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antioxidants
Review
Effects of Mulberry Fruit (Morus alba L.)
Consumption on Health Outcomes: A Mini-Review
Hongxia Zhang 1, †, Zheng Feei Ma 2 ,3 ,*, † ID , Xiaoqin Luo 4and Xinli Li 5
1Department of Food Science, University of Otago, Dunedin 9016, New Zealand;
zhanghongxia326@hotmail.com
2Department of Public Health, Xi’an Jiaotong-Liverpool University, Suzhou 215123, China
3School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu 15200, Malaysia
4Department of Nutrition and Food Safety, School of Public Health, Xi’an Jiaotong University Health
Science Center, Xi’an 710061, China; luoxiaoqin2012@mail.xjtu.edu.cn
5Department of Nutrition and Food Hygiene, School of Public Health, Medical College of Soochow
University, Suzhou 215123, China; lixinli@suda.edu.cn
*Correspondence: Zhengfeei.Ma@xjtlu.edu.cn; Tel.: +86-512-8188-4938
† These authors contributed equally to this work.
Received: 22 March 2018; Accepted: 18 May 2018; Published: 21 May 2018
Abstract:
Mulberry (Morus alba L.) belongs to the Moraceae family and is widely planted in
Asia. Mulberry fruits are generally consumed as fresh fruits, jams and juices. They contain
considerable amounts of biologically active ingredients that might be associated with some potential
pharmacological activities that are beneficial for health. Therefore, they have been traditionally used
in traditional medicine. Studies have reported that the presence of bioactive components in mulberry
fruits, including alkaloids and flavonoid, are associated with bioactivities such as antioxidant. One of
the most important compounds in mulberry fruits is anthocyanins which are water-soluble bioactive
ingredients of the polyphenol class. Studies have shown that mulberry fruits possess several potential
pharmacological health benefits including anti-cholesterol, anti-obesity and hepatoprotective effects
which might be associated with the presence of some of these bioactive compounds. However, human
intervention studies on the pharmacological activities of mulberry fruits are limited. Therefore, future
studies should explore the effect of mulberry fruit consumption on human health and elucidate
the detailed compounds. This paper provides an overview of the pharmacological activities of
mulberry fruits.
Keywords: mulberry; polyphenols; anthocyanins; health; nutrition
1. Introduction
Natural products have always been a rich source of biologically active compounds [
1
–
3
].
These substances present in fruits and vegetables have received increasing attention because of their
antioxidant properties and potential strategy in reducing the risk of certain types of diseases such as
metabolic syndrome [
1
,
4
,
5
]. About 50% of the drugs approved are natural products [
5
]. About 80%
of the populations living in many countries rely on the phytomedicines and the plant-derived drug
market is estimated to reach approximately $35 billion in 2020 [5,6].
Mulberry (Morus alba L.) belongs to the Morus genus of the Moraceae family [
7
]. Mulberry is also
known as Ramulus Mori or Sangzhi [
8
]. To date, this genus has 24 species and 100 varieties that have
been known [
7
]. Mulberry is a species native to China and has been widely cultivated in many regions
including Asia, Africa, America, Europe and India [
9
]. China has planted mulberry for more than
5000 years and mulberry is a traditional Chinese edible fruit that can be eaten fresh [
10
]. According to
Antioxidants 2018,7, 69; doi:10.3390/antiox7050069 www.mdpi.com/journal/antioxidants
Antioxidants 2018,7, 69 2 of 13
traditional Chinese Medicine, mulberry fruits are used to improve eyesight and protect against liver
damage [
11
]. They are grown to feed silkworms [
12
,
13
] The season of fresh mulberry fruit in China
is usually less than 1 month. Mulberry fruits are difficult to preserve because they have high water
content (i.e., ~80%) [
11
]. Mulberry has been used in traditional Oriental medicine to treat diabetes and
premature white hair [14].
Mulberry fruits are appetising and low in calories [
15
]. Mulberry fruits have a sour taste
with a pH < 3.5, providing a more concentrated flavour for fruit production and fresh-eating [
16
].
Mulberry fruits possess several potential pharmacological properties including anti-cholesterol,
anti-diabetic, antioxidative and anti-obesity effects [
8
,
17
–
19
]. These pharmacological properties are
due to the presence of polyphenol compounds including anthocyanins, however, different colours
of mulberry fruits even from the same species may have different amounts of anthocyanins [
20
].
Cyanidin-3-rutinoside and cyanidin-3-glucoside are the major anthocyanins isolated from mulberry
fruits [21,22].
Although different mulberry varieties with the same genotype are likely to have differences
in nutritional values and pharmacological properties [
23
], the aim of this work was to review some
potential roles of mulberry fruits (Morus alba L.) and their bioactive compounds in health. Also, some of
the potential mechanisms of their actions will be discussed briefly. We hope that this work would
provide a valuable reference resource for future studies in this area.
Search Strategy
An electronic literature search was conducted using Google Scholar, Medline (OvidSP) and
PubMed until February 2018. Additional articles were identified and obtained from references in the
retrieved articles. Search terms included combinations of the following: mulberry, fruits, hypertension,
diabetes, anti-tumour, hepatoprotective, anti-obesity, anti-oxidative stress and phytochemicals. For the
purpose of this mini-review, the search was restricted to experimental, epidemiological and clinical
studies published in English that address the phytochemical constituents and pharmacological
properties of mulberry fruits (Morus alba L.).
2. Phytochemical Compounds
Compared with mulberry leaves and barks, mulberry fruits are less commonly used in traditional
Chinese Medicine. The possible reasons might be due to the lack of awareness of their health benefits
and limited production [
24
]. However, there is increasing interest in isolating and quantifying the
phytochemical compounds from mulberry fruits. This is because mulberry fruits can be also consumed
as foods [
24
]. Mulberry fruits have strong antioxidant property which is due primarily to the presence
of polyphenols [25]. Figure 1shows the major polyphenol composition found in mulberry fruits.
Antioxidants 2018, 7, x FOR PEER REVIEW 2 of 13
against liver damage [11]. They are grown to feed silkworms [12,13] The season of fresh mulberry
fruit in China is usually less than 1 month. Mulberry fruits are difficult to preserve because they
have high water content (i.e., ~80%) [11]. Mulberry has been used in traditional Oriental medicine to
treat diabetes and premature white hair [14].
Mulberry fruits are appetising and low in calories [15]. Mulberry fruits have a sour taste with a
pH < 3.5, providing a more concentrated flavour for fruit production and fresh-eating [16]. Mulberry
fruits possess several potential pharmacological properties including anti-cholesterol, anti-diabetic,
antioxidative and anti-obesity effects [8,17–19]. These pharmacological properties are due to the
presence of polyphenol compounds including anthocyanins, however, different colours of mulberry
fruits even from the same species may have different amounts of anthocyanins [20].
Cyanidin-3-rutinoside and cyanidin-3-glucoside are the major anthocyanins isolated from mulberry
fruits [21,22].
Although different mulberry varieties with the same genotype are likely to have differences in
nutritional values and pharmacological properties [23], the aim of this work was to review some
potential roles of mulberry fruits (Morus alba L.) and their bioactive compounds in health. Also, some
of the potential mechanisms of their actions will be discussed briefly. We hope that this work would
provide a valuable reference resource for future studies in this area.
Search Strategy
An electronic literature search was conducted using Google Scholar, Medline (OvidSP) and
PubMed until February 2018. Additional articles were identified and obtained from references in the
retrieved articles. Search terms included combinations of the following: mulberry, fruits,
hypertension, diabetes, anti-tumour, hepatoprotective, anti-obesity, anti-oxidative stress and
phytochemicals. For the purpose of this mini-review, the search was restricted to experimental,
epidemiological and clinical studies published in English that address the phytochemical
constituents and pharmacological properties of mulberry fruits (Morus alba L.).
2. Phytochemical Compounds
Compared with mulberry leaves and barks, mulberry fruits are less commonly used in
traditional Chinese Medicine. The possible reasons might be due to the lack of awareness of their
health benefits and limited production [24]. However, there is increasing interest in isolating and
quantifying the phytochemical compounds from mulberry fruits. This is because mulberry fruits can
be also consumed as foods [24]. Mulberry fruits have strong antioxidant property which is due
primarily to the presence of polyphenols [25]. Figure 1 shows the major polyphenol composition
found in mulberry fruits.
Figure 1. Major polyphenol composition in mulberry fruits.
Figure 1. Major polyphenol composition in mulberry fruits.
Antioxidants 2018,7, 69 3 of 13
Phytochemical compounds of mulberry fruits (Morus nigra,Morus indica and Morus rubra)
have been reported in several studies [
26
–
28
]. Kang, Hur, Kim, Ryu and Kim [
17
] isolated
cyanidin-3-O-
β
-D-glucopyranoside (C3G) from 1% HCI-MeOH mulberry fruit extracts using
Amberlite IRC-50 ion exchange chromatography. C3G was identified and quantified by liquid
chromatography-mass spectroscopy (LC-MS) and High-Performance Liquid Chromatography
(HPLC) [
17
]. C3G is an aglycon of anthocyanin that has inflammation-suppressing and free radical
scavenging activity, which might protect against endothelial dysfunction [17].
In a study assessing the polyphenolic composition of five major mulberry fruit varieties
(i.e., Pachungsipyung, Whazosipmunja, Suwonnosang, Jasan and Mocksang) cultivated in Korea using
spectrophotometric methods, Bae and Suh [
29
] reported that the total phenols, total anthocyanins,
coloured (ionised) anthocyanins and total flavanols ranged from 960 to 2570
µ
g/g gallic acid
equivalents, 137 to 2057
µ
g/g malvidin-3-glucoside equivalents, 10 to 190
µ
g/g malvidin-3-glucoside
equivalents and 6 to 65 µg/g catechin equivalents.
Kusano, Orihara, Tsukamoto, Shibano, Coskun, Guvenc and Erdurak [
24
] isolated
five new nortropane alkaloids (i.e., 2
α
,3
β
-dihydroxynortropane, 2
β
,3
β
-dihydroxynortropane,
2
α
,3
β
-6exo-trihydroxynortropane, 2
α
,3
β
,4
α
-trihydroxynortropane, 3
β
,6exo-dihydroxynortropane)
along with nor-
ψ
-tropine from ripened mulberry fruits grown in Turkey. In addition, Kusano, Orihara,
Tsukamoto, Shibano, Coskun, Guvenc and Erdurak [
24
] also isolated and determined the new
structures of six amino acids, which were morusimic acid A, morusimic acid B, morusimic acid
C, morusimic acid D, morusimic acid E and morusimic acid F using spectroscopic data.
Kim, et al. [
30
] identified five pyrrole alkaloids in mulberry fruits, which were morrole B, morrole
C, morrole D, morrole E and morrole F based on spectroscopic data. In addition, the authors [
30
] also
isolated 11 pyrrole alkaloids, which were 4-[formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl]butanoate,
2-(5-hydroxymethyl-2
0
,5
0
-dioxo-2
0
,3
0
,4
0
,5
0
-tetrahydro-1
0
H-1,3
0
-bipyrrole)carbaldehyde, 4-[formyl-5-
(hydroxymethyl)-1H-pyrrol-1-yl]butanoate, 4-[formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]butanoic
acid, methyl 2-[2-formyl-5-(methoxymethyl)-1H-pyrrole-1-
yl]propanoate, 2-(50-hydroxymethyl-20-
formylpyrrol-1
0
-yl)-3-phenyl-propionic acid lactone, methyl 2-[2-formyl-5-(methoxymethyl)-1H-pyrrol-
1-yl]-3-(4-hydroxyphenyl)propanoate, 2-(5
0
- hydroxymethyl-2
0
-formylpyrrol-1
0
-yl)-3-(4-hydroxyphenyl)-
propionic acid lactone, 2-(5-hydroxymethyl- 2-formylpyrrole-1-yl)propionic acid lactone,
2-(5-hydroxymethyl-2-formylpyrrol-1-yl)isovaleric acid lactone, 2-(5-hydroxymethyl-2-formylpyrrole-
1-yl)isocaproic acid lactone and 2-[2-formyl-5-(hydroxymethyl)-1-pyrrolyl-]3-methylpentanoic
acid lactone.
Nati´c, et al. [
31
] isolated epigallocatechin, epigallocatechin gallate, gallocatechin, gallocatechin
gallate, isorhamnetin glucuronide, isorhamnetin hexoside, isorhamnetin hexosylhexoside, kaempferol
glucuronide, kaempferol hexoside, kaempferol hexosylhexoside, kaempferol rhamnosylhexoside,
morin and naringin from mulberry fruits grown in Vojvodina, North Serbia. Quercetin glucoronide,
quercetin hexoside, quercetin hexosylhexoside, quercetrin from mulberry fruits were also isolated
using ultra HPLC (UHPLC) system coupled to a high resolution mass spectrophotometer [
31
].
In addition, the authors [
31
] also reported the presence of cyanidin galloylhexoside, cyanidin
hexoside, cyanidin hexosylhexoside, cyanidin pentoside, cyanidin rhamnosylhexoside, delphinidin
acetylhexoside, delphinidin hexoside, delphinidin rhamnosylhexoside, pelargonidin hexoside,
pelargonidin rhamnosylhexoside and petunidin rhamnosylhexoside from mulberry fruits.
Qin, et al. [
32
] isolated cyanidin 3-O-glucoside, cyanidin 3-O-rutinoside,
pelargonidin 3-O-glucoside and pelargonidin 3-O-rutinoside ultraviolet-visible from
mulberry fruits grown in Shaanxi, China using UV-Visible spectroscopy, HPLC-pulsed
amperometric detector (PAD), LC-MS and proton nuclear magnetic resonance
(1HNMR). Du, et al. [
33
] isolated cyanidin 3-O-
β
-D-galactopyranoside, cyanidin
3-O-
β
-D-glucopyranoside and cyanidin 7-O-
β
-D-glucopyranoside from mulberry fruits
bought from local stores in Hangzhou, China. In addition, the authors [
33
] also
isolated cyanidin 3-O-(6
00
-O-
α
-rhamnopyranosyl-
β
-D-galactopyranoside) and cyanidin
Antioxidants 2018,7, 69 4 of 13
3-O-(6
00
-O-
α
-rhamnopyranosyl-
β
-D-glucopyranoside) from mulberry fruits. While Memon, et al. [
34
]
isolated gallic acid, protocatechuic acid, protocatechuic aldehyde, p-hydroxybenzoic acid, vanillic acid,
chlorogenic acid, syringic acid, syringealdehyde and m-coumaric acid from mulberry fruits grown
in Pakistan. A study by Peng, et al. [
35
] identified eight major compounds which were gallic acid,
chlorogenic acid, protocatechuic acid, rutin, caffeic acid, 3-caffeoyl quinic acid, 4-caffeoyl quinic acid
and quercetin-3-O-glucoside in mulberry fruit water extract.
Another study by Kim, et al. [
36
] identified four pyrrole alkaloids from mulberry
fruits planted in Chonbuk, Korea which were 2-formyl-5-(hydroxymethyl)-1H-pyrrole-1-butanoic
acid, 5-(hydroxymethyl)-1H-pyrrole-2-carboxaldehyde, 2-formyl-1H-pyrrole-1-butanoic acid and
2-formyl-5-(methoxymethyl)-1H-pyrrole-1-butanoic acid. In addition, the authors [
36
] also isolated
a new pyrrole alkaloid, which was morrole A. All the structures of isolated pyrrole alkaloids were
determined using 1D and 2D nuclear magnetic resonance (NMR) analyses [36].
Isabelle, et al. [
37
] reported the presence of 3-caffeoyl quinic acid, 5-caffeoyl quinic
acid, cyanidin-3-glucoside, 4-caffeoyl quinic acid, cyanidin-3-rutinoside, pelargonidin-3-glucoside,
rutin, quercetin and kaempferol-3-rutinoside in the Chinese mulberry fruit cultivar Guo-2.
In addition, the authors [
37
] also found the presence of
α
-tocopherol,
α
-tocotrienol,
δ
-tocopherol,
γ
-tocopherol,
β
-carotene, lutein, neoxanthin and violaxanthin in the Chinese mulberry fruit
cultivar Bei-2-5, Guiyou-154, Heipisang, Xuan-27 and Tang-10. Rutin, 1-deoxynojirimycin (DJN),
cyanidin-3-O-
β
-glucoside, cyanidin-3-O-
β
-rutinoside, resveratrol and oxyresveratrol were also present
in the Chinese mulberry fruits [38,39].
Wang, Xiang, Wang, Tang and He [
15
] isolated quercetin-3-O-
β
-D-glucopyranoside,
quercetin 3-O-(6
00
-O-acetyl)-
β
-D-glucopyranoside, quercetin 3-O-
β
-D-rutinoside, quercetin
7-O-
β
-D-glucopyranoside, quercetin 3,7-di-O-
β
-D-glucopyranoside, kaempferol 3-O-
β
-D-glucopyranoside,
kaempferol 3-O-
β
-D-rutinoside, isobavachalcone, 2,4,2
0
,4
0
,-tetrahydroxy-3
0
-(3-methyl-2-butenyl)-
chalcone (morachalcone), (2E)-1-[2,3-dihydro-4-hydroxy-2-(1-methylethenyl)-5-benzofuranyl]-3-(4-
hydroxyphenyl)-1-propanone, 5,7,3
0
-trihydroxy-flavanone-49-O-
β
-D-glucopyranoside, 5,7,4
0
-trihydroxy-
flavanone-3
0
-O-
β
-D-glucopyranoside, dihydrokaempferol 7-O-ß-D-glucopyranoside, 2-O-(3,4-
dihydroxybenzoyl)-2,4,6-trihydroxyphenylacetic acid, 2-O-(3,4-dihydroxybenzoyl)-2,4,6-
trihydroxyphenylmethylacetate (jaboticabin), p-hydroxybenzoic acid, protocatechuic acid, 3-methoxy-4-
hydroxybenzoic acid (vanillic acid), protocatechuic acid methyl ester, protocatechuic acid ethyl ester,
4-hydroxyphenylacetic acid methyl ester, 5,7-dihydroxychromone, 2-(4-hydroxyphenyl)ethanol
(tyrosol) and pyrocatecholin in ethyl acetate-soluble extract of mulberry fruits. The authors [
15
]
determined the structures of isolated compounds based on MS and NMR analysis.
Jiang and Nie [
40
] reported that mulberry fruit cultivar Hetianbaisang contains many types
of essential amino acids (i.e., isoleucine, leucine, threonine, lysine, valine, phenylalanine, tyrosine,
tryptophan, histidine, methionine and cysteine) and seven non-essential amino acids (i.e., arginine,
alanine, proline, glutamic acid, glycine, serine and aspartic acid). In addition, the authors [
40
]
also found the presence of minerals including potassium, calcium, magnesium, iron, sodium,
zinc, copper, selenium and manganese in mulberry fruit cultivar Hetianbaisang. Mulberry fruit cultivar
Hetianbaisang also contains organic acids including malic acid, succinic acid, citric acid, tartaric acid,
acetic acid [
40
]. In addition, linoleic acid, myristic acid, stearic acid, palmitic acid and
α
-linoleic acid
were also detected in mulberry fruit cultivar Hetianbaisang [40].
Yang, Yang and Zheng [
11
] reported that the total phenolics, total flavonoids and anthocyanins in
the freeze-dried powder of mulberry fruits were 23.0 mg/g gallic acid equivalents, 3.9 mg/g rutin
equivalents, 0.87 mg/g cyanidin-3-glucoside equivalents, respectively. The major flavonol in mulberry
fruit powder was rutin (0.43 mg/g), followed by morin (0.16 mg/g), quercetin (0.01 mg/g) and
myricetin (0.01 mg/g) [
11
]. HPLC was used to determine the flavonols in mulberry fruit powder [
11
].
In addition, the freeze-dried powder of mulberry fruits also contained 1.20 mg/g ascorbic acid,
0.32 mg/g vitamin E and 243.0 mg/g dietary fibre [11].
Antioxidants 2018,7, 69 5 of 13
Fatty acid content and composition of mulberry can vary according to different ecological
conditions. For example, Yang, Yang and Zheng [
11
] found that Chinese mulberry fruits had 7.55%
total lipids, with 87.5% of unsaturated fatty acids. The highest fatty acid content in Chinese mulberry
fruits was linoleic acid C18:2 (79.4%), followed by palmitic acid C16:2 (8.6%) and oleic acid C18:1
(7.5%) [
11
]. In addition, Chinese mulberry also contained 0.6%
α
-linolenic acid C18:3 [
11
]. Although
the highest fatty acid content in Turkish mulberry was linoleic acid C18:2 (57.3%) followed by palmitic
acid C16:0 (22.4%); no presence of linolenic acid C18:3 was reported [7].
Different colours of mulberry fruits (M. alba L) such as red, purple and purple-red have been
reported [
41
]. Aramwit, Bang and Srichana [
41
] reported that purple mulberry fruit extract had higher
contents of total sugars and anthocyanins than red and purple-red mulberry fruit extracts. This is
because sugars are needed as the precursors to synthesis anthocyanins [
41
]. However, red mulberry
fruit had a higher ascorbic acid and ß-carotene than purple and purple-red mulberry fruit extracts [
41
].
Many volatile compounds have also been found in mulberry fruits [
42
]. Calin-Sanchez,
Martinez-Nicolas, Munera-Picazo, Carbonell-Barrachina, Legua and Hernandez [
42
] reported
that volatile compounds found in mulberry fruits grown in Spain included acetic acid,
3-hydroxyl-2-butanone, ethyl butyrate, ethyl acetate, 3-methylbutanal, 2-methybutanal, heptanal,
methional, hexanal, trans-2-hexanal, 2-octenone,hexanoic acid, benzaldehyde, methyl hexanoate,
2-ethylhexanal, octanal, limonene, 6-methyl-5-hepten-2on, ethyl hexanoate, 2,4-nonanadienal,
phenylacetaldehyde, trans-2-octenal, cis-
α
-ocimene, terpinonene, 2-nonanone, nonanal, octanoic acid,
cis-2-nonenal, dodecanoic acid, terpinen-4-ol, ethyl octanoate, ethyl dodecanoate, decanal, decanoic
acid and ethyl decanoate. The authors [
42
] suggested that these volatile compounds in mulberry fruits
might present better sensory profiles for the market demands from consumers.
Chen, et al. [
43
] reported that the levels of phenolic compounds in mulberry fruits are higher than
blackberry, blueberry, raspberry and strawberry, suggesting that mulberry fruits can be used as good
sources of phenolic compounds. Therefore, mulberry fruits are rich in diverse phenolic compounds
including polyhenols, anthocyanins and flavonoids.
3. Pharmacological Properties
As mentioned previously, mulberry fruits are rich in anthocyanins [
44
], which have attracted
attention of researchers and consumers because of their potential pharmacological activities on
health [
45
–
49
]. Anthocyanins from mulberry fruits can inhibit the oxidation of low-density lipoprotein
(LDL) and scavenge free radicals [
33
,
50
]. Many studies have showed that mulberry leaves exhibit
a wide range of pharmacological activities [
51
–
57
]. However, there are limited studies that have
been conducted on the pharmacological properties of mulberry fruits [
15
,
58
,
59
]. Also, most studies
have been conducted in animal models using mulberry fruits as a dietary supplement [
15
,
58
,
59
].
Although existing literature shows that there is relationship between mulberry fruit consumption and
improved health outcomes, these studies often infer a causal correlation between a bioactive substance
of mulberry fruits and the observed health outcomes. This approach is more likely to oversimplify the
complicated body mechanisms that will eventually lead to the observed health outcomes. Therefore,
the conclusions based on such studies should always be interpreted with caution [
60
] because the
observed health outcomes may not be attributed to the action of a single bioactive compound of
mulberry fruits.
3.1. Hypolipidemic
Cardiovascular disease (CVD) is one of the most common causes of deaths, with about 17 million
people die of CVD (including stroke and coronary heart disease) every year worldwide [
61
,
62
]. It is
estimated that CVD will continue to be the largest contributor to global mortality in the future [
63
]
Hyperlipidemia is one of the major risk factors for CVD [
64
]. Therefore, an increasing focus has been
reported in research studies that determine the effectiveness of natural alternative medicine in reducing
Antioxidants 2018,7, 69 6 of 13
blood lipid levels [
11
]. This is because majority of the hypolipidemic drugs can potentially cause side
effects and they are expensive [11].
Yang, Yang and Zheng [
11
] reported that rat fed with high fat diet supplemented with 5% or 10%
mulberry fruit powder had a significant decrease in the concentration of serum and liver triglyceride,
total cholesterol and serum LDL cholesterol. An increase in the serum high-density lipoprotein (HDL)
cholesterol was reported in rat fed with high fat diet supplemented with 5% or 10% mulberry fruit
powder [
11
]. It is suggested that the presence of dietary fiber in mulberry fruits inhibits the hepatic
lipogenesis and increases LDL-receptor activity [
65
]. In addition, the authors suggested that mulberry
fruits might have a hypolipidemic effect because mulberry fruits have high content of dietary fiber
and linoleic acid [11].
Chen, Liu, Hsu, Huang, Yang and Wang [
50
] reported that New Zealand white rabbits fed with
high cholesterol diet (HCD) (containing 95.7% standard Purina chow, 3% lard oil and 1.3% cholesterol)
plus 0.5% or 1.0% water extract of mulberry fruits for 10 weeks had lower levels of total cholesterol,
LDL cholesterol, and triglycerides than those fed with only lard oil diet. The authors [
50
] also showed
that rabbits fed with HCD plus 0.5% or 1.0% water extract of mulberry fruits had significantly reduced
severe atherosclerosis in the aorta by 42–63% and these findings were supported by histopathological
examination of blood vessel of rabbits. The effect of water extract of mulberry fruits on the levels of
total cholesterol and LDL cholesterol was reported to be dose-dependent [
50
]. No adverse effects on
the changes of liver or renal functions in rabbits fed with HCD plus 0.5% or 1.0% water extract of
mulberry fruits were reported [50].
In a randomised controlled study of 58 hypercholesterolemic adults aged 30–60 years,
Sirikanchanarod, et al. [
66
] reported that after 6 weeks of 45 g freeze-dried mulberry fruit consumption
(325 mg anthocyanins), the intervention group had a significantly lower level of total cholesterol
and LDL (both p-values < 0.001) than the control group. The authors [
66
] suggested that mulberry
fruits might be used as an alternative treatment for hypercholesterolemic patients. Therefore,
the consumption of mulberry fruits might reduce the risk of atherosclerosis because mulberry fruits
possess anti-hyperlipidemic and anti-oxidative abilities to prevent the oxidation of LDL [50].
3.2. Anti-Diabetic
Diabetes is characterised by hyperglycemia which results from the defects of secretion of
insulin [
67
]. It is associated with a series of health complications including CVD and failure of
various organs [
67
]. Jiao, Wang, Jiang, Kong, Wang and Yan [
59
] reported that diabetic rats fed
with two different fractions of mulberry fruit polysaccharides (MFP50 and MFP90) for seven weeks
had a significant decrease in the levels of fasting glucose, fasting serum insulin, homeostasis
model of assessment-insulin resistance, triglyceride and oral glucose tolerance test-area under the
curve. The MFP50 and MFP90 had a final ethanol concentration of 50% and 90%, respectively [
59
].
When compared with diabetic rats fed with pure water, diabetic rats fed with MFP50 and MFP90 had
a lower serum insulin level at a rate of 26.5% and 32.5%, respectively [
59
]. The MFP50 group had
a significant increase in the level of HDL cholesterol and the proportion of HDL cholesterol to total
cholesterol [
59
]. The authors [
59
] also found that both MFP50 and MFP90 reduced the levels of serum
alanine transaminase (ALT), suggesting that they have potential hepatoprotective effects. Although
MFP50 had a more stable hypoglycemic effect than MFP90, MFP90 had a better hypolipidemic effect
than MFP50 [59].
Similar findings were also reported by Guo, Li, Zheng, Xu, Liang and He [
58
] who found that
diabetic rats fed with mulberry fruit polysaccharides for 2 weeks had a decrease in fasting blood
glucose. Another study by Wang, Xiang, Wang, Tang and He [
15
] reported that diabetic rats fed
with ethyl acetate-soluble extract of mulberry fruits for 2 weeks had a significant decrease in the
levels of fasting blood glucose and glycosylated serum protein. The authors [
15
] also found that
ethyl acetate-soluble extract of mulberry fruits had significantly increased the antioxidant activities
of catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in diabetic
Antioxidants 2018,7, 69 7 of 13
rats. Ethyl acetate-soluble extract of mulberry fruits also possesses strong
α
-glucoside inhibitory
activity and radical-scavenging activities against 2,2-diphenyl-1-picrylhdrazyl (DPPH) and superoxide
anion radicals [
15
]. A study by Xu, et al. [
68
] reported that diabetic mice fed with mulberry fruit
polysaccharides had a lower level of haemoglobin A1c (HbA1c) and a reduction in streptozotocin
(STZ)-lesioned pancreatic cells. In addition, diabetic mice fed with mulberry fruit polysaccharides also
had an increase in insulin level and B-cell lymphoma 2 (bcl-2) expression [68].
Yan, et al. [
69
] reported that male C57BL6/J genetic background (db/db) mice fed with
anthocyanin extract of mulberry fruit in the doses of 50 and 125 mg/kg body weight per day for
8 weeks had a significant decrease in the levels of cholesterol, fasting blood glucose, leptin, serum
insulin and triglyceride as well as an increase in adiponectin level. Therefore, the authors [
69
] suggested
that anthocyanin extract of mulberry fruit can be used to improve the resistance of insulin and leptin.
Taken together, these results [
15
,
58
,
59
] suggest that mulberry fruits might play an important role in the
treatment of diabetes because of their anti-hyperglycemic and anti-hyperlipidemic effects.
3.3. Anti-Obesity
Several studies have shown that obesity plays a major role in contributing to dyslipidemia [
70
–
73
].
Lim, et al. [
74
] reported that high fat diet-induced obese mice fed with a combination of mulberry leaf
extract and mulberry fruit extract at low and high doses had a significant decrease in body weight gain,
fasting plasma glucose, insulin and homeostasis model assessment of insulin resistance. The low dose
of combination of mulberry leaf extract and mulberry fruit extract was 133 mg mulberry leaf extract and
67 mg mulberry fruit extract/kg/day, while the high dose of combination of mulberry leaf extract and
mulberry fruit extract was 333 mg mulberry leaf extract and 167 mg mulberry fruit extract/kg/day [
74
].
The high dose of combination of mulberry leaf extract and mulberry fruit extract had significantly
improved the glucose control [
74
]. In addition, the high dose of combination of mulberry leaf extract
and mulberry fruit extract also decreased the protein levels of manganese superoxide dismutase,
inducible nitric oxide synthase, monocyte chemoattractant protein-1, C-reactive protein (CRP), tumour
necrosis factor-
α
and interleukin-1 [
74
]. Therefore, it is suggested that the combination of mulberry leaf
extract and mulberry fruit extract possess the anti-obesity and anti-diabetic properties by modulating
oxidative stress and inflammation induced by obesity [74].
Peng, Liu, Chuang, Chyau, Huang and Wang [
35
] reported that male hamsters fed with
mulberry fruit water extract for 12 weeks had a lower high fat diet-induced body weight and
visceral fat, accompanied with a decrease in serum triacylglycerol, cholesterol, LDL/HDL ratio
and free fatty acid. In addition, mulberry fruit water extract also reduced fatty acid synthase and
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and elevated hepatic peroxisome
proliferator-activated receptor αand carnitine palmitoyltransferase-1 [35]. No physiological burdens
in terms of levels of serum blood urea nitrogen, creatinine, potassium and sodium ions were exerted
by the administration of mulberry fruit extract [
35
]. The authors [
35
] suggested that mulberry fruit
water extracts regulate lipolysis and lipogenesis, which can be used to reduce the body weight.
3.4. Anti-Tumour
Gastrointestinal tract cancers are also one of the most common types of cancers in the world [
75
,
76
]
and Helicobacter pylori is one of the common suspects in triggering the gastric carcinogenesis [
77
,
78
].
Huang, et al. [
79
] reported that after male balb/c nude mice were fed with anthocyanin-rich mulberry
fruit extract for 7 weeks, atypical glandular cells (AGS) tumour xenograft growth in mice was inhibited,
suggesting that anthocyanins from mulberry fruits might be used to prevent gastric carcinoma formation.
3.5. Hepatoprotective
In a study investigating the protective effect of mulberry fruit marc (the solid component after
juicing) anthocyanins on carbon tetrachloride (CC14)-induced liver fibrosis in male Sprague Dawley
rats, Li, et al. [
80
] reported that rats fed with mulberry fruit marc anthocyanins had a decrease in the
Antioxidants 2018,7, 69 8 of 13
levels of ALT, aspartate amino transferase, collagen type-III hyaluronidase acid and hydroxyproline.
Another study by Chang, et al. [
81
] reported that mulberry fruit extracts suppressed the synthesis and
enhanced the oxidation of fatty acids. Therefore, the mulberry fruits might prevent the non-alcoholic
fatty liver disease.
3.6. Protective against Cytotoxicity and Oxidative Stress
In a study investigating the protective effect of mulberry fruit extract against ethyl carbamate
(EC)-induced cytotoxicity in human liver HepG2 cells, Chen, Li, Bao and Gowd [
43
] reported no
decrease in cell viability with the treatments of mulberry fruit extract (0.5 mg/mL, 1.0 mg/mL and
2.0 mg/mL). Therefore, the authors [
43
] suggested that mulberry fruits can be used to protect against
EC-induced cytotoxicity and oxidative stress. Also, in a study investigating the effect of mulberry fruit
consumption on the anti-fatigue activity in mice using a weight-loaded swimming test, Jiang, Guo, Xu,
Huang, Yuan and Lv [
44
] reported that mice fed with mulberry juice purification and mulberry marc
purification had an increase endurance capacity than the control group. The authors [
44
] suggested that
the presence of anthocyanins in mulberry fruits might act as an antioxidant to reduce exercise-induced
oxidative stress and physical fatigue.
3.7. Protective against Brain Damage
Kang, Hur, Kim, Ryu and Kim [
17
] reported that that C3G isolated from mulberry fruit extracts
had shown a cytoprotective effect on PC12 cells exposed to hydrogen peroxide
in vitro
and a
neuroprotective effect on cerebral ischemic damage caused by oxygen glucose deprivation (OGD)
in vivo
. Therefore, it is suggested that mulberry fruits possess neuroprotective effects
in vivo
and
vitro ischemic oxidative stress [
17
]. Table 1shows an overview of animal studies investigating the
pharmacological properties of mulberry fruits.
Table 1.
An overview of animal studies investigating the pharmacological properties of mulberry fruits.
Pharmacological Properties References
Hypolipidemic
Yang et al. [
11
]; Chen et al. [
50
]; Sirikanchanarod et al. [
66
]
Anti-diabetic Wang et al. [15]; Jiao et al. [59]; Guo et al. [58];
Xu et al. [68]; Yan et al. [69]
Anti-obesity Peng et al. [35]; Lim et al. [74]
Anti-tumour Huang et al. [79]
Hepatoprotective Li et al. [80]; Chang et al. [81]
Protective against cytotoxicity and oxidative stress Jiang et al. [44]; Chang et al. [81]
Protective against brain damage Kang et al.[17]
3.8. Adverse Effects
Due to a limited number of human studies, it is difficult to assess the safety of mulberry fruit
consumption. Moreover, there is insufficient evidence regarding the recommended consumption of
mulberry fruits (i.e., dosage) and its treatment duration. It is necessary that all future clinical studies that
investigate the effects of mulberry fruit consumption on health should follow the Consolidated Standards
of Reporting Trials (CONSORT) guidelines for generating scientifically rigorous evidence [82–84].
4. Conclusions and Future Research
Literature reviews have highlighted that mulberry fruits contain high content of polyphenolic
compounds and antioxidants [
85
]. This suggests that there are many opportunities for the food and
healthcare industry to explore the health benefits of mulberry fruits because there is a potential growing
market for mulberry fruits. However, the contents of bioactive compounds such as anthocyanins,
alkaloids, flavonoids and polyphenols are dependent on the cultivars. Although the bioactive
compounds may work synergistically to promote health, such claims still require further investigation
in order to establish the causative relationship between mulberry fruit consumption and health.
Antioxidants 2018,7, 69 9 of 13
There are limited studies with sufficient data to support whether mulberry fruits are beneficial
to human health especially in terms of the management and prevention of chronic diseases such as
diabetes and CVD. The majority of the studies that reported beneficial effects of mulberry fruits on
health are animal-based studies. Moreover, these studies used different varieties of mulberry fruits,
types of solvents and methods of preparation, which cause the evaluation of activity of mulberry fruits
to be difficult and these studies involve quite heterogeneous data. Therefore, larger well-designed,
randomised controlled trials are needed to examine the effects of mulberry fruit consumption on human
health. Similar to other plants and food products [
1
,
86
], the fate of polyphenol compounds in the body,
especially after undergoing intestinal transformations by enzymes produced by gut microbiota should
also be addressed. The elucidation of some active ingredient structures in mulberry fruits and their
mechanisms in promoting pharmacological properties are also worthy of further research.
Author Contributions:
The project idea was developed by Z.F.M. Z.F.M. wrote the first draft of the manuscript.
Z.F.M., H.X., X.L. and X.L. conducted the literature search and revised the manuscript.
Acknowledgments: The authors received no specific funding for this work.
Conflicts of Interest: The authors declare no conflict of interest.
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