Mulberry (桑葚子 Sang Shèn Zǐ) and its Bioactive Compounds, the Chemoprevention Effects and Molecular Mechanisms In Vitro and In Vivo

Hui-Pei Huang；Ting-Tsz Ou；Chau-Jong Wang

Chemoprevention effects ； Cyanidin-3-glucoside ； Mulberry extracts (ME) ； Traditional Chinese medicine (TCM)

Journal of Traditional and Complementary Medicine

3卷1期（2013 / 01 / 01）

7 - 15

英文

Mulberry (桑葚子 sāng shèn zǐ), a traditional Chinese medicine (TCM) in Taiwan, has many bioactive substances, including polyphenol and anthocyanins compounds. Over the past decade, many scientific and medical studies have examined mulberry fruit for its antioxidation and antiinflammation effects both in vitro and in vivo. This review thus focuses on the recent advances of mulberry extracts (MEs) and their applications in the prevention and treatment of human cancer, liver disease, obesity, diabetes, and cardiovascular disease. The ME modulates several apoptotic pathways and matrix metalloproteinases (MMPs) to block cancer progression. Mulberry can increase detoxicated and antioxidant enzyme activities and regulate the lipid metabolism to treat hepatic disease resulting from alcohol consumption, high fat diet, lipopolysaccharides (LPS) and CCl_4 exposure. Of the various compounds in ME, cyanidin 3-glucoside (C3G) is the most abundant, and the active compound studied in mulberry research. Herein, the antioxidant and antiinflammatory actions of C3G to improve diabetes and cardiovascular disease are also discussed. These studies provide strong evidence ME may possess the bioactivity to affect the pathogenesis of several chronic diseases.

1. Andallu, B,Suryakantham, V,Lakshmi Srikanthi, B,Reddy, GK(2001).Effect of mulberry (Morus indica L.) therapy on plasma and erythrocyte membrane lipids in patients with type 2 diabetes.Clin Chim Acta,314,47-53.
2. Arabshahi-Delouee, S,Urooj, A(2007).Antioxidant properties of various solvent extracts of mulberry (Morus indica L.) leaves.Food Chem,102,1233-1240.
3. Arfan, M,Khan, R,Rybarczyk, A,Amarowicz, R(2012).Antioxidant activity of mulberry fruit extracts.Int J Mol Sci,13,2472-2480.
4. Bhuiyan, MI,Kim, HB,Kim, SY,Cho, KO(2011).The neuroprotective potential of cyanidin-3-glucoside fraction extracted from mulberry following oxygen-glucose deprivation.Korean J Physiol Pharmacol,15,353-361.
5. Chen, CC,Hsu, JD,Huang, HP,Yang, MY,Wang, CJ(2005).Mulberry extract inhibits the development of atherosclerosis in cholesterol-fed rabbits.Food Chem,91,601-607.
6. Chen, CC,Liu, LK,Hsu, JD,Huang, HP,Yang, MY,Wang, CJ(2005).Mulberry extract inhibits the development of atherosclerosis in holesterol-fed rabbits.Food Chem,91,601-607.
7. Chen, PN,Chu, SC,Chiou, HL,Kuo, WH,Chiang, CL,Hsieh, YS(2006).Mulberry anthocyanins, cyanidin 3-rutinoside and cyanidin 3-glucoside, exhibited an inhibitory effect on the migration and invasion of a human lung cancer cell line.Cancer Lett,235,248-259.
8. Cui, X,Jin, Y,Hofseth, AB,Pena, E,Habiger, J,Chumanevich, A(2010).Resveratrol suppresses colitis and colon cancer associated with colitis.Cancer Prev Res,3,549-559.
9. Darias-Martin, J,Lobo-Rodrigo, G,Hernandez-Cordero, J,Diaz-Diaz, E,Diaz-Romero, C(2003).Alcoholic beverages obtained from black mulberry.Food Technol Biotechnol,41,173-176.
10. Despres, JP(2006).Is visceral obesity the cause of the metabolic syndrome?.Ann Med,38,52-63.
11. Du, Q,Zheng, J,Xu, Y(2008).Composition of anthocyanins in mulberry and their antioxidant activity.J Food Compos Anal,21,390-395.
12. El-Beshbishy, HA,Singab, AN,Sinkkonen, J,Pihlaja, K(2006).Hypolipidemic and antioxidant effects of Morus alba L. (Egyptian mulberry) root bark fractions supplementation in cholesterol-fed rats.Life Sci,78,2724-2733.
13. Elmacı, Y,Altuğ, T(2002).Flavour evaluation of three black mulberry (Morus nigra) cultivars using GC/MS, chemical and sensory data.J Sci Food Agric,82,632-635.
14. El-Serag, HB,Rudolph, KL(2007).Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis.Gastroenterology,132,2557-2576.
15. Ercisli, S,Orhan, E(2007).Chemical composition of white (Morus alba), red (Morus rubra) and black (M. nigra) mulberry fruits.Food Chem,103,1380-1384.
16. Fang, SH,Hou, YC,Chao, PD(2005).Pharmacokinetic and pharmacodynamic interactions of morin and cyclosporin.Toxicol Appl Pharmacol,205,65-70.
17. Gao, X,Ohlander, M,Jeppsson, N,Björk, L,Trajkovski, V(2000).Changes in antioxidant effects and their relationship to phytonutrients in fruits of sea buckthorn (Hippophae rhamnoides L.) during maturation.J Agric Food Chem,48,1485-1490.
18. Gerasopoulos, D,Stavroulakis, G(1997).Quality characteristics of four mulberry (Morus sp.) cultivars in the area of Chania, Greece.J Sci Food Agric,73,261-264.
19. Ghavami, G,Sardari, S,Ali Shokrgozar, M(2011).Cheminformatics-based selection and synergism of herbal extracts with anticancer agents on drug resistance tumor cells-ACHN and A2780/cp cell lines.Comput Biol Med,41,665-674.
20. Guengerich, FP(1996).In vitro techniques for studying drug metabolism.J Pharmacokinet Biopharm,24,521-533.
21. Ha, US,Koh, JS,Kim, HS,Woo, JC,Kim, SJ,Jang, H(2012).Cyanidin-3-O-beta-D-glucopyranoside concentrated materials from mulberry fruit have a potency to protect erectile function by minimizing oxidative stress in a rat model of diabetic erectile dysfunction.Urol Int,88,470-476.
22. Harborne, JB,Williams, CA(2000).Advances in flavonoid research since 1992.Phytochemistry,55,481-504.
23. Hassimotto, NM,Genovese, MI,Lajolo, FM(2008).Absorption and metabolism of cyanidin-3-glucoside and cyanidin-3-rutinoside extracted from wild mulberry (Morus nigra L.) in rats.Nutr Res,28,198-207.
24. Hassimotto, NM,Genovese, MI,Lajolo, FM(2005).Antioxidant activity of dietary fruits, vegetables, and commercial frozen fruit pulps.J Agric Food Chem,53,2928-2935.
25. Hidaka, M,Okumura, M,Fujita, K,Ogikubo, T,Yamasaki, K,Iwakiri, T(2005).Effects of pomegranate juice on human cytochrome p450 3A (CYP3A) and carbamazepine pharmacokinetics in rats.Drug Metab Dispos,33,644-648.
26. Hsu, LS,Ho, HH,Lin, MC,Chyau, CC,Peng, JS,Wang, CJ(2012).Mulberry water extracts (MWEs) ameliorated carbon tetrachloride-induced liver damages in rat.Food Chem Toxicol,50,3086-3093.
27. Huang, HP,Chang, YC,Wu, CH,Hung, CN,Wang, CJ(2011).Anthocyanin-rich Mulberry extract inhibit the gastric cancer cell growth in vitro Food Chemistry and xenograft mice by inducing signals of p38/p53 and c-jun.Food Chem,129,1703-1709.
28. Huang, HP,Shih, YW,Chang, YC,Hung, CN,Wang, CJ(2008).Chemoinhibitory effect of mulberry anthocyanins on melanoma metastasis involved in the Ras/PI3K pathway.J Agric Food Chem,56,9286-9293.
29. Imran, M,Khan, H,Shah, M,Khan, R,Khan, F(2010).Chemical composition and antioxidant activity of certain Morus species.J Zhejiang Univ Sci B,11,973-980.
30. Isabelle, M,Lee, BL,Ong, CN,Liu, X,Huang, D(2008).Peroxyl radical scavenging capacity, polyphenolics, and lipophilic antioxidant profiles of mulberry fruits cultivated in southern China.J Agric Food Chem,56,9410-9416.
31. Jeong, JC,Jang, SW,Kim, TH,Kwon, CH,Kim, YK(2010).Mulberry fruit (Moris fructus) extracts induce human glioma cell death in vitro through ROS-dependent mitochondrial pathway and inhibits glioma tumor growth in vivo.Nutr Cancer,62,402-412.
32. Kaewkaen, P,Tong-Un, T,Wattanathorn, J,Muchimapura, S,Kaewrueng, W,Wongcharoenwanakit, S(2012).Effects of mulberry fruit powder in animal model of stroke.Am J Agric Biol Sci,7,322-329.
33. Kahkonen, MP,Heinonen, M(2003).Antioxidant activity of anthocyanins and their aglycons.J Agric Food Chem,51,628-633.
34. Kang, TH,Hur, JY,Kim, HB,Ryu, JH,Kim, SY(2006).Neuroprotective effects of the cyanidin-3-O-beta-d-glucopyranoside isolated from mulberry fruit against cerebral ischemia.Neurosci Lett,391,122-126.
35. Kim, AJ,Park, S(2006).Mulberry extract supplements ameliorate the inflammation-related hematological parameters in carrageenan-induced arthritic rats.J Med Food,9,431-435.
36. Kim, H,Yoon, YJ,Shon, JH,Cha, IJ,Shin, JG,Liu, KH(2006).Inhibitory effects of fruit juices on CYP3A activity.Drug Metab Dispos,34,521-523.
37. Kim, HG,Ju, MS,Shim, JS,Kim, MC,Lee, SH,Huh, Y(2010).Mulberry fruit protects dopaminergic neurons in toxin-induced Parkinson’s disease models.Br J utr,104,8-16.
38. Kimura, T,Nakagawa, K,Kubota, H,Kojima, Y,Goto, Y,Yamagishi, K(2007).Food-grade mulberry powder enriched with 1-deoxynojirimycin suppresses the elevation of postprandial blood glucose in humans.J Agric Food Chem,55,5869-5874.
39. Krishnaswamy, K,Raghuramulu, N.(1998).Bioactive phytochemicals with emphasis on dietary practices.Indian J Med Res,108,167-181.
40. Kwon, HJ,Kim, YY,Choung, SY(2005).Amelioration effects of traditional Chinese medicine on alcohol-induced fatty liver.World J Gastroenterol,11,5512-5516.
41. Lazzè, MC,Savio, M,Pizzala, R,Cazzalini, O,Perucca, P,Scovassi, AI(2004).Anthocyanins induce cell cycle perturbations and apoptosis in different human cell lines.Carcinogenesis,25,1427-1433.
42. Lin, JY,Tang, CY(2007).Determination of total phenolic and flavonoid contents in selected fruits and vegetables, as well as their stimulatory effects on mouse splenocyte proliferation.Food Chem,101,140-147.
43. Liu, LK,Lee, HJ,Shih, YW,Chyau, CC,Wang, CJ(2008).Mulberry anthocyanin extracts inhibit LDL oxidation and macrophage-derived foam cell formation induced by oxidative LDL.J Food Sci,73,H113-H121.
44. Lodovici, M,Guglielmi, F,Meoni, M,Dolara, P(2001).Effect of natural phenolic acids on DNA oxidation in vitro.Food Chem Toxicol,39,1205-1210.
45. Lu Xi, WL,Wei, H,Yang, Z,Wei, W(2006).Structure-activity relationship of flavonoids in antioxidant activity.Food Sci,27,233-237.
46. Mahmood, T,Anwar, F,Abbas, M,Saari, N(2012).Effect of maturity on phenolics (phenolic acids and flavonoids) profile of strawberry cultivars and mulberry species from pakistan.Int J Mol Sci,13,4591-4607.
47. Manson, MM(2003).Cancer prevention - the potential for diet to modulate molecular signalling.Trends Mol Med,9,11-18.
48. Meyer, C,Blissett, J,Oldfield, C(2001).Sexual orientation and eating psychopathology: the role of masculinity and femininity.Int J Eat Disord,29,314-318.
49. Naderi, GA,Asgary, S,Sarraf-Zadegan, N,Oroojy, H,Afshin-Nia, F(2004).Antioxidant activity of three extracts of Morus nigra.Phytother Res,18,365-369.
50. Ou, TT,Hsu, MJ,Chan, KC,Huang, CN,Ho, HH,Wang, CJ(2011).Mulberry extract inhibits oleic acid-induced lipid accumulation via reduction of lipogenesis and promotion of hepatic lipid clearance.J Sci Food Agric,91,2740-2748.
51. Ou, TT,Kuo, CY,Chyau, CC,Lee, HJ,Peng, JS,Wang, CJ(2012).Improvement of lipopolysaccharides-induced hepatic injuries and inflammation with mulberry extracts.J Sci Food Agric
52. Pawlowska, AM,Oleszek, W,Braca, A(2008).Quali-quantitative analyses of Flavonoids of Morus nigra L. and Morus alba L. (Moraceae) fruits.J Agric Food Chem,56,3377-3380.
53. Peng, CH,Liu, LK,Chuang, CM,Chyau, CC,Huang, CN,Wang, CJ(2011).Mulberry water extracts possess an anti-obesity effect and ability to inhibit hepatic lipogenesis and promote lipolysis.J Agric Food Chem,59,2663-2671.
54. Robbins, RJ(2003).Phenolic acids in foods: an overview of analytical methodology.J Agric Food Chem,51,2866-2887.
55. Sakagami, H,Asano, K,Satoh, K,Takahashi, K,Terakubo, S,Shoji, Y(2006).Anti-stress activity of mulberry juice in mice.In Vivo,20,499-504.
56. Sardari, S,Shokrgozar, MA,Ghavami, G(2009).Cheminformatics based selection and cytotoxic effects of herbal extracts.Toxicol In Vitro,23,1412-1421.
57. Sass-Kiss, A(2005).Differences in anthocyanin and carotenoid content of fruits and vegetables.Food Res Int,38,1023-1029.
58. Satoh, H,Yamashita, F,Tsujimoto, M,Murakami, H,Koyabu, N,Ohtani, H(2005).Citrus juices inhibit the function of human organic anion-transporting polypeptide OATP-B.Drug Metab Dispos,33,518-523.
59. Seeram, NP,Momin, RA,Nair, MG,Bourquin, LD(2001).Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries.Phytomedicine,8,362-369.
60. Serraino, I,Dugo, L,Dugo, P,Mondello, L,Mazzon, E,Dugo, G(2003).Protective effects of cyanidin-3-O-glucoside from blackberry extract against peroxynitrite-induced endothelial dysfunction and vascular failure.Life Sci,73,1097-1114.
61. Shih, PH,Chan, YC,Liao, JW,Wang, MF,Yen, GC(2010).Antioxidant and cognitive promotion effects of anthocyanin-rich mulberry (Morus atropurpurea L.) on senescence-accelerated mice and prevention of Alzheimer’s disease.J Nutr Biochem,21,598-605.
62. Singh, UP,Singh, NP,Singh, B,Hofseth, LJ,Price, RL,Nagarkatti, M(2010).Resveratrol (trans-3,5,4’-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis.J Pharmacol Exp Ther,332,829-839.
63. Surh, YJ(2003).Cancer chemoprevention with dietary phytochemicals.Nat Rev Cancer,3,768-780.
64. Tsuda, T,Majumder, K,Linask, KK(1998).Differential expression of flectin in the extracellular matrix and left-right asymmetry in mouse embryonic heart during looping stages.Dev Genet,23,203-214.
65. Wang, CJ,Wang, JM,Lin, WL,Chu, CY,Chou, FP,Tseng, TH(2000).Protective effect of Hibiscus anthocyanins against tert-butyl hydroperoxide-induced hepatic toxicity in rats.Food Chem Toxicol,38,411-416.
66. Yang, CS,Landau, JM,Huang, MT,Newmark, HL(2001).Inhibition of carcinogenesis by dietary polyphenolic compounds.Annu Rev Nutr,21,381-406.
67. Yang, X,Yang, L,Zheng, H(2010).Hypolipidemic and antioxidant effects of mulberry (Morus alba L.) fruit in hyperlipidaemia rats.Food Chem Toxicol,48,2374-2379.
68. Yang, XY,Park, GS,Lee, MH,Chang, IA,Kim, YC,Kim, SY(2009).Toll-like receptor 4-mediated immunoregulation by the aqueous extract of Mori Fructus.Phytother Res,23,1713-1720.
69. Zadernowski, R,Naczk, M,Nesterowicz, J(2005).Phenolic acid profiles in some small berries.J Agric Food Chem,53,2118-2124.

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