Phenolic constituents from the root bark of Morus alba with emphasis on morusin and its anti-cancer properties

doi:10.5246/jcps.2019.02.008

Abstract

Abstract:

The root bark of Morus alba L. or white mulberry is widely used as traditional medicine in China, Japan and Korea. Major classes and types of phenolic compounds isolated from the root bark are flavonoids (kuwanons, morusin, cyclomorusin and sanggenons), benzofurans (moracins and mulberrofurans), and stilbenoids (mulberrosides). Some of the flavonoids and benzofurans are products of Diel-Alder type adducts. Other classes of compounds include triterpenes, phenolic acids and coumarins. Morusin, a prenylated flavonoid, was first isolated from the root bark of M. alba, and later from the leaf, stem bark and twig of the plant. The potent anti-cancer properties of morusin have attracted much attention with research on-going and new findings being published. The compound inhibits angiogenesis, tumour progression and tumour migration, and triggers apoptosis, cell cycle arrest and autophagy in colorectal, cervical, prostate, breast, hepatoma, pancreatic, glioblastoma, gastric, ovarian and lung cancer cell lines. The anti-cancer activities of morusin are executed via various molecular targets and signalling pathways. It is anticipated that on-going in vitro studies will progress gradually to in vivo studies using animal models before efforts towards drug development can be initiated for clinical trials.

CLC Number:

R284

Supporting:

Eric Wei Chiang Chan, Siu Kuin Wong, Tomomi Inoue, Hung Tuck Chan. Phenolic constituents from the root bark of Morus alba with emphasis on morusin and its anti-cancer properties[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(2): 75-87.

References

[1] Wu, Z.; Zhou, Z.K.; Gilbert, M.G. Morus L. Flora China. 2003, 5, 22-26.

[2] Chan, E.W.C.; Lye, P.Y.; Wong, S.K. Phytochemistry, pharmacology, and clinical trials of Morus alba. Chin. J. Nat. Med. 2016, 14, 17-30.

[3] Ercisli, S.; Orhan, E. Chemical composition of white (Morus alba), red (Morus rubra) and black (Morus nigra) mulberry fruits. Food Chem. 2007, 103, 1380-1384.

[4] Wei, H.; Zhu, J.J.; Liu, X.Q.; Feng, W.H.; Wang, Z.M.; Yan, L.H. Review of bioactive compounds from root barks of Morus plants (Sang-Bai-Pi) and their pharmacological effects. Cogent Chem. 2016, 2, 1212320.

[5] Singab, A.N.; El-Beshbishy, H.A.; Yonekawa, M.; Nomura, T.; Fukai, T. Hypoglycemic effect of Egyptian Morus alba root bark extract: effect on diabetes and lipid peroxidation of streptozotocin-induced diabetic rats. J. Ethnopharmacol. 2005, 100, 333-338.

[6] El-Beshbishy, H.A.; Singab, A.N.; Sinkkonen, J.; Pihlaja, K. Hypolipidemic and antioxidant effects of Morus alba L. (Egyptian mulberry) root bark fractions supplementation in cholesterol-fed rats. Life Sci. 2006, 78, 2724-2733.

[7] Khan, M.A.; Rahman, A.A.; Islam, S.; Khandokhar, P.; Parvin, S.; Islam, M.B.; Hossain, M.; Rashid, M.; Sadik, G.; Nasrin, S.; Haque Mollah, M.N.; Khurshid Alam, A.H.M. A comparative study on the antioxidant activity of methanolic extracts from different parts of Morus alba L. (Moraceae). BMC Res. Notes. 2013, 6, 24.

[8] Kim, H.J.; Lee, H.J.; Jeong, S.J.; Lee, H.J.; Kim, S.H.; Park, E.J. Cortex Mori Radicis extract exerts anti-asthmatic effects via enhancement of CD4+ CD25+ Foxp3+ regulatory T cells and inhibition of Th2 cytokines in a mouse asthma model. J. Ethnopharmacol. 2011, 138, 40-46.

[9] Kang, K.B.; Lee, D.Y.; Kim, T.B.; Kim, S.H.; Kim, H.J.; Kim, J.; Sung, S.H. Prediction of tyrosinase inhibitory activities of Morus alba root bark extracts from HPLC fingerprints. Microchem. J. 2013, 110, 731-738.

[10] Yang, Z.G.; Matsuzaki, K.; Takamatsu, S.; Kitanaka, S. Inhibitory effects of constituents from Morus alba var. multicaulis on differentiation of 3T3-L1 cells and nitric oxide production in RAW264.7 cells. Molecules. 2011, 16, 6010-6022.

[11] Lee, M.S.; Park, W.S.; Kim, Y.H.; Kwon, S.H.; Jang, Y.J.; Han, D.; Morita, K.; Her, S. Antidepressant-like effects of Cortex Mori Radicis extract via bidirectional phosphorylation of glucocorticoid receptors in the hippocampus. Behav. Brain Res. 2013, 236, 56-61.

[12] Lim, H.J.; Jin, H.G.; Woo, E.R.; Lee, S.K.; Kim, H.P. The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. J. Ethnopharmacol. 2013, 149, 169-175.

[13] Eo, H.J.; Park, J.H.; Park, G.H.; Lee, M.H.; Lee, J.R.; Koo, J.S.; Jeong, J.B. Anti-inflammatory and anti-cancer activity of mulberry (Morus alba L.) root bark. BMC Complement. Alternat. Med. 2014, 14, 200.

[14] Nam, S.Y.; Yi, H.K.; Lee, J.C.; Kim, J.C.; Song, C.H.; Park, J.W.; Lee, D.Y.; Kim, J.S.; Hwang, P.H. Cortex mori extract induces cancer cell apoptosis through inhibition of microtubule assembly. Arch. Pharm. Res. 2002, 25, 191-196.

[15] Chen, H.D.; Ding, Y.Q.; Yang, S.P.; Li, X.C.; Wang, X.J.; Zhang, H.Y.; Ferreira, D.; Yue, J.M. Morusalbanol A, a neuro-protective Diels-Alder adduct with an unprecedented architecture from Morus alba. Tetrahedron. 2012, 68, 6054-6058.

[16] Yin, N.; Hong, X.; Han, Y.; Duan, Y.; Zhang, Y.; Chen, Z. Cortex Mori Radicis extract induces neurite outgrowth in PC12 cells activating ERK signalling pathway via inhibiting Ca2+ influx. Int. J. Clin. Exper. Med. 2015, 8, 5022-5032.

[17] Kuk, E.B.; Jo, A.R.; Oh, S.I.; Sohn, H.S.; Seong, S.H.; Roy, A.; Choi, J.S.; Jung, H.A. Anti-Alzheimer’s disease activity of compounds from the root bark of Morus alba L. Arch. Pharm. Res. 2017, 40, 338-349.

[18] Ha, M.T.; Tran, M.H.; Ah, K.J.; Jo, K.J.; Kim, J.; Kim, W.D.; Cheon, W.J.; Woo, M.H.; Ryu, S.H.; Min, B.S. Potential pancreatic lipase inhibitory activity of phenolic constituents from the root bark of Morus alba L. Bioorg. Med. Chem. Lett. 2016, 26, 2788-2794.

[19] Qi, S.Z.; Li, N.; Tuo, Z.D.; Li, J.L.; Xing, S.S.; Li, B.B.; Zhang, L.; Lee, H.S.; Chen, J.G.; Cui, L. Effects of Morus root bark extract and active constituents on blood lipids in hyperlipidemia rats. J. Ethnopharmacol. 2016, 180, 54-59.

[20] Lian, J.; Chen, J.; Yuan, Y.; Chen, J.; Sayed, M.D.; Luo, L.; Zhu, Y.; Li, S.; Bu, S. Cortex Mori Radicis extract attenuates myocardial damages in diabetic rats by regulating ERS. Biomed. Pharmacother. 2017, 90, 777-785.

[21] Zheng, X.K.; Cao, Y.G.; Ke, Y.Y.; Zhang, Y.L.; Li, F.; Gong, J.H.; Zhao, X.; Kuang, H.X.; Feng, W.S. Phenolic constituents from the root bark of Morus alba L. and their cardioprotective activity in vitro. Phytochemistry. 2017, 135, 128-134.

[22] Zuo, G.Y.; Yang, C.X.; Han, J.; Li, Y.Q.; Wang, G.C. Synergism of prenylflavonoids from Morus alba root bark against clinical MRSA isolates. Phytomedicine. 2018, 39, 93-99.

[23] Yuvaraj, K.; Arumugam, G. Anti-inflammatory and preventive activity of white mulberry root bark extract in an experimental model of pancreatitis. J. Tradit. Complement. Med. 2018, 1-9.

[24] Butt, M.S.; Nazir, A.; Sultan, M.T.; Schroën, K. Morus alba L. nature’s functional tonic. Trends Food Sci. Technol. 2008, 19, 505-512.

[25] Devi, B.; Sharma, N.; Kumar, D.; Jeet, K. Morus alba Linn: A phytopharmacological review. Int. J. Pharm. Pharm. Sci. 2013, 5, 14-18.

[26] Singh, R.; Bagachi, A.; Semwal, A.; Kaur, S.; Bharadwaj, A. Traditional uses, phytochemistry and pharmacology of Morus alba Linn: A review. J. Med. Plants Res. 2013, 7, 461-469.

[27] Zafar, M.S.; Muhammad, F.; Javed, I.; Akhtar, M.; Khaliq, T.; Aslam, B.; Waheed, A.; Yasmin, R.; Zafar, H. White mulberry (Morus alba): A brief phytochemical and pharmacological evaluations account. Int. J. Agric. Biol. 2013, 15, 612-620.

[28] Hussain, F.; Rana, Z.; Shafique, H.; Malik, A.; Hussain, Z. Phytopharmacological potential of different species of Morus alba and their bioactive phytochemicals: A review. Asian Pac. J. Trop. Biomed. 2017, 7, 950-956.

[29] Kikuchi, T.; Nihei, M.; Nagai, H.; Fukushi, H.; Tabata, K.; Suzuki, T.; Akihisa, T. Albanol A from the root bark of Morus alba L. induces apoptotic cell death in HL60 human leukemia cell line. Chem. Pharm. Bull. 2010, 58, 568-571.

[30] Qin, J.; Fan, M.; He, J.; Wu, X.D.; Peng, L.Y.; Su, J.; Cheng, X.; Li, Y.; Kong, L.M.; Li, R.T.; Zhao, Q.S. New cytotoxic and anti-inflammatory compounds isolated from Morus alba L. Nat. Prod. Res. 2015, 29, 1711-1718.

[31] Guo, Y.Q.; Tang, G.H.; Lou, L.L.; Li, W.; Zhang, B.; Liu, B.; Yin, S. Prenylated flavonoids as potent phosphodiesterase-4 inhibitors from Morus alba: Isolation, modification, and structure-activity relationship study. Eur. J. Med. Chem. 2018, 144, 758-766.

[32] Yang, D.S.; Li, Z.L.; Yang, Y.P.; Xiao, W.L.; Li, X.L. A new geranylated 2-arylbenzofuran from Morus alba. Chin. Herbal Med. 2015, 7, 191-194.

[33] Geng, C.A.; Yao, S.; Xue, D.; Zuo, A.; Zhang, X.; Jiang, Z.; Ma, Y.; Chen, J. New isoprenylated flavonoid from Morus alba. China J. Chin. Mater. Med. 2010, 35, 1560-1565.

[34] Nomura, T.; Fukai, T.; Yamada, S.; Katayanagi, M. Phenolic constituents of the cultivated mulberry tree (Morus alba L.). Chem. Pharm. Bull. 1976, 24, 2898-2900.

[35] Du, J.; He, Z.D.; Jiang, R.W.; Ye, W.C.; Xu, H.X.; But, P.P. Antiviral flavonoids from the root bark of Morus alba L. Phytochemistry. 2003, 62, 1235-1238.

[36] Jung, J.W.; Ko, W.M.; Park, J.H.; Seo, K.H.; Oh, E.J.; Lee, D.Y.; Lee, D.S.; Kim, Y.C.; Lim, D.W.; Han, D.; Baek, N.I. Isoprenylated flavonoids from the root bark of Morus alba and their hepatoprotective and neuroprotective activities. Arch. Pharm. Res. 2015, 38, 2066-2075.

[37] Zhao, Y.; Kongstad, K.T.; Jäger, A.K.; Nielsen, J.; Staerk, D. Quadruple high-resolution α-glucosidase/α-amylase/PTP1B/radical scavenging profiling combined with high-performance liquid chromatography-high-resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy for identification of antidiabetic constituents in crude root bark of Morus alba L. J. Chromatogr. A. 2018, 1556, 55-63.

[38] Nomura, T. Chemistry and biosynthesis of prenylflavonoids. J. Pharm. Soc. Jpn. 2001, 121, 535-556.

[39] Li, M.; Wu, X.; Wang, X.; Shen, T.; Ren, D. Two novel compounds from the root bark of Morus alba L. Nat. Prod. Res. 2018, 32, 36-42.

[40] Huang, Q.H.; Lei, C.; Wang, P.P.; Li, J.Y.; Li, J.; Hou, A.J. Isoprenylated phenolic compounds with PTP1B inhibition from Morus alba. Fitoterapia. 2017, 122, 138-143.

[41] Nomura, T.; Fukai, T.; Katayanagi, M. Isolation of four new flavones, kuwanon A, B, C, and oxydihydromorusin from the root bark of Morus alba L. Chem. Pharm. Bull. 1978, 26, 1453-1458.

[42] Nomura, T.; Fukai, T. Kuwanon G, a new flavone derivative from the root barks of the cultivated mulberry tree (Morus alba L.). Chem. Pharm. Bull. 1980, 28, 2548-2552.

[43] Ueda, S.; Matsumoto, J.; Nomura, T. Four new natural Diels-Alder type adducts, mulberrofuran E, kuwanon Q, R, and V from callus culture of Morus alba L. Chem. Pharm. Bull. 1984, 32, 350-353.

[44] Park, K.M.; You, J.S.; Lee, H.Y.; Baek, N.I.; Hwang, J.K. Kuwanon G: an antibacterial agent from the root bark of Morus alba against oral pathogens. J. Ethnopharmacol. 2003, 84, 181-185.

[45] Cui, L.; Na, M.; Oh, H.; Bae, E.Y.; Jeong, D.G.; Ryu, S.E.; Kim, S.; Kim, B.Y.; Oh, W.K.; Ahn, J.S. Protein tyrosine phosphatase 1B inhibitors from Morus root bark. Bioorg. Med. Chem. Lett. 2006, 16, 1426-1429.

[46] Lee, J.J.; Yang, H.; Yoo, Y.M.; Hong, S.S.; Lee, D.; Lee, H.J.; Lee, H.J.; Myung, C.S.; Choi, K.C.; Jeung, E.B. Morusinol extracted from Morus alba inhibits arterial thrombosis and modulates platelet activation for the treatment of cardiovascular disease. J. Atheroscler. Thromb. 2012, 19, 516-522.

[47] Zhang, M.; Rong-Rong, W.A.; Man, C.H.; Zhang, H.Q.; Shi, S.U.; Zhang, L.Y. A new flavanone glycoside with anti-proliferation activity from the root bark of Morus alba. Chin. J. Nat. Med. 2009, 7, 105-107.

[48] Fu, W.; Lei, Y.F.; Cai, Y.L.; Zhou, D.N.; Ruan, J.L. A new alkylene dihydrofuran glycoside with antioxidation activity from the root bark of Morus alba L. Chin. Chem. Lett. 2010, 21, 821-823.

[49] Nomura, T.; Fukai, T.; Uno, J.; Arai, T. Mulberrofuran A, a new isoprenoid 2-arylbenzofuran from root bark of cultivated mulberry tree (Morus alba L). Heterocycles. 1978, 9, 1593-1601.

[50] Nomura, T.; Fukai, T. Mulberrofuran B, a new isoprenoid 2-arylbenzofuran from the root bark of the cultivated mulberry tree. Planta Med. 1981, 42, 197-199.

[51] Zhang, M.; Chen, M.; Zhang, H.Q.; Sun, S.; Xia, B.; Wu, F.H. In vivo hypoglycemic effects of phenolics from the root bark of Morus alba. Fitoterapia. 2009, 80, 475-477.

[52] Qiu, F.; Komatsu, K.; Kawasaki, K.; Saito, K.; Yao, X.; Kano, Y. A novel stilbene glucoside, oxyresveratrol 3’-O-β-glucopyranoside, from the root bark of Morus alba. Planta Med. 1996, 62, 559-561.

[53] Jung, J.W.; Park, J.H.; Jung, Y.J.; Lee, C.H.; Han, D.; Baek, N.I. Isolation and identification of triterpenoids from the mulberry (Morus alba) root bark. J. Appl. Biol. Chem. 2014, 57, 295-299.

[54] Bravo, L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr. Rev. 1998, 56, 317-333.

[55] Keservani, R.K.; Sharma, A.K. Flavonoids: emerging trends and potential health benefits. J. Chin. Pharm. Sci. 2014, 23, 815-822.

[56] Khanam, H.; Shamsuzzaman. Bioactive benzofuran derivatives: A review. Eur. J. Med. Chem. 2015, 97, 483-504.

[57] Han, X.; Shen, T.; Lou, H. Dietary polyphenols and their biological significance. Int. J. Mol. Sci. 2007, 8, 950-988.

[58] Patočka, J. Biologically active pentacyclic triterpenes and their current medicine signification. J. Appl. Biomed. 2003, 1, 7-12.

[59] Furtado, N.A.J.C.; Pirson, L.; Edelberg, H.; Miranda, L.M.; Loira-Pastoriza, C.; Preat, V.; Larondelle, Y.; André, C.M. Pentacyclic triterpene bioavailability: an overview of in vitro and in vivo studies. Molecules. 2017, 22, 400.

[60] Robbins, R.J. Phenolic acids in foods: an overview of analytical methodology. J. Agric. Food Chem. 2003, 51, 2866-2887.

[61] Balasundram, N.; Sundram, K.; Samman, S. Phenolic compounds in plants and agri-industrial by-products: antioxidant activity, occurrence, and potential uses. Food Chem. 2006, 99, 191-203.

[62] Bubols, G.B.; da Rocha Vianna, D.; Medina-Remon, A.; von Poser, G.; Lamuela-Raventos, R.M.; Eifler-Lima V.L.; Cristina Garcia, S. The antioxidant activity of coumarins and flavonoids. Mini-Rev. Med. Chem. 2013, 13, 318-334.

[63] Hano, Y; Nomura, T. Constituents of the Chinese crude drug Sang-Bai-Pi (Morus root barks) IV. Structures of four new flavonoids, sanggenon H, I, J and K. Heterocycles. 1983, 20, 1071-1076.

[64] Hano, Y.; Ichikawa, K.; Okuyama, M.; Yamanaka, J.; Miyoshi, T.; Nomura, T. Sanggenons R, S, and T, three new isoprenylated phenols from the Chinese crude drug Sang-Bai-Pi (Morus root bark). Heterocycles. 1995, 2, 953-965.

[65] Hano, Y.; Kohno, H.; Itoh, M.; Nomura, T. Structures of three new 2-arylbenzofuran derivatives from the Chinese crude drug Sang-Bai-Pi (Morus root bark). Chem. Pharm. Bull. 1985, 33, 5294-5300.

[66] Dat, N.T.; Binh, P.T.; van Minh, C.; Huong, H.T.; Lee, J.J. Cytotoxic prenylated flavonoids from Morus alba. Fitoterapia. 2010, 81, 1224-1227.

[67] Gupta, G.; Dua, K.; Kazmi, I.; Anwar, F. Anticonvulsant activity of morusin isolated from Morus alba: Modulation of GABA receptor. Biomed. Aging Pathol. 2014, 4, 29-32.

[68] Tran, H.N.; Nguyen, V.T.; Kim, J.A.; Rho, S.S.; Woo, M.H.; Choi, J.S.; Lee, J.H.; Min, B.S. Anti-inflammatory activities of compounds from twigs of Morus alba. Fitoterapia. 2017, 120, 17-24.

[69] Vochyánová, Z.; Pokorná, M.; Rotrekl, D.; Smékal, V.; Fictum, P.; Suchý, P.; Gajdziok, J.; Šmejkal, K.; Hošek, J. Prenylated flavonoid morusin protects against TNBS-induced colitis in rats. PLoS One. 2017, 12, e0182464.

[70] Terao, J.; Mukai, R. Prenylation modulates the bioavailability and bioaccumulation of dietary flavonoids. Arch. Biochem. Biophy. 2014, 559, 12-16.

[71] Tseng, T.H.; Chuang, S.K.; Hu, C.C.; Chang, C.F.; Huang, Y.C.; Lin, C.W.; Lee, Y.J. The synthesis of morusin as a potent anti-tumour agent. Tetrahedron. 2010, 66, 1335-1340.

[72] Lim, S.L.; Park, S.Y.; Kang, S.; Park, D.; Kim, S.H.; Um, J.Y.; Jang, H.J.; Lee, J.H.; Jeon, C.H.; Jang, J.H.; Ahn, K.S.; Lee, S.G. Morusin induces cell death through inactivating STAT3 signalling in prostate cancer cells. Amer. J. Cancer Res. 2015, 5, 289-299.

[73] Kang, S.; Kim, E.O.; Kim, S.H.; Lee, J.H.; Ahn, K.S.; Yun, M.; Lee, S.G. Morusin induces apoptosis by regulating expression of Bax and Survivin in human breast cancer cells. Oncol. Lett. 2017, 13, 4558-4562.

[74] Li, H.; Wang, Q.; Dong, L.; Liu, C.; Sun, Z.; Gao, L.; Wang, X. Morusin suppresses breast cancer cell growth in vitro and in vivo through C/EBPβ and PPARγ mediated lipoapoptosis. J. Exper. Clin. Cancer Res. 2015, 34, 137.

[75] Lee, J.C.; Won, S.J.; Chao, C.L.; Wu, F.L.; Liu, H.S.; Ling, P.; Lin, C.N.; Su, C.L. Morusin induces apoptosis and suppresses NF-κB activity in human colorectal cancer HT-29 cells. Biochem. Biophy. Res. Commun. 2008, 372, 236-242.

[76] Wang, L.; Guo, H.; Yang, L.; Dong, L.; Lin, C.; Zhang, J.; Lin, P.; Wang, X. Morusin inhibits human cervical cancer stem cell growth and migration through attenuation of NF-κB activity and apoptosis induction. Mol. Cell. Biochem. 2013, 379, 7-18.

[77] Lin, W.L.; Lai, D.Y.; Lee, Y.J.; Chen, N.F.; Tseng, T.H. Anti-tumour progression potential of morusin suppressing STAT3 and NF-κB in human hepatoma SK-Hep1 cells. Toxicol. Lett. 2015, 232, 490-498.

[78] Kim, C.; Kim, J.H.; Oh, E.Y.; Nam, D.; Lee, S.G.; Lee, J.; Kim, S.H.; Shim, B.S.; Ahn, K.S. Blockage of STAT3 signalling pathway by morusin induces apoptosis and inhibits invasion in human pancreatic tumour cells. Pancreas. 2016, 45, 409-419.

[79] Ding, B.; Lv, Y.; Zhang, Y.Q. Anti-tumour effect of morusin from the branch bark of cultivated mulberry in Bel-7402 cells via the MAPK pathway. RSC Adv. 2016, 6, 17396-17404.

[80] Park, D.; Ha, I.J.; Park, S.Y.; Choi, M.; Lim, S.L.; Kim, S.H.; Lee, J.H.; Ahn, K.S.; Yun, M.; Lee, S.G. Morusin induces TRAIL sensitization by regulating EGFR and DR5 in human glioblastoma cells. J. Nat. Prod. 2016, 79, 317-323.

[81] Wang, F.; Zhang, D.; Mao, J.; Ke, X.X.; Zhang, R.; Yin, C.; Gao, N.; Cui, H. Morusin inhibits cell proliferation and tumour growth by down-regulating c-Myc in human gastric cancer. Oncotarget. 2017, 8, 57187.

[82] Yin, X.L.; Lv, Y.; Wang, S.; Zhang, Y.Q. Morusin suppresses A549 cell migration and induces cell apoptosis by down-regulating the expression of COX-2 and VEGF genes. Oncol. Rep. 2018, 40, 504-510.

[83] Guo, H.; Liu, C.; Yang, L.; Dong, L.; Wang, L.; Wang, Q.; Li, H.; Zhang, J.; Lin, P.; Wang, X. Morusin inhibits glioblastoma stem cell growth in vitro and in vivo through stemness attenuation, adipocyte trans-differentiation, and apoptosis induction. Mol. Carcinogen. 2016, 55, 77-89.

[84] Cho, S.W.; Na, W.; Choi, M.; Kang, S.J.; Lee, S.G.; Choi, C.Y. Autophagy inhibits cell death induced by the anti-cancer drug morusin. Amer. J. Cancer Res. 2017, 7, 518-530.

[85] Gao, L.; Wang, L.; Sun, Z.; Li, H.; Wang, Q.; Yi, C.; Wang, X. Morusin shows potent anti-tumour activity for human hepatocellular carcinoma in vitro and in vivo through apoptosis induction and angiogenesis inhibition. Drug Design Dev. Ther. 2017, 11, 1789-1802.

[86] Xue, J.; Li, R.; Zhao, X.; Ma, C.; Lv, X.; Liu, L.; Liu, P. Morusin induces paraptosis-like cell death through mitochondrial calcium overload and dysfunction in epithelial ovarian cancer. Chem-Biol. Interact. 2018, 283, 59-74.

[87] Lee, H.J.; Ryu, J.; Park, S.H.; Woo, E.R.; Kim, A.R.; Lee, S.K.; Yim, Y.S.; Kim, J.O.; Hong, J.H.; Lee, C.J. Effects of Morus alba L. and natural products including morusin on in vivo secretion and in vitro production of airway MUC5AC mucin. Tuberc. Respir. Dis. 2014, 77, 65-72.

[88] Gupta, G.; Dua, K.; Kazmi, I.; Anwar, F. Anticonvulsant activity of morusin isolated from Morus alba: Modulation of GABA receptor. Biomed. Aging Pathol. 2014, 4, 29-32.

[89] De Souza, M.M.; Bittar, M.; Cechinel-Filho, V.; Yunes, R.A.; Messana, I.; Delle Monache, F.; Ferrari, F. Antinociceptive properties of morusin, a prenylflavonoid isolated from Morus nigra root bark. Z. Naturforsch. C. 2000, 55, 256-260.

[90] Gupta, G.; Chellappan, D.K.; Agarwal, M.; Ashwathanarayana, M.; Nammi, S.; Pabreja, K.; Dua, K. Pharmacological evaluation of the recuperative effect of morusin against aluminium trichloride (AlCl3)-induced memory impairment in rats. Cent. Nerv. Syst. Agents Med. Chem. 2017, 17, 196-200.

[91] Cheng, P.S.; Hu, C.C.; Wang, C.J.; Lee, Y.J.; Chung, W.C.; Tseng, T.H. Involvement of the antioxidative property of morusin in blocking phorbol ester-induced malignant transformation of JB6 P+ mouse epidermal cells. Chem-Biol. Interact. 2017, 264, 34-42.

[92] Shi-De, L.; Nemec, J.; Bing-Mei, N. Anti-HIV flavonoids from Morus alba. Acta Bot. Yunnanica. 1995, 17, 89-95.