Mulberry leaves and their potential effects against cardiometabolic risks: a review of chemical compositions, biological properties and clinical efficacy

Figures & data

Table 1. Chemical compositions of mulberry leaves.

Chemical compositions	Content	References
Crude protein	13.4–19.4%	(Sanchez-Salcedo et al. 2017)
	18.41–24.63%	(Iqbal et al. 2012)
	21.24–21.66%	(Adeduntan and Oyerinde 2010)
Total carbohydrate	47.27–56.42%	(Adeduntan and Oyerinde 2010)
Crude fat	4.24–6.57%	(Iqbal et al. 2012)
	5.31–8.02%	(Adeduntan and Oyerinde 2010)
Vitamin
Ascorbic acid	0.97–1.49 mg/g	(Iqbal et al. 2012)
Minerals
Nitrogen	2.1–3.1 g/100 g	(Sanchez-Salcedo et al. 2017)
Phosphorus	0.1–0.2 g/100 g	(Sanchez-Salcedo et al. 2017)
Potassium	1.2–3.9 g/100 g	(Sanchez-Salcedo et al. 2017)
Calcium	1.7–3.9 g/100 g	(Sanchez-Salcedo et al. 2017)
Sodium	0.01 g/100 g	(Sanchez-Salcedo et al. 2017)
Magnesium	0.5–1.4 g/100 g	(Sanchez-Salcedo et al. 2017)
Sulphur	0.2–0.3 g/100 g	(Sanchez-Salcedo et al. 2017)
Iron	119.3–241.8 mg/kg	(Sanchez-Salcedo et al. 2017)
Zinc	23.9–39.5 mg/kg	(Sanchez-Salcedo et al. 2017)
Manganese	35.8–90.5 mg/kg	(Sanchez-Salcedo et al. 2017)
Boron	253.5–825.3 mg/kg	(Sanchez-Salcedo et al. 2017)
Copper	4.2–5.9 mg/kg	(Sanchez-Salcedo et al. 2017)
Molybdenum	0.8–2.3 mg/kg	(Sanchez-Salcedo et al. 2017)
Nickel	1.7–5.4 mg/kg	(Sanchez-Salcedo et al. 2017)
Lead	0.3–0.8 mg/kg	(Sanchez-Salcedo et al. 2017)
Carbon	37.4–41.4 g/100 g	(Sanchez-Salcedo et al. 2017)
Lithium	1.9–17.2 mg/kg	(Sanchez-Salcedo et al. 2017)
Titanium	5.4–10.8 mg/kg	(Sanchez-Salcedo et al. 2017)
Organic acids
Citric acid	32.2–105.5 mg/100 g	(Sanchez-Salcedo et al. 2017)
Malic acid	43.7–72.6 mg/100 g	(Sanchez-Salcedo et al. 2017)

Table 2. Preclinical studies demonstrating biological properties of mulberry leaves.

	Mulberry leaves interventions
Models	Species	Solvent extracts	Preparation	Dose	Duration	References
Antihyperglycaemic effect
Healthy rats	M. alba	Water	Dried powder dissolved in distilled water	1 g/kg	Single dose	(Kim GN et al. 2011)
(A) Healthy rats (B) Non-obese diabetic rats	M. alba	Water	Extract (0.16 g DNJ/100 g) included into the diet	3.75 g/kg (6 mg/kg DNJ)	Single dose	(Park et al. 2009)
(A) Healthy rats (B) STZ-induced diabetic rats	M. alba	Ethanol	ND	400 and 600 mg/kg/day (ad libitum)	5 weeks	(Mohammadi and Naik 2008)
(A) Healthy rats (B) Non-obese diabetic rats	M. alba	–	Dried powder of grinded leaves (0.05 g DNJ/100 g) included into the diet	25% of the diet (ad libitum)	8 weeks	(Park et al. 2009)
(A) Healthy rats (B) STZ-induced diabetic rats	M. alba	–	Brewed tea (0.25% and 0.50%)	Ad libitum	4 weeks	(Wilson and Islam 2015)
(A) High fat diet-induced overweight rats (B) High sucrose diet-induced overweight rats	M. alba	Water	Extract (0.365 ± 0.025 g/100 g) included into the diet	5% of the diet	6 weeks	(Kim JY et al. 2011)
Antihyperlipidaemic effect
(A) Healthy rats (B) STZ-induced diabetic rats	M. alba	–	Brewed tea (0.25% and 0.50%)	Ad libitum	4 weeks	(Wilson and Islam 2015)
High cholesterol diet-fed rats	M. alba	Methanol	Extract dissolved in drinking water (0.1 and 1 mg/mL)	Ad libitum	4 weeks	(Kobayashi et al. 2015)
STZ-induced diabetic rats	M. alba	(A) Ethanol (B) Crude extract	(A) Solution (B) Dried powder included into the diet	(A) 600 mg/kg (B) 25% of the diet	6 weeks	(Tond et al. 2016)
High fat diet-fed mice	M. alba	(A) Water (B) Ethanol	Extract included into the diet	0.5 and 1.5% of the diet	6 weeks	(Chang et al. 2016)
High fat diet-induced diabetic mice	M. alba	Ethanol	Extract included into the diet	133 and 666 mg/kg	12 weeks	(Ann et al. 2015)
High fat diet-fed mice	ND	–	Dried powder of grinded leaves included into the diet	1 and 3% of the diet	5 days	(Sun et al. 2015)
Anti-obesity effect
High fat diet-fed mice	M. alba	(A) Water (B) Ethanol	Extract included into the diet	0.5 and 1.5% of diet	6 weeks	(Chang et al. 2016)
High fat diet-induced diabetic mice	M. alba	Ethanol	Extract included into the diet	133 and 666 mg/kg	12 weeks	(Ann et al. 2015)
Anti-hypertensive effect
STZ-induced diabetic rats	M. alba	Ethanol	Extract dissolved in distilled water	0.25, 0.50 and 1 g/kg/day	8 weeks	(Naowaboot, Pannangpetch, Kukongviriyapan, Kukongviriyapan, et al. 2009)
Spontaneously hypertensive rats	M. alba	Water	Dried powder	0.53, 1.05 and 5.26 g/kg	(A) Single dose (B) 8 weeks	(Yang et al. 2012)
Antioxidative effect
STZ-induced diabetic mice	M. indica	–	Dried powder of grinded leaves included into the diet	25% of the diet	8 weeks	(Andallu and Varadacharyulu 2003)
STZ-induced diabetic rats	M. alba	Ethanol	Extract dissolved in distilled water	0.25, 0.50 and 1 g/kg/day	6 weeks	(Naowaboot, Pannangpetch, Kukongviriyapan, Kongyingyoes, et al. 2009; Naowaboot, Pannangpetch, Kukongviriyapan, Kukongviriyapan, et al. 2009)
ISO-treated rats	M. alba	Methanol	Extract suspended in distilled water	25, 50 and 100 mg/kg	3 weeks	(Nade et al. 2013)
Anti-inflammatory effect
Murine macrophage RAW 264.7 cells	M. alba	Ethanol	–	1, 10 and 50 μg/mL	24 hours	(Park et al. 2013)
Human aortic endothelial cells	M. alba	Methanol–water	–	25, 50 and 100 μg/mL	1 hour	(Chao et al. 2013)
Anti-atherosclerosis
J774A.1 macrophage cells	M. alba	(A) Water (B) Ethanol	–	0.005–10 mg/mL	–	(Yang et al. 2011)
A7r5 aortic VSMCs	M. alba	Water	Dried powder suspended in distilled water	0.05, 0.1, 0.2, 0.5 and 1.0 mg/mL	72 hours	(Chan et al. 2009)
A7r5 aortic VSMCs	M. alba	(A) Water (B) Methanol–ethyl acetate	Dried powder suspended in distilled water	(A) 0.5–2.0 mg/mL (B) 0.2–0.6 mg/mL	24 hours	(Chan et al. 2010)
STZ-induced diabetic rats fed with atherosclerotic diet	M. rubra	Water	Extract included into diet	100, 200 and 400 mg/kg	30 days	(Sharma et al. 2010)
High cholesterol diet-fed rabbits	M. alba	(A) Water (B) Methanol–ethyl acetate	Dried powder suspended in distilled water	1 and 2% extract	25 weeks	(Chan et al. 2013)
Cardioprotective effect
ISO-induced myocardial infarction rats	M. alba	Methanol	Extract suspended in distilled water	25, 50 and 100 mg/kg	3 weeks	(Nade et al. 2013)
Myosin-induced myocarditis rats	M. alba	–	Powder included into the diet	5% w/w of the diet	3 weeks	(Arumugam et al. 2012)

ND: not defined; STZ: streptozotocin.

Table 3. Clinical studies demonstrating clinical efficacy of mulberry leaves.

		Mulberry leaf interventions
Design	Populations (N)	Species	Solvent extracts	Preparation	Dose	Duration	Outcomes	References
Antihyperglycaemic effect
Parallel, double-blinded, RCT	Healthy volunteers (24)	M. alba	Ethanol–water	DNJ-enriched powder (1.5% DNJ) dissolved in water	0.4, 0.8 and 1.2 g (equivalent to 6, 12 and 18 mg DNJ, respectively)	Single dose	PPG and postprandial insulin during sucrose tolerance test	(Kimura et al. 2007)
Parallel, double-blinded, RCT	Healthy volunteers (50)	M. alba	Water	Dried powder of extract (0.36% DNJ) dissolved in water	1.25, 2.5 and 5 g (equivalent to 4.5, 9 and 18 mg DNJ, respectively)	Single dose	PPG during maltose tolerance test	(Chung et al. 2013)
Cross-over, double-blinded, RCT	Patients with impaired glucose metabolism (baseline FPG 100–140 mg/dL) (12)	M. alba	Ethanol–water	DNJ-enriched powder (1.5% DNJ) in capsule	3, 6 and 9 mg DNJ	Single dose	PPG during high-carbohydrate meal tolerance test	(Asai et al. 2011)
Cross-over, double-blinded, RCT	(A) Healthy volunteers (10) (B) Patients with T2DM (10)	M. alba	ND	Extract dissolved in water	1 g	Single dose	PPG during sucrose tolerance test and breath hydrogen concentration	(Mudra et al. 2007)
Parallel, double-blinded, RCT	Patients with T2DM (48)	ND	–	Brewed tea	70 mL	Single dose	PPG during high-carbohydrate meal tolerance test	(Banu et al. 2015)
Parallel, single-blinded, RCT	(A) Healthy volunteers (10) (B) Patients with untreated T2DM (5) (C) Patients with T2DM and treated with sulfonylurea (5)	ND	ND	3.3 g of extract (0.77% DNJ) included into jelly	254 µg DNJ	Single dose	PPG, postprandial insulin, HOMA-IR and breath hydrogen concentration	(Nakamura et al. 2011)
Parallel, double-blinded, RCT	Healthy volunteers (12)	M. alba	Ethanol–water	DNJ-enriched powder (1.5% DNJ) dissolved in water	1.2 g (equivalent to 18 mg DNJ) thrice daily before meals	38 days	FPG and FPI	(Kimura et al. 2007)
Parallel, double-blinded, RCT	Prediabetic subjects (42)	M. alba	Water	Tablet (0.36% DNJ)	6 tablets (equivalent to 6 mg DNJ) thrice daily with meals	4 weeks	PPG, postprandial insulin and postprandial c-peptide	(Kim et al. 2015)
Cross-over, double-blinded, RCT	Patients with impaired glucose metabolism (baseline FPG 110–140 mg/dL) (76)	M. alba	Ethanol–water	DNJ-enriched powder (1.5% DNJ) in capsule	3 capsules (equivalent to 6 mg DNJ) thrice daily before meals	12 weeks	FPG, FPI, HbA1c, glycated albumin and 1,5-AG	(Asai et al. 2011)
Antihyperlipidaemic effect
Repeated measures, single group study	Patients with mild dyslipidaemia (baseline LDL-C 140–189 mg/dL) (23)	M. alba	ND	Tablet (0.367 mg DNJ/tablet)	3 tablets thrice daily before meals	12 weeks	Plasma TC, LDL-C, HDL-C and TG	(Aramwit et al. 2011)
Repeated measures, single group study	Patients with hypertriglyceridemia (baseline TG ≥200 mg/dL) (10)	ND	ND	Capsule (4 mg DNJ/capsule)	3 capsules (equivalent to 12 mg DNJ) thrice daily before meals	12 weeks	Plasma TC, LDL-C, HDL-C, TG, adiponectin, leptin and apolipoprotein-B	(Kojima et al. 2010)
Parallel, open-labelled, RCT	Patients with dyslipidaemia (baseline TC ≥200, LDL-C 101–190 or TG ≥150 mg/dL) (46)	M. alba	–	Brewed tea	2 g	8 weeks	Plasma TC, LDL-C, HDL-C and TG	(Banchobphutsa 2012)
Parallel, open-labelled, RCT	Patients with mild T2DM (12)	M. indica	ND	Capsule (500 mg/capsule)	2 capsules thrice daily before meals	4 weeks	Plasma TC, LDL-C, HDL-C and TG Erythrocyte membrane TC, LDL-C, HDL-C, TG and phospholipid	(Andallu et al. 2001)
Antioxidative and anti-inflammatory effects
Parallel, open-labelled, RCT	Patients with mild T2DM (12)	M. indica	ND	Capsule (500 mg/capsule)	2 capsules thrice daily before meals	4 weeks	Plasma-, erythrocyte membrane-, urine-peroxides	(Andallu et al. 2001)
Repeated measures, single group study	Patients with mild dyslipidaemia (baseline LDL-C 140–189 mg/dL) (25)	M. alba	ND	Tablet (0.367 mg DNJ/tablet)	3 tablets thrice daily before meals	12 weeks	Erythrocyte glutathione peroxidase activity, 8-isoprostane and CRP	(Aramwit et al. 2013)

ND: not defined; RCT: randomized controlled trial; HOMA-IR: homeostasis of model assessment of insulin resistance; FPI: fasting plasma insulin.

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