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Comprehensive Review of Phytochemical Profiles and Health- Promoting Effects of Different Portions of Wampee (Clausena lansium)

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Abstract

Clausena lansium, commonly known as wampee, is a subtropical fruit from the Rutaceae family characterized by its high nutrient content and numerous bioactive substances. This low-fat fruit is abundant in fiber, vitamins, minerals, and essential amino acids. Wampee has been found to contain several bioactive compounds, including essential oils, phenolic compounds, and alkaloids. These bioactive constituents provide numerous health-enhancing properties, such as antioxidant, neuroprotective, anticarcinogenic, anti-inflammatory, hepatoprotective, antidiabetic, and antimicrobial effects. The relationship between these compounds and their impacts on health has been explored in various studies. While the disease-prevention efficacy of C. lansium has been established, additional research is necessary to elucidate the precise mechanisms and metabolic pathways involved. This paper presents a comprehensive review of wampee, focusing on its bioactive compounds, the beneficial effects derived from its consumption, and the evidence supporting the development of wampee-based functional foods in future studies.
Comprehensive Review of Phytochemical Profiles and Health-
Promoting Eects of Dierent Portions of Wampee (Clausena
lansium)
Published as part of the ACS Omega virtual special issue “Phytochemistry”.
Xin Huang,
#
Minghe Wang,
#
Saiyi Zhong, and Baojun Xu*
Cite This: https://doi.org/10.1021/acsomega.3c02759
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ABSTRACT: Clausena lansium, commonly known as wampee, is a
subtropical fruit from the Rutaceae family characterized by its high
nutrient content and numerous bioactive substances. This low-fat
fruit is abundant in fiber, vitamins, minerals, and essential amino
acids. Wampee has been found to contain several bioactive
compounds, including essential oils, phenolic compounds, and
alkaloids. These bioactive constituents provide numerous health-
enhancing properties, such as antioxidant, neuroprotective,
anticarcinogenic, anti-inflammatory, hepatoprotective, antidiabetic,
and antimicrobial eects. The relationship between these
compounds and their impacts on health has been explored in
various studies. While the disease-prevention ecacy of C. lansium
has been established, additional research is necessary to elucidate
the precise mechanisms and metabolic pathways involved. This paper presents a comprehensive review of wampee, focusing on its
bioactive compounds, the beneficial eects derived from its consumption, and the evidence supporting the development of wampee-
based functional foods in future studies.
1. INTRODUCTION
Clausena lansium (Lour.) Skeel, commonly referred to as
wampee, is a subtropical fruit belonging to the Rutaceae family,
whose origins are traced back to China.
1
It has been cultivated
in China for more than 1500 years, and several varieties have
been developed through selective breeding.
2
The fruit is
commercially grown in China, Vietnam, Thailand, Malaysia,
the Philippines, and India due to its high-value status. Wampee
typically exhibits an oval shape and measures approximately 2.0
cm in diameter. Its yellow peel encases 15 seeds, as shown in
Figure 1. It generally ripens from May to August in dierent
cultivation areas due to geographical and climatic dierences.
3
The edible part of the wampee includes the pulp and peel.
Besides being consumed as fresh fruit, wampee also can be
processed into long-shelf-life food products, such as jams,
beverages, preserved fruits, and wines. Dried wampee in
Thailand is popular with locals.
4
Processing is a possible way to
expand the wampee market.
In addition, wampee could be employed in medicine rather
than just being consumed as a typical food. In the view of
Asian folk medicine, such as traditional Chinese medicine
(TCM), the leaves, stem, bark, root, peel, and seeds of
wampees can be used to treat various diseases. The water
extraction of wampee leaves and peel can be used to treat
certain dermatological disorders, acute and chronic viral
hepatitis, as well as asthma.
5
The therapeutic properties of
the wampee’s root, bark, and stem were eective in addressing
bronchitis and malarial fever, while the pulp and seeds were
purportedly beneficial in alleviating symptoms of cough,
dyspepsia, and specific gastrointestinal disorders.
6,7
The
wampee is renowned not only for its fruit but also for its
substantial medicinal properties. Clausenolide-1-ethyl ether, a
limonoid extracted from wampee, has been scientifically
demonstrated to exhibit anti-HIV activity. Another compound,
clausine-D, also derived from the wampee plant, possesses an
antiplatelet eect that can aid in preventing blood clot
formation. Additional pharmacological benefits attributed to
the wampee include antibacterial, antifungal, and antimalarial
activities. The myriad of therapeutic potentials this plant oers
thus emphasizes its significance in medical research.
8
In
previous decades, with the help of advanced research
Received: April 26, 2023
Accepted: July 6, 2023
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techniques, the chemical composition and nutrient profiles of
the wampee were explored. Relevant research has demon-
strated that wampee is a rich source of various nutrients and
phytochemicals, such as polyphenols, minerals, vitamins, and
flavonoids, which possess health-promoting properties. These
beneficial eects include antioxidative, anti-inflammatory, and
antimicrobial activity.
9
Several researchers have reported the bioactive compounds
isolated from wampee, but no comprehensive information
about the chemical profiles and bioactivities of wampee has
been reported. This review aims to summarize the chemical
constituents and corresponding bioactivities of dierent parts
of the wampee. This comprehensive review is helpful for the
better development of wampee fruit and related products.
2. CHEMICAL COMPOSITIONS
2.1. Proximate Compositions. The nutritional value of
wampee is primarily attributed to its pulp, which serves as the
primary edible portion. Supplemental Table 1 demonstrates
the major macronutrient composition of wampee determined
in several types of research. Wampee is a kind of tropical fruit
with a high water content, and water occupies around 78.93 to
84.00% of the fresh weight (FW) of wampee pulp. The ash
content in the wampee ranges from 0.9 to 2.6 g/100 g of FW.
In every 100 g of the consumable pulp of the wampee fruit, the
composition comprises 0.61 to 3.78 g of protein, 0.10 to 0.28 g
of fat, and 9.9 to 14.1 g of carbohydrates by fresh weight. The
fiber content is up to 4.58 g/100 g of wampee, establishing it as
an outstanding source of dietary fiber. Additionally, the
appropriate ratio between soluble sugar (10.16 g/100 g on
average) and total acid (1.55 g/100 g on average) balances the
sweet and sour taste to wampee. The low fat and sugar
contents in wampee result in a low energy level of around 47
kcal/100 g. The variance of constituent content in other
research may be attributed to the growing conditions,
geographic factors, and analytical methods.
4,10,11
2.2. Vitamins and Minerals. Wampee could be a good
supplement for vitamins and minerals in a daily diet. The most
abundant vitamin in wampee is vitamin C (548 mg/kg), higher
than other tropical fruits like lychee (364 mg/kg) and papaya
(512 mg/kg).
12,13
Other vitamins and precursors, including
vitamin E (1.58 mg/kg), vitamin B1 (1.35 mg/kg), vitamin B2
(0.72 mg/kg), and niacin (0.33 mg/kg), as well as β-carotene
(0.016 mg/kg), are also found in wampee. The wampee fruit
also serves as a significant source of essential minerals. Each
kilogram of wampee contains significant amounts of essential
minerals such as 3500 mg potassium, 710 mg calcium, and 220
mg phosphorus, which are crucial for maintaining homeostasis
in the body.
11
The contents of vitamins and minerals for fresh
wampee are summarized in Supplemental Table 1.
2.3. Protein and Amino Acid. The protein content of
wampee is 6.20%, while abundant amino acids were found in
wampee pulp.
14
A total of 17 amino acids were isolated and
quantified from wampee and summarized in Supplemental
Table 2.
1416
Among the identified amino acids in wampee
pulp, alanine was the most abundant, with a concentration of
10.50 mg/g, followed by asparagine (6.10 mg/g), glutamine
(4.10 mg/g), serine (3.00 mg/g), lysine (2.30 mg/g), and
leucine (2.00 mg/g).
Amino acid assessment indicates that wampee contains nine
essential amino acids (EAA), including histidine, isoleucine,
leucine, lysine, methionine, phenylalanine, threonine, valine,
and arginine, which make up around 28% of the total amount
of amino acids. Therefore, the consumption of wampee may
contribute to the sucient daily intake of essential amino
acids. Amino acids play a crucial role in physiological activities
and food taste development. Based on their taste properties in
foods, amino acids could be classified into three groups: bitter,
sweet, and umami. The amino acid assessment reveals that the
sweet amino acids (Thr, Ser, Gly, and Ala) are the dominant
group of amino acids accounting for nearly 41% of the total
amino acids. Additionally, the umami amino acids (Asp and
Glu) make up about 28% of the total amino acids in wampee.
As a result, it is reasonable that the amino acids in wampee
contribute to developing its sweet and umami taste profile.
2.4. Carbohydrates. The carbohydrate content of wampee
is primarily made up of free sugars and polysaccharides.
Fructose, glucose, and sucrose are the most dominant free
sugars in wampee. Some research reported a slight dierence in
soluble sugar content among dierent species of wampee
fruit.
17
The total soluble sugar content could be up to 87.35
mg/g, consisting of fructose (40.14 mg/g), glucose (28.39 mg/
g), and sucrose (18.81 mg/g). The median total soluble sugar
content in wampee is 100 mg/g, including 50.6 mg/g of
sucrose.
18
Besides the free sugars, the polysaccharides occupy a
considerable portion of carbohydrates in the wampee.
Polysaccharide is a group of bioactive compounds with
dierent health benefits, such as antioxidative and anti-
inflammatory activities, etc. Additionally, it involves immunor-
egulation and cell activities, thus playing a critical role in
health.
19
Polysaccharides in wampee are mainly composed of
pectin, cellulose, and hemicellulose. Various methodologies,
such as microwave-assisted extraction and ethanol sedimenta-
tion, have obtained crude polysaccharide extracts from
wampee.
The composition of monosaccharides in the wampee may
exhibit variations, which can be attributed to the dierence in
extraction methodologies and the specific portions of the
wampee fruit utilized. For example, the polysaccharides
obtained from the seed and peel of wampee were composed
of mannose, galacturonic acid, galactose, arabinose, and
glucose with a ratio of 11.70:55.37:9.58:17.81:2.03 and
2.76:48.28:15.83:27.63:2.74, respectively.
20,21
Figure 1. Wampee fruits on the tree.
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Furthermore, the dierence in extraction method may cause
the variation in monosaccharide composition, even from the
same portion of the wampee. For example, galacturonic acid is
one of the dominant monosaccharides in the pulp extract
obtained through ethanol sedimentation, accounting for
62.16% of the total content. However, the ultrasonic
microwave-assisted enzymatic method resulted in arabinose
being the most abundant polysaccharide present in the
pulp.
22,23
The characteristics of polysaccharides extracted
from a dierent portion of wampee have been summarized
in Supplemental Table 3.
2.5. Volatile Compounds. Essential oils are natural
bioactive products consisting of volatile compounds found in
plants. The essential oils derived from wampee fruit exhibit
potent health-promoting and pharmacological properties,
including anti-inflammatory, antibacterial, and anticancer
activities. These volatile components also contribute to the
distinctive and appealing aroma of fruits. Thus, examining the
chemical composition of essential oils and volatiles from
wampee fruit is crucial, as they play a role in both its bioactivity
and aroma. The volatile constituents of wampee essential oils
can be classified into several major groups: terpenoids and
their derivatives as well as alcohols and olefin compounds.
Various extraction methods could be applied to extract
volatile compounds in plants, such as supercritical fluid
extraction, hydrodistillation, steam distillation, and hydro-
diusion, etc.
24
In addition, gas chromatography and mass
spectrometry (GC-MS) are frequently utilized techniques to
identify volatile compounds.
Volatile compounds were isolated and identified from fresh
pulp, leaves, and seeds of wampee using GC-MS with a
headspace sampler.
25
It is reported that the volatile
compounds from wampee pulp are mainly made up of
monoterpenes (76.0%) and alcohols (17.5%). In the wampee
leaves, 86% of the entire volatile fraction was characterized.
The primary components among these constituents were
sesquiterpenes, accounting for 28%, and monoterpenes,
comprising 22%. The major volatile components in the seed
of wampee were found to be sabinene, β-phellandrene, and 4-
terpineol by using GC-MS analysis.
26
Volatile oil was extracted
from wampee pulp by supercritical fluid extraction.
27
The main
compositions in wampee essential oil were 4-terpineol
(26.94%), followed by γ-terpinene (14.39%), β-phellandrene
(8.24%), sabinene (5.58%), and cymene (5.01%). Among
these substances, β-phellandrene is an attractive resource for its
potential antifungal activities.
26,28
There are some dierences
between the characterized volatile compositions in the studies,
possibly due to the dierences in temperature, pressure, and
polarity of dierent extraction methods.
29
Table 1. Volatile and Phenolic Compounds of Wampee
a
Volatile compounds of wampee
% Relative area
Compound Leaves Pulp Peel Seed
Sabinene 14.92 50.64 69.07 83.56
β-Bisabolene 9.88 ND ND 0.15
β-Caryophyllene 7.72 ND ND 0.55
α-Zingiberene 6.52 ND ND 0.06
3-Cyclohexen-1-ol ND 15.17 0.28 0.51
Cyclohexene ND 6.5 0.17 0.39
1,4-Cyclohexadiene ND 6.19 0.32 ND
α-Phellandrere 1.38 5.03 10.63 3.08
α-Pinene 1.99 2.08 9.41 4.26
Myrcene 1.1 1.7 3.15 2.94
Acetic acid 0.94 2.65 0.08 0.03
Hexanal 1.55 0.47 0.04 ND
Isosativene 0.38 ND 0.07 0.01
Butanal 8.61 ND ND ND
Reference Chokeprasert et al., 2007
25
Phenolic content of wampee (based on dry weight)
Portion Phenolic
compounds Content (mg/100 g
DW) References
Leaves
Gallic acid 224.7
Chen et al.,
2017
38
(+)-Catechin 762.3
Vanillic acid 609.1
Caffeic acid 1514.1
Leaves
Syringic acid 216.4
Epicatechin 424.5
p-Coumaric acid 12836.2
Ferulic acid 5417.2
Rutin 9241.5
Isoquercitrin 2760.9
Quercitrin 2730.7
Quercetin 5641.3
Peel Proanthocyanidins 1.88 Chai et al., 2017
39
Phenolic content of wampee (based on fresh weight)
Portion Phenolic compounds Content
(mg/100 g FW) References
Leaves
Gallic acid 90.3
Kong et al.,
2018
36
Chlorogenic acid 221.8
Caffeic acid 67.7
Rutin 1700.5
Ferulic acid 82.4
Mature
leaves
Quercetin 2.87
Chang, Lu et al.,
2018
67
Catechin 1.91
Feurlic acid 2.94
Chlorogenic acid 1.39
Vanillic acid 1.66
Pulp
Vanillic acid 1.77
Ye et al., 2019
32
Ferulic acid 2.43
Rutin 15.87
Syringin 15.85
Catechin 262.7
Hesperetin 1.63
Leaves
p-Coumaric acid 9.87
Li et al., 2019
35
7-Hydroxycoumarin 12.03
Ferulic acid 13.15
Rutin 98.94
Pulp
Syringin 9.8
Chang et al.,
2022
40
Rutin 656.8
Benzoic acid 350.1
2-Methoxycinnamic
acid 29.1
Kaempferol 20.7
Hesperetin 20.9
Nobiletin 39.1
Tangeretin 48
a
“ND”: Not detected.
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Furthermore, the content of identical substances may exhibit
considerable dierences in various studies because of variations
in climate, growing environment, and plucking. The volatile
compositions in dierent parts of the wampee were also
investigated, and it was found that monoterpene dominates the
total volatile content.
25
Sabinene was found to have the highest
amount in all parts of the wampee: leaves (14.92%), pulp
(50.64%), peel (69.07%), and seed (83.56%). The volatile
compounds in the wampee were summarized in Table 1.
2.6. Phenolic Compounds. Phenolic compounds are a
massive group of phytochemicals, which are secondary
metabolites synthesized through the shikimic acid and
phenylpropanoid pathways in plants.
30
The typical chemical
structure of phenolic compounds comprises an aromatic ring
with one or more hydroxyls groups. Phenolic compounds can
be divided into several classes, including phenolic acids (e.g.,
hydroxycinnamic acid, hydroxybenzoic acid), flavonoids (e.g.,
flavonols, flavanols, and anthocyanidins), tannins (e.g., hydro-
lyzable tannins, condensed tannins), stilbenes, coumarins, and
lignans.
31
The phenolic composition and concentrations of wampee
may exhibit considerable discrepancies across various studies
owing to the diversity in numerous aspects, such as
geographical distribution, sample preparation, analytical
approaches, and statistical analysis. Consequently, it is essential
to consider these variables when evaluating the phenolic
compound profiles derived from dierent studies.
The studies identifying phenolic compounds primarily
focused on the pulp, peel, and leaf portion of wampee. Ye et
al.
32
extracted phytochemicals from wampee pulp using
ethanol as the solvent and measured the phenolic content by
the FolinCiocalteu method. The total phenolic content in
wampee pulp was reported to be up to 907.8 mg gallic acid
equivalent (GAE)/100 g FW, while the total flavonoid content
in wampee pulp was up to 536.6 mg catechin equivalent (CE)/
100 g FW. In another study, Prasad et al.
33
investigated the
phenolic content in wampee peel using the FolinCiocalteu
method and found that the total phenolic content in the
ethanol extract fraction is 4.62 GAE mg/100 g dry weight
(DW). The highest level of total phenolic content was
observed in the ethyl acetate fraction, which was 33 mg
GAE/100 g DW. In addition, Chang et al.
34
found that as the
wampee leaves grow there is an accumulation of total phenolic
content.
At least 20 phenolic compounds have been isolated and
identified from dierent parts of wampee, including hydrox-
ybenzoic acid (gallic acid, vanillic acid, and benzoic acid),
hydroxycinnamic acid (ferulic acid, 2-methoxycinnamic acid,
chlorogenic acid, caeic acid, and p-coumaric acid), flavonol
(rutin, kaempferol, quercetin, and isoquercitrin), flavanone
(hesperetin), flavone (nobiletin, tangerretin), flavanol (cat-
echin), and phenolic glycosides (syringin).
32,3540
In addition,
coumarin is a class of phenolic compounds widely existing in
wampee. All of these identified compounds were summarized
in Table 1.
2.7. Alkaloids. Alkaloids represent a significant class of
plant-derived secondary metabolites exhibiting pharmacolog-
ical activity, and their biodynamic activities may benefit human
health.
41
Alkaloids are abundant in dierent parts of the
wampee and could be classified into several types.
2.7.1. Carbazole Alkaloid. Carbazole alkaloid is an
important subgroup of alkaloids. The fundamental chemical
composition of carbazole is characterized by a central pyrrole
ring, which is coalesced with two benzene rings on either
side.
42
This class of compounds is considered as an anticancer
agent because of their biological activities.
43
Serving as a significant source of carbazole alkaloids, various
compounds have been extracted and identified from multiple
sections of the wampee plant. Ten carbazole alkaloids named
claulansines AJ were extracted from the stem of the wampee.
Among these alkaloids, 10 μM of claulansines A, F, H, I, and J
eectively protected pheochromocytoma (PC12) cells from
apoptosis.
44
Furthermore, claulansine F was found to be able
to promote neuritogenesis in PC12 cells by activating the ERK
signaling pathway, thus exerting its neuroprotective activity.
Moreover, a new carbazole alkaloid, claulansine K, was first
isolated from wampee peels and exhibited in vitro α-
glucosidase inhibitory activity.
45
One year later, Du et al.
46
characterized two new carbazole alkaloid claulansine S and T
in the stem of the wampee. This research group extracted
another seven carbazole alkaloids named claulansines LR
from the wampee stem in the same year. They subsequently
discovered that claulansines N, P, Q, and S demonstrated
hepatoprotective properties in human HepG2 hepatoma
cells.
47
Subsequently, Liu et al.
48
extensively studied the
alkaloid profiles in wampee fruits and isolated 16 carbazole
alkaloids, while six were first reported. The research group also
evaluated the neuroprotective activities of these alkaloids
toward the human neuroblastoma SH-SY5Y cell line,
proposing that wampee could potentially serve as a
preventative and therapeutic agent for Parkinson’s disease.
Additionally, five new carbazole alkaloids were extracted from
the stem of wampee, named claulansine A (Figure 2A),
claulansine U, claulansine V, claulansine W, and ()-(2R)-
claulamine A, respectively. These compounds presented
potential protective eects on PC12 cells against serum
deprivation and anticancer activities.
49
Recently, a new
carbazole alkaloid, called claulansine X, has been identified in
Figure 2. Structures of some important secondary metabolites: (A)
claulansine A; (B) clausenalansamide C; (C) rutin; (D) gallic acid.
The image was extracted from PubChem.
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Table 2. Alkaloids in Wampee
Carbazole alkaloid in wampee
No. Name Molecular formula Source Bioactivities References
1 3-Formyl-6-methoxycarbazole C14H11NO2Root - Li et al., 1991
6
2 Methyl 6-methoxycarbazole-3-carboxylate C15H13NO3-
3 3-Formyl-1,6-dimethoxycarbazole C15H13NO3-
4 Mafaicheenamines A C19H19NO4Twigs Anticancer Maneerat & Laphookhieo, 2010
88
5 Mafaicheenamine B C19H21NO5
6 Mafaicheenamines C C19H19NO3
7 Mafaicheenamines D C19H18NO2Root Anticancer Maneerat et al., 2012
89
8 Mafaicheenamines E C19H18NO3
9 Claulansine A C19H19NO3
Stem Neuroprotective Liu et al., 2012
44
10 Claulansine B C19H19NO4
11 Claulansine C C19H20NO5
12 Claulansine D C19H19NO5
13 Claulansine E C16H13NO3
14 Claulansine F C19H17NO3
15 Claulansine G C19H17NO2
16 Claulansine H C19H19NO4
17 Claulansine I C18H18NO2
18 Claulansine J C14H11NO4
19 Claulansine K C25H23NO8Peel - Deng et al., 2014
45
20 6-Methoxy-9H-carbazole-3-carboxylic acid C14H11NO3Stem Anticancer Jiang et al., 2014
90
21 Claulansine L C25H23NO8
Stem Hepatoprotective Du, Liu, Li, Ma et al., 2015
5
22 Claulansine M C18H15NO2
23 Claulansine N C14H12NO3
24 Claulansine O C15H14NO3
25 Claulansine P C21H23NO4
26 Claulansine Q C15H15NO
27 Claulansine R C16H17NO2
28 Claulansine S C17H19NO Stem Hepatoprotective Du, Liu, Li, Yang et al., 2015
46
29 Claulansine T C18H21NO2
30 Claulansium A C19H17NO4Branches Anticancer Peng et al., 2018
91
31 Claulansium B C19H21NO3
32 Clausenalansine A C18H16NO3
Fruit Neuroprotective Liu, Guo, Liu et al., 2019
48
33 Clausenalansine B C14H14NO2
34 Clausenalansine C C15H12NO4
35 Clausenalansine D C15H14NO3
36 Clausenalansine E C14H14NO2
37 Clausenalansine F C15H16NO2
38 Claulansine U C19H17NO4
Stem
Against serum deprivation injury
Sun et al., 2020
49
39 Claulansine V C19H15NO4Against serum deprivation injury
40 Claulansine W C19H19NO3Anticancer
41 ()-(2R)-Claulamine A C19H17NO3/
42 Claulansine X C19H20NO4Stem Neuroprotective Sun et al., 2021
50
Amine alkaloid in wampee
No. Name Molecular formula Source Bioactivities References
1 Clausenamide C18H19NO3Leaves Hepatoprotective Yang, Chen et al., 1987
92
2 Neoclausenamide C18H19NO3
3 Dehydroccloclausenamide C18H17NO2
4 Cycloclausenamide C18H17NO2Leaves Hepatoprotective Yang et al., 1988
93
5 (E)-N-(4-Methoxyphenethyl)-2-methylbut-2-enamide C14H19NO2Leaves - Zhao et al., 2011
94
6 Lansiumamide B C18H17NO Leaves Anti-inflammatory Matsui et al., 2013
55
7 Lansiumamide C C17H18NO
8 Lansamide I C18H18NO
9 SB-204900 C18H17NO2
10 Clausenalansamides C C19H21NO3Na Leaves - Shen et al., 2017
54
11 Clausenalansamides D C18H18ClNO2Na
12 Clausenalansamides E C18H18ClNO2Na
13 Clausenalansamides F C19H21SNO4Na
14 Clausenalansamides G C23H29NO8Na
15 Lansiumamide A C17H15NO Seeds - Lin, 1989
56
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the ethanol extract of the wampee stem, exhibiting a moderate
neuroprotective influence on the PC12 cell line.
50
In short, more than 40 carbazole alkaloids have been isolated
and identified from dierent parts of the wampee and are
summarized in Table 2. They are an essential and characteristic
feature of a wampee.
Fan et al. recently reported that the pivotal regulatory
enzymes, shikimate kinase and anthranilate synthase, upregu-
late carbazole alkaloid production in wampee through the
carbazole alkaloid biosynthetic pathway.
51
Alkaloids were
discovered in dierent portions of the wampee, including the
pulp, stem, branch, leaf, twig, root, and peel, and the stem
contains the most abundant alkaloid profiles. Hence, the
wampee stem can be considered an important source of
carbazole alkaloids. Some of these carbazole alkaloids
demonstrated antineoplastic, hepatoprotective, and neuro-
protective properties in in vitro tests. In addition, Li et al.
also suggested that carbazoles isolated from Clausena plants are
a vital heterocyclic class of anticancer agents.
52
However,
further in-depth studies are needed to investigate the potential
mechanisms of the bioactivities of these carbazole alkaloids to
illustrate the health benefits of wampee.
2.7.2. Amine Alkaloid. Amide alkaloids are another
important category of alkaloids abundant in various portions
of the wampee. This group of compounds has attracted
attention due to their excellent biological activities.
An amide alkaloid named clausenamide was first isolated and
characterized from wampee leaves.
53
In a later study, a greater
variety of amide alkaloids were found in the leaves of wampee,
such as clausenalansamides C (in Figure 2B) through G and
clausenaline G,
54
lansiumamide C, lansamide I, lansiumamide
B, and SB-204900.
55
Additionally, the wampee seed is another
important source of amide alkaloids. Lin identified four
cinnamamide derivatives in wampee seeds: lansiumamide A,
lansumide-I, lansiumamide B, and lansiumamide C.
56
Later,
Fan, Chen, Mei, and Kong et al. isolated amide alkaloids from
wampee seeds, including 1-methoxyl-clausenalansamide B, 3-
dehydroxy-3-methoxyl-secoclausenamide, 2-dehydroxy-2-ace-
toxyl-clausenalansamide B, neoclausenamide-A, clausenalansa-
mide A, clausenalansamide B, and neoclausenamide-B, and
confirmed their nematicidal activity.
57
Among the amide
alkaloids derived from wampee seeds, lansiumamide B exhibits
the broadest biological activities. These include an antiobesity
eect,
58
larvicidal activity,
59
antibacterial activity,
60
and
fungicidal activity.
61
Furthermore, continued research into the bioactive com-
pounds in the wampee plant revealed the discovery of new
amide alkaloids in the stem of the wampee. Du et al. reported
clauamide A, isolated from wampee seeds, has potential
hepatoprotective capacity.
46
Liu et al. extracted
(+)-(3S,4R,5S,6S)-clauselansine C from wampee seeds and
confirmed its neuroprotective activity.
62
Recently, three more
new amide alkaloids were found in wampee seeds, including
acetylclausenamide, anhydroclausenamide, and 1-chloro-ben-
zenepropanamide.
50
At least 30 amide alkaloids were extracted and characterized
from dierent portions of the wampee. The amide alkaloids
isolated from wampee were summarized in Table 2. The
biological activities of amide alkaloids have been extensively
investigated, revealing an array of potential therapeutic
applications such as neuroprotective, anti-inflammatory,
nematicidal, hepatoprotective, antidepressant, and antinoci-
ceptive eects. Hence, analyzing the amide alkaloid composi-
tion of wampee could potentially oer novel perspectives on its
utilization, including the development of health-enhancing
products. Also, developing the byproducts of wampee, like
seeds, peels, leaves, and twigs, is a sustainable strategy that
promotes the valorization of low-value products in the food
industry.
3. HEALTH-PROMOTING EFFECTS OF WAMPEE
As mentioned in the previous section, wampee is a rich source
of several bioactive compounds. The health-promoting eects
of wampee reported in previous research include antioxidative,
anti-inflammatory, hepatoprotective, antibacterial, and antineo-
plastic properties, etc. Most of the work was conducted using
the in vitro model. However, these outcomes obtained from in
vitro studies provide fundamental evidence for in-depth animal
and clinical research.
3.1. Antioxidative Eects. Excessive production of
reactive oxygen species (ROS) can result in an imbalanced
redox reaction in tissues, leading to oxidative stress or even
oxidative damage in the body.
63
ROS are produced both
endogenously, as metabolic byproducts stemming from cellular
oxygen metabolism within the organism, and exogenously,
originating from environmental factors including ultraviolet
Table 2. continued
Amine alkaloid in wampee
No. Name Molecular formula Source Bioactivities References
16 Lansiumamide B C18H17NO
17 Lansiumamide C C18H19NO
18 Lansumide I C18H17NO
19 Clausenalansamide A C18H19NO3Seeds Nematicidal Fan, Chen, Mei, Xu et al., 2018
95
20 Clausenalansamide B C18H19NO2
21 1-Methoxyl-clausenalansamide B C19H21NO3Seeds Nematicidal Fan, Chen, Mei, Kong et al., 2018
57
22 3-Dehydroxy-3-methoxyl-secoclausenamide C18H21NO3
23 2-Dehydroxy-2-acetoxyl-clausenalansamide B C20H21NO3Na
24 Neoclausenamide A C20H21NO3Na
25 Neoclausenamide B C27H25NO4Na
26 Acetylclausenamide C20H19O3N Stem Neuroprotective Sun et al., 2021
50
27 Anhydroclausenamide C18H18O2N
28 1-Chloro-benzenepropanamide C17H19O2NCl
29 Clauamide A C16H17NO3Stem Hepatoprotective Du, Liu, Li, Yang et al., 2015
46
30 (+)-(3S,4R,5S,6S)-Clauselansine C C18H17NO2Stem Neuroprotective Liu, Du et al., 2017
62
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radiation, ionizing radiation, pollutants, heavy metals, and
xenobiotics.
64
The most common ROS include hydroxyl
radicals, hydrogen peroxide, and superoxide anions. Excessive
ROS may cause irreversible cellular damage by inducing DNA/
RNA damage, protein oxidation, and lipid peroxidation of
polyunsaturated fatty acids. Consequently, increased oxidative
stress heightens the risk of chronic diseases such as cancer,
neurodegenerative disorders, and diabetes.
65
Hence, the
dietary intake of antioxidants could be a feasible strategy to
neutralize ROS and reduce the risk of related health problems.
To evaluate the antioxidative properties of wampee, a range
of in vitro assays were used, including 2,2-azinobis(3-
ethylbenzothiazoline-6-sulfonate) (ABTS), oxygen radical
absorbance capacity (ORAC), ferric reducing antioxidant
power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH), Trolox
equivalent antioxidant capacity (TEAC), peroxide radical
scavenging capacity (PSC), cellular antioxidant activity
(CAA), self-oxidation of 1,2,3-phentriol, and lipid peroxidation
assays.
The antioxidant capacity of wampee pulp can be primarily
attributed to its rich phenolic compound content. Ye et al.
32
examined the correlation between total phenolic content and
antioxidant properties across five wampee pulp varieties. The
total phenolic content was positively associated with both in
vitro and in vivo antioxidant assays. The variety with the highest
total phenolic content (907.8 mg of GAE/100 g) displayed the
most potent antioxidant capacity in the ORAC, DPPH, and
FRAP assays, with values of 11.03 mmol of Trolox equivalent/
100 g, 208.1 mg ascorbic acid equivalent/100 g, and 279.7
mmol Fe2+/100 g, respectively. On the contrary, the variety
with the lowest level of total phenolics (49.25 mg GAE/100 g)
exhibited the weakest antioxidant capacity, with corresponding
assay values of 1.08 mmol Trolox equivalent/100 g, 10.55 mg
ascorbic acid equivalent/100 g, and 72.84 mmol Fe2+/100 g,
respectively. Other research has similarly observed that
wampee pulp with higher phenolic content displays enhanced
free radical scavenging capabilities.
34,40
In addition, Ye et al.
analyzed the association between phenolic monomers and
antioxidant properties, finding that in vitro antioxidant capacity
was primarily attributable to phenolic monomers such as
ferulic acid, catechin, and syringic acid, while hesperetin
contributed most to the in vivo antioxidant capacity of wampee
pulp.
32
Moreover, Zeng et al. reported that the ethanol extract
of wampee fruit inhibited the expression of NF-κB, thereby
protecting PC-12 cells from oxidative stress.
66
Wampee leaves exhibit remarkable antioxidant potential due
to their rich phenolic composition. Chang et al. observed that
wampee leaf buds with the highest total phenolic content
(2046 mg GAE/100 g) yielded the highest ORAC value (415.8
μmol Trolox equivalent/g).
67
As the leaves developed, the
total phenolic content consistently decreased, causing an initial
reduction in antioxidant potential, followed by a subsequent
increase. Interestingly, the total flavonoid content displayed an
upward trend during leaf development. This observation can
be attributed to the fact that despite the decline in total
phenolic content aecting the antioxidant potential of wampee
leaves the simultaneous production of flavonoid compounds
may compensate for and sustain their antioxidant capacity.
Thus, flavonoids represent a significant subgroup of total
phenolics that may considerably contribute to the antioxidant
properties of wampee leaves.
Prasad et al. examined the antioxidative properties of
wampee peel extracts using four solvents: ethanol, hexane,
ethyl acetate, butanol, and water.
33
The ethyl acetate extract
demonstrated significant antioxidative potential, surpassing
that of butylated hydroxytoluene (BHT) in in vitro tests. In the
DPPH assay, antioxidative capacities were ranked as follows at
a concentration of 50 μg/mL: ethyl acetate > BHT > water >
ethanol > butanol > hexane. This outcome is likely due to the
total phenolic content in the dierent fractions, with ethyl
acetate, water, ethanol, butanol, and hexane fractions
containing 330.0, 54.0, 46.2, 30.3, and 7.9 μg/g DW,
respectively.
33
A similar study also reported higher total
phenolic content in the ethyl acetate fraction.
1
Ethyl acetate is a polar solvent, whereas hexane is typically
used to extract nonpolar substances, indicating that the
Table 3. Antioxidative Activity of Wampee
a
Portion Peel Pulp Pulp
Bioactive
compound Phenolics Phenolics Phenolics
Solvent Ethyl acetate Acetone Acetone
TPC 330 ±9.9 μg/g dry weight, expressed as gallic acid
equivalents
7.92 mg/g GAE FW 9.07 mg/g GAE FW
TFC 7.16 mg/g CE FW 3.50 mg/g CE FW
DPPH 50 μg/mL (95% scavenging activity) 76.72 mg AsA equiv/100 g FW 208.1 mg AsA equiv/100 g FW
FRAP 264.3 mmol Fe2+/100 g FW 279.7 mmol Fe2+/100 g FW
ABTS
Superoxide anion
radical scaveng-
ing activity
50 μg/mL (88% scavenging activity)
PSC 34.7 μmol Vit. C equiv/100 g FW 4927 μmol AsA equiv per 100 g FW
ORAC 5.44 mmol TE/100 g FW 11.03 mmol TE/100 g FW
Cell antioxiant in
vivo
Major finding Ethyl acetate extract of wampee peel exhibits
superior antioxidative capacity, which is mainly
related to phenolic content.
Antioxidant capacity of wampee fruit is
related to the total phenolic and total
flavonoid contents.
It was apparent that wampee fruits had higher phenolic
and flavonoid contents resulting in better antioxidant
activities in vitro and cellular.
Reference Prasad et al., 2010
1
Chang, Ye et al., 2018
34
Ye et al., 2019
32
a
“TPC”: Total phenolic content; “TFC”: Total flavonoid content; “DPPH”: 1,1-diphenyl-2-picrylhydrazyl; “FRAP”: Ferric reducing antioxidant
power; “ABTS”: 2,2-Azinobis(3-ethylbenzthiazoline-6-sulfonate); “PSC”: Peroxide radical scavenging capacity; “ORAC”: Oxygen radical
absorbance capacity.
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phenolic compounds in the wampee peel may possess high
polarity. Moreover, the total phenolic content in the water
fraction was significantly lower than that in the ethyl acetate
fraction, suggesting that most antioxidative compounds in the
wampee peel were not water-soluble. Thus, an appropriate
solvent with both polar and hydrophobic properties can
enhance the ecacy of isolating the predominant antioxidant
constituents from the wampee peel.
In addition to phenolic substances, other compounds, such
as polysaccharides extracted from wampee, have been
identified as potential antioxidants.
20
The antioxidative
capacity of acidic heteropolysaccharide extracted from wampee
seed exhibited a concentration-dependent manner in both in
vitro and in vivo tests. Polysaccharide extracts significantly
reduced the malondialdehyde (MDA) level while increasing
the SOD and glutathione (GSH) levels in high-fat diet-fed rats,
demonstrating their potent ability to manage oxidative stress in
vivo.
21
However, dierent fractions of polysaccharide extracts
might exhibit varying antioxidative properties. Peng et al.
20
attributed the variation to the phenols attached to poly-
saccharides, while Wu et al.
21
ascribed it to dierences in
uronic acid content and structural characteristics.
Overall, various portions of the wampee exhibit significant
antioxidant properties. Most research has primarily focused on
the in vitro antioxidant capacity of wampee. Nonetheless, it is
crucial to acknowledge that outcomes derived from in vitro
tests may not simply be extrapolated to in vivo circumstances.
The chemical and molecular targets of in vitro tests, such as
ABTS and DPPH, are sterically hindered stable radicals that do
not accurately represent short-lived radicals in the body.
68
In summary, phenolic compounds and polysaccharides in
wampee are the primary constituents contributing to its
antioxidative activity. Table 3 summarizes the antioxidant
activity of wampee. Further comprehensive in vivo antioxidant
tests are necessary to provide more evidence of the antioxidant
properties of the wampee and determine the specific
mechanisms.
3.2. Neuroprotection. Neurodegenerative diseases com-
prise a group of progressive disorders that impact neurons in
the nervous system, leading to a wide array of symptoms,
including cognitive dysfunction, impaired movement, memory
loss, and, ultimately, death. Some of the most prevalent
neurodegenerative diseases include Alzheimer’s disease (AD),
Parkinson’s disease (PD), Huntington’s disease (HD), and
amyotrophic lateral sclerosis (ALS).
69
The pathogenesis of
these diseases, however, remains incompletely understood.
Presently, there is a burgeoning interest in exploring natural
products for their potential to target the hypothesized
pathogenesis of neurodegenerative diseases. Adrenal pheo-
chromocytoma (PC12) cells and human neuroblastoma SH-
SY5Y cells are two widely used cell lines for establishing
neuron injury models and investigating neuroprotective
compounds.
70,71
Prior studies have demonstrated that
numerous bioactive compounds derived from wampee exhibit
promising potential in protecting neuronal cells and may oer
new insights into innovative treatments for neurodegenerative
diseases.
Alkaloids comprise a large family of compounds with
potential neuroprotective activity isolated from wampee.
()-Clausenamide was one of the first compounds discovered
with potential neuroprotective activity derived from wampee.
Hu et al. demonstrated that ()-clausenamide (1100 μM)
significantly alleviates Aβ-induced neurotoxicity in dier-
entiated PC12 cells in a dose-dependent manner, as indicated
by cell viability assays.
72
This compound inhibited the
production of reactive oxygen species (ROS) and the
activation of caspase-3, which serve as markers for oxidative
stress and apoptosis, respectively. Additionally, ()-clausena-
mide activates the Nrf2/HO-1 antioxidant pathways, which
play a crucial role in regulating oxidative stress and
inflammation. Consequently, ()-clausenamide may have
potential as a natural neuroprotective agent for preventing
and treating neurodegenerative diseases such as Alzheimer’s
disease. However, further research, including in vivo studies, is
required to fully understand the mechanisms of action and
potential therapeutic applications of this compound. Liu et al.
developed a neuron injury model using a PC12 cell line and
sodium nitroprusside (SNP) as an inducer.
44
They discovered
that four alkaloids extracted from the wampee stem
significantly increased cell viability against SNP-induced
neurotoxicity. In a subsequent study, Liu et al. investigated
the neuroprotective eects of alkaloids derived from the
wampee stem.
62
They observed that 5 out of 14 alkaloids
moderately alleviate neurotoxicity induced by okadaic acid in
PC12 cells. A total of 13 alkaloids were identified, while 5 of
them could moderately alleviate the neurotoxicity induced by
okadaic acid in PC12 cells.
Liu, Guo, and Liu et al. discovered that 16 carbazole
alkaloids extracted from wampee pulp demonstrated significant
protective capabilities against 6-OHDA-induced apoptosis in
human neuroblastoma SH-SY5Y cells, similar to the positive
control, curcumin.
48
Subsequently, Liu et al. isolated 12
geranylated carbazole alkaloids from the leaves and stems of
the wampee, which exhibited similar protective activity with
curcumin against 6-OHDA-induced neurotoxicity in SH-SY5Y
cells.
73
More recently, Sun et al. reported that two carbazole
alkaloids isolated from wampee stems showed only moderate
protective eects on PC12 cells against serum deprivation
injury.
49
Collectively, these studies underscore the neuro-
protective potential of alkaloids derived from wampee,
suggesting possible therapeutic applications for neurodegener-
ative diseases. However, as most of these investigations were
preliminary, the mechanisms underlying the compounds’
neuroprotective eects remain unclear, necessitating further
research.
In addition to alkaloids, phenolic compounds have also
demonstrated potential as neuroprotective agents. Li et al.
extracted a flavonoid, Bu-7, from wampee leaves, which
significantly enhanced the viability of PC12 cells following
rotenone-induced injury.
74
Bu-7 inhibited the JNK and p38
signaling pathways via phosphorylation, consequently prevent-
ing rotenone-induced apoptosis in PC12 cells. Moreover, Bu-7
treatment attenuated mitochondrial membrane permeabiliza-
tion and the collapse of the mitochondrial membrane potential
(MMP), indicating the significant neuroprotective potential of
Bu-7 and its possible application in treating Parkinson’s
disease. Later, Zeng et al. investigated the activity of wampee
fruit ethanol extract in a hydrogen-peroxide-induced PC12 cell
model.
66
The wampee fruit extracts significantly reversed cell
apoptosis in PC12 cells in a dose-dependent manner, reduced
intracellular ROS generation, and prevented MMP collapse.
Furthermore, the extract treatment inhibited the NF-κB
pathway and downregulated caspase-3 expression, suggesting
that the intracellular antioxidative capacity of wampee
contributes to its protective eects against neurodegenerative
diseases.
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Further investigation of the neuroprotective eects of
wampee using in vivo models is necessary. Tongun and
Phachonpai developed a memory impairment model in rats
induced by chronic restraint stress.
75
In the object recognition
assessment, rats administered wampee peel extract (600 mg/
kg) exhibited a higher discrimination index, while in the Morris
water maze evaluation, they exhibited reduced escape latency
and increased retention duration. The activity of the
antioxidant enzyme in rat brain tissue, such as superoxide
dismutase (SOD), catalase (CAT), and glutathione peroxidase
(GSH-Px), was enhanced after wampee peel extract
supplementation. The treatment group exhibited lower
acetylcholinesterase (AChE) activity, indicating a higher
essential neurotransmitter (ACh) level. Phachonpai and
Tongun
76
reported similar findings and suggested that
phenolic compounds might be the primary bioactive
substances responsible for the antidementia activity of the
wampee. In another study, Phachonpai and Tongun
77
induced
focal cerebral ischemia in rats through middle cerebral artery
occlusion (MCAO). Rats supplemented with the wampee peel
extract displayed higher cognition test scores than the MCAO
control group. Additionally, wampee peel extract treatment
reduced inflammatory biomarkers and improved neuronal
survival and cholinergic neurons in the hippocampal regions.
The specific experiment design for the wampee neuro-
protection eect was shown in Figure 3.
Both the in vitro and in vivo studies presented above
demonstrate the considerable potential of wampee for
addressing neurological issues. Alkaloids and phenolic
compounds appear to be the primary categories of bioactive
substances in wampee that contribute to its neuroprotective
properties. However, further research is needed to elucidate
the precise mechanisms of action of these bioactive
compounds. Table 4 provides a summary of the neuro-
protective eects of wampee.
3.3. Anti-Inflammation Eects. Inflammation is a
multifaceted physiological response to tissue injury, infection,
and other forms of cellular stress. Acute inflammation is an
essential defense mechanism protecting the body from harmful
stimuli. However, chronic inflammation contributes to the
pathogenesis of numerous diseases such as arthritis,
cardiovascular disease, and cancer. This persistent inflamma-
tory state is characterized by the continuous activation of
immune cells, tissues, and signaling pathways, leading to the
production of pro-inflammatory cytokines, chemokines, and
other mediators that may harm healthy tissues and exacerbate
disease.
78
Wampee contains various bioactive compounds known for
their anti-inflammatory properties. Inflammation can be
induced by carrageenin, leading to the formation of edema
in rat paws. A 200 mg/kg methanolic extract of wampee leaves
and indomethacin treatments reduced rat paw edema by 55.5%
and 64.0% within four hours, respectively, suggesting the
potential of wampee extract as an anti-inflammatory agent.
7
Similarly, Huang et al. discovered that wampee leaf extract
diminished TNF-αproduction by suppressing the TLR4/
MYD88/TRAF6 signaling pathways in LPS-treated RAW
264.7 cells.
79
Matsui et al. identified two cinnamamides,
lansiumamide B and SB-204900, that inhibited histamine
release and decreased IL-6, COX-2, and TNF-αformation,
thus exhibiting anti-inflammatory activity in rat basophilic
leukemia cells.
55
The mechanism of the wampee anti-
inflammation eect is shown in Figure 4. Wampee stem-
derived alkaloids demonstrated anti-inflammatory potential
comparable to curcumin in LPS-induced murine microglial
BV2 cells.
80
The alkaloid 3-formyl-6-methoxycarbazole,
isolated from wampee roots, showed anti-inflammatory activity
similar to dexamethasone, significantly suppressing TNF-αat a
concentration of 50 μg/mL in LPS-induced monocyte cells.
81
Shen et al. reported that alkaloids from the wampee stem not
only inhibited TNF-αand NO production but also suppressed
fMLP/CB-induced superoxide anion generation in LPS-
induced RAW 264.7 cells.
82
Likewise, coumarin and alkaloid
compounds from wampee leaves, such as wampetin and
imperatorin, eectively reduced superoxide anion generation in
RAW 264.7 cells with IC50 values of 6.8 and 1.7 μM,
respectively.
54
In summary, both in vivo and in vitro studies have
demonstrated the potent anti-inflammatory properties of
wampee. It has been posited that the notable anti-
inflammatory compound present in the wampee could be
attributed to alkaloids, which exhibit their eects by inhibiting
inflammatory signaling cascades and reducing the production
of reactive species. Table 5 summarizes the anti-inflammation
eect of wampee.
3.4. Hepatoprotection. In recent years, increasing interest
has emerged in exploring the potential hepatoprotective
activity of the wampee and its constituents. Du et al. isolated
several novel carbazole alkaloids from the wampee stem and
assessed their hepatoprotective activity against N-acetyl-p-
aminophenol (APAP)-induced toxicity in HepG2 cells, a
human hepatocellular carcinoma cell line.
47
The study
discovered that five of these alkaloids demonstrated
hepatoprotective activity comparable to bicyclol, a drug with
Figure 3. Experimental design of wampee neuroprotection eect and test index.
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Table 4. Neuroprotective Eects of Wampee
No. Sources Model Study design Result References
1 ()-Clausenamide
isolated from wam-
pee leaves
Aβ2535-induced cell
apoptosis in PC12 cells
Cell viability, Western blot, MMP, flow cytometry ()-Clausenamide (10 μM) reduces the collapse of MMP by 42.4% Hu et al.,
2010
72
()-Clausenamide (10 μM) treatment increased the viability of PC12 to 90%
from 70%
()-Clausenamide inactivated the p38 MAPK pathway and inhibited the
expression of P53 and caspase 3
2 Alkaloids isolated
from wampee stem
SNP-induced toxicity in
PC12 cells
Cell viability The cell viability of negative control group was 76%, while the treatment of four
alkaloids (10 μM) with neuroprotective potential restored the value to 91.0,
88.2, 84.8, and 83.7%, respectively.
Liu et al.,
2012
44
3 Alkaloids isolated
from wampee stem
Okadaic acid-induced injury
in PC12 cells
Cell viability The cell viability of negative control group was 70.5%, while the treatment of
five alkaloids (10 μM) with neuroprotective potential restored the value to
91.2, 89.7, 83.5, 83.4, and 83.3%, respectively.
Liu, Du et al.,
2017
62
4 Alkaloids isolated
from wampee pulp
6-Hydroxydopamine-in-
duced cell apoptosis in
human neuroblastoma SH-
SY5Y cells
Cell viability The EC50 value of 16 carbazole alkaloids ranged from 0.36 to 10.69 μM, while
the EC50 value for curcumin (positive control) was 5.82 μM.
Liu, Guo, Liu
et al., 2019
48
5 Alkaloids isolated
from wampee stem
and leaves
6-Hydroxydopamine-in-
duced cell apoptosis in
human neuroblastoma SH-
SY5Y cells
Cell viability The EC50 value of 12 geranylated carbazole alkaloids ranged from 0.48 to
12.36 μM, while the EC50 value for curcumin (positive control) was 6.03
μM.
Liu, Guo,
Wang et al.,
2019
73
6 Alkaloids isolated
from wampee stem
Serum deprivation injury in
PC12 cells
Cell viability The cell viabilities of negative control, positive control, and alkaloid treatment
groups (10 μM) were 47.4, 83.8, 67.8, and 63.3%, respectively
Sun et al.,
2020
49
7 Flavonoid isoalted
from wampee
leaves
Rotenone-induced injury in
PC12 cells
Cell viability, Western blot, flow cytometry, measurement of mitochondrial
membrane potential
The cell viability of cells treated with rotenone was 69.2%, and this increased
significantly by 14.4%, 3.1%, and 18.1% after treated with 0.1, 1, and 10 μM
Bu-7, respectively.,
Li et al.,
2011
74
Bu-7 attenuated the rotenone-induced mitochondrial potential reduction in
cells.
Bu-7 inhibited activation of the JNK and p38 signaling pathways and
suppressed caspase 3 activity in the rotenone-treated cells.
Bu-7 excerted its activities in a bell-shaped doseresponse relationship.
8 Ethanol extract of
wampee pulp
H2O2-induced neurotoxicity
in PC12 cells
Cell viability, Western blot, measurement of mitochondrial membrane
potential
The cell viability of negative control group was 55%, but the wampee fruit
extract (1, 10, 20 μM) increased this value to 64.12, 72.13, and 76.26%,
respectively.
Zeng et al.,
2014
66
Wampee pulp extract downregulated caspase-3 and pnf-κB p65 and suppressed
NF-κB p65 entry to the nucleus from the cytoplasm.
9 Ethanol extract of
wampee peel
Memory impairment in-
duced by chronic restraint
stress in rats
Object recognition test, Morris water maze test, ache activity lipid
peroxidation, SOD activity determination
High dose of wampee peel extract (600 mg/kg) significantly increased the
discrimination index of rats. The rats received wampee peel extract treatment
displayed shorter time of escape of latency and longer retention time.
Tongun &
Phachonpai,
2020
75
Wampee peel extract decreased the lipid peroxidation index. It improved the
antioxidant enzymes activities while inhibiting pain.
10 Ethanol extract of
wampee peel
Rats received permanent
right middle cerebral ar-
tery occlusion
Morris water maze test, passive avoidance test, determination of cerebral
infarct volume, Nissl staining and survival neuron densities counts,
determination of the cholinergic neuron densities, measurement of lipid
peroxidation
Medium dose of wampee peel extract treatment (400 mg/kg) significantly
reduced the brian infract volume of rats; decreased the MDA level in the
brain; and enhanced the neuronal survival and cholinergic neurons in
hippocampal regions.
Phachonpai &
Tongun,
2021b
77
11 Ethanol extract of
wampee peel
Memory impairment in-
duced by chronic restraint
stress in rats
Object recognition test, Morris water maze test, superoxide dismutase
(SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and ache
activities and the malondialdehyde (MDA) determination
High dose of wampee peel extract treatment (600 mg/kg) increased the
discrimination index of rats. The rats that received wampee peel extract
treatment displayed shorter time of escape of latency and longer retention
time.
Phachonpai &
Tongun,
2021a
76
Wampee peel extract alleviated oxidative stress. It improved the antioxidant
enzyme activities while inhibiting pain.
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established hepatoprotective eects. Similarly, Liu et al.
identified a monoterpenoid from the stem of the wampee
that exhibited similar activity to bicyclol in protecting HepG2
cells from APAP-induced toxicity.
83
The hepatoprotective properties of wampees have been
investigated in animal models. Carbon tetrachloride (CCl4) is
a widely used agent to induce liver injury in mice by generating
the trichloromethyl-oxygen radical through hepatic cyto-
chrome P450 activation, leading to lipid peroxidation. Liu et
al. demonstrated that administering eight alkaloids isolated
from wampee leaves at a dosage of 250 mg/kg significantly
decreased serum alanine transaminase (ALT) levels in CCl4-
intoxicated mice.
84
Moreover, the two alkaloids protected
against acetaminophen- and thioacetamide-induced liver
damage. It is hypothesized that these alkaloids might exhibit
hepatoprotective eects by inhibiting the interaction between
CCl4and hepatic cytochrome P450, consequently diminishing
the production of subsequent free radicals.
Additionally, carbon tetrachloride (CCl4)-induced liver
injury results in the rapid release of alanine transaminase
(ALT), aspartate transaminase (AST), and alkaline phospha-
tase (ALP) into the bloodstream. Elevated serum levels of
these enzymes were indicative of liver damage. Adebajo et al.
discovered that administering a 200 mg/kg dosage of
methanolic wampee leaf extract improved the activities of
ALT, AST, and ALP in the livers of CCl4-intoxicated mice
while simultaneously downregulating these enzymes’ activity in
plasma.
7
The mechanism of the wampee hepatoprotective
eect is also illustrated in Figure 5. Consequently, these
findings indicate that wampee extract could potentially
mitigate hepatocellular damage induced by CCl4in vivo.
Table 5 summarizes the hepatoprotective eect of wampee.
3.5. Antidiabetic Eects. Numerous extracts from
wampee have demonstrated antidiabetic properties. Adebajo
et al.
7
discovered that wampee stem extract eectively reduced
glucose levels in rats. This extract treatment increased insulin
secretion in both in vivo and in vitro experiments. Additionally,
the wampee peel extract (3.4 mL/kg/day) significantly
mitigated the physiological abnormalities associated with
diabetes, while decreasing swelling and lipid accumulation in
rat organs. Furthermore, an 8-week oral administration of
lansiumamide B (20 mg/kg), an alkaloid isolated from the
seeds of wampee, significantly reduced the body weight of
HFD-fed mice by diminishing the visceral and subcutaneous
fat tissues. The serum cholesterol, high-density lipoprotein
(HDL), and low-density lipoprotein (LDL) levels in high-fat
diet fed mice were reduced by 30.4%, 22.1%, and 47.7%,
respectively.
58
Kong et al. investigated the impact of polyphenol extracts
from the wampee leaf on streptozotocin (STZ)-induced type 2
diabetic rats.
36
The extract exhibited potent antihyperlipidemic
properties, which eectively reduced the concentrations of
total cholesterol (TC), triglycerides (TG), low-density lip-
oprotein cholesterol (LDL-C), and high-density lipoprotein
cholesterol (HDL-C) within a four-week duration. The test
index was illustrated in Figure 6. The bioactive constituents in
wampee peel extract, including rutin (in Figure 2C), gallic acid
(in Figure 2D), ferulic acid, chlorogenic acid, and caeic acid,
were identified to exhibit potential antidiabetic properties.
36
α-Glucosidase is an enzyme responsible for breaking down
complex carbohydrates into simple sugars in the small
intestine. This process is crucial for the absorption of
carbohydrates into the bloodstream. However, in individuals
with diabetes mellitus, α-glucosidase activity can result in
elevated blood sugar levels after a meal, a phenomenon termed
postprandial hyperglycemia. Condensed tannins and proan-
thocyanidins isolated from wampee have demonstrated
inhibitory eects against α-glucosidase through competitive
inhibition and conformational alteration in a dose-dependent
manner.
85
Moreover, Shen et al. found that a high-fat diet
altered gut microbiota composition in mice and increased the
expression of inflammatory cytokines, such as tumor necrosis
factor-α(TNF-α), while oral administration of wampee extract
could reverse these changes.
86
Consequently, wampee may
attenuate hyperglycemia and hyperlipidemia by inhibiting α-
glucosidase and positively modulating the abundance of gut
microbiota associated with metabolic parameters, thereby
exhibiting antidiabetic activity.
These findings suggest the potential of wampee in
preventing diabetes and provide scientific evidence for
developing wampee-based functional food. Table 5 summar-
ized the antidiabetic activities of the wampee.
3.6. Antimicrobial Eects. Wampee has potential
antimicrobial activity. Both He et al.
87
and Ma et al.
26
found
that the essential oils (EOs) of Clausena lansium played an
important role in inhibiting the growth of five Candida species.
The EOs, extracted from chicken heart wampee (CHW)
pericarp and abundant in β-phellandrene and β-sesquiphellan-
drene, showed the most significant antimicrobial ecacy. For
example, He et al.
87
reported a 23.1 mm inhibition zone
diameter for β-phellandrene, while Ma et al.
26
observed
comparable outcomes. Following β-phellandrene treatment,
the inhibition zone diameters for the five Candida species
Figure 4. Mechanism of wampee anti-inflammation eect.
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Table 5. Health Benefit Eects of Wampee
Health eect Sources Cell model Result Reference
Anti-inflammation
eect
Alkaloids isolated from wampee
stem
Murine microglial BV2 cells Carbazole alkaloids displayed considerable anti-inflammatory potential against LPS-stimulated NO production in cell model,
with IC50 values of around 5 μM
Liu et al.,
2015
80
Alkaloids and coumarins isolated
from wampee stem
Human neutrophils and RAW264.7
cell lines
Imperatorin, isoheraclenin. and osthol were the most potent inhibitors for fMLP/CB-induced superoxide anion generation with
IC 50 values of 0.20, 0.81, and 0.0086 μM, respectively.
Shen et al.,
2012
82
The extracted alkaloid, such as wampetin, decreases up to 98.9% NO of control which is higher than positive control
(indomethacin, 30.9%).
Wampetin also downregulated the expression of TNF-α.
Alkaloids and coumarins isolated
from wampee leaves
Human neutrophils Imperatorin and wampetin exhibited potent inhibitory ability toward fMLP/CB-induced superoxide anion generation with IC50
values of 1.7 and 6.8 μM, respectively.
Shen et al.,
2017
54
Anti-inflammation
eect
Ethyl acetate extract of wampee
leaves
RAW264.7 cell lines Wampee extract inactivated TNF-αin a dose-dependent manner, through suppressing TLR4/MYD88/TRAF6 pathways, while
up to 100 μg/mL wampee extract inhibited 80.6% TNF-αexpression.
Huang et al.,
2019
79
Alkaloid isolated from wampee
root
Monocyte cell line U937, human
gingival fibroblast (HGF) cell
line
3-Formyl-6-methoxycarbazole (50 μg/mL) displayed comparable inhibitory ability to dexamethasone (positive control) in
suppressing TNF-α.
Rodanant et
al., 2015
81
Methanol extract of wampee
stem
Rats fed with high-fat diet 100 mg/kg wampee extract had comparable inflammatiory eect to indomethacin that significantly alleviated the rat paw edema
induced by inflammation.
Adebajo et
al., 2009
7
Hepatoprotective
Methanol extract of wampee
stem
Rats fed with high-fat diet The low dose (100 mg/kg) and high dose (200 mg/kg) could decrease sleep duration time 5.3% and 8.4%, respectively. The
methanol extract increased AST, ALT and ALP activity in serum and decreased these enzymes’ activity in plasma.
Adebajo et
al., 2009
7
Leaves of wampee including
eight compounds
CCl4-induced hepatotoxicity in
mice
These eight compounds (250 mg/kg) could decrease the elevated SGPT of CCl4-intoxicated mice. The cyclo-clausenamide was
the most potent one among these compounds. The inhibition rate reached 76.7% after the cyclo-clausenamide treatment.
Liu et al.,
1996
84
Glucopyranoside isolated from
wampee stem
HepG2 (human hepatocellular
liver carcinomacell line) cells
The HepG2 cell survival rate was increased around 10% after the extracted compound (10 μM) treatment. Liu et al.,
2017
62
Antidiabetes
Polyphenol extract from wampee
leaves
Streptozotocin-induced type 2
diabetic rats
Higher body weight. Kong et al.,
2018
36
Lower food intake.
Less excretion.
Lower level of fasting blood glucose.
Lower organ coecient.
Less liver damage and lipid accumulation.
Methanol extract of wampee
stem
Glucose-induced INS-1 cell line,
rat
The rat treated with methanol extract of wampee stem (100 mg/kg) showed 15.8% lower level of glucose than control group. Adebajo et
al., 2009
7
The extract also increased the insulin secretion in both in vivo (38.5% higher than control) and in vitro (1.74 times over control)
tests.
Proanthocyanidins isolated from
wampee pulp
Chemical reaction model Proanthocyanidins isolated from wampee (0.26 μg/mL) suppressed the enzyme activity to 50%. Yang et al.
2020
83
Antimicrobial
Essential oils extracted from
pericarps
Candida strains The essential oil extracted from chicken heart wampee which was rich in β-phellandrene and β-sesquiphellandrene had the most
powerful eect. The inhibition zone diameter of C. glabrata was 23.1 mm after the essential oils (10 μL/disc) treatment.
He et al.,
2019
87
Essential oils and three main
compounds extracted from
seed
Candida strains The 4-terpineol was the most potent compound among the essential oils and its main compound. The inhibition zone diameters
of five Candida species was 26.735.6 mm after the 4-terpineol (10 μL/disc) treatment.
Ma et al.,
2021
96
Three carbazole alkaloids
extracted from twigs roots
Porphyromonas gingivalis Inhibition zone diameters of Porphyromonas gingivalis was 19.0620.94 mm after the lansine (50 μg/mL) treatment. The lansine
was the most powerful compound among extracted carbazole alkaloids.
Rodanant et
al., 2015
81
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examined ranged from 15.6 mm to 22.1 mm. In addition to β-
phellandrene, the principal constituents of the EOs, sabinene,
and 4-terpineol, they also demonstrated inhibitory eects on
the growth of the bacterial strain. The compound 4-terpineol
demonstrated the most significant ecacy, with inhibition
zone diameters ranging from 26.7 to 35.6 mm when tested
against five distinct Candida species.
26
The extracts from the
twigs and roots of Clausena lansium also showed antimicrobial
activity. The P. gingivalis growth was habited after three
carbazole alkaloid treatments. Among the investigated
carbazole alkaloids, lansine exhibited the most potent ecacy,
as evidenced by its inhibition zone diameters ranging from
19.06 to 20.94 mm.
81
Based on the current studies, dierent
bioactive compounds isolated from wampee exhibited
potential antimicrobial activity.
Nonetheless, no research has been conducted to investigate
the precise mechanisms underlying the eects of these
compounds. Therefore, further investigation is required to
understand the antimicrobial eect of wampee. These
compounds could be extracted from wampee and made into
an antimicrobial drug for further application. Table 5
summarized the antimicrobial eects of wampee.
4. CONCLUSIONS
The wampee fruit has been the subject of numerous studies
due to its abundant nutrient content. This comprehensive
review thoroughly studies the health implications and chemical
constituents of wampee. In summary, wampee is an excellent
source of dietary fiber with low-fat and low-calorie content and
is enriched with significant levels of vitamin C, potassium,
calcium, and nine essential amino acids. It is a good source of
low-calorie food. Numerous bioactive constituents in wampee
contribute to an array of health-promoting eects, such as
antioxidative properties and neuroprotection and anticancer,
anti-inflammatory, hepatoprotective, antidiabetic, and anti-
microbial activities. The beneficial promoting eect and its
corresponding bioactive substances have been studied and
identified from wampee. However, the specific mechanism of
these substances has not been explained clearly. The metabolic
pathways and toxicology research of the bioactive substances
extracted from wampee still require further study.
ASSOCIATED CONTENT
*
Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsomega.3c02759.
Figure 5. Mechanism of the wampee hepatoprotective eect.
Figure 6. Wampee extract was used for diabetes treatment.
ACS Omega http://pubs.acs.org/journal/acsodf Review
https://doi.org/10.1021/acsomega.3c02759
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M
Supplemental Tables 13 as mentioned in the text
(PDF)
AUTHOR INFORMATION
Corresponding Author
Baojun Xu Food Science and Technology Program,
Department of Life Sciences, BNU-HKBU United
International College, Zhuhai, Guangdong 519087, China;
orcid.org/0000-0003-0739-3735; Phone: +86-756-
3620636; Email: baojunxu@uic.edu.cn
Authors
Xin Huang Food Science and Technology Program,
Department of Life Sciences, BNU-HKBU United
International College, Zhuhai, Guangdong 519087, China
Minghe Wang Food Science and Technology Program,
Department of Life Sciences, BNU-HKBU United
International College, Zhuhai, Guangdong 519087, China
Saiyi Zhong College of Food Science and Technology,
Guangdong Ocean University, Guangdong Provincial Science
and Technology Innovation Center for Subtropical Fruit and
Vegetable Processing, Zhanjiang 524088, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsomega.3c02759
Author Contributions
#
These authors contributed equally.
Funding
This study is supported by a research grant (project code:
UICR020000723) from BNU-HKBU United International
College.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to all the members of the Food Science and
Technology Program at BNU-HKBU United International
College for their scientific assistance.
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