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Phytochemistry, pharmacology, and clinical trials of Morus alba

Article · January 2016

DOI: 10.3724/SP.J.1009.2016.00017

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 Chinese
Journal of
Natural
Chinese Journal of Natural Medicines 2016, 14(1): 00170030 Medicines
doi: 10.3724/SP.J.1009.2016.00017

·Review·

Phytochemistry, pharmacology, and clinical trials of Morus alba

Eric Wei-Chiang CHAN 1*, Phui-Yan LYE 1, Siu-Kuin WONG 2
1
Faculty of Applied Sciences, UCSI University, 56000 Cheras, Kuala Lumpur, Malaysia;
2
School of Science, Monash University Sunway, 46150 Petaling Jaya, Selangor, Malaysia
Available online 20 Jan., 2016

[ABSTRACT] The present review is aimed at providing a comprehensive summary on the botany, utility, phytochemistry,
pharmacology, and clinical trials of Morus alba (mulberry or sang shu). The mulberry foliage has remained the primary food for
silkworms for centuries. Its leaves have also been used as animal feed for livestock and its fruits have been made into a variety of food
products. With flavonoids as major constituents, mulberry leaves possess various biological activities, including antioxidant,
antimicrobial, skin-whitening, cytotoxic, anti-diabetic, glucosidase inhibition, anti-hyperlipidemic, anti-atherosclerotic, anti-obesity,
cardioprotective, and cognitive enhancement activities. Rich in anthocyanins and alkaloids, mulberry fruits have pharmacological
properties, such as antioxidant, anti-diabetic, anti-atherosclerotic, anti-obesity, and hepatoprotective activities. The root bark of
mulberry, containing flavonoids, alkaloids and stilbenoids, has antimicrobial, skin-whitening, cytotoxic, anti-inflammatory, and
anti-hyperlipidemic properties. Other pharmacological properties of M. alba include anti-platelet, anxiolytic, anti-asthmatic,
anthelmintic, antidepressant, cardioprotective, and immunomodulatory activities. Clinical trials on the efficiency of M. alba extracts in
reducing blood glucose and cholesterol levels and enhancing cognitive ability have been conducted. The phytochemistry and
pharmacology of the different parts of the mulberry tree confer its traditional and current uses as fodder, food, cosmetics, and medicine.
Overall, M. alba is a multi-functional plant with promising medicinal properties.

[KEY WORDS] Mulberry; Multi-purpose; Medicinal properties; Morus alba

[CLC Number] Q5 [Document code] A [Article ID] 2095-6975(2016)01-0017-14

Introduction
Morus alba L. (mulberry or sang shu) has long been used
as fodder and traditional medicine. There has been much
research work that has been done since several published
reviews on the species [1-4]. Herein, we attempted to
provide a comprehensive update on its botany, applications,
phytochemistry, medicinal properties, and clinical trials.
Morus alba L. of the family Moraceae is native to Chinaand
is also widely cultivated in Japan and Korea [5-6]. The
species is a fast-growing tree, which can reach up to 20
meters in height. Under cultivation with regular harvesting,
pruning, and pollarding, the trees are reduced to a
low-growing bush to facilitate the harvesting of leaves or
fruits. The bark is dark grey-brown with horizontal lenticels.
The leaves are glossy green, alternate, cordate at the base,
[Received on] 04-Feb.-2015
[*Corresponding author] E-mail: chanwc@ucsiuniversity.edu.my.
These authors have no conflict of interest to declare.
Published by Elsevier B.V. All rights reserved
and acuminate at the apex, the margins are serrated, and the
petioles are long and slender. Varying from 5.0−7.5 cm in
length, the leaves are very variable in form. Even on the
same tree, some are unlobed while others may be almost
palmate. In the temperate and sub-tropical areas, the trees
are commonly dioecious (separate male and female plants),
but may be monoecious (male and female flowers on the
same plants), and sometimes can change from one sex to
another. The flowers comprising male and female catkins
are inconspicuous, pendulous, and greenish. The fruit
consists of many drupes formed by individual flowers to
form a sorosis, the characteristic mulberry fruit. The fruit
color is green when young, turning orange to red and finally
to purplish black when fully ripened. Fig. 1 shows the
leaves and fruits of M. alba.
Mulberry foliage is valued as the primary food for
silkworms, supporting the silk industry for centuries [7-9]. The
silkworm eats only mulberry leaves to make its cocoon, which
produces the silk, and there is a high correlation between the
content of leaf protein and the efficiency of cocoon
production [9]. The amino acids (threonine, valine, methionine,

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 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730
Fig. 1 Leaves and fruits of Morus alba
leucine, phenylalanine, lysine, histidine, and arginine) found
in mulberry leaves are needed for silkworm growth. It is well
established that the growth of silkworms as well as the
cocoon and raw silk quality depend on the quality of mulberry
leaves, which in turn is closely related to the plant varieties,
environmental conditions, and cultivation practice [10]. In
China, 15−18 kg of mulberry leaves is needed to produce 1 kg
of cocoon at the farm level [7].
Mulberry leaves are also used as fodder for livestock.
They are nutritious, palatable, and non-toxic and can improve
milk production when fed to dairy animals [11]. The high crude
protein content and organic matter digestibility of mulberry
leaves are superior to most tropical grasses commonly used as
cattle feed [12].
In traditional Chinese medicine (TCM), leaves, fruits,
and bark of M. alba have long been used to treat fever, protect
liver damage, improve eyesight, strengthen joints, facilitate
discharge of urine, and lower blood pressure [13]. In Korea and
Japan, patients with diabetes consume mulberry leaves as an
anti-hyperglycemic supplement [14]. Mulberry leaves are
effective against high blood pressure and hangover from
alcohol and in lowering blood sugar level related to
diabetes [9]. In East and Southeast Asia, the drinking of
mulberry tea is gaining popularity. The tea is rich in
γ-aminobutyric acid (2.7 mg·g−1 dry weight) which is 10
times higher than that of green tea [6]. The compound is
known to lower blood pressure.
In Turkey and Greece, trees of M. alba are grown for
fruits rather than foliage [15]. The fruits are used to produce
mulberry juice, jam, liquor, and canned mulberries. In China,
the leaves of M. alba are processed into tea while fruit juice
is consumed as a health beverage [7]. Other uses of mulberry
include paper and mushroom production [9]. Woodchips of
mulberry trees have been used as pulp for paper production
and as media for mushroom culture. In India, mulberry
– 18 –
wood is made into sports equipment, furniture, household
utensils, and agricultural implements [8].
Phytochemistry
Photochemical studies have identified terpenoids,
alkaloids, flavonoids (including chalcones and anthocyanins),
phenolic acids, stilbenoids, and coumarins in Morus alba.
Compounds isolated from the leaf, fruit, root, bark, root bark,
twig, and stem of the plant are listed in Table 1. Mulberry
fruits yield the most number of compounds.
Leaf
Three flavonol glycosides, quercetin 3-(6-malonylglucoside),
rutin, and isoquercitrin, are identified as the major antioxidant
compounds in the ethanol leaf extract of M. alba [14]. Their
contents are 9.0, 5.7, and 1.9 mg·g−1 dry weight, respectively.
From the ethanol leaf extract of mulberry, four new
2-arylbenzofuran derivatives (moracins V−Y), together with
two known compounds (moracins N and P) are isolated [37].
From the butanol leaf extract, two novel prenylflavanes and a
glycoside, along with six known compounds, isoquercitrin,
astragalin, scopolin, skimmin, roseoside II, and benzyl
D-glucopyranoside, are isolated [23]. From the methanol leaf
extract, a new and ten known flavonoids are isolated [21] (Fig. 2).
From the ethanol leaf extract of M. alba, morachalcones
B and C have been isolated [19]. They are unusual chalcones
having a five-membered furan ring with an oxygen molecule.
Further bioassay-guided fractionation of the extract leads to
the isolation of 15 flavonoids, including five new
compounds [24].
Fruit
Extraction of fresh fruits of M. alba has yielded five
anthocyanins [33]. From the ethanol fruit extract of M. alba,
bioactivity-guided fractionation has led to the isolation of 25
phenolic compounds, all of which are isolated from the
mulberry fruit for the first time [20]. Some of the phyto-
chemicals and their molecular structures are shown in Fig. 3.
 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730

Table 1 Classes and names of compounds isolated from the various parts of Morus alba
Compound class and name Part Reference
Terpenoids
Betulinic acid Root bark [30]
Ursolic acid Root bark [30]
Uvaol Root bark [30]
Alkaloids
Calystegins B2, C1 Root [18]
1-Deoxynojirimycin Root [18]
2α, 3β-Dihydroxynortropane Fruit [16]
2β, 3β-Dihydroxynortropane Fruit [16]
3β, 6exo-Dihydroxynortropane Fruit [16]
1, 4-Dideoxy-1, 4-imino-pD-arabinitol Root [18]
1, 4-Dideoxy-1, 4-imino-pD-ribitol Root [18]
1, 4-Dideoxy-1, 4-imino-(2-O-β-pD-glucopyranosyl)-d-glucopyranosyl)-D-arabinitol Root [18]
Fagomine Root [18]
3-epi-Fagomine Root [18]
2-[2-Formyl-5-(hydroxymethyl)-1-pyrrolyl-]3-methyl pentanoic acid lactone Fruit [17]
4-[Formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl] butanoate Fruit [17]
4-[Formyl-5-(methoxymethyl)-1H-pyrrol-1-yl] butanoic acid Fruit [17]
2-O-α-D-Galactopyranosyl-1-deoxynojirimycin Root [18]
6-O-α-D-Galactopyranosyl-1-deoxynojirimycin Root [18]
2-O-α-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
3-O-α-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
4-O-α-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
2-O-β-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
3-O-β-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
4-O-β-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
6-O-β-D-Glucopyranosyl-1-deoxynojirimycin Root [18]
2-(5′-Hydroxymethyl-2′-formylpyrrol-1′-yl)-3-(4-hydroxyphenyl) propionic lactone Fruit [17]
2-(5′-Hydroxymethyl-2′-formylpyrrol-1′-yl)-3-phenylpropionic acid lactone Fruit [17]
2-(5-Hydroxymethyl-2′, 5′-dioxo-2′, 3′, 4′, 5′-tetrahydrobipyrrole) carbaldehyde Fruit [17]
2-(5-Hydroxymethyl-2-formylpyrrol-1-yl) isovaleric acid lactone Fruit [17]
2-(5-Hydroxymethyl-2-formylpyrrole-1-yl) propionic acid lactone Fruit [17]
2-(Hydroxymethyl-2-formylpyrrole-1-yl) isocaproic acid lactone Fruit [17]
N-Methyl-1-deoxynojirimycin Root [18]
Methyl 2-[2-formyl-5-(methoxymethyl)-1H-pyrrol-1-yl]-3-(4-hydroxyphenyl) propanoate Fruit [17]
Methyl 2-[2-formyl-5-(methoxymethyl)-1H-pyrrole-1-yl] propanoate Fruit [17]
Morroles B−F Fruit [17]
2α, 3β, 4α-Trihydroxynortropane Fruit [16]
2α, 3β, 6exo-Trihydroxynortropane Fruit [16]
Chalcones
Morachalcones B, C Leaf [19]
Flavonoids
Astragalin Leaf [23]
Atalantoflavone Leaf [21]

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 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730

Continued
Compound class and name Part Reference
Benzyl d-glucopyranoside Leaf [23]
Cyclomorusin Leaf, Root bark [21, 23, 27]
Cyclomulberrin Leaf [21]
Dihydrokaempferol 7-O-β-D-glucopyranoside Leaf [20]
3′, 8-Diprenyl-4′, 5, 7-trihydroxyflavone Leaf [21]
Epigallocatechin Fruit [25]
Epigallocatechin gallate Fruit [25]
Euchrenone a7 Leaf [24]
Gallocatechin Fruit [25]
Gallocatechin gallate Fruit [25]
6-Geranylapigenin Twig [31]
8-Geranylapigenin Leaf [21]
6-Geranylnorartocarpetin Twig [31]
7-Hydroxyl-8-hydroxyethyl-4′-methoxylflavane-2′-O-β-D-glucopyranoside Leaf [24]
8-Hydroxyethyl-7, 4′-dimethoxylflavane2′-O-β-D-glucopyranoside Leaf [24]
Isoquercitrin Leaf [14, 22, 23]
Isorhamnetin glucuronide Fruit [25]
Isorhamnetin hexoside Fruit [25]
Isorhamnetin hexosylhexoside Fruit [25]
Kaempferol Leaf [21, 24]
Kaempferol 3-O-β-D-rutinoside Leaf [20]
Kaempferol 3-O-β-D-glucopyranoside Leaf [20]
Kaempferol glucuronide Fruit [25]
Kaempferol hexoside Fruit [25]
Kaempferol hexosylhexoside Fruit [25]
Kaempferol rhamnosylhexoside Fruit [25]
Kuwanons A−C, E, G, H, J, S, T Leaf, Root bark [21, 28, 30]
7-Methoxyl-8-ethyl-2′, 4′-dihydroxylflavane-2′′-O-β-D-glucopyranoside Leaf [24]
7-Methoxyl-8-hydroxyethyl-2′, 4′-dihydroxylflavane Leaf [24]
7-Methoxyl-8-hydroxyethyl-4′-hydroxylflavane-2′-O-β-D-glucopyranoside Leaf [24]
Morin Fruit [25]
Morusin Leaf, Root bark [21, 27]
Naringin Fruit [25]
Norartocarpetin Leaf [24]
Oxydihydromorusin Root bark [28]
Quercetin Leaf, Fruit, Twig [20, 24, 25, 31]
Quercetin 3, 7-di-O-β-D-glucopyranoside Leaf [20]
Quercetin 3-O-(6′′-O-acetyl)-β-D-glucopyranoside Leaf [20]
Quercetin 7-O-β-D-glucopyranoside Leaf [20]
Quercetin-3, 7-di-O-β-D-glucopyranoside Leaf [22]
Quercetin glucuronide Fruit [25]
Quercetin hexoside Fruit [25]
Quercetin hexosylhexoside Fruit [25]
Quercetin 3-(6-malonylglucoside) Leaf [14]
Quercetrin Fruit [25]

– 20 –
 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730

Continued
Compound class and name Part Reference
Roseoside Leaf [23]
Rutin Leaf, Fruit [14, 20, 25]
Sanggenons F, J, K Leaf, Root bark [21, 30]
Scopolin Leaf [23]
Skimmin Leaf [23]
7, 2′, 4′, 6′-Tetrahydroxy-6-geranylflavanone Root [26]
5, 7, 3′-Trihydroxy-flavanone-4′-O-β-D-glucopyranoside Leaf [20]
5, 7, 4′-Trihydroxy-flavanone-3′-O-β-D-glucopyranoside Leaf [20]
Anthocyanins
Cyanidin 3-O-glucoside Fruit [34]
Cyanidin 3-O-rutinoside Fruit [34]
Cyanidin 3-O-β-D-galactopyranoside Fruit [33]
Cyanidin 3-O-β-D-glucopyranoside Fruit [33]
Cyanidin 7-O-β-D-glucopyranoside Fruit [33]
Cyanidin galloylhexoside Fruit [25]
Cyanidin hexoside Fruit [25]
Cyanidin hexosylhexoside Fruit [25]
Cyanidin pentoside Fruit [25]
Cyanidin 3-O-(6′′-O-α-rhamnopyranosyl-β-D-galactopyranoside) Fruit [33]
Cyanidin 3-O-(6′′-O-α-rhamnopyranosyl-β-D-glucopyranoside) Fruit [33]
Cyanidin rhamnosylhexoside Fruit [25]
Delphinidin acetylhexoside Fruit [25]
Delphinidin hexoside Fruit [25]
Delphinidin rhamnosylhexoside Fruit [25]
Pelargonidin 3-O-glucoside Fruit [34]
Pelargonidin 3-O-rutinoside Fruit [34]
Pelargonidin hexoside Fruit [25]
Pelargonidin rhamnosylhexoside Fruit [25]
Petunidin rhamnosylhexoside Fruit [25]
Phenolic acids
3-O-Caffeoylquinic acid Fruit [26]
5-O-Caffeoylquinic acid Leaf, Fruit [26, 35]
m-Coumaric acid Leaf, Fruit [35]
p-Coumaric acid Leaf, Fruit [26, 35]
Ellagic acid Fruit [26]
Ferulic acid Leaf, Fruit [26, 35]
Gallic acid Leaf, Fruit [26, 35]
Gentisic acid Fruit [26]
Hydroxybenzoic acid Leaf, Fruit [35]
p-Hydroxybenzoic acid Fruit [21, 26]
Hydroxyphenylacetic acid methyl ester Fruit [21]
Jaboticabin Fruit [21]
Methyl 3-O-caffeoylquinate Fruit [26]
Methyl 4-O-caffeoylquinate Fruit [26]
Methyl 5-O-caffeoylquinate Fruit [26]

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 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730

Continued
Compound class and name Part Reference
Methyl dicaffeoylquinate Fruit [26]
Protocatechuic acid Leaf, Fruit [21, 26, 35]
Protocatechuic acid ethyl ester Fruit [21]
Protocatechuic acid methyl ester Fruit [21]
Protocatechuic aldehyde Leaf, Fruit [35]
Syringaldehyde Leaf, Fruit [35]
Syringic acid Leaf, Fruit [35]
Vanillic acid Leaf, Fruit [21, 26, 35]
Stilbenoids
Alabafuran A Root bark [30]
Artoindonesianin O Root bark [30]
Chalcomoracin Leaf [24]
Dihydromorin Stem [39]
2, 3-trans-Dihydromorin-7-O-β-glucoside Stem [39]
3′, 5′-Dihydroxy-6-methoxy-7-prenyl-2-arylbenzofuran Root bark [30]
Moracins C, D, M−P, R, V−Y Leaf, Stem, Root bark [24, 30, 37, 39]
Mulberrofurans L, Y Root bark [30]
Mulberrosides A, B, F Leaf, Stem, Root bark [30, 36, 39]
Oxyresveratrol Twig, Stem [32, 39]
Oxyresveratrol 2-O-β-D-glucopyranoside Root bark [30]
Resveratrol Twig, Stem [32, 39]
Steppogenin Stem [39]
Coumarins
5, 7-Dihydroxycoumarin 7-(6-O-β-D-apiofuranosyl-β-d-glucopyranoside) Bark [38]
5, 7-Dihydroxycoumarin 7-O-β-d-apiofuranosyl-(1→6)-O-β-D-glucopyranoside Root bark [30]
5, 7-Dihydroxycoumarin 7-O-β-D-glucopyranoside Root bark [30]
6, 7-Dihydroxycoumarin 7-(6-O-α-rhamnopyranosyl-β-D-glucopyranoside) Bark [38]
Isoscopoletin 6-(6-O-β-apiofuranosyl-β-glucopyranoside) Stem [39]
Notes: compounds of each class are in alphabetical order. Anthocyanins are a sub-class of flavonoids.

3′-Geranyl-3-prenyl-2′, 4′, 5, 7-tetrahydroxyflavone

(R1 = prenyl, R2 = H, R3 = geranyl, R4 = OH)
a a
3′, 8-Diprenyl-4′, 5, 7-trihydroxyflavone
(R1 = H, R2 = prenyl, R3 = prenyl, R4 = H)

Kuwanon S (R1 = H, R2 = H, R3 = geranyl, R4 = H)

8-Geranylapigenin (R1 = H, R2 = geranyl, R3 = H, R4 = H)

b b Kaempferol (R1 = OH, R2 = H, R3 = H, R4 = H)

Morusin (R1 = prenyl, R2 = OH)

Atalantoflavone (R1 = H, R2 = H)

The new flavonoid is 3′-geranyl-3-prenyl-2′, 4′, 5, 7-tetrahydroxyflavone, and the 10 known flavonoids are 3′, 8-diprenyl-4′, 5,
7-trihydroxyflavone, kuwanon S, 8-geranylapigenin, kaempferol, morusin, atalantoflavone, cyclomulberrin, sanggenon J, sanggenon K,
and cyclomorusin.
Fig. 2 Selected flavonoids isolated from mulberry leaves [21]

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 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730

Anthocyanins
Cyanidin 3-O-(6′′-O-α-rhamnopyranosyl-β-D-glucopyranoside), Cyanidin 3-O-(6′′-O-α-rhamnopyranosyl-β-D-galactopyranoside),
Cyanidin 3-O-β-D-glucopyranoside, Cyanidin 3-O-β-D-galactopyranoside, Cyanidin 7-O-β-D-glucopyranoside
Flavonoids

a b

Quercetin (R1 = H, R2 = H)
Quercetin 3-O-β-D-glucopyranoside (R1 = H, R2 = β-D-glc)
Quercetin 3-O-(6′′-O-acetyl)-β-D-glucopyranoside (R1 = H, R2 = (6′′-O-acetyl)-β-D-glc)
a
Quercetin 3-O-β-D-rutinoside (R1 = H, R2 = α-L-rha-(1→6)-β-D-glc)
Quercetin 7-O-β-D-glucopyranoside (R1 = β-D-glc, R2 = H)
Quercetin 3,7-di-O-β-D-glucopyranoside (R1 = β-D-glc, R2 = β-D-glc)

Kaempferol 3-O-β-D-glucopyranoside (R = β-D-glc)

b
Kaempferol 3-O-β-D-rutinoside (R = α-L-rha-(1→6)-β-D-glc)
Fig. 3 Selected phytochemicals isolated from Morus alba fruits [33]

Root and root bark
From the root bark of M. alba, polyhydroxylated
alkaloids have been isolated, including 1-deoxynojirimycin
(DNJ) and its derivatives [18]. The contents of DNJ in leaves
from 132 varieties of nine Morus species are determined [40].
Of them, 58 varieties are from M. alba. The younger leaves
have higher DNJ content than the older leaves. The DNJ
contents in mature leaves of M. alba vary from 0.13−1.46
mg·g−1 dry weight. Other compounds identified from the root
and root bark include terpenoids, flavonoids, stilbenoids, and
coumarins. Some compounds isolated from the root bark of M.
alba are shown in Fig. 4.
Twig and stem
From the twig and stem of M. alba, flavonoids,
stilbenoids, and coumarins have been reported. Bioactive
compounds include mulberroside, morusin, resveratrol, and
oxyresveratrol.
Pharmacology
Antioxidant properties
Antioxidant properties of ethanol fruit extract of M. alba
have shown significant difference between varieties [13].
Mature fruits are rich in anthocyanins, which are excellent
antioxidant agents with stronger free radical scavenging
activity than vitamin C [33]. Based on total phenolic content
(TPC), free radical scavenging (FRS), ferric reducing power
(FRP), and ferrous ion chelating (FIC), our research has
shown that aqueous methanol leaf extracts of M. alba have
significantly higher values than that of fruits [41]. The
ranking is of the order: developing leaves > young leaves ~
mature leaves > mature fruits. Our recent work on the
antioxidant properties of herbs have shown that M. alba
displays enhancement effects of drying [42, 43]. Increase in
values was up to 27% for oven-drying, 16%−44% for
freeze-drying, and up to 91% for microwave-drying. Out of
12 herbal teas assessed, TPC, FRS, and FRP of M. alba tea
are in the moderate category [44]. However, its FIC value of
0.8 mg·mL−1, based on CEC50 (50% chelating efficiency
concentration), is stronger than that of green, oolong, and
black teas.
Antimicrobial activity
Kuwanon G isolated from the methanol root bark extract
of M. alba has been reported to exhibit antibacterial activity
against oral pathogens such as Streptococcus mutans,
Streptococcus sanguis, Streptococcus sobrinus, and Porphyromonas
gingivalis, with the minimum inhibitory concentration (MIC)
of 8 µg·mL−1 [45]. From the root bark, mulberrofuran G and

Fig. 4 Selected compounds isolated from the root bark of Morus alba [30]

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 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730
albanol B strongly inhibit Salmonella typhimurium,
Staphylococcus epidermis, and Staphyloccoccus aureus, with
MIC being 5.0−7.5 µg·mL−1 [46]. Besides antibacterial activity,
leaf extracts of M. alba also possess antifungal properties [47].
At concentrations of 20, 40, 60, and 80 mg·mL−1, all three
sequential leaf extracts (methanol, chloroform, and petroleum
ether) strongly inhibit Candida albicans and Aspergillus niger
with inhibition zones being 12−28 mm. Of eight flavonoids
isolated from the root bark of M. alba, leachianone G shows
potent antiviral activity (IC50 1.6 mg·mL−1), whereas
mulberroside C shows weak activity (IC50 75 mg·mL−1)
against herpes simplex type 1 virus (HSV-1) [48].
Skin-whitening properties
Mulberroside F isolated from the methanol leaf extract of
M. alba exhibits anti-tyrosinase activity that is 4.5-fold
stronger than kojic acid and hasan inhibitory effect on
melanin formation in melan-a cells [49]. Oxyresveratrol
exhibits an inhibitory activity that is 32-fold stronger than
kojic acid [50]. Oxyresveratrol with four OH-groups and
resveratrol with three OH-groups are two hydroxystilbenes
found in M. alba. At 100 μmol·L−1, their tyrosinase inhibitory
effects are 97% and 64%, compared to 77% for kojic acid [51].
The number and position of hydroxyl groups seem to play an
important role in the inhibitory effects of these compounds
[50]
. cells, deguelin (standard drug) has IC50 values of 6.4, 5.3,
Among the 15 flavonoids isolated from the ethanol leaf
extract of M. alba, norartocarpetin, euchrenone, and quercetin
display antityrosinase activity, which is significantly stronger
than kojic acid [24]. Their IC50 values are 0.08, 0.26, 0.52, and
15.9 μmol·L−1, respectively. It is noted that the flavonoids
having both the 2′-OH and 4′-OH groups are more potent
inhibitors that those with only the 4′-OH group. Using HPLC
analysis, morin, resveratrol, maclurin, rutin, isoquercitrin, and
morin are identified in the ethanol mulberry twig extract [52].
Morin (21%) and resveratrol (16%) are the major compounds,
known to be potent tyrosinase inhibitors. Besides
skin-whitening activity, resveratrol also possesses many
pharmacological properties that are beneficial in treating
human diseases such as neurodegenerative disease,
cardiovascular disease, diabetes, and cancer [53].
Cytotoxic activity
Isolated from the aqueous methanol leaf extract of M.
alba, two flavonoids, quercetin-3-O-β-D-glucopyranoside (1) and
quercetin-3-7-di-O-β-D-glucopyranoside (2) are found to inhibit
the growth of human leukemia HL-60 cells [54]. At 2 × 10-4
mol·L−1 concentration, inhibitory effects of Compounds 1 and
2 are 51% and 57%, respectively. A flavanone (7, 2′, 4′,
6′-tetrahydoroxy-6-geranylflavanone) isolated from the ethyl
acetate root extract of M. alba exhibits cytotoxic activity
against rat hepatoma dRLh84 cells with an IC50 value being
53 µg·mL−1 [26].
A novel flavanone glycoside isolated from the root bark
– 24 –
of M. alba exhibits anti-proliferative activity [31]. IC50 values
of the compound against human ovarian cancer HO-8910
cells are 3.7 and 1.9 μmol·L−1 for 48 h and 72 h, of exposure,
respectively. Albanol Aisolated from the root bark of M. alba,
is reported to have cytotoxic and apoptotic activities in human
leukemia HL-60 cells [55]. The compound shows potent
cytotoxic activity with IC50 value being 1.7 μmol·L−1. In addition,
albanol A induces early apoptosis with marked reduction in
procaspases-3, -8, and -9, and activation of caspase-2. It is
postulated that the compound induces apoptotic cell death in
HL-60 cells via both the cell death receptor pathway by
stimulation of death receptor, and the mitochondrial pathway
through caspase-2 activation. The study concludes that
albanol A may be a promising compound for developing as an
effective drug for treatment of leukaemia. Morusinisolated
from the root bark of mulberry, induces apoptosis and
suppresses NF-κB in human colorectal cancer HT-29 cells [56].
All the 11 flavonoids isolated from the methanol leaf
extract of M. alba display cytotoxic activity against human
cancer HeLa, MCF-7, and Hep-3B cells [21]. Based on IC50,
the strongest activities are observed with morusin against
HeLa cells (0.6 μmol·L−1), 8-geranylapigenin against MCF-7
cells (3.2 μmol·L −1 ) and sanggenon K against Hep-3B
cells (3.1 μmol·L −1 ), respectively. Against these cancer
and 29 μmol·L−1, respectively. Two new chalcones
(morachalcones B and C) isolated from leaves of M. alba
have moderate cytotoxic activity against human cancer
HCT-8 and BGC-823 cells [19].
A recent study shows that water, aqueous MeOH, and
MeOH leaf extracts of M. alba exhibit highly significant
inhibitory effects on the proliferation of human hepatocellular
carcinoma HepG2 cells [57]. It is postulated that the extracts
suppress nuclear factor kappa B gene expression with
significant declines in α-fetoprotein, γ-glutamyl transpeptidase,
and alkaline phosphatase in the cells.
Another recent study also shows the anti-cancer activity
of the methanol root bark extract of M. alba [58]. The extract
induces cell growth arrest and apoptosis in human colorectal
cancer SW480 cells. At 6.25, 12.5, and 25.0 μg·mL−1 of extract,
the cell viability is reduced by 43%, 71%, and 83%,
respectively. The cytotoxic activity of the extract is associated
with ROS-dependent cyclin D1 proteasomal degradation and
with ROS/GSK3β-dependent ATF3 expression.
Anti-inflammatory activity
The methanol root bark extract of M. alba has been
reported to possess anti-inflammatory activity [58]. Nitric
oxide is measured using the Griess method, and iNOS and
proteins regulating NF-κB and ERK1/2 signalling are
analyzed by Western blotting. Results show that the
anti-inflammatory effect of the extract is mediated via
inhibition of NF-κB and activation of ERK1/2. Of the
 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730
compounds isolated from the methanol root bark extract,
kuwanons C and G possess anti-inflammatory activity.
Similarly, the methanol branch extract of M. alba and its
active compound oxyresveratrol also have anti-inflammatory
activity [59]. The likely mechanism involves the inhibition of
CXCR- 4-mediated chemotaxis and MEK/ERK pathway in T
and other immune cells.
Anti-diabetic properties
Studies have reported the anti-diabetic properties of M.
alba leaves and fruits in rat models. Postprandial
hypoglycemic effects of aqueous leaf extract and leaf powder
of M. alba have been studied using Goto-Kakizaki (GK) and
Wistar rats [60]. The effect of a single oral administration of
leaf extract at 3.75 g·kg−1 on postprandial glucose responses is
determined using maltose or glucose as substrate. With
maltose, the extract reduces peak responses of blood glucose
significantly in both GK and Wistar rats, supporting the
inhibition of α-glucosidase in the small intestine. With
glucose, the extract also significantly reduces blood glucose
concentrations, measured at 30 min, in both animal models,
proposing the inhibition of glucose transport. After the leaf
powder (10%) has been administered by inclusion in the diet,
fasting blood glucose is significantly reduced at weeks 4 and
5. Overall, the findings indicate that the leaf extract has
significant postprandial hypoglycemic effect, possibly
through the inhibition of α-glucosidase and glucose transport.
Earlier studies have also reported hypoglycemic activities
in leaves and root bark of M. alba. A single dose of aqueous
extracts of leaves and root bark at 200 mg·kg−1 significantly
reduce blood glucose level and increase glucose uptake [61].
The administration of the mulberry root bark extract at 600
mg·kg−1·d−1 to streptozotocin (STZ)-induced diabetic rats for
10 days significantly reduces serum glucose and lipid
peroxides, and increases insulin levels [62].
In a recent reported study, Wistar rats were fed with
mulberry leaf extract at doses of 400 and 600 mg·kg−1, and
after 35 days, blood glucose, glycosylated hemoglobin,
triglyceride, blood urea, cholesterol, number of β-cells, and
diameter of the islets of Langerhans were measured [63]. Blood
glucose level and other parameters (except HDL), elevated in
the diabetic group, were brought to the control level in the
diabetic group treated with 600 mg·kg−1 of leaf extract. The
diameter of the islets and the number of β-cells reduced in the
diabetic group, were brought to the control level after
treatment with the extract. The study concludes that the
mulberry leaf extract, at a dose of 600 mg·kg−1, has
therapeutic effects in diabetes-induced rats and can restore the
diminished number of β-cells.
After administration of 250 or 750 mg·kg−1 of the
aqueous ethanol leaf extract of M. alba, a decrease in blood
glucose levels of type II diabetic rats has been observed after
11 days [64]. The anti-diabetic activity of the extract is
– 25 –
attributed to chlorogenic acid and rutin present in the extract.
After Zucker diabetic fatty rats were fed with mulberry
fruit extract at doses of 125 or 250 mg·kg−1 twice daily for
five weeks, the glucose levels were significantly lower than
that of the control group [65]. At 250 mg·kg−1, the insulin
levels did not decline and no discernable changes in the
histology of the pancreatic β-cells were observed.
Another study has also reported that flavonoids in the
ethanol fruit extract (100 and 200 mg·kg−1) significantly
decreases blood glucose and serum protein, and increases
antioxidant enzymatic activities in STZ-induced diabetic
mice [20]. The extract, which also shows potent α-glucosidase
inhibition, may be partially responsible for the anti-diabetic
activity of the fruit extract.
Anti-hyperlipidemic effects
Mulberroside A prepared from ethanol root extract of M.
alba and its aglycone derivative (oxyresveratrol) produced
from mulberroside A by enzymatic conversion have been
evaluated for their anti-hyperlipidemic effects in two rat
models [66]. Oral pre-treatment with mulberroside A or
oxyresveratrol (1−5 mg·kg−1) significantly reduces serum
lipids levels in hyperlipidemic rats and in high-cholesterol diet
hyperlipidemic rats. Oxyresveratrol also shows more
pronounced serum lipid lowering capacity than mulberroside
A. Findings of this study further support the hypolipidemic
effects of the root bark [67] and hypotriglyceridemic effects of
leaves [68] of mulberry.
Anti-atherosclerotic effects
Studies have shown that leaves and fruits of M. alba have
anti-atherosclerotic effects in rodents. The effects of a dietary
intake of 1% mulberry leaf (ML) powder on atherogenesis in
apolipoprotein E-deficient mice have been reported [69]. After
12 weeks of treatment, a significant increase in the lag time of
lipoprotein oxidation has been detected in the ML group
compared with the control group. The ML group also shows
40% reduction in atherosclerotic lesion size in the aorta. The
results show that mulberry leaves contain antioxidative
compounds with strong free radical scavenging and
lipoprotein oxidation inhibition that can help prevent
atherosclerosis.
In a study with New Zealand white rabbits on normal diet
or high cholesterol diet (HCD), the animals were fed with or
without 0.5% or 1.0% aqueous mulberry fruit extract for 10
weeks [70]. The levels of triglyceride, cholesterol and
low-density lipoprotein (LDL) cholesterol in the serum of
HCD rabbits fed with the fruit extract were lower than that in
the control group. The rabbits fed with 0.5% or 1.0% of the
extract significantly reduced atherosclerosis in the aorta by
42%–63%, compared with the controls. In a related study,
freeze-dried mulberry fruit powder (5% and 10%) lowered
serum and liver total cholesterol, and triglyceride content,
inhibited lipid peroxidation, and increased antioxidant
 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730
enzyme activity in rats on a high-fat diet, repressing the
development of atherosclerosis in hyperlipidemic rats [71].
Anti-obesity activity
The effects of the ethanol leaf extract of M. alba on
melanin-concentrating hormone receptor activity and on
anti-obesity in diet-induced obese mice have been studied [72].
The results of the hormone receptor assay show that the
extract (10−100 μg·mL−1) exhibits a potent inhibitory activity,
with IC50 value being 2.3 μg·mL−1. In an anti-obesity study,
administration of the extract at 100, 250, and 500 μg·mL−1 for
32 consecutive days resulted in a decrease in body weight and
adiposity, and regulated hepatic lipid accumulation in the
mice. The anti-obesity effects of the extract might be due to
receptor antagonism.
Male hamsters on high fat diet when fed with aqueous
mulberry leaf extract had significantly lower body weight [73].
Decrease in serum triacylglycerol, cholesterol and free fatty
acid concentrations as well as increase in HDL/LDL ratios
were also observed. Another recent study showed that the
combined leaf and fruit extract of M. alba had positive
beneficial effects on obese mice [74]. The results showed that
the extract ameliorated cholesterol transfer proteins and
reduced oxidative stress in the obese mice fed daily with the
extract at 500 mg·kg−1 for 12 weeks.
Hepatoprotective activity
The protective mechanisms of aqueous mulberry fruit
extract in male Wistar rats with CCl4-induced hepatic injury
have been elucidated [75]. Oral administration of the extract
(0.5%, 1%, and 2%) significantly reduces the lipid
peroxidation and inhibits lipid deposition and liver fibrosis.
The extract attenuates the expression of pro-inflammatory
genes such as cyclooxygenase 2, nuclear factor kappa B, and
inducible NO synthase. The results suggest that the extract
exhibits protective and curative effects against liver damage
and fibrosis via decreased lipid peroxidation and inhibition of
pro-inflammatory gene expression.
The hepatoprotective effect has earlier been reported with
leaves of M. alba. At 800 mg·kg−1 dose, the hydroalcoholic
leaf extract exhibits significant hepatoprotective effect in
mice with CCl4-induced liver injury [76]. Compared to the
CCl4 group, the serum levels of aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) are lower, with
shorter sleeping time, and there is no evidence of fibrosis or
inflammation in the extract administered group.
Other pharmacological properties
Other pharmacological properties of M. alba include anti-
platelet [77], anxiolytic [78], anti-asthmatic [79-80], anthelmintic [47, 81],
antidepressant [82], immunomodulatory [83-84], and cardiopro-
tective [85] activities.
Clinical trials
Hypoglycemic effects
In a study conducted at the Minneapolis VA Medical
– 26 –
Center, the participants were 10 healthy control subjects (aged
24–61 years) and 10 type-2 diabetic subjects (aged 59–75
years) who were receiving oral hypoglycemic agents [86].
Changes in the blood glucose concentration of the healthy
subjects and the type-2 diabetic subjects after ingestion of
75 g sucrose in 500 mL of hot water with 1 g of mulberry leaf
extract or placebo were monitored. The results showed that
there was a significant difference in the blood glucose level
between mulberry and placebo over the first 120 min for the
control and diabetic subjects.
Another clinical study on the hypoglycemic effects of M.
alba leaf extract on postprandial glucose and insulin levels in
patients with type 2 diabetes treated with sulfonylurea
hypoglycemic agents was conducted at the Miharadai
Hospital in Nagasaki City, Japan [87]. Ten patients (5 males
and 5 females) with type 2 diabetes mellitus and ten healthy
subjects (4 males and 6 females) participated in this study.
The results from this study confirmed that postprandial
glucose and insulin levels in type 2 diabetic patients treated
with sulfonylurea were markedly suppressed after the
ingestion of jelly containing 3.3 g of leaf extract. For the
patients, the blood glucose was 148 mg·dL−1 after ingestion of
the extract jelly and 209 mg·dL−1 after ingestion of the
placebo jelly at 30 min. For the healthy subjects, the blood
glucose increment after the ingestion of the extract jelly was
97 mg·dL−1, compared to 125 mg·dL−1 after ingestion of the
placebo jelly. The insulin level was also significantly
suppressed at 30 min after ingestion of the extract jelly,
compared to ingestion of the placebo jelly for both the
patients and healthy subjects.
1-Deoxynojirimycin (DNJ), isolated from mulberry leaves,
is a potent glucosidase inhibitor that is beneficial in
suppressing abnormally high blood glucose levels, thereby
preventing diabetes mellitus [88]. A food-grade mulberry
powder enriched with DNJ (1.5%) was produced and
clinically tested to determine the optimal dose. Healthy
volunteers received 0.4, 0.8, and 1.2 g of the powder
(corresponding to 6, 12, and 18 mg of DNJ, respectively)
followed by 50 g of sucrose. The plasma glucose and insulin
levels were determined before and 30−180 min after oral
administration of DNJ cum sucrose. The results of the clinical
trial showed that a single administration of 0.8 and 1.2 g of
DNJ-enriched powder significantly suppressed the elevation
of postprandial blood glucose and secretion of insulin. Its
effective dose and efficacy in humans suggest that the
DNJ-enriched powder can be used as a dietary supplement for
treating diabetes mellitus.
Hypolipidemic effects
The hypolipidemic effects of encapsulated mulberry leaf
powder have been evaluated in comparison with
glibenclamide, the standard anti-diabetic drug [89]. Conducted
at the Anantapur K.M. Hospital in Andhra Pradesh, India, the
 Eric Wei-Chiang CHAN, et al. / Chin J Nat Med, 2016, 14(1): 1730
clinical study involved 24 mild type 2 diabetic patients (males
and aged 40–60 years) who were divided into two treatment
groups. The mulberry patients were each given six capsules,
three times a day (two capsules after each meal), amounting to a
daily dose of 3 g·d−1 for 30 days. The glibenclamide patients
were each given one tablet of 5 mg·d−1 for 30 days. The
serum and erythrocyte membrane lipid profiles of the patients
were analyzed before and after the treatments. Pre- and
post-treatment analysis of blood plasma and urine samples
showed that the mulberry therapy significantly decreased the
concentration of serum cholesterol (12%), triglycerides (16%),
plasma free fatty acids (12%), LDL-cholesterol (23%),
VLDL-cholesterol (17%), plasma peroxides (25%), and
urinary peroxides 55%, while significantly increased
HDL-cholesterol (18%). For the glibenclamide patients,
changes in the lipid profile were not statistically significant
except for triglycerides (10%), plasma peroxides (15%), and
urinary peroxides (19%).
Having reported that DNJ-enriched mulberry leaf extract
can suppress the elevation of postprandial blood glucose in
humans [88], a follow-up study has been conducted at the
Medical Corporation Kenshokai Kinki Kenshin Center in
Osaka, Japan, to evaluate the effects of the leaf extract on
plasma lipid profiles in humans [90]. Ten male subjects aged
between 20 and 64 years with initial serum triglyceride (TG)
levels ≥200 mg·dL−1, ingested capsules containing 12 mg of
the DNJ-rich mulberry leaf extract three times daily before
meals for 12 weeks. The mean serum TG level decreased from
312 ± 90 mg·dL−1 to 269 ± 66 mg·dL−1 at week 6 and to 252 ±
78 mg·dL−1 at week 12, but the differences were not
statistically significant. No significant changes were observed
in total cholesterol, LDL-cholesterol or HDL-cholesterol.
A clinical trial on the hypolipidemic effects of mulberry
leaf tablets has been conducted in non-diabetic patients with
mild dyslipidemia at an outpatient clinic in Thailand [91].
Produced by Kitayamakit Co., Ltd., Kyoto, Japan, each leaf
tablet weighed 280 mg and contained 255 mg mulberry leaf
powder with 0.37 mg of DNJ as the active ingredient.
Twenty-three patients received three tablets three times a day
before meals for 12 weeks. Routine blood analyses including
lipid parameters and liver function tests were performed
monthly. At weeks 4 and 8, triglyceride was significantly
decreased by 10% and 13%, respectively. At the end of the
study, total cholesterol, triglyceride and LDL were decreased
by 4.9%, 14%, and 5.6%, respectively, whereas HDL was
significantly increased by 20%. Even though some patients
experienced some side effects such as mild diarrhoea,
dizziness or constipation and bloating, the tablets were
effective in reducing cholesterol levels and enhancing HDL in
patients with mild dyslipidemia.
Cognitive enhancing effects
In a clinical trial conducted in Thailand, the cognitive
– 27 –
enhancing effects of M. alba leaf extract have been tested in
60 healthy middle-aged and elderly volunteers [92]. They were
randomly assigned to receive the standardized plant extract at
doses of 1 050 mg and 2 100 mg once daily for 3 months. The
subjects who consumed the extract at both doses showed
working memory and cognitive enhancement without any
toxic effects.
Conclusion
From being the primary food for silkworms, which
supported the silk industry over centuries, M. alba has come a
long way to be a multi-purpose plant with uses as animal feed,
food, cosmetics, and medicine. Its leaves, fruits, and root bark
containing flavonoids, anthocyanins, alkaloids, and stilbenoids,
possess pharmacological properties, including antioxidant,
antimicrobial, skin-whitening, cytotoxic, anti-inflammatory,
anti-diabetic, anti-hyperlipidemic, anti-atherosclerotic, anti-
obesity, hepatoprotective, and cardioprotective activities.
Other pharmacological properties of M. alba include anti-
platelet, anxiolytic, anti-asthmatic, anthelmintic, antidepressant,
cardioprotective, and immunomodulatory activities. Clinical
trials on the hypoglycemic and hypolipidemic effects of M.
alba extracts in reducing blood glucose and cholesterol levels,
and in enhancing cognitive ability have been conducted.
Compounds from M. alba with a wide array of bioactivities
can serve as lead compounds for drug development. However,
the extracts from mulberry would be difficult to standardize
as the species has many varieties and cultivarsand can vary in
the contents of chemical constituents, particularly the active
principle(s). Without proper procedures for authentication and
control measures, obtaining reliable and repeatable results of
studies in human subjects would be difficult. This poses
additional challenges to clinical trials in the future.
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Cite this article as: Eric Wei-Chiang CHAN, Phui-Yan LYE, Siu-Kuin WONG. Phytochemistry, pharmacology, and clinical trials of Morus alba
[J]. Chinese Journal of Natural Medicines, 2016, 14(1): 17-30.
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