexane in vitro antimicrobial activity against MSSA and
MRSA strains [95]
polyphenols,
glycosides, terpenoids
contained in shoots
extracts
ethyl acetate in vitro
inhibitory activities against Staphylococcus
aureus,Shigella dysenteriae and Escherichia
coli
[50]
Immunopotentiation
leaves extracts water in vivo: tilapia
improve the immune response and
resistance of tilapia to hydrophilic
bacteroides infection
[13]
polysaccharide TSP-3a
(seeds) water
in vivo: CY induced
immunodeficiency
mice model
significant immune restoring activity and
enhance phagocytosis [17]
rutin (183, leaves) methanol in vivo enhance immunity of shrimp [9]
Effects on the male
reproductive system
leaves extracts water in vivo: rats
ROS
↓
, aintained MMP, restored the sperm
motility [96]
leaves extracts water in vitro: primary
mouse Leydig cells inhibited testosterone production [97]
leaves extracts ethanol
in vitro: the human
spermatozoa treated
with H2O2
ROS↓, cell death↓[98]
Other aspects
leaves extracts water in vitro: a visceral pain
mouse model anti-visceral pain properties [99]
essential oil (leaves) water in vivo: CMS rats anti-depression [100]
limonoids (leaves and
buds) ethanol
in vitro:
6-hydroxydopamine-
induced SH-SY5Y cells
neuroprotective effects [32]
a↑upregulation; ↓downregulation.
5.1. Antidiabetic Activity
Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia.
In recent decades, the hypoglycemic effects of T. sinensis have attracted increasing attention.
All parts of T. sinensis have different degrees of inhibition of DM. The non-polar extracts
of T. sinensis leaves (TSLs) prepared using supercritical-CO
2
fluid have been shown to

Molecules 2024,29, 718 20 of 31
prevent the progression of DM and liver fibrosis, increase triglyceride levels and decrease
adiponectin levels in low-dose streptozotocin (STZ)-induced mice with type-2 diabetes
mellitus (T2DM) [
52
]. Hence, TSL non-polar extracts might contain active ingredients to
prevent T2DM [
52
]. The effects of TSL water extracts on alloxan-induced diabetic Long-
Evans rats have been studied. After administration of TSL extract or gallic acid (154), the
mRNA and protein expression of glucose transporter 4 (GLUT4) increased significantly in
rats suffering from DM. Therefore, TSLs have hypoglycemic effects, and the mechanism of
action involves an increase in the insulin level mediating the action of GLUT4 in fat [
53
].
Cellular glucose uptake with a combination of TSL water extracts and insulin has been
found to be inhibited significantly by treatment of 3T3-L1 adipocytes with cycloheximide
(inhibitor of protein synthesis) and calphostin C (inhibitor of protein kinase C) in normal-,
medium- and high-glucose media [
54
]. The anti-DM effects and mechanism of action of
95% ethanol (EtOH) extracts from TSLs have also been studied
in vitro
and
in vivo
. TSL
EtOH extracts have been shown to stimulate glucose uptake via adenosine monophosphate-
activated protein kinase (AMPK) activation in skeletal muscles, promote the expression of
peroxisome proliferator-activated receptor-gamma and normalize adiponectin expression
in adipose tissues, thereby ameliorating insulin resistance [55].
Rutin (183) from TSL water extracts can improve glucose uptake in C57BL/6 mice
with insulin-resistant T2DM by increasing insulin-dependent receptor kinase (IRK) activ-
ity [
56
]. Quercetin (179), a flavonoid isolated from TSL ethyl acetate (EtOAc) extracts, can
reduce hyperglycemia induced by the consumption of a high-carbohydrate/high-fat diet
(HFD) and alloxan in mice suffering from DM. Quercetin (179) significantly inhibits the
activation of p65/nuclear factor-kappa B (NF-
κ
B) and the extracellular signal-regulated
kinase 1/2/mitogen-activated protein kinase (ERK1/2/MAPK) pathways, as well as the
levels of caspase-9 and caspase-3 in the liver tissue of mice with DM [
57
]. These actions can
reduce the risk of DM and its secondary complications by lessening oxidative stress in the
liver [57].
5.2. Antidiabetic Nephropathy Activity
The petroleum-ether extracts of T. sinensis seeds could reduce the blood glucose level,
urinary albumin level, serum creatinine level and urea nitrogen level, as well as indices
of renal function and oxidative stress. Renal abnormalities could be improved in rats
suffering from diabetic nephropathy (DN). Protein expression of transforming growth
factor-
β
1 (TGF-
β
1), collagen IV (Col IV) and connective tissue growth factor (CTGF) could
be reduced using the petroleum-ether extracts of T. sinensis seeds, and the petroleum-ether
extracts of T. sinensis seeds have been shown to have protective effects on rats DN by
inhibiting oxidative stress and protein expression of TGF-
β
1, Col IV and CTGF [
58
]. The
n-butanol extracts of T. sinensis seeds (NBAE) could significantly reduce the blood glucose
level, urinary albumin level, serum creatinine level and urea nitrogen level, as well as
the indices of kidney function and oxidative stress. NBAE could increase the activities of
total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase
(GSH-Px) and catalase (CAT), and reduce the level of malondialdehyde (MDA) in the serum
of rats with STZ-induced DN, showing significant antioxidant activity
in vivo
. NBAE have
been found to inhibit the expression of TGF-
β
1, Col IV and CTGF protein in rats with
STZ-induced DN, showing protective effects on the kidney in these animals [
59
]. High
glucose (HG) induces oxidative stress injury after stimulating glomerular mesangial cells
(GMCs). This action leads to an increased reactive oxygen species (ROS) level, decreased
nitric oxide (NO) level, increased expression of p47phox and decreased expression of
nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins NAD(P)H
quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). NBAE can significantly
increase the expression of Nrf2, NQO1 and HO-1, thereby inhibiting HG-induced ROS
elevation, inhibiting p47phox expression and stabilizing NO content [
60
]. Compared with
the DN group, in the DN+NBAE group, the blood glucose level was reduced significantly
and injury was alleviated. Otherwise, levels of monocyte chemoattractant protein-1 (MCP-

Molecules 2024,29, 718 21 of 31
1), intercellular adhesion molecule 1 (ICAM-1) and phosphorylated-p65 were reduced.
In vitro
, NBAE decreased the expression of MCP-1 and ICAM-1 significantly, which was
similar to the effect elicited by treatment with a blocker of NF-κB p65 [61] (Figure 9).
Molecules 2024, 29, x FOR PEER REVIEW 22 of 32
Figure 9. Antidiabetic and antidiabetic nephropathy activities of extracts or compounds from T.
sinensis.
5.3. Antioxidant Activity
The α,α-diphenyl-β-pricryl-hydrazyl (DPPH) radical scavenging test showed that the
DPPH free-radical scavenging activities of extracts of the leaves, roots and barks of T.
sinensis were concentration-dependent, and the half-maximal inhibitory concentrations
(IC
50
) were 2.09 × 10
−1
, 2.85 × 10
−1
and 2.77 × 10
−1
mg/mL, respectively. These extracts could
also reduce the accumulation of amyloid β-protein, thiobarbituric acid-reactive substances
(TBARS) and cognitive deterioration in mice and increase the activities of SOD, CAT and
GSH-Px to promote the antioxidant defense system. The compounds of T. sinensis extracts
could delay the aging process in mice, which merits further study [63]. The antioxidant
activities of TSL acetone extracts, including oxygen radical absorption capacity (ORAC),
peroxyl radical scavenging capacity (PSC) and cellular antioxidant activity (CAA), were
evaluated. Anti-proliferative activities against human liver cancer (HepG2) cells were as-
sessed using the methylene-blue assay. TSL acetone extracts possessed significant antiox-
idant properties and anti-proliferative effects against HepG2 cells in vitro [64]. TSL aque-
ous extracts and gallic acid (154) treatment significantly inhibited ROS generation and
MDA formation in 2,2′-azo-bis (2-amidinopropane) hydrochloride (AAPH)-stimulated
human umbilical vein endothelial cells. Furthermore, pretreatment with TSL aqueous ex-
tracts/gallic acid significantly augmented AAPH-depleted SOD/CAT activity in endothe-
lial cells. However, AAPH-induced Bax/B-cell lymphoma-2 (Bcl-2) dysregulation was re-
versed significantly by pretreatment with TSL aqueous extracts/gallic acid. Therefore, T.
sinensis might have antioxidant effects to protect endothelial cells from oxidative stress
[65]. TSL also showed that the aqueous extracts and gallic acid (154) had effective antiox-
idant activity against various oxidative systems in vitro, including the scavenging of free-
radicals and superoxide anion radicals, total reducing power and metal chelation. Fur-
thermore, AAPH-induced oxidative hemolysis, lipid peroxidation and a decline in SOD
Figure 9. Antidiabetic and antidiabetic nephropathy activities of extracts or compounds from
T. sinensis.
GMCs were cultured and induced by advanced glycosylation end products (AGEs) to
simulate DN
in vitro
. The mechanism of action of kaempferitrin (178, KM) from T. sinensis
seeds to protect GMCs from AGE-induced damage was investigated. KM could increase
SOD activity, reduce the level of MDA, inhibit ROS production and protect against oxidative
stress in AGE-induced GMCs. These findings suggest that KM might be a drug for treating
DN in the future [
43
]. KAE (175) significantly reduced levels of ROS, NADPH oxidase
(NOX) and MDA and enhanced SOD activity in HG-induced GMCs. The production of
TGF-
β
1, Col IV, NOX4 and p22phox was also inhibited by KAE treatment. In addition,
KAE increased the expression of sestrin2 and AMPK in HG-induced GMCs [
62
]. Three
apotirucallane-type triterpenoids, toonasinensin B (39), 21
β
-O-methylmelianodiol (26) and
21
α
-O-methylmelianodiol (25), from the pericarps of T. sinensis, could increase SOD activity
significantly and reduce the levels of MDA and ROS, thereby preventing DN by reducing
oxidative stress in GMCs cultured under HG conditions [
15
]. Additionally, in this model,
the cytotoxicity and polyol pathway inhibitory activities of active constituents from the
pericarps of T. sinensis were evaluated. Toonasinensin B (39), toonasinensin D (41), 21
β
-
O-methylmelianodiol (26) and 21
α
-O-methylmelianodiol (25) had good inhibitory effects
on GMCs. Moreover, it was shown that toonasinensin B (39), 21
β
-O-methylmelianodiol

Molecules 2024,29, 718 22 of 31
(26) and 21
α
-O-methylmelianodiol (25) inhibited the production of NADPH and sorbitol
in HG-induced GMCs for the first time. These compounds could be developed for the
treatment of DN [
27
]. Two acyclic diterpenoids (141 and 142) were isolated from the seeds
of T. sinensis. They could significantly upregulate Nrf2/HO-1 expression and reduce the
expression of NF-
κ
B, tumor necrosis factor-alpha (TNF-
α
) and interleukin-6 (IL-6), thereby
improving oxidative stress in HG-induced GMCs [25] (Figure 9).
5.3. Antioxidant Activity
The
α
,
α
-diphenyl-
β
-pricryl-hydrazyl (DPPH) radical scavenging test showed that the
DPPH free-radical scavenging activities of extracts of the leaves, roots and barks of T. sinen-
sis were concentration-dependent, and the half-maximal inhibitory concentrations (IC
50
)
were 2.09
×
10
−1
, 2.85
×
10
−1
and 2.77
×
10
−1
mg/mL, respectively. These extracts could
also reduce the accumulation of amyloid
β
-protein, thiobarbituric acid-reactive substances
(TBARS) and cognitive deterioration in mice and increase the activities of SOD, CAT and
GSH-Px to promote the antioxidant defense system. The compounds of T. sinensis extracts
could delay the aging process in mice, which merits further study [
63
]. The antioxidant
activities of TSL acetone extracts, including oxygen radical absorption capacity (ORAC),
peroxyl radical scavenging capacity (PSC) and cellular antioxidant activity (CAA), were
evaluated. Anti-proliferative activities against human liver cancer (HepG2) cells were
assessed using the methylene-blue assay. TSL acetone extracts possessed significant an-
tioxidant properties and anti-proliferative effects against HepG2 cells
in vitro
[
64
]. TSL
aqueous extracts and gallic acid (154) treatment significantly inhibited ROS generation
and MDA formation in 2,2
′
-azo-bis (2-amidinopropane) hydrochloride (AAPH)-stimulated
human umbilical vein endothelial cells. Furthermore, pretreatment with TSL aqueous
extracts/gallic acid significantly augmented AAPH-depleted SOD/CAT activity in en-
dothelial cells. However, AAPH-induced Bax/B-cell lymphoma-2 (Bcl-2) dysregulation
was reversed significantly by pretreatment with TSL aqueous extracts/gallic acid. There-
fore, T. sinensis might have antioxidant effects to protect endothelial cells from oxidative
stress [
65
]. TSL also showed that the aqueous extracts and gallic acid (154) had effective
antioxidant activity against various oxidative systems
in vitro
, including the scavenging
of free-radicals and superoxide anion radicals, total reducing power and metal chelation.
Furthermore, AAPH-induced oxidative hemolysis, lipid peroxidation and a decline in SOD
activity in human erythrocytes were prevented by TSL extracts and gallic acid (154). In
conclusion, TSL aqueous extracts and gallic acid (154) have antioxidant properties [66].
The IC
50
values of 2,2
′
-azinobis (3-ethylbenzothiazoline-6-sulphonic acid ammonium
salt) (ABTS) and DPPH free-radical scavenging activities of seven flavonoids and methyl
gallate (155) extracted from the 70% methanol extracts of T. sinensis buds were 1.4–3.6
and 2.6–671.0
µ
g/mL, respectively, indicating that these compounds showed significant
antioxidant activity [
67
]. 1,2,3,4,6-Penta-O-galloyl-
β
-D-glucose (167) and ethyl gallate (156)
were obtained from the young leaves of T. sinensis by establishing a liquid–liquid refined
extraction-guided bioassay. The EC
50
(the concentration for 50% of maximal effect) values
of ethyl gallate (156) scavenging ABTS and DPPH were 4.46
±
0.05 and 7.61
±
0.13
µ
g/mL,
respectively, and those of 1,2,3,4,6-penta-O-galloyl-
β
-D-glucose (167) scavenging ABTS
and DPPH were 12.90
±
0.16 and 16.29
±
0.20
µ
g/mL, respectively, indicating that they
were good antioxidants [
68
]. Four chemical-induced oxidative models were applied in the
previous study, including DPPH free-radical scavenging assay, phenazine methosulphate
(PMS) nicotinamide adenine dinucleotide (NADH) PMS-NADH-NBT superoxide anion
scavenging assay, FeCl
3
-K
3
Fe (CN)
6
reducing power assay and FeCl
2
-FerroZine metal
chelation assay. Quercetin (179), kaempferol-3-O-
α
-L-rhamopyranoside (176), astragalin
(177), KAE (175), methyl gallate (155), ethyl gallate (156) and 1,2,3,4,6-penta-O-galloyl-
β
-D-
glucopyranose (167) isolated from the young leaves of T. sinensis had several significant
antioxidant properties [
41
]. Twelve limonoids were isolated from TSLs. Their antioxidant
evaluation showed that toonasinenine D (103), E (82), G (81), H (80), I (114) and J (115) had
significant anti-radical activities compared with the radicals tested using DPPH and ABTS.

Molecules 2024,29, 718 23 of 31
Toonasinenine D (103) seemed to possess higher anti-radical activities on ABTS but lower
scavenging activity on DPPH than other compounds [31].
5.4. Anti-Inflammatory Activity
TSL water extracts could upregulate the expression of HO-1 and downregulate the
expression of TNF-
α
to inhibit the lipopolysaccharide (LPS)-induced inflammatory re-
sponse from macrophages [
69
]. TSL aqueous extracts increased the level of total GSH
and the ratio of GSH/glutathione oxide (GSSG) in RAW264.7 cells treated with LPS but
decreased the levels of GSSG, total NO, nitrate, nitrite, MDA and superoxide anion. TSL
water extracts reversed the effects of LPS-induced cytokines, including IL-6 and IL-10,
to modulate autophagy during inflammation [
70
]. The adventitious shoot extracts of
T. sinensis showed good anti-inflammatory activity on LPS-treated RAW 264.7 cells and
Propionibacterium acnes-treated HaCaT cells. Hence, the adventitious shoot extracts of T.
sinensis could be used as a drug for the treatment of inflammatory skin diseases. The
effects were regulated by suppression of the MAPK pathway [
71
]. TSL aqueous extracts
possessed effective anti-inflammatory features, including the suppression of LPS-induced
NO production, as well as TNF-
α
secretion and protein expression of inducible nitric oxide
synthase (iNOS) in BV-2 microglial cells without cytotoxicity. The results indicated that TSL
aqueous extracts could inhibit the inflammatory response of microglia in neurodegenerative
diseases [
72
]. Polyphenols extracted from T. sinensis seeds alleviated 6-hydroxydopamine-
induced neuroinflammation by inhibiting the p38 MAPK signaling pathway in a rat model
of Parkinson′s disease [73].
7-Deacetylgedunin (63, 7-DGD) from T. sinensis fruits inhibited inflammation
in vitro
and
in vivo
by activating Kelch-like ECH-associated protein-1 (Keap1)/Nrf2/HO-1 signal-
ing in macrophages and LPS-induced septic-shock models [
74
]. 7-DGD (63) also suppressed
the proliferation of human synovial fibroblasts from patients with rheumatoid arthritis
through the activation of Nrf2/ARE signaling [
75
]. Deacetylgudunin (63, DAG) from T.
sinensis has excellent anti-inflammatory potential. DAG can inhibit the ASC oligomeriza-
tion and weaken the interaction of NLR family pyrin domain-containing 3 (NLRP3)-ASC
and NLRP3-NEK7 by inhibiting K
+
efflux and ROS production, which affects assembly of
the NLRP3 inflammasome in RAW264.7 cells stimulated by LPS [
76
]. Toonasinenine A (99),
B (101), C (102), D (103) and toonafolin (100) from TSL EtOH extracts exhibited inhibition of
cyclo-oxygenase (COX)-1 and COX-2 and had anti-inflammatory activity [
31
]. Toonasinem-
ine A (120), B (121), F (123) and I (73), which were isolated from dichloromethane (CH
2
Cl
2
)
extracts of T. sinensis root barks, inhibited NO production significantly at non-toxic con-
centrations in LPS-activated RAW 264.7 cells [
30
]. Two new acyclic diterpenes (141 and
142) isolated from T. sinensis seeds significantly increased the levels of Nrf2/HO-1 and
decreased the levels of NF-
κ
B, TNF-
α
and IL-6 in HG-induced GMCs, thereby showing
an anti-inflammatory effect [
25
]. In an acetaminophen (APAP)-treated HepG2 cell model,
quercitrin (180) from TSL EtOH extracts exhibited anti-inflammatory properties by inhibit-
ing the release of pro-inflammatory mediators, including iNOS and COX-2, as well as
the cytokine IL-1
β
[
77
]. Polyacetylene compounds isolated from the CH
2
Cl
2
extracts of
T. sinensis root barks inhibited NO production in RAW 264.7 cells induced by LPS [
46
]
(Figure 10).
T. sinensis has important research value for hypoglycemia. It could be used as medic-
inal plant material with anti-DM and anti-DN activities. T. sinensis extracts and their
chemical constituents exert antioxidant and anti-inflammatory effects, mainly by activating
the Nrf2/HO-1 pathway and inhibiting the NF-
κ
B pathway in cell and animal models. They
have certain curative effects by preventing and relieving oxidative stress and inflammation
in DM or DN.

Molecules 2024,29, 718 24 of 31
Molecules 2024, 29, x FOR PEER REVIEW 24 of 32
extracts exhibited inhibition of cyclo-oxygenase (COX)-1 and COX-2 and had anti-inflam-
matory activity [31]. Toonasinemine A (120), B (121), F (123) and I (73), which were isolated
from dichloromethane (CH2Cl2) extracts of T. sinensis root barks, inhibited NO production
significantly at non-toxic concentrations in LPS-activated RAW 264.7 cells [30]. Two new
acyclic diterpenes (141 and 142) isolated from T. sinensis seeds significantly increased the
levels of Nrf2/HO-1 and decreased the levels of NF-κB, TNF-α and IL-6 in HG-induced
GMCs, thereby showing an anti-inflammatory effect [25]. In an acetaminophen (APAP)-
treated HepG2 cell model, quercitrin (180) from TSL EtOH extracts exhibited anti-inflam-
matory properties by inhibiting the release of pro-inflammatory mediators, including
iNOS and COX-2, as well as the cytokine IL-1β [77]. Polyacetylene compounds isolated
from the CH2Cl2 extracts of T. sinensis root barks inhibited NO production in RAW 264.7
cells induced by LPS [46] (Figure 10).
T. sinensis has important research value for hypoglycemia. It could be used as medic-
inal plant material with anti-DM and anti-DN activities. T. sinensis extracts and their
chemical constituents exert antioxidant and anti-inflammatory effects, mainly by activat-
ing the Nrf2/HO-1 pathway and inhibiting the NF-κB pathway in cell and animal models.
They have certain curative effects by preventing and relieving oxidative stress and inflam-
mation in DM or DN.
Figure 10. Antioxidant and anti-inflammatory activities of extracts or compounds from T. sinensis
via Nrf-2/NF-κB pathway.
5.5. Antitumor Activity
It has been found that TSL aqueous extracts can inhibit the viability of osteosarcoma
cell lines (MG-63, Saos-2 and U2OS) by increasing mRNA expression of pro-apoptotic fac-
tors. These data suggest that TSL extracts suppress the growth of osteosarcoma cells by
inducing apoptosis and are promising anti-osteosarcoma plant extracts [78]. TSL aqueous
extracts exhibit anti-leukemia activity in murine mouse blood cells (WEHI-3). After treat-
ment with TSL aqueous extracts, the activities of WEHI-3 cells were reduced significantly,
protein expression of cytochrome-C, caspase-3 and Bax increased significantly and
Figure 10. Antioxidant and anti-inflammatory activities of extracts or compounds from T. sinensis via
Nrf-2/NF-κB pathway.
5.5. Antitumor Activity
It has been found that TSL aqueous extracts can inhibit the viability of osteosarcoma
cell lines (MG-63, Saos-2 and U2OS) by increasing mRNA expression of pro-apoptotic
factors. These data suggest that TSL extracts suppress the growth of osteosarcoma cells by
inducing apoptosis and are promising anti-osteosarcoma plant extracts [
78
]. TSL aqueous
extracts exhibit anti-leukemia activity in murine mouse blood cells (WEHI-3). After treat-
ment with TSL aqueous extracts, the activities of WEHI-3 cells were reduced significantly,
protein expression of cytochrome-C, caspase-3 and Bax increased significantly and protein
expression of Bcl-2 decreased significantly. The potential therapeutic effects of TSL aqueous
extracts on leukemia were confirmed [
79
]. TSL aqueous extracts have anti-proliferative
effects in human pre-myelocytic leukemia (HL-60) cells by apoptosis induction that is
associated with cytochrome-C translocation, caspase-3 activation, poly (ADP-ribose) poly-
merase (PARP) degradation and dysregulation of Bcl-2 and Bax. Hence, TSL aqueous
extracts may have potential as an agent of chemotherapeutic and cytostatic activity in
human leukemia [
80
]. TSL aqueous extracts effectively blocked cell-cycle progression by
inhibiting the expression of cyclin D1 and E in lung cancer (A549) cells. In addition, the
incubation of these extracts led to the activation of caspase-3-like proteases and apoptotic
cell death. These results suggest that T. sinensis components have potent anti-cancer effects
in vitro
. The identification of the useful components in these extracts may lead to the
development of a novel class of anti-cancer drugs [
81
]. The activity of TSL aqueous extracts
against small-cell lung cancer is mainly through inhibition of the expression of cyclin D1
and cyclin-dependent kinase 4 (CDK4) in H441 cells (lung adenocarcinoma) and H661 cells
(lung large cell carcinoma) (IC
50
of 0.20 and 0.12 mg/mL, respectively) and the blockade of
the cell cycle in the G1 phase. TSL aqueous extracts have an anti-proliferative effect on non-
small-cell lung cancer [
82
,
83
]. Other studies have shown that treatment with TSL aqueous
extracts arrested human renal carcinoma cells in the G0/G1 phase through at decrease in
the expression of cyclin D1, CDK2 and CDK4, as well as an induction of the expression

Molecules 2024,29, 718 25 of 31
of p53 and FOXO3a protein. These results suggest that TSL aqueous extracts may be
employed for cancer treatment [84]. TSL aqueous extracts were more cytotoxic than other
fractions and exhibited selectivity for ovarian cancer cell lines. TSL aqueous extracts ar-
rested ovarian cancer (SKOV3) cells in the G2/M phase and induced their apoptosis. These
results indicate that TSL could be developed into a promising anti-ovarian cancer drug [
85
].
In addition, TSL aqueous extracts can inhibit the proliferation and induce the apoptosis of
hamster cheek pouch squamous cell carcinoma induced by 7,12-dimethylbenz[a]anthracene
(DMBA). Downregulation of the protein expression of survivin, X chromosome-linked
inhibitor of apoptosis (XIAP), proliferating cell nuclear antigen (PCNA), iNOS and COX-2
and increased apoptotic activity suggested that TSL therapy might aid the prevention of
oral cancer [86].
The phenolic in TSL extracts inhibited the proliferation of colon cancer cells, HepG2
cells and breast cancer (MCF-7) cells significantly, with EC
50
values of 4.00
±
0.39,
153.16
±
13.49 and 193.46
±
14.68
µ
g/mL, respectively [
87
]. Gallic acid (154) has been iden-
tified as the major anti-cancer compound in TSL extracts. It is cytotoxic to prostate cancer
(DU145) cells (IC
50
15.6
±
2.1
µ
g/mL) through ROS generation and mitochondria-mediated
apoptosis. These results suggest that gallic acid (154) could be developed into a drug to
counteract prostate cancer [
88
]. In addition, gallic acid (154) extracted from TSL induced
the death of human oral squamous cell carcinoma (HOSCC) cells by upregulating expres-
sion of the pro-apoptotic genes TNF-
α
, TP53BP2 and GADD45A and downregulating the
expression of the anti-apoptotic genes survivin and cIAP1. There was no effect on normal
oral epithelial cells [
89
]. Betulinic acid (130) and 3-oxours-12-en-28-oic acid (133) extracted
from T. sinensis roots inhibited the proliferation of human gastric cancer (MGC-803) cells
and human prostate cancer (PC3) cells and led to apoptosis (IC
50
17.7 and 13.6
µ
M, 26.5 and
21.9
µ
M, respectively) [
90
]. The limonin-type triterpenoids toonasinenine A (99), B (101), C
(102), D (103) and toonafolin (100) from TSL extracts had significant effects on all tumor cell
lines, except glioma cell lines. Toonasinenine I (114) and J (115) from TSL extracts showed
high cytotoxic activity against glioma cell lines [
31
]. T. sinensis extracts and compounds
have a wide range of anti-cancer effects. TSL have been studied extensively and could be a
source of antitumor drugs. The antitumor activities of T. sinensis extracts might be related
to their high content of phenolic and limonin-type triterpenoids.
5.6. Hepatoprotective Activity
TSL water extracts showed anti-fibrotic effects on rats with liver injury treated with
thioacetamide (TAA), including reduced collagen formation and inflammatory factors (TGF-
β
1). These data demonstrate the beneficial effects of TSL water extracts on human liver
injury by increasing detoxification and metabolic pathways [
90
]. Polysaccharides from TSL
extracts reduced the levels of alanine aminotransferase (ALT), aspartate aminotransferase
(AST) and MDA, increased the activities of SOD, GSH-Px, CAT and GSH, decreased the
expression of TNF-
α
and IL-6 and improved the liver injury induced by CCl
4
in mice. Hence,
the polysaccharides in TSL extracts may have a hepatoprotective effect [
91
]. Polyphenols
extracted from the barks and fruits of T. sinensis could be used to treat non-alcoholic fatty
liver disease by reducing lipoprotein expression in HepG2 cells treated with free fatty
acid (FFA), activating the AMPK pathway, promoting lipid metabolism and reducing lipid
accumulation [
92
]. In mice with HFD and alloxan-induced DM, quercetin (179) from TSL
EtOH extracts alleviated oxidative stress and liver damage significantly according to the
measurement of lipid peroxidation, NO content and iNOS activity [
57
]. Quercitrin (180)
alleviated APAP-induced liver injury by inhibiting Janus kinase (JNK) and p38 signaling
pathways, activating defense genes and inhibiting pro-inflammatory genes in HepG2 cells
and animal models [
77
]. TSL extracts have good hepatoprotective activity and could be
used as raw materials to protect against liver damage.

Molecules 2024,29, 718 26 of 31
5.7. Antiviral and Antibacterial Activity
Extracts from the tender leaves of T. sinensis had an obvious inhibitory effect on
severe acute respiratory syndrome coronavirus (SARS-CoV), and the selectivity index
was 12–17. These leaves may be an important resource for the prevention and control of
SARS-CoV [
93
]. Aqueous extracts of the tender leaves of T. sinensis had a highly selective
inhibitory effect on the formation of MDCK plaque by the influenza A (H1N1) virus on
A549 cells. They inhibited viral attachment by significantly downregulating the expression
of adhesion molecules and chemokines (VCAM-1, ICAM-1, E-selectin, IL-8 and fractalkine).
These results suggest that aqueous extracts of the tender leaves of T. sinensis might be an
alternative treatment or prevention for H1N1 virus infection [94].
The essential oil of T. sinensis leaves (TSL-EO) contains many sesquiterpenes. Standard
broth-microdilution methods were used to evaluate the antibacterial activity of 20 strains of
methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococ-
cus aureus (MRSA). TSL-EO therapy revealed inhibitory activity against MSSA and MRSA,
and the minimum inhibitory concentration (MIC) was 0.125 and 1 mg/mL, respectively.
The biological activity of TSL-EO may be related to the high content of sesquiterpenes [
95
].
EtOAc extracts of T. sinensis shoots contain many polyphenols, glycosides and terpenoids.
Antibacterial activity was determined using the agar hole-diffusion method and microdi-
lution method. TSL-EO showed high inhibitory activity against Staphylococcus aureus,
Shigella dysentery and Escherichia coli with MIC values of 1.56, 0.78 and 0.39 mg/mL, respec-
tively [
50
]. In summary, T. sinensis has an inhibitory effect on various viruses and bacteria.
The antiviral and antibacterial effects of TSL are the most extensive, and they can be used
as a potential source of antiviral and antibacterial drugs.
5.8. Immunopotentiation
A type of fish (tilapia) that received TSL hot-water extracts (
≤
8
µ
g/g) exhibited signif-
icant stimulatory effects on non-specific immune mechanisms and disease resistance. TSL
hot-water extracts could be used as an immunostimulant in tilapia, but continuous adminis-
tration may be necessary to maintain the protective response [
13
]. The immunomodulatory
activities of T. sinensis seeds were evaluated using cyclophosphamide-induced immunode-
ficiency in mice. The polysaccharide TSP-3a had a significant immune-restoring activity
and enhanced phagocytosis [
17
]. Rutin (183) extracted from TSL methanol extracts could
regulate various functions of crustaceans. The survival rate of the littoral shrimp was
improved significantly after rutin injection, indicating that a certain dose of rutin could
improve the immunity of littoral shrimp to alginolytic Vibrio infection [9].
5.9. Effects on the Male Reproductive System
TSL aqueous extracts repressed the ROS level, maintained the mitochondrial mem-
brane potential (MMP) and restored sperm motility to improve sperm and testicular
function under oxidative stress [
96
]. Studies have shown that increased levels of oxidative
stress may be one of the main causes of decreased semen quality. T. sinensis can improve
the dynamic activity of human sperm. Primary Leydig cells from mice were purified and
tested
in vitro
. TSL aqueous extracts significantly inhibited the production of testosterone
stimulated by basal and human chorionic gonadotropin (HCG) in a dose-dependent man-
ner [
97
]. The protective effects of TSL EtOH extracts on oxidative stress were studied
using H
2
O
2
-treated human sperm. Sperm motility, MMP, denosine triphosphate level
and maintenance of chromatin structural integrity were investigated. Therapy with TSL
EtOH extracts improved sperm function under oxidative stress by reducing ROS levels and
cell death [
98
]. In conclusion, T. sinensis extracts are good natural bioactive products that
increase the dynamic activity of human sperm and have great potential for development.
5.10. Other Aspects
In addition to the pharmacological effects stated earlier, T. sinensis has effects against
visceral pain and depression and has neuroprotective effects. The effects of TSL aqueous

Molecules 2024,29, 718 27 of 31
extracts on antinociceptive activity were studied in a mouse model of visceral pain. The
extracts had the same anti-visceral pain properties as those of Rofecoxib and Diclofenac,
which have research value in the treatment of refractory visceral pain in humans [
99
].
Essential oil isolated from T. ciliata Roem. var. yunnanensis leaves could increase the
contents of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT) and brain-
derived neurotrophic factor (BDNF) in the hippocampus of rats with chronic mild stress
(CMS) and could have anti-depression effects [
100
]. EtOH extracts of limonin compounds
isolated from the young leaves and buds of T. sinensis showed significant neuroprotective
effects on 6-hydroxydopamine-induced death of human neuroblastoma (SH-SY5Y) cells,
with EC
50
values ranging from 0.27
±
0.03 to 17.28
±
0.16
µ
M
in vitro
[
32
]. In summary, the
pharmacological activities of different parts of T. sinensis are extensive, and it is a natural
bioactive product with great potential for development.
Given the current situation of T. sinensis resources, the selection, propagation and
large-scale cultivation of new varieties should be strengthened. We should also strive to
increase the number of populations, improve the quality of varieties and seedlings, as well
as perform large-scale and standardized production in suitable growth areas to ensure the
sustainable use of resources [101].
6. Conclusions
T. sinensis is a unique and precious tree species and traditional woody vegetable. It is
used widely in the international market and enjoys the reputation of “Chinese mahogany”.
It is a famous medicine and edible plant in China, whose leaves, stems, seeds, barks and
pericarps can be used as medicines. The chemical constituents and biological activities of T.
sinensis have been investigated widely.
In this review, 206 compounds were compiled from T. sinensis, including triterpenoids,
sesquiterpenoids, diterpenoids, sterols, phenols, flavonoids and phenylpropanoids. Ter-
penoids are the main constituents isolated from plants of the Meliaceae family. With
regard to the pharmacological activities described for T. sinensis, studies performed us-
ing different
in vivo
and
in vitro
experimental biological methods have supported most
of their traditional medicinal uses. Its extracts and chemical constituents have excellent
biological activities, such as anti-DM, anti-DN, antioxidant, anti-inflammatory, antitumor,
hepatoprotective, antiviral/antibacterial and immunopotentiation effects.
In summary, the chemical constituents, compound cracking laws and pharmacological
activities of different parts of T. sinensis were reviewed systematically. This information
might highlight the importance of this plant and provide some directions for its future
development. In addition, further studies of the biological activities of T. sinensis extracts
and compounds are needed.
Author Contributions: Conceptualization, W.L. and H.S.; methodology, data curation, writing—ori-
ginal draft preparation, M.Z. and H.L.; investigation, M.Z., H.L., S.L., Y.W. and Y.Z.; writing—review
and editing, R.W. and W.L.; project administration, W.L. and H.S.; funding acquisition, W.L., R.W.
and Y.Z. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the National Nature Science Foundation of China, grant
number 82304700 and 81274049; the Natural Science Foundation of Shandong Province, grant num-
bers ZR2022QH093, ZR2021MH124 and ZR2021QE276; the Graduate Quality Education and Teach-
ing Resource Project of Shandong Province, grant number SDYKC2022141; the Shandong Science
and Technology Research Project of Traditional Chinese Medicine, grant numbers 2020Q057; the
Government-Sponsored Visiting Scholar Research Program of Weifang Medical University, grant
numbers 2022 7-16.
Acknowledgments: We thank LetPub (www.letpub.com) for its linguistic assistance during the
preparation of this manuscript.
Conflicts of Interest: The authors declare no conflicts of interest.

Molecules 2024,29, 718 28 of 31
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