Morin: A promising natural drug

Current Medicinal Chemistry

Volumn 23, Issue 8, 2016, Pages 774-791

  Caselli, Anna ^a   Cirri, Paolo ^a   Santi, Alice ^a   Paoli, Paolo ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

Author keywords

Anti diabetic; Anti inflammatory; Anti oxidant; Flavonoid; Morin; Natural drug; Polyphenol

Indexed keywords

MORIN; MULTIDRUG RESISTANCE PROTEIN; NATURAL PRODUCT; POLYPHENOL; ANTIDIABETIC AGENT; ANTIHYPERTENSIVE AGENT; ANTIINFECTIVE AGENT; ANTINEOPLASTIC AGENT; ANTIOXIDANT; BIOLOGICAL PRODUCT; FLAVONOID; NEUROPROTECTIVE AGENT; NONSTEROID ANTIINFLAMMATORY AGENT;

ANTIBACTERIAL ACTIVITY; ANTIDIABETIC ACTIVITY; ANTIHYPERTENSIVE ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; CHRONIC DRUG ADMINISTRATION; DRUG CYTOTOXICITY; DRUG TOLERABILITY; FRUIT; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MORACEAE; NEUROPROTECTION; NONHUMAN; PLANT LEAF; PLANT STEM; SIGNAL TRANSDUCTION; ANIMAL; CHEMISTRY; METABOLISM;

ANIMALS; ANTI-BACTERIAL AGENTS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTIHYPERTENSIVE AGENTS; ANTINEOPLASTIC AGENTS; ANTIOXIDANTS; BIOLOGICAL PRODUCTS; FLAVONOIDS; HUMANS; HYPOGLYCEMIC AGENTS; NEUROPROTECTIVE AGENTS;

EID: 84964413483     PISSN: 09298673     EISSN: 1875533X     Source Type: Journal    
DOI: 10.2174/0929867323666160106150821     Document Type: Article

References (171)

1. Harvey, A.L. Natural products in drug discovery. Drug Discov. Today, 2008, 13, 894-901.
2. Ramalingum, N.; Mahomoodally, M.F. The therapeutic potential of medicinal foods. Adv. Pharmacol. Sci., 2014, 2014, 354264.
3. Gutierrez, R.M.; Mitchell, S.; Solis, R.V. Psidium guajava: a review of its traditional uses, phytochemistry and pharmacology. J. Ethnopharmacol., 2008, 117, 1-27.
4. Wijeratne, S.S.; Abou-Zaid, M.M.; Shahidi, F. Antioxidant polyphenols in almond and its coproducts. J. Agric. Food Chem., 2006, 54, 312-318.
5. Rattanachaikunsopon, P.; Phumkhachorn, P. Contents and antibacterial activity of flavonoids extracted from leaves of Psidium guajava. J. Med. Plants Res., 2010, 4, 393-396.
6. Aggarwal, B.B.; Shishodia, S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol., 2006, 71, 1397-1421.
7. Hussain, J.; Ali, L.; Khan, A.L.; Rehman, N.U.; Jabeen, F.; Kim, J.S.; Al-Harrasi, A. Isolation and bioactivities of the flavonoids morin and morin-3-O-I2-D-glucopyranoside from acridocarpus orientalis-A wild arabian medicinal plant. Molecules, 2014, 19, 17763-17772.
8. Romero, I.; Paez, A.; Ferruelo, A.; Lujan, M.; Berenguer, A. Polyphenols in red wine inhibit the proliferation and induce apoptosis of LNCaP cells. BJU Int., 2002, 89, 950-954.
9. Yoshie,Y.; Hsieh, Y.P.; Suzuki, T. Distribution of flavonoids and related compounds from seaweeds in japan. J. Tokyo Univ. Fisheries, 2003, 89, 1-6.
10. Uyar, Z.; Boke, N.; Turkay, E.; Koz, O.; Yaaÿa, I.; Kirmizigul, S. Flavonoid glycosides and methylinositol from Ebenus haussknechtii. Nat. Prod. Res., 2006, 20, 999-1007.
11. Arima, H.Danno, G. Isolation of antimicrobial compounds from guava (Psidium guajava, L.) and their structural elucidation. Biosci. Biotechnol. Biochem., 2002, 66, 1727-1730.
12. Manach, C.; Donovan, J.L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic. Res., 2004, 38, 771-785.
13. Hollman, P.C.; Katan, M.B. Dietary flavonoids: intake, health effects and bioavailability. Food Chem. Toxicol., 1999, 37, 937-942.
14. Schramm, D.D.; Collins, H.E.; German, J.B. Flavonoid transport by mammalian endothelial cells. J. Nutr. Biochem., 2004, 10, 193-197.
15. Tian, X.J.; Yang, X.W.; Yang, X.; Wang, K. Studies of intestinal permeability of 36 flavonoids using Caco-2 cell monolayer model. Int. J. Pharm., 2008, 367, 58-64.
16. Zhang, J.; Peng, Q.; Shi, S.; Zhang, Q.; Sun, X.; Gong, T.; Zhang, Z. Preparation, characterization, and in vivo evaluation of a self-nanoemulsifying drug delivery system (SNEDDS) loaded with morin-phospholipid complex. Int. J. Nanomedicine, 2012, 6, 3405-3414.
17. Tian, X.; Yang, X.; Wang, K.; Yang, X. The efflux of flavonoids morin, isorhamnetin-3-O-rutinoside and diosmetin-7-O-beta-D-xylopyranosyl-(1-6)-beta-D-glucopyranoside in the human intestinal cell line caco-2. Pharm. Res., 2006, 23, 1721-1728.
18. Manach, C.; Scalbert, A.; Morand, C.; Remesy, C.; Jimenez, L. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr., 2004, 79, 727-747.
19. Hou, Y.C.; Tsai, Y.C.; Lee Chao, P.D.; Hsiu, S.L. Nonlinear pharmacokinetics of morin in rabbits. Mid Taiwan, J. Med., 2003, 8, 134-140.
20. Barnes, S.; Prasain, J.; D'Alessandro, T.; Arabshahi, A.; Botting, N.; Lila, M.A.; Jackson, G.; Janle, E.M.; Weaver, C.M. The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems. Food Funct., 2011, 2, 235-244.
21. Sergediene, E.; Jonsson, K.; Szymusiak, H.; Tyrakowska, B.; Rietjens, I.M.; Cenas, N. Prooxidant toxicity of polyphenolic antioxidants to HL-60 cells: description of quantitative structure-activity relationships. FEBS Lett., 2000, 462, 392-396.
22. Cho, Y.M.; Onodera, H.; Ueda, M.; Imai, T.; Hirose, M. A 13-week subchronic toxicity study of dietary administered morin in F344 rats. Food Chem. Toxicol., 2006, 44, 891-897.
23. Hong, H; Lee.; M.S.; Bae, E.Y.; Kim, Y.H.; Oh, H.; Oh, W.K.; Kim, B.Y.; Ahn, J.S. Screening for the inhibitory activity of medicinal plants against protein tyrosine phosphatase 1B. Korean J. Pharmacognosy, 2004, 35, 16-21.
24. Elchebly, M.; Payette, P.; Michaliszyn, E.; Cromlish, W.; Collins, S.; Loy, A.L.; Normandin, D.; Cheng, A.; Himms-Hagen, J.; Chan, C.C.; Ramachandran, C.; Gresser, M.J.; Tremblay, M.L.; Kennedy, B.P. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science, 1999, 283, 1544-1548.
25. Oh, W.K.; Lee, C.H.; Lee, M.S.; Bae, E.Y.; Sohn, C.B.; Oh, H.; Kim, B.Y.; Ahn, J.S. Antidiabetic effects of extracts from Psidium guajava. J. Ethnopharmacol., 2004, 96, 411-415.
26. Huang, C.S.; Yin, M.C.; Chiu, L.C. Antihyperglycemic and antioxidative potential of Psidium guajava fruit in streptozotocin-induced diabetic rats. Food Chem. Toxicol., 2011, 49, 2189-2195.
27. Cheng, J.T.; Yang, R.S. Hypoglycemic effect of guava juice in mice and human subjects. Am. J. Chin. Med., 1983, 11, 74-76.
28. Paoli, P.; Cirri, P.; Caselli, A.; Ranaldi, F.; Bruschi, G.; Santi, A.; Camici, G. The insulin-mimetic effect of Morin: a promising molecule in diabetes treatment. Biochim. Biophys. Acta, 2013, 1830, 3102-3111.
29. Vanitha, P.; Uma, C.; Suganya, N.; Bhakkiyalakshmi, E.; Suriyanarayanan, S.; Gunasekaran, P.; Sivasubramanian, S.; Ramkumar, K.M. Modulatory effects of morin on hyperglycemia by attenuating the hepatic key enzymes of carbohydrate metabolism and I2-cell function in streptozotocininduced diabetic rats. Environ. Toxicol. Pharmacol., 2014, 37, 326-335.
30. Sendrayaperumal, V.; Iyyam Pillai, S.; Subramanian, S. Design, synthesis and characterization of zinc-morin, a metal flavonol complex and evaluation of its antidiabetic potential in HFD-STZ induced type 2 diabetes in rats. Chem. Biol. Interact., 2014, 219, 9-17.
31. Bellomo, E.; Massarotti, A.; Hogstrand, C.; Maret, W. Zinc ions modulate protein tyrosine phosphatase 1B activity. Metallomics, 2014, 6, 1229-1239.
32. Haase, H.; Maret, W. Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulinlike growth factor-1 signaling. Exp. Cell Res., 2003, 291, 289-298.
33. Asgary, S.; Naderi, G.A.; Zadegan, N.S.; Vakili, R. The inhibitory effects of pure flavonoids on in vitro protein glycosylation. J. Herb. Pharmacother., 2004, 2, 47-55.
34. Ola, M.S.; Aleisa, A.M.; Al-Rejaie, S.S.; Abuohashish, H.M.; Parmar, M.Y.; Alhomida, A.S.; Ahmed, M.M. Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurol. Sci., 2014, 35, 1003-1008.
35. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol., 2006, 39, 44-84.
36. Kim, H.S.; Quon, M.J.; Kim, J.A. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. Redox Biol., 2014, 2, 187-195.
37. Wolfe, K.L.; Liu, R.H. Structure-activity relationships of flavonoids in the cellular antioxidant activity assay. J. Agric. Food Chem., 2008, 56, 8404-8411.
38. Farkas, O.; Jakus, J.; Heberger, K. Quantitative structureantioxidant activity relationships of flavonoid compounds. Molecules, 2007, 9, 1079-1088.
39. Mendoza-Wilson, A.M.; Santacruz-Ortega, H.; Balandran-Quintana, R.R. Spectroscopic and computational study of the major oxidation products formed during the reaction of two quercetin conformers with a free radical. Spectrochm. Acta. A Mol. Biomol. Spectrosc., 2011, 81, 481-488.
40. Morales, J.; Gunther, G.; Zanocco, A.L.; Lemp, E. Singlet oxygen reactions with flavonoids. A theoreticalexperimental study. PLoS One, 2012, 7, e40548.
41. Burda, S.; Oleszek, W. Antioxidant and antiradical activities of flavonoids. J. Agric. Food Chem., 2001, 49, 2774-2779.
42. Rice-Evans, C.A.; Miller, N.J.; Paganga, G. Structureantioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med., 1996, 20, 933-956.
43. Wu, T.W.; Fung, K.P.; Wu, J.; Yang, C.C.; Lo, J.; Weisel, R.D. Morin hydrate inhibits azo-initiator induced oxidation of human low density lipoprotein. Life Sci., 1996, 58, PL17-PL22.
44. Lian, T.W.; Wang, L.; Lo, Y.H.; Huang, I.J.; Wu, M.J. Fisetin, morin and myricetin attenuate CD36 expression and oxLDL uptake in U937-derived macrophages. Biochim. Biophys. Acta, 2008, 1781, 601-609.
45. Wu, T.W.; Zeng, L.H.; Wu, J.; Fung, K.P. Morin: a wood pigment that protects three types of human cells in the cardiovascular system against oxyradical damage. Biochem. Pharmacol., 1994, 47, 1099-1103.
46. Zeng, L.H.; Fung, K.P.; Wu, T.W. Morin hydrate protects cultured rat glomerular mesangial cells against oxyradical damage. Life Sci., 1994, 55, PL351-PL357.
47. Zeng, L.H.; Rootman, D.S.; Burnstein, A.; Wu, J.; Wu, T.W. Morin hydrate: a better protector than purpurogallin of corneal endothelial cell damage induced by xanthine oxidase and SIN-1. Curr. Eye Res., 1998, 17, 149-152.
48. Sivaramakrishnan, V.; Shilpa, P.N.; Praveen Kumar, V.R.; Niranjali Devaraj, S. Attenuation of N-nitrosodiethylamineinduced hepatocellular carcinogenesis by a novel flavonol-Morin. Chem. Biol. Interact., 2007, 171, 79-88.
49. Ibarretxe, G.; Sanchez-Gomez, M.V.; Campos-Esparza, M.R.; Alberdi, E.; Matute, C. Differential oxidative stress in oligodendrocytes and neurons after excitotoxic insults and protection by natural polyphenols. Glia, 2005, 53, 201-211.
50. Jonnalagadda, V.P.; Pittala, S.; Lahkar, M.; Pradeep, V. Ameliorative effect of morin hydrate, a flavonoid against gentamicin induced oxidative stress and nephrotoxicity in sprague-dawley rats. Int. J. Pharm. Pharm. Sci., 2013, 6(1), 851-856.
51. Banday, A.A.; Farooq, N.; Priyamvada, S.; Yusufi, A.N.; Khan, F. Time dependent effects of gentamicin on the enzymes of carbohydrate metabolism, brush border membrane and oxidative stress in rat kidney tissues. Life Sci., 2008, 82, 450-459.
52. Zhang, R.; Kang, K.A.; Piao, M.J.; Maeng, Y.H.; Lee, K.H.; Chang, W.Y.; You, H.J.; Kim, J.S.; Kang, S.S.; Hyun, J.W. Cellular protection of morin against the oxidative stress induced by hydrogen peroxide. Chem. Biol. Interact., 2008, 177, 21-27.
53. Zhang, R.; Kang, K.A.; Kang, S.S.; Park, J.W.; Hyun, J.W. Morin (2',3,4',5,7-pentahydroxyflavone) protected cells against I3-radiation-induced oxidative stress. Basic Clin. Pharmacol. Toxicol., 2010, 108, 63-72.
54. Parihar, V.K.; Prabhakar, K.R.; Veerapur, V.P.; Priyadarsini, K.I.; Unnikrishnan, M.K.; Rao, C.M. Anticlastogenic activity of morin against whole body gamma irradiation in Swiss albino mice. Eur. J. Pharmacol., 2007, 557, 58-65.
55. Kapoor, R.; Kakkar, P. Protective role of morin, a flavonoid, against high glucose induced oxidative stress mediated apoptosis in primary rat hepatocytes. PLoS One, 2012, 7, e41663.
56. Merwid-Lad, A.; Trocha, M.; Chlebda-Sieragowska, E.; Sozanski, T.; Szandruk, M.; Magdalan, J.; Ksiadzyna, D.; Piesniewska, M.; Fereniec-Gołebiewska, L.; Kwiatkowska, J.; Szelag, A.The impact of morin, a natural flavonoid, on cyclophosphamide-induced changes in the oxidative stress parameters in rat livers. Adv. Clin. Exp. Med., 2014, 23, 505-509.
57. Ray, S.; Chowdhury, P.; Pandit, B.; Ray, S.D.; Das, S. Exploring the antiperoxidative potential of morin on cyclophosphamide and flutamide-induced lipid peroxidation and changes in cholesterol profile in rabbit model. Acta Pol. Pharm., 2010, 67, 35-44.
58. Kok, L.D.; Wong, Y.P.; Wu, T.W.; Chan, H.C.; Kwok, T.T.; Fung, K.P. Morin hydrate: a potential antioxidant in minimizing the free-radicals-mediated damage to cardiovascular cells by anti-tumor drugs. Life Sci., 2000, 67, 91-99.
59. Wu, T.W.; Zeng, L.H.; Wu, J.; Fung, K.P. Morin hydrate is a plant-derived and antioxidant-based hepatoprotector. Life Sci., 1993, 53, PL213-PL218.
60. Wu, T.W.; Fung, K.P.; Zeng, L.H.; Wu, J.; Hempel, A.; Grey, A.A.; Camerman, N. Molecular properties and myocardial salvage effects of morin hydrate. Biochem. Pharmacol., 1995, 49, 537-543.
61. Sreedharan, V.; Venkatachalam, K.K.; Namasivayam, N. Effect of morin on tissue lipid peroxidation and antioxidant status in 1, 2-dimethylhydrazine induced experimental colon carcinogenesis. Invest. New Drugs, 2008, 27, 21-30.
62. Subash, S.; Subramanian, P. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study. Mol. Cell. Biochem., 2009, 327, 153-161.
63. Park, J.Y.; Kang, K.A.; Kim, K.C.; Cha, J.W.; Kim, E.H.; Hyun, J.W. Morin induces heme oxygenase-1 via ERKNrf2 signaling pathway. J. Cancer Prev., 2014, 18, 249-256.
64. Mira, L.; Fernandez, M.T.; Santos, M.; Rocha, R.; Florencio, M.H.; Jennings, K.R. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic. Res., 2003, 36, 1199-208.
65. Beker, B.Y.; Sonmezoglu, I.; Imer, F.; Apak, R. Protection of ascorbic acid from copper(II)-catalyzed oxidative degradation in the presence of flavonoids: quercetin, catechin and morin. Int. J. Food Sci. Nutr., 2011, 62, 504-512.
66. Kostyuk, V.A.; Potapovich, A.I.; Vladykovskaya, E.N.; Korkina, L.G.; Afanas'ev, I.B. Influence of metal ions on flavonoid protection against asbestos-induced cell injury. Arch. Biochem. Biophys., 2001, 385, 129-137.
67. Lowe, D.B.; Storkus, W.J. Chronic inflammation and immunologic-based constraints in malignant disease. Immunotherapy, 2011, 3, 1265-1274.
68. Kaneto, H.; Katakami, N.; Matsuhisa, M.; Matsuoka, T.A. Role of reactive oxygen species in the progression of type 2 diabetes and atherosclerosis. Mediators Inflamm., 2010, 2010, 453892.
69. Kim, H.K.; Cheon, B.S.; Kim, Y.H.; Kim, S.Y.; Kim, H.P. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships. Biochem. Pharmacol., 1999, 58, 759-765.
70. Raso, G.M.; Meli, R.; Di Carlo, G.; Pacilio, M.; Di Carlo, R. Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage J774A.1. Life Sci., 2001, 68, 921-931.
71. Tianzhu, Z.; Shihai, Y.; Juan, D. The effects of morin on lipopolysaccharide-induced acute lung injury by suppressing the lung NLRP3 inflammasome. Inflammation, 2014, 37, 1976-1983.
72. Ocete, M.A.; Galvez, J.; Crespo, M.E.; Cruz, T.; Gonzalez, M.; Torres, M.I.; Zarzuelo, A. Effects of morin on an experimental model of acute colitis in rats. Pharmacology, 1998, 57, 261-270.
73. Manna, S.K.; Aggarwal, R.S.; Sethi, G.; Aggarwal, B.B.; Ramesh, G.T. Morin (3,5,7,2',4'-Pentahydroxyflavone) abolishes nuclear factor-kappaB activation induced by various carcinogens and inflammatory stimuli, leading to suppression of nuclear factor-kappaB-regulated gene expression and up-regulation of apoptosis. Clin. Cancer Res., 2007, 13, 2290-2297.
74. Okamoto, T.; Sanda, T.; Asamitsu, K. NF-kappa B signaling and carcinogenesis. Curr. Pharm. Des., 2007, 13, 447-462.
75. Qureshi, A.A.; Guan, X.Q.; Reis, J.C.; Papasian, C.J.; Jabre, S.; Morrison, D.C.; Qureshi, N. Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids Health Dis., 2012, 11, 76.
76. Alvarez, S.E.; Harikumar, K.B.; Hait, N.C.; Allegood, J.; Strub, G.M.; Kim, E.Y.; Maceyka, M.; Jiang, H.; Luo, C.; Kordula, T.; Milstien, S.; Spiegel, S. Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature, 2010, 465, 1084-1088.
77. Cowart, L.A. Sphingolipids: players in the pathology of metabolic disease. Trends Endocrinol. Metab., 2008, 20, 34-42.
78. Wang, X.; Zhang, D.M.; Gu, T.T.; Ding, X.Q.; Fan, C.Y.; Zhu, Q.; Shi, Y.W.; Hong, Y.; Kong, L.D. Morin reduces hepatic inflammation-associated lipid accumulation in high fructose-fed rats via inhibiting sphingosine kinase 1/sphingosine 1-phosphate signaling pathway. Biochem. Pharmacol., 2013, 86, 1791-804.
79. Lee, H.S.; Jung, K.H.; Hong, S.W.; Park, I.S.; Lee, C.; Han, H.K.; Lee, D.H.; Hong, S.S. Morin protects acute liver damage by carbon tetrachloride (CCl(4)) in rat. Arch. Pharm. Res., 2008, 31, 1160-1165.
80. Gupta, S.C.; Tyagi, A.K.; Deshmukh-Taskar, P.; Hinojosa, M.; Prasad, S.; Aggarwal, B.B. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch. Biochem. Biophys., 2014, 559, 91-99.
81. Fang, S.H.; Hou, Y.C.; Chang, W.C.; Hsiu, S.L.; Chao, P.D.; Chiang, B.L. Morin sulfates/glucuronides exert antiinflammatory activity on activated macrophages and decreased the incidence of septic shock. Life Sci., 2003, 74, 743-756.
82. Galvez, J.; Coelho, G.; Crespo, M.E.; Cruz, T.; Rodriguez-Cabezas, M.E.; Concha, A.; Gonzalez, M.; Zarzuelo, A. Intestinal anti-inflammatory activity of morin on chronic experimental colitis in the rat. Aliment. Pharmacol. Ther., 2001, 15, 2027-2039.
83. Kempuraj, D.; Madhappan, B.; Christodoulou, S.; Boucher, W.; Cao, J.; Papadopoulou, N.; Cetrulo, C.L.; Theoharides, T.C. Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br. J. Pharmacol., 2005, 145, 934-944.
84. Shichijo, M.; Yamamoto, N.; Tsujishita, H.; Kimata, M.; Nagai, H.; Kokubo, T. Inhibition of syk activity and degranulation of human mast cells by flavonoids. Biol. Pharm. Bull., 2003, 26, 1685-90.
85. Rivera, J.; Gilfillan, A.M. Molecular regulation of mast cell activation. J. Allergy Clin. Immunol., 2006, 117, 1214-1225.
86. Kim, J.W.; Lee, J.H.; Hwang, B.Y.; Mun, S.H.; Ko, N.Y.; Kim, d.o.K.; Kim, B.; Kim, H.S.; Kim, Y.M.; Choi, W.S. Morin inhibits Fyn kinase in mast cells and IgE-mediated type I hypersensitivity response in vivo. Biochem. Pharmacol., 2009, 77, 1506-1512.
87. Reddy, L.; Odhav, B.; Bhoola, K.D. Natural products for cancer prevention: a global perspective. Pharmacol. Ther., 2003, 99, 1-13.
88. De Robertis, M.; Massi, E.; Poeta, M.L.; Carotti, S.; Morini, S.; Cecchetelli, L.; Signori, E.; Fazio, V.M. The AOM/DSS murine model for the study of colon carcinogenesis: From pathways to diagnosis and therapy studies. J. Carcinog., 2011, 10, 9.
89. Sak, K.; Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn. Rev., 2014, 8, 122-146.
90. Nandhakumar, R.; Salini, K.; Devaraj, N.S. Morin augments anticarcinogenic and antiproliferative efficacy against 7,12-dimethylbenz(a)-anthracene induced experimental mammary carcinogenesis. Mol. Cell Biochem., 2012, 364, 79-92.
91. Hsiang, C.Y.; Wu, S.L.; Ho, T.Y. Morin inhibits 12-Otetradecanoylphorbol-13-acetate-induced hepatocellular transformation via activator protein 1 signaling pathway and cell cycle progression. Biochem. Pharmacol., 2005, 69, 1603-1611.
92. Brown, J.; O'Prey, J.; Harrison, P.R. Enhanced sensitivity of human oral tumours to the flavonol, morin, during cancer progression: involvement of the Akt and stress kinase pathways. Carcinogenesis, 2003, 24, 171-177.
93. Kuo, H.M.; Chang, L.S.; Lin, Y.L.; Lu, H.F.; Yang, J.S.; Lee, J.H.; Chung, J.G. Morin inhibits the growth of human leukemia HL-60 cells via cell cycle arrest and induction of apoptosis through mitochondria dependent pathway. Anticancer Res., 2007, 27, 395-405.
94. Gupta, S.C.; Phromnoi, K.; Aggarwal, B.B. Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. Biochem. Pharmacol., 2013, 85, 898-912.
95. Jin, H.; Lee, W.S.; Eun, S.Y.; Jung, J.H.; Park, H.S.; Kim, G.; Choi, Y.H.; Ryu, C.H.; Jung, J.M.; Hong, S.C.; Shin, S.C.; Kim, H.J. Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB-231 partly through suppression of the Akt pathway. Int. J. Oncol., 2014, 45, 1629-1637.
96. Panhwar, Q.K.; Memon, S. Synthesis of Cr(III)-morin complex: characterization and antioxidant study. Sci. World, J., 2014, 2014, 845208.
97. Pieniazek, E.; Kalembkiewicz, J.; Dranka, M.; Woznicka, E. Syntheses, crystal structures and antioxidant study of Zn(II) complexes with morin-5'-sulfonic acid (MSA). J. Inorg. Biochem., 2014, 141, 180-187.
98. Qadeer, K.P.; Shahabuddin, M.; Bhanger, M.I. Synthesis, characterization, spectroscopic and antioxidation studies of Cu(II)-morin complex. J. Mol. Struct., 2010, 967, 47-53.
99. Martinez, C.; Garcia-Martin, E.; Pizarro, R.M.; Garcia-Gamito, F.J.; Agundez, J.A. Expression of paclitaxelinactivating CYP3A activity in human colorectal cancer: implications for drug therapy. Br. J. Cancer, 2002, 87, 681-686.
100. Lee, H.; Yeom, H.; Kim, Y.G.; Yoon, C.N.; Jin, C.; Choi, J.S.; Kim, B.R.; Kim, D.H. Structure-related inhibition of human hepatic caffeine N3-demethylation by naturally occurring flavonoids. Biochem. Pharmacol., 1999, 55, 1369-1375.
101. Si, D.; Wang, Y.; Zhou, Y.H.; Guo, Y.; Wang, J.; Zhou, H.; Li, Z.S.; Fawcett, J.P. Mechanism of CYP2C9 inhibition by flavones and flavonols. Drug Metab. Dispos., 2008, 37, 629-634.
102. Hodek, P.; Trefil, P.; Stiborova, M. Flavonoids-potent and versatile biologically active compounds interacting with cytochromes P450. Chem. Biol. Interact., 2002, 139, 1-21.
103. Amin, M.L. P-glycoprotein Inhibition for Optimal Drug Delivery. Drug Target Insights, 2013, 7, 27-34.
104. Germann, U.A. P-glycoprotein - a mediator of multidrug resistance in tumour cells. Eur. J. Cancer, 1996, 32A, 927-944.
105. Suzuki, H.Sugiyama, Y. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur., J. Pharm. Sci., 2000, 12, 3-12.
106. Singh, M.S.; Francis, P.A.; Michael, M. Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. Breast, 2010, 20, 111-118.
107. Li, X.; Yun, J.K.; Choi, J.S. Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm. Drug Dispos., 2007, 28, 151-156.
108. Shin, S.C.; Piao, Y.J.; Choi, J.S. Effects of morin on the bioavailability of tamoxifen and its main metabolite, 4-hydroxytamoxifen, in rats. In Vivo, 2008, 22, 391-395.
109. Nguyen, H.; Zhang, S.; Morris, M.E. Effect of flavonoids on MRP1-mediated transport in Panc-1 cells. J. Pharm. Sci., 2003, 92, 250-257.
110. Piao, Y.J.; Choi, J.S. Effects of morin on the pharmacokinetics of nicardipine after oral and intravenous administration of nicardipine in rats. J. Pharm. Pharmacol., 2008, 60, 625-629.
111. Hong, S.S.; Jin, M.J.; Han, H.K. Enhanced systemic availability of methotrexate in the presence of morin in rats. Biopharm. Drug Dispos., 2008, 29, 189-193.
112. Choi, B.C.; Choi, J.S.; Han, H.K. Altered pharmacokinetics of paclitaxel by the concomitant use of morin in rats. Int. J. Pharm., 2006, 323, 81-85.
113. Chung, S.Y.; Sung, M.K.; Kim, N.H.; Jang, J.O.; Go, E.J.; Lee, H.J. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch. Pharm. Res., 2005, 28, 823-828.
114. Pathak, S.M.; Udupa, N. Pre-clinical evidence of enhanced oral bioavailability of the P-glycoprotein substrate talinolol in combination with morin. Biopharm. Drug Dispos., 2010, 31, 202-214.
115. Yang, S.H.; Choi, H.G.; Lim, S.J.; Lee, M.G.; Kim, S.H. Effects of morin on the pharmacokinetics of etoposide in 7,12-dimethylbenz[a]anthracene-induced mammary tumors in female Sprague-Dawley rats. Oncol. Rep., 2012, 29, 1215-1223.
116. Brand, W.; Schutte, M.E.; Williamson, G.; van Zanden, J.J.; Cnubben, N.H.; Groten, J.P.; van Bladeren, P.J.; Rietjens, I.M. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed. Pharmacother., 2006, 60, 508-519.
117. Deftereos, S.; Bouras, G. Editorial: targeting inflammation in cardiovascular disease). Med. Chem., 2014, 10, 641-2.
118. Baradaran, A.; Nasri, H.; Rafieian-Kopaei, M. Oxidative stress and hypertension: Possibility of hypertension therapy with antioxidants. J. Res. Med. Sci., 2014, 19, 358-67.
119. Gonzalez, J.; Valls, N.; Brito, R.; Rodrigo, R. Essential hypertension and oxidative stress: New insights. World J. Cardiol., 2014, 6, 353-366.
120. Herrera, M.D.; Zarzuelo, A.; Jimenez, J.; Marhuenda, E.; Duarte, J. Effects of flavonoids on rat aortic smooth muscle contractility: structure-activity relationships. Gen. Pharmacol., 1996, 27, 273-277.
121. Prahalathan, P.; Kumar, S.; Raja, B. Effect of morin, a flavonoid against DOCA-salt hypertensive rats: a dose dependent study. Asian Pac. J. Trop. Biomed., 2013, 2, 443-448.
122. Prahalathan, P.; Kumar, S.; Raja, B. Morin attenuates blood pressure and oxidative stress in deoxycorticosterone acetate-salt hypertensive rats: a biochemical and histopathological evaluation. Metab. Clin. Exp., 2012, 61, 1087-1099.
123. Kang, D.G.; Moon, M.K.; Sohn, E.J.; Lee, D.H.; Lee, H.S. Effects of morin on blood pressure and metabolic changes in fructose-induced hypertensive rats. Biol. Pharm. Bull., 2004, 27, 1779-83.
124. Taguchi, K.; Hida, M.; Matsumoto, T.; Ikeuchi-Takahashi, Y.; Onishi, H.; Kobayashi, T. Effect of short-term polyphenol treatment on endothelial dysfunction and thromboxane A2 levels in streptozotocin-induced diabetic mice. Biol. Pharm. Bull., 2014, 37, 1056-1061.
125. von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Habich, D. Antibacterial natural products in medicinal chemistry - exodus or revival? Angew. Chem. Int. Ed. Engl., 2006, 45, 5072-5129.
126. Butler, M.S.; Buss, A.D. Natural products - the future scaffolds for novel antibiotics? Biochem. Pharmacol., 2005, 71, 919-929.
127. Kang, S.S.; Kim, J.G.; Lee, T.H.; Oh, K.B. Flavonols inhibit sortases and sortase-mediated Staphylococcus aureus clumping to fibrinogen. Biol. Pharm. Bull., 2006, 29, 1751-1755.
128. Xu, H.; Ziegelin, G.; Schroder, W.; Frank, J.; Ayora, S.; Alonso, J.C.; Lanka, E.; Saenger, W. Flavones inhibit the hexameric replicative helicase RepA. Nucleic Acids Res., 2002, 29, 5058-5066.
129. Kopacz, M.; WoAonicka, E.; Gruszecka, J. Antibacterial activity of morin and its complexes with La(III), Gd(III) and Lu(III) ions. Acta Pol Pharm, 2005, 62, 65-67.
130. Marangella, M.; Uric acid elimination in the urine. Pathophysiological implications. Contrib. Nephrol., 2004, 147, 132-148.
131. Enomoto, A.; Kimura, H.; Chairoungdua, A.; Shigeta, Y.; Jutabha, P.; Cha, S.H.; Hosoyamada, M.; Takeda, M.; Sekine, T.; Igarashi, T.; Matsuo, H.; Kikuchi, Y.; Oda, T.; Ichida, K.; Hosoya, T.; Shimokata, K.; Niwa, T.; Kanai, Y.; Endou, H. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature, 2002, 417, 447-452.
132. Yu, Z.; Fong, W.P.; Cheng, C.H. The dual actions of morin (3,5,7,2',4'-pentahydroxyflavone) as a hypouricemic agent: uricosuric effect and xanthine oxidase inhibitory activity. J. Pharmacol. Exp. Ther., 2005, 316, 169-175.
133. Mo, S.F.; Zhou, F.; Lv, Y.Z.; Hu, Q.H.; Zhang, D.M.; Kong, L.D. Hypouricemic action of selected flavonoids in mice: structure-activity relationships. Biol. Pharm. Bull., 2007, 30, 1551-1556.
134. Yu, Z.; Fong, W.P.; Cheng, C.H. Morin (3,5,7,2',4'-pentahydroxyflavone) exhibits potent inhibitory actions on urate transport by the human urate anion transporter (hURAT1) expressed in human embryonic kidney cells. Drug Metab. Dispos., 2007, 35, 981-986.
135. Wang, C.P.; Wang, X.; Zhang, X.; Shi, Y.W.; Liu, L.; Kong, L.D. Morin improves urate excretion and kidney function through regulation of renal organic ion transporters in hyperuricemic mice. J. Pharm. Pharm. Sci., 2010, 13, 411-427.
136. Shi, Y.W.; Wang, C.P.; Wang, X.; Zhang, Y.L.; Liu, L.; Wang, R.W.; Ye, J.F.; Hu, L.S.; Kong, L.D. Uricosuric and nephroprotective properties of Ramulus Mori ethanol extract in hyperuricemic mice. J. Ethnopharmacol., 2012, 143, 896-904.
137. Schapira, A.H. Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurol., 2007, 7, 97-109.
138. Okazawa, H.; Ikawa, M.; Tsujikawa, T.; Kiyono, Y.; Yoneda, M. Brain imaging for oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Q. J. Nucl. Med. Mol. Imaging, 2014, 58, 387-397.
139. Zhang, Z.T.; Cao, X.B.; Xiong, N.; Wang, H.C.; Huang, J.S.; Sun, S.G.; Wang, T. Morin exerts neuroprotective actions in Parkinson disease models in vitro and in vivo. Acta Pharmacol. Sin., 2010, 31, 900-906.
140. Llorens-Martin, M.; Jurado, J.; Hernandez, F.; Avila, J. GSK-3I2, a pivotal kinase in Alzheimer disease. Front. Mol. Neurosci., 2014, 7, 46.
141. Gong, E.J.; Park, H.R.; Kim, M.E.; Piao, S.; Lee, E.; Jo, D.G.; Chung, H.Y.; Ha, N.C.; Mattson, M.P.; Lee, J. Morin attenuates tau hyperphosphorylation by inhibiting GSK3I2. Neurobiol. Dis., 2011, 44, 223-230.
142. Noor, H.; Cao, P.; Raleigh, D.P. Morin hydrate inhibits amyloid formation by islet amyloid polypeptide and disaggregates amyloid fibers. Protein Sci., 2012, 21, 373-382.
143. Kim, H.; Park, B.S.; Lee, K.G.; Choi, C.Y.; Jang, S.S.; Kim, Y.H.; Lee, S.E. Effects of naturally occurring compounds on fibril formation and oxidative stress of betaamyloid. J. Agric. Food Chem., 2005, 53, 8537-8541.
144. Ono, K.; Yoshiike, Y.; Takashima, A.; Hasegawa, K.; Naiki, H.; Yamada, M. Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease. J. Neurochem., 2003, 87, 172-181.
145. Lemkul, J.A.Bevan, D.R. Destabilizing Alzheimer's Abeta(42) protofibrils with morin: mechanistic insights from molecular dynamics simulations. Biochemistry, 2010, 49, 3935-3946.
146. Lemkul, J.A.; Bevan, D.R. Morin inhibits the early stages of amyloid I2-peptide aggregation by altering tertiary and quaternary interactions to produce "off-pathway" structures. Biochemistry, 2012, 51, 5990-6009.
147. Remya, C.; Dileep, K.V.; Tintu, I.; Variyar, E.J.; Sadasivan, C. Design of potent inhibitors of acetylcholinesterase using morin as the starting compound. Front. Life Sci., 2012, 6, 107-117.
148. Shimmyo, Y.; Kihara, T.; Akaike, A.; Niidome, T.; Sugimoto, H. Flavonols and flavones as BACE-1 inhibitors: structure-activity relationship in cell-free, cell-based and in silico studies reveal novel pharmacophore features. Biochim. Biophys. Acta, 2008, 1780, 819-825.
149. Caruana, M.; Neuner, J.; Hogen, T.; Schmidt, F.; Kamp, F.; Scerri, C.; Giese, A.; Vassallo, N. Polyphenolic compounds are novel protective agents against lipid membrane damage by I}-synuclein aggregates in vitro. Biochim. Biophys. Acta, 2012, 1818, 2502-2510.
150. Chinnam, N.; Dadi, P.K.; Sabri, S.A.; Ahmad, M.; Kabir, M.A.; Ahmad, Z. Dietary bioflavonoids inhibit Escherichia coli ATP synthase in a differential manner. Int. J. Biol. Macromol., 2010, 46, 478-486.
151. Iglesias, C.V.; Aparicio, R.; Rodrigues-Simioni, L.; Camargo, E.A.; Antunes, E.; Marangoni, S.; de Oliveira Toyama, D.; Beriam, L.O.; Monteiro, H.S.; Toyama, M.H. Effects of morin on snake venom phospholipase A2 (PLA2). Toxicon, 2005, 46, 751-758.
152. Gledhill, J.R.; Montgomery, M.G.; Leslie, A.G.; Walker, J.E. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc. Natl. Acad. Sci., U.S.A., 2007, 104, 13632-13637.
153. Cotrim, C.A.; de Oliveira, S.C.; Diz Filho, E.B.; Fonseca, F.V.; Baldissera, L.; Antunes, E.; Ximenes, R.M.; Monteiro, H.S.; Rabello, M.M.; Hernandes, M.Z.; de Oliveira Toyama, D.; Toyama, M.H. Quercetin as an inhibitor of snake venom secretory phospholipase A2. Chem. Biol. Interact., 2010, 189, 9-16.
154. Xie, M.X.; Long, M.; Liu, Y.; Qin, C.; Wang, Y.D. Characterization of the interaction between human serum albumin and morin. Biochim. Biophys. Acta, 2006, 1760, 1184-1191.
155. Chen, W.P.; Hu, P.F.; Bao, J.P.; Wu, L.D. Morin exerts antiosteoarthritic properties: an in vitro and in vivo study. Exp. Biol. Med. (Maywood), 2012, 237, 380-386.
156. Lee, H.S.; Jung, K.H.; Park, I.S.; Kwon, S.W.; Lee, D.H.; Hong, S.S. Protective effect of morin on dimethylnitrosamine-induced hepatic fibrosis in rats. Dig. Dis. Sci., 2008, 54, 782-788.
157. Lambert, J.D.; Elias, R.J. The antioxidant and pro-oxidant activities of green tea polyphenols: a role in cancer prevention. Arch. Biochem. Biophys., 2010, 501, 65-72.
158. Dimassi, K.; Gharsa, A.; Chanoufi, M.B.; Sfar, E.; Chelli, D. Conservative treatment of breast cancer: experience of a Tunisian team. Pan. Afr. Med. J., 2014, 19, 148.
159. Maliar, T.; Jedinak, A.; Kadrabova, J.; Sturdik, E. Structural aspects of flavonoids as trypsin inhibitors. Eur. J. Med. Chem., 2004, 39, 241-248.
160. Constantinou, A.; Mehta, R.; Runyan, C.; Rao, K.; Vaughan, A.; Moon, R. Flavonoids as DNA topoisomerase antagonists and poisons: structure-activity relationships. J. Nat. Prod., 1995, 58, 217-225.
161. Tian, W.X. Inhibition of fatty acid synthase by polyphenols. Curr. Med. Chem., 2006, 13, 967-977.
162. Li, P.; Callery, P.S.; Gan, L.S.; Balani, S.K. Esterase inhibition by grapefruit juice flavonoids leading to a new drug interaction. Drug Metab. Dispos., 2007, 35, 1203-1208.
163. Zheng, J.; Ramirez, V.D. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br. J. Pharmacol., 2000, 130, 1115-1123.
164. Wang, Q.; Morris, M.E. Flavonoids modulate monocarboxylate transporter-1-mediated transport of gammahydroxybutyrate in vitro and in vivo. Drug Metab. Dispos., 2006, 35, 201-208.
165. de Oliveira, T.; Nagem, T.J.; de Miranda, L.C.; de Paula, V.F.; Teixeira, M.A. Inhibitory action on aldose reductase by soybean flavonoids. J. Braz. Chem. Soc., 1997, 8, 211-213.
166. Thuillier, P.; Brash, A.R.; Kehrer, J.P.; Stimmel, J.B.; Leesnitzer, L.M.; Yang, P.; Newman, R.A.; Fischer, S.M. Inhibition of peroxisome proliferator-activated receptor (PPAR)-mediated keratinocyte differentiation by lipoxygenase inhibitors. Biochem. J., 2002, 366, 901-910.
167. Zhang, K.; Wong, K.P. Inhibition of the efflux of glutathione S-conjugates by plant polyphenols. Biochem. Pharmacol., 1996, 52, 1631-1638.
168. Zhang, K.; Yang, E.B.; Tang, W.Y.; Wong, K.P.; Mack, P. Inhibition of glutathione reductase by plant polyphenols. Biochem. Pharmacol., 1997, 54, 1047-1053.
169. Brinkworth, R.I.; Stoermer, M.J.; Fairlie, D.P. Flavones are inhibitors of HIV-1 proteinase. Biochem. Biophys. Res. Commun., 1992, 188, 631-637.
170. van Zanden, J.J.; Wortelboer, H.M.; Bijlsma, S.; Punt, A.; Usta, M.; Bladeren, P.J.; Rietjens, I.M.; Cnubben, N.H. Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem. Pharmacol., 2005, 69, 699-708.
171. Fawzy, A.A.; Vishwanath, B.S.; Franson, R.C. Inhibition of human non-pancreatic phospholipases A2 by retinoids and flavonoids. Mechanism of action. Agents Actions, 1988, 25, 394-400.