White Mulberry

Scientific Name(s): Morus alba L. Family: Moreaceae.

Common Name(s): White mulberry , common mulberry , silkworm mulberry , pawi bush

Uses

The medical literature includes numerous references for white mulberry use in atherosclerosis, cancer, diabetes, infection, and neurodegenerative disorders. However, there are no clinical trials to support these uses.

Dosing

In mild dyslipidemia, 1 g of white mulberry leaf tablets containing 1.3 mg of 1-deoxynojirimycin (DNJ) 3 times a day before meals has been used. A dose of 1 g of powdered leaf 3 times a day has been used to treat diabetes or high cholesterol. White mulberry is available in numerous dosage forms and is also marketed to maintain healthy blood sugar levels and to support cardiovascular health.

Contraindications

Hypersensitivity to any of the components of white mulberry.

Pregnancy/Lactation

Avoid use during pregnancy and lactation due to lack of clinical data.

Interactions

Because white mulberry may alter blood sugar levels, it should be used cautiously with medications (eg, insulin) that lower blood sugar in diabetes. White mulberry may also increase the side effects of cholesterol-lowering medications and should also be used with caution in patients using benzodiazepines, barbiturates, or antidepressants. White mulberry may also interact with medications used for gout.

Adverse Reactions

The pollen extract may cause airborne-contact urticaria. Patients with nasobronchial allergies may be sensitive to the pollen extract. One clinical study found that some patients experienced mild diarrhea, dizziness, constipation, and bloating.

Toxicology

No deaths were associated with 2, 5, and 10 g/kg doses in animal toxicity studies.

Botany

The genus Morus is widely distributed throughout the world. As the primary food source for silkworms, the plant is cultivated in many regions of Asia for silk production. White mulberry is a medium-sized, monoecious, deciduous tree growing to 30 m tall and 1.8 m wide in both temperate and tropical areas. The leaves are ovately shaped and may be lobed or unlobed. The fruit is white to pinkish in color, in contrast to red or black in most other Morus species. 1 , 2

History

The medicinal use of the leaves, root bark, branches, and fruits of white mulberry is documented in the Pharmacopoeia of the People's Republic of China . It is also an official drug of the British Herbal Pharmacopoeia . It has been included in historical documents since AD 659. The root bark has cathartic and anthelmintic properties and is bitter in taste. The root juice agglutinates the blood and also kills worms in the digestive system. The stem bark has purgative and vermifuge properties. The leaves have diaphoretic and emollient properties, and the leaf juice has been used to prevent throat infections and inflammation. The fruit juice has a cooling and laxative property and is used to treat fevers, colds, diarrhea, malaria, amoebiasis, constipation, and intestinal worms (eg, tapeworm). 2 , 3

The fruits may be eaten fresh and are used in juice, preserves, and stews, 4 and can be fermented into a sweet and sour tasting wine. White mulberry leaves are used in animal feed for sheep, goats, and cattle. 5 Mulberries are used in syrup preparations as well as to flavor and color medicine: in Chinese markets, mulberry is mixed with various herb combinations to cure or treat conditions such as productive cough, fever, irritability, superficial edema related to urinary problems, and diabetes. 2 , 6

Chemistry

Proteins, carbohydrates, fats, fibers, minerals, and vitamins have been isolated from white mulberry. 7

On a dry-weight basis, white mulberry leaves contain 15% to 30% protein, 2% to 8% fat, 10% to 14% crude fiber, 28% to 44% dietary fiber, and 11% to 17% ash content. 7 The proteins in mulberry leaves are used with wheat flour to make bread in India. The leaves also contain ascorbic acid, beta-carotenes, iron, zinc, calcium, phosphorous, and magnesium. 7 Sialic acid-binding lectins, MLL 1 and MLL 2, were purified from the leaves of white mulberry and may be involved in defense against pathogens. 8 The leaves also contain several antioxidative flavonoids including quercetin. 9 Many antioxidant phenolic compounds and moracins have been identified, with highest concentrations reported in the leaves and roots. 10 , 11 Chalcone derivatives isolated from the leaves have moderate cytotoxic activity. 12

Linoleic (57%), followed by palmitic acid (22%), are the dominate fatty acids in white mulberry fruits. The fruit also contains 1.1% total fat. The moisture content of the fruit is 72%, pH 5.6, total soluble solids 20%, and 22.4 mg per 100 mL of ascorbic acid. A total of 10 mineral elements were identified in white mulberry fruits, with potassium having the highest concentration. 13 Several alkaloids and amino acids have been isolated. 14 The fruit is also rich in anthocyanins, which may be used for commercial production as a natural red food colorant. 15

Stilbenes, flavonoids, benzofuran derivatives, and coumarins have been isolated from the bark. Mulberroside A, a stilbene derivative, has antitussive and antiasthmatic activity. 16 Kuwanon C and G have antibacterial 7 , 17 activity, while kuwanons G and H have hypotensive activity. 18 Flavonoids from the root bark have antiviral 19 activity and a flavanone glycoside 20 exhibited anticancer activity.

Uses and Pharmacology

The medical literature includes references for white mulberry use in atherosclerosis, cancer, diabetes, infection, and neurodegenerative disorders.

Antibacterial and antiviral activity
In vitro data

Antibacterial activity is associated with kuwanon C, mulberrofuran G, and albanol B from mulberry leaves with minimum inhibitory concentrations (MICs) ranging from 5 to 30 mg/mL. 2 , 7 Chloroform mulberry extracts have antibacterial activity against Bacillus subtilis and acetic acid extracts against Staphylococcus aureus and Escherichia coli . Chemical constituents (eg, morusin, kuwanon C, sanggenon B and D) from the bark have activity against S. aureus , Streptococcus faecalis , B. subtilis , Mycobacterium smegmatis , and mold species. Kuwanon G from a leaf methanol extract has a MIC (8 mg/mL) against the oral pathogen Streptococcus mutans and the cariogenic bacteria Streptococcus sobrinus , Streptococcus sanguis and Porpyromonas gingivalis , which causes periodontitis. 17 At a concentration of 20 mcg/mL kuwanon G completely inactivated S. mutans in 1 minute. Similar studies of other isolated leaf compounds found antibacterial activity against S. mutans . 21 Leachianone G from the root bark showed potent antiviral activity (concentration that inhibits 50% [IC 50 ], 1.6 mcg/mL) against herpes simplex type 1 virus (HSV-1). 19

Clinical data

No human clinical data are available regarding the antibacterial or antiviral activity of white mulberry.

Antioxidant activity
In vitro data

The numerous flavonoids 9 from the leaves and the phenols 10 from the roots, branches, and fruits all have free radical scavenging properties. Mulberroside A and oxyresveratrol show inhibitory activity against induced lipid peroxidation in rat microsomes and free radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. 7 The DPPH scavenging activity is associated with caffeoylquinic acids in immature white mulberry fruits and anthocyanins in mature white mulberry fruits. 22 A white mulberry water extract increased the IC 50 of doxorubicin ( P < 0.05) in a dose-dependent manner in a study examining the cardioprotective effect of plant extracts. 23

Clinical data

No human clinical data are available regarding the antioxidant activity of white mulberry.

Cancer
In vitro and animal data

The anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside from white mulberry inhibited the migration and invasion of highly metastatic A549 human lung carcinoma cells. 24 The anticancer activity may be associated with decreased expression of matrix matalloprotinase-2 and urokinase-plasminogen activator and enhanced expression of tissue inhibitor of matrix matalloprotinase-2 and plasminogen activator inhibitor. A prenylated flavanone, isolated from an ethyl acetate extract of white mulberry root, exerted cytotoxic activity against rat hepatoma cells with an IC 50 of 52.8 mg/mL. 7 A white mulberry root bark extract exhibited cytotoxic activity by inducing apoptosis and inhibiting microtubule assembly on K-562, B380 human leukemia cells, and B16 mouse melanoma cells. 25 White mulberry leaf extracts inhibited the growth of HL60 human promyelocytic leukemia and multidrug resistance HL60 cells (HL60/VINC and HL60/DOX). 26 The anthocyanins from the fruit controlled tumor metastasis and motility of a melanoma murine cancer cell line by (a) inhibiting tumor cell migration, spreading and tissue invasion of tumor cells, (b) inhibiting signaling pathways, and (c) decreasing DNA binding to nuclear factor kappa-B and AP-1. 27 Albanol A, from the root bark of white mulberry, induced apoptosis in HL60 cells. 28 Albanol A exhibited potent DNA topoisomerase II inhibitory activity (IC 50 , 22.8 mcM) similar to that of the control etoposide (IC 50 , 34.5 mcM), which may trigger apoptosis of HL60 cells.

Clinical data

No human clinical data are available regarding the anticancer activity of white mulberry.

Cardiovascular disease
In vitro and animal data

White mulberry leaf extracts suppressed gene expression of proinflammatory stimuli in vascular endothelial cells. 29 A leaf ethyl acetate extract exhibited dual vasoactive effects on rat aorta. 30 Relaxation of the aorta was caused by inhibition of voltage- and receptor-dependent calcium channels in vascular smooth muscle cells and contraction of the aorta through activation of ryanodine receptors in the sarcoplasmic reticulum. The leaf extracts may also inhibit the activity of matrix metalloproteinases, protein expression and phosphorylation, and signaling pathways in rat thoracic aorta smooth muscle cells involved in the pathophysiology of atherosclerosis. 31

Dietary consumption of white mulberry leaf (containing quercetin) reduced atherosclerotic lesion development in low-density lipoprotein (LDL) receptor deficient mice by increasing LDL resistance to oxidative modification. 32 Supplementation of white mulberry methanol root bark extract (500 mg/kg/day for 15 days) in cholesterol-fed rats resulted in decreased total cholesterol, LDL-cholesterol, very low-density lipoprotein-cholesterol, and triglycerides and improved high-density lipoprotein-cholesterol (HDL-C). 33 White mulberry fruit extracts also improved the lipid profile in hyperlipidemic rats 34 and in hamsters fed a high cholesterol diet. 35 The hypolipidemic activity is associated with enhanced hepatic LDL receptor expression, which improves clearance of LDL and decreases lipid biosynthesis. Liver lipid accumulation was suppressed in rats administered either DNJ, a constituent of white mulberry leaves, or white mulberry extract enriched in DNJ. 36

Clinical data

Twenty-three patients meeting the National Cholesterol Education Program ATP III criteria guidelines for dyslipidemia were administered three 280 mg white mulberry leaf tablets 3 times a day before meals over 12 weeks. 37 Lipid profiles and liver function tests were performed every 4 weeks. At 4 and 8 weeks, triglycerides were reduced 10.2% and 12.5% when compared with baseline. At the conclusion of the study, total cholesterol, triglycerides, and LDLs were decreased by 4.9%, 14.1%, and 5.6%, respectively, and HDL increased by 19.7% when compared with baseline. Therefore, for mild dyslipidemia consumption of 1 g of white mulberry leaf tablets (1.3 mg of DNJ) 3 times a day before meals may be effective. Several mechanisms of action may be involved with the effect of white mulberry leaf tablet therapy on lipid profiles, including (a) regulation of hepatic gene expression involved in lipid and lipoprotein metabolism; (b) the leaves contains DNJ, which can reduce plasma glucose levels; reduced levels result in decreased fatty acid influx to the liver from adipose tissue, leading to decreased triglyceride and cholesterol levels; (c) antiatherosclerotic effects of the leaf flavonoids; (d) the water soluble fiber in white mulberry leaves may lead to decreased absorption of dietary cholesterol.

Diabetes
In vitro and animal data

A dose of 600 mg/kg/day of 70% white mulberry alcohol bark extract to streptozotocin-induced diabetic rats over 10 consecutive days reduced serum glucose by 41% and increased serum insulin by 44%. 38 The bark extract may reduce lipid peroxidation and oxidative stress in pancreatic beta cells. The glycoprotein, moran 20K, from a white mulberry aqueous methanolic root bark extract also lowered blood glucose in streptozotocin-induced diabetic rats. The amino acid composition of moran 20K is similar to insulin as it contains above 20% serine and cysteine. 39 In vivo hypoglycemic activity is documented for moracin M, steppogenin-4′-O-beta-D-glucosiade, and mullberroside A, which are common types of benzofurans, flavanones, and stilbene glycosides in white mulberry root bark. 40

Streptozotocin-induced diabetic rats fed white mulberry aqueous leaf extract had decreased nitric oxide synthase expression in the hypothalamus reducing the desire for food under diabetic conditions. 41 DNJ from the leaves inhibited human and rat small intestinal disaccharidase activity 42 of sucrase, maltase, and isomaltase competitively. A white mulberry ethanol leaf extract reduced glucose in diabetic rats by increasing glucose uptake and glucose transporter 4 translocation in adipose tissue. 43 A similar study documented how white mulberry leaf improved postprandial hyperglycemia in rats, possibly by inhibiting glucose transport and alpha-glucosidase at the gut brush border. 44 Antioxidant activity in white mulberry leaf may restore free radical-induced vascular dysfunction in diabetic rats. 45 A white mulberry leaf extract stimulated 5-AMP-activated protein kinase (AMPK) in rat skeleton muscle. 46 AMPK is a major signaling pathway in exercise-stimulated, insulin-independent glucose transport in skeletal muscle. Dietary supplementation of purified quercetin from white mulberry leaves in obese mice led to improved plasma glucose levels and reduced oxidative stress in the liver. 47

Clinical data

A human study documented that a single oral dose of 0.8 and 1.2 g of DNJ-enriched powder suppressed the elevation of postprandial blood glucose and secretion of insulin. 48 A similar study documented a ratio of 1:10 white mulberry leaf extract to sucrose in suppressing postprandial blood glucose and insulin. 49

Skin tone
In vitro data

Because tyrosinase is a key enzyme involved in melanin biosynthesis, tyrosinase inhibitors may improve the appearance of skin by preventing the overproduction of melanin. 7 Betulinic acid from white mulberry extracts was shown to have anti-inflammatory and antityrosinase activity. 50 , 51 A white mulberry leaf methanol extract containing mulberroside F inhibited tyrosinase activity and exhibited superoxide scavenging activity. 52

Clinical data

In a randomized clinical trial, an over-the-counter cosmetic product containing white mulberry improved the appearance of facial wrinkles by helping to restore fibrillin-1. 53

Other pharmacological uses
Alcohol-induced fatty liver

A polyherbal Chinese medicine that included white mulberry was administered to rats with alcohol-induced fatty acid livers and improved their liver/body weight, serum triglycerides and total cholesterol, liver triglycerides and total cholesterol, and ALT and AST. 54

Anxiety

White mulberry leaf extracts exhibited anxiolytic and muscle relaxant activity in different animal models of anxiety based on exploratory behavior in mice. 55

Gout

Morin from white mulberry, at a concentration of 80 mg/kg, exhibited a hypouricemic action and inhibited xanthine oxidase in oxonate-induced hyperuricemic rats. 56 The inhibitory activity on urate uptake in rat renal brush border membrane vesicles was more potent than that of the prescription agent probenecid. Morin exhibited similar activity on urate transport in the human kidney. 57

Immune system activity

Pretreatment with a white mulberry root bark extract inhibited induced mast cell degranulation and histamine release in rat peritoneal mast cells. 58

Inflammation

Anti-inflammatory activity is documented for mulberroside A and oxyresveratrol from the root bark of white mulberry in reducing carrageenin-induced paw edema in rats. 59 A white mulberry leaf methanol extract and its fractions inhibited inflammatory mediators nitric oxide, prostaglandin E2, and cytokines in a mouse macrophage cell line. 60 White mulberry leaf extracts protected rat organ tissues (eg, liver, adrenal glands, kidneys, spleen) against inflammation and peroxidation induced by stress. 61 The antioxidant activity was more effective than pure rutin, and the adrenal glands were the primary target organs for antioxidants.

Obesity

A mixture of 3 herbs that included white mulberry regulated lipid metabolism, body weight gain, and adipose tissue mass by changing the expression of hepatic target genes in high-fat, diet-induced, obese mice. 62 Melanin-concentrating hormone (MCH) is involved in feeding and energy metabolism. White mulberry leaf extract exhibited an antagonistic effect to MCH1 receptor in diet-induced obese mice, resulting in decreased body weight and adiposity, food intake, and hepatic lipid accumulation. 63

Parkinson disease

Some neurological diseases, such as Parkinson disease, are associated with gamma-aminobutyric acid (GABA) depletion in the brain. White mulberry leaves have antioxidant activity and are GABA-enriched, which may provide a neuroprotective effect against cerebral ischemia 64 as well as neurotoxins. 65 White mulberry leaf extracts have antidopaminergic activity 66 , 67 mediated through dopamine D2 receptors as documented by (a) reducing haloperidol and metoclopramide-induced catalepsy in mice; (b) blocking amphetamine-induced stereotyped behavior (such as schizophrenia); (c) and increasing the sensitivity to barbiturates.

Snake venom

White mulberry leaf extract completely blocked in vitro proteolytic and hyaluronolytic activities of Vipera / Daboia russelii venom, therefore protecting against tissue degradation. The extract also neutralized the edema, hemorrhage, and myonecrotic activities of the venom. Procoagulant activity was partially inhibited, while complete inhibition was attained against degradation of A-alpha chain of human fibrinogen. 68

Stress

An animal study documented that white mulberry root extract may have adaptogenic effects against induced neurological, behavioral, and biochemical changes due to long-term stress. 69

Dosage

In mild dyslipidemia, 1 g of white mulberry leaf tablets (1.3 mg of DNJ) 3 times a day before meals has been used. A dose of 1 g of powdered leaf 3 times a day has been used to treat diabetes or high cholesterol. White mulberry is available in numerous dosage forms and is also marketed to maintain healthy blood sugar levels and to support cardiovascular health.

Pregnancy/Lactation

Avoid use during pregnancy and lactation due to lack of clinical data.

Interactions

Because white mulberry may alter blood sugar levels it should be used cautiously with medications (eg, insulin) that lower blood sugar in diabetes. White mulberry may also increase the side effects of cholesterol-lowering medications and should be sued with caution in patients using benzodiazepines, barbiturates, or antidepressants. White mulberry may also interact with medications used for treating gout.

Adverse Reactions

Avoid use with hypersensitivity to any of the components of white mulberry. The pollen extract may cause airborne-contact urticaria. 2 Patients with nasobronchial allergies may be sensitive to the pollen extract. 70 One clinical study found that some patients experienced mild diarrhea, dizziness, constipation, and bloating. 37

Toxicology

No deaths were associated with 2, 5, and 10 g/kg doses in animal toxicity studies. High doses produced depression of locomotor activity, decreased alertness, passivity, and abnormal gait in mice. 3

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