Antidiabetic, Antihyperlipidemic and Antioxidant Effects of the Flavonoids

Polyphenols in Human Health and Disease

Volumn 1, Issue , 2013, Pages 143-161

  Unnikrishnan, M K ^a   Veerapur, Veeresh ^b   Nayak, Yogendra ^a   Mudgal, Piya Paul ^c   Mathew, Geetha ^a  

^a MANIPAL COLLEGE OF PHARMACEUTICAL SCIENCES   (India)

^b SREE SIDDAGANGA COLLEGE OF PHARMACY   (India)

^c MANIPAL UNIVERSITY   (India)

Author keywords

Antidiabetic; Antihyperlipidemic; Antioxidant; Clinical trial; Flavonoid; Pleiotropic

Indexed keywords

EID: 84899585426     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-398456-2.00013-X     Document Type: Chapter

References (195)

1. Mohan V., Sandeep S., Deepa R., Shah B., Varghese C. Epidemiology of type 2 diabetes: Indian scenario. Indian J Med Res 2007, 125(3):217-230.
2. Evans J.L., Goldfine I.D., Maddux B.A., Grodsky G.M. Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction?. Diabetes 2003, 52(1):1-8.
3. Kregel K.C., Zhang H.J. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations. Am J Physiol Regul Integr Comp Physiol 2007, 292(1):R18-36.
4. Veerapur V.P., Prabhakar K.R., Kandadi M.R., Srinivasan K.K., Unnikrishnan M.K. Antidiabetic effect of Dodonaea viscosa aerial parts in high fat diet and low dose streptozotocin-induced type 2 diabetic rats: a mechanistic approach. Pharm Biol 2010, 48(10):1137-1148.
5. Zilva S.S. Vitamin P. Biochem J 1937, 31(6):915-919.
6. Bacharach A.L., Coates M.E., Middleton T.R. A biological test for vitamin P activity. Biochem J 1942, 36(5-6):407-412.
7. Narayana K.R., S R.M., Chaluvadi M.R., Krishna D.R. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J Pharmacol 2001, 33:2-16.
8. Erdman J.W., Balentine D., Arab L., Beecher G., Dwyer J.T., Folts J., et al. Flavonoids and heart health: proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC. J Nutr 2007, 137(3):718S-737S.
9. Pietta P.G. Flavonoids as antioxidants. J Nat Prod 2000, 63(7):1035-1042.
10. Havsteen B.H. The biochemistry and medical significance of the flavonoids. Pharmacol Ther 2002, 96(2-3):67-202.
11. Zimmet P., Alberti K.G., Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001, 414(6865):782-787.
12. Mukherjee P.K., Maiti K., Mukherjee K., Houghton P.J. Leads from Indian medicinal plants with hypoglycemic potentials. J Ethnopharmacol 2006, 106(1):1-28.
13. Vlahos C.J., Matter W.F., Hui K.Y., Brown R.F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 1994, 269(7):5241-5248.
14. Smith L.K., Vlahos C.J., Reddy K.K., Falck J.R., Garner C.W. Wortmannin and LY294002 inhibit the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes. Mol Cell Endocrinol 1995, 113(1):73-81.
15. Nakamura M., Nakashima S., Katagiri Y., Nozawa Y. Effect of wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) on N-formyl-methionyl-leucyl-phenylalanine-induced phospholipase D activation in differentiated HL60 cells: possible involvement of phosphatidylinositol 3-kinase in phospholipase D activation. Biochem Pharmacol 1997, 53(12):1929-1936.
16. Hazeki K., Kinoshita S., Matsumura T., Nigorikawa K., Kubo H., Hazeki O. Opposite effects of wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride on toll-like receptor-mediated nitric oxide production: negative regulation of nuclear factorκB by phosphoinositide 3-kinase. Mol Pharmacol 2006, 69(5):1717-1724.
17. Andreadi C.K., Howells L.M., Atherfold P.A., Manson M.M. Involvement of Nrf2, p38, B-Raf, and nuclear factorκB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Mol Pharmacol 2006, 69(3):1033-1040.
18. Yousif M.H., Benter I.F., Hares N., Canatan H., Akhtar S. Phosphoinositide 3-kinase mediated signalling contributes to development of diabetes-induced abnormal vascular reactivity of rat carotid artery. Cell Biochem Funct 2006, 24(1):13-22.
19. Pinent M., Castell A., Baiges I., Montagut G., Arola L., Ardévol A. Bioactivity of flavonoids on insulin-secreting cells. Compr Rev Food Sci Food Safety 2008, 7(4):299-308.
20. Jayaprakasam B., Vareed S.K., Olson L.K., Nair M.G. Insulin secretion by bioactive anthocyanins and anthocyanidins present in fruits. J Agric Food Chem 2005, 53(1):28-31.
21. Kamalakkannan N., Stanely Mainzen Prince P. Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues. Mol Cell Biochem 2006, 293(1-2):211-219.
22. Kim M.K., Jung H.S., Yoon C.S., Ko J.H., Chun H.J., Kim T.K., et al. EGCG and quercetin protected INS-1 cells in oxidative stress via different mechanisms. Front Biosci Elite (Ed) 2010, 2:810-817.
23. Fu Z., Zhang W., Zhen W., Lum H., Nadler J., Bassaganya-Riera J., et al. Genistein induces pancreatic β-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes in mice. Endocrinology 2010, 151(7):3026-3037.
24. Mor V., Unnikrishnan M.K. 5-adenosine monophosphate-activated protein kinase and the metabolic syndrome. Endocr Metab Immune Disord Drug Targets 2011, 11(3):206-216.
25. Musi N., Hirshman M.F., Nygren J., Svanfeldt M., Bavenholm P., Rooyackers O., et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002, 51(7):2074-2081.
26. Zygmunt K., Faubert B., Mac Neil J., Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun 2010, 398(2):178-183.
27. Cai E.P., Lin J.K. Epigallocatechin gallate (EGCG) and rutin suppress the glucotoxicity through activating IRS2 and AMPK signaling in rat pancreatic β cells. J Agric Food Chem 2009, 57(20):9817-9827.
28. Takikawa M., Inoue S., Horio F., Tsuda T. Dietary anthocyanin-rich bilberry extract ameliorates hyperglycemia and insulin sensitivity via activation of AMP-activated protein kinase in diabetic mice. J Nutr 2010, 140(3):527-533.
29. Krentz A.J., Bailey C.J. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005, 65(3):385-411.
30. Goldwasser J., Cohen P.Y., Yang E., Balaguer P., Yarmush M.L., Nahmias Y. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARα, PPARγ and LXRα. PLoS One 2010, 5(8):e12399.
31. Matin A., Gavande N., Kim M.S., Yang N.X., Salam N.K., Hanrahan J.R., et al. 7-Hydroxy-benzopyran-4-one derivatives: a novel pharmacophore of peroxisome proliferator-activated receptor α and γ (PPAR α and γ) dual agonists. J Med Chem 2009, 52(21):6835-6850.
32. Akiyama S., Katsumata S., Suzuki K., Nakaya Y., Ishimi Y., Uehara M. Hypoglycemic and hypolipidemic effects of hesperidin and cyclodextrin-clathrated hesperetin in Goto-Kakizaki rats with type 2 diabetes. Biosci Biotechnol Biochem 2009, 73(12):2779-2782.
33. Jang J., Na M., Thuong P.T., Njamen D., Mbafor J.T., Fomum Z.T., et al. Prenylated flavonoids with PTP1B inhibitory activity from the root bark of Erythrina mildbraedii. Chem Pharm Bull (Tokyo) 2008, 56(1):85-88.
34. Veerapur V.P., Prabhakar K.R., Thippeswamy B.S., Bansal P., Srinivasan K.K., Unnikrishnan M.K. Antidiabetic effect of Dodonaea viscosa (L). Lacq. aerial parts in high fructose-fed insulin resistant rats: a mechanism based study. Indian J Exp Biol 2010, 48(8):800-810.
35. Peet G.W., Li J. IκB kinases α and β show a random sequential kinetic mechanism and are inhibited by staurosporine and quercetin. J Biol Chem 1999, 274(46):32655-32661.
36. Shukla R., Barve V., Padhye S., Bhonde R. Synthesis, structural properties and insulin-enhancing potential of bis (quercetinato) oxovanadium (IV) conjugate. Bioorg Med Chem Lett 2004, 14(19):4961-4965.
37. Cazarolli L.H., Zanatta L., Jorge A.P., de Sousa E., Horst H., Woehl V.M., et al. Follow-up studies on glycosylated flavonoids and their complexes with vanadium: their anti-hyperglycemic potential role in diabetes. Chem Biol Interact 2006, 163(3):177-191.
38. von Geldern T.W., Tu N., Kym P.R., Link J.T., Jae H.-S., Lai C., et al. Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes. J Med Chem 2004, 47(17):4213-4230.
39. Hale C., Wang M. Development of 11β-HSD1 inhibitors for the treatment of type 2 diabetes. Mini Rev Med Chem 2008, 8(7):702-710.
40. Torres-Piedra M., Ortiz-Andrade R., Villalobos-Molina R., Singh N., Medina-Franco J.L., Webster S.P., et al. A comparative study of flavonoid analogues on streptozotocin-nicotinamide induced diabetic rats: quercetin as a potential antidiabetic agent acting via 11β-hydroxysteroid dehydrogenase type 1 inhibition. Eur J Med Chem 2010, 45(6):2606-2612.
41. Bansal P., Paul P., Mudgal J., Nayak P G., Thomas Pannakal S., Priyadarsini K.I., et al. Antidiabetic, antihyperlipidemic and antioxidant effects of the flavonoid rich fraction of Pilea microphylla (L.) in high fat diet/streptozotocin-induced diabetes in mice. Exp Toxicol Pathol 2012, 64(6):651-658.
42. Willard F.S., Bueno A.B., Sloop K.W. Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp Diabetes Res 2012, 2012:709893.
43. Koole C., Wootten D., Simms J., Valant C., Sridhar R., Woodman O.L., et al. Allosteric ligands of the glucagon-like peptide 1 receptor (GLP-1R) differentially modulate endogenous and exogenous peptide responses in a pathway-selective manner: implications for drug screening. Mol Pharmacol 2010, 78(3):456-465.
44. Wootten D., Simms J., Koole C., Woodman O.L., Summers R.J., Christopoulos A., et al. Modulation of the glucagon-like peptide-1 receptor signaling by naturally occurring and synthetic flavonoids. J Pharmacol Exp Ther 2011, 336(2):540-550.
45. Torres-Piedra M., Ortiz-Andrade R., Villalobos-Molina R., Singh N., Medina-Franco J.L., Webster S.P., et al. A comparative study of flavonoid analogues on streptozotocin-nicotinamide induced diabetic rats: quercetin as a potential antidiabetic agent acting via 11β-hydroxysteroid dehydrogenase type 1 inhibition. Eur J Med Chem 2010, 45(6):2606-2612.
46. Tadera K., Minami Y., Takamatsu K., Matsuoka T. Inhibition of α-glucosidase and α-amylase by flavonoids. J Nutr Sci Vitaminol (Tokyo) 2006, 52(2):149-153.
47. Matsui T., Tanaka T., Tamura S., Toshima A., Tamaya K., Miyata Y., et al. α-Glucosidase inhibitory profile of catechins and theaflavins. J Agric Food Chem 2007, 55(1):99-105.
48. Wang S., Yan J., Wang X., Yang Z., Lin F., Zhang T. Synthesis and evaluation of the α-glucosidase inhibitory activity of 3-[4-(phenylsulfonamido)benzoyl]-2H-1-benzopyran-2-one derivatives. Eur J Med Chem 2010, 45(3):1250-1255.
49. Jung U.J., Lee M.-K., Park Y.B., Kang M.A., Choi M.-S. Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int J Biochem Cell Biol 2006, 38(7):1134-1145.
50. Prince P.S.M., Kamalakkannan N. Rutin improves glucose homeostasis in streptozotocin diabetic tissues by altering glycolytic and gluconeogenic enzymes. J Biochem Mol Toxicol 2006, 20(2):96-102.
51. Jakobs S., Fridrich D., Hofem S., Pahlke G., Eisenbrand G. Natural flavonoids are potent inhibitors of glycogen phosphorylase. Mol Nutr Food Res 2006, 50(1):52-57.
52. Anton S., Melville L., Rena G. Epigallocatechin gallate (EGCG) mimics insulin action on the transcription factor FOXO1a and elicits cellular responses in the presence and absence of insulin. Cell Signal 2007, 19(2):378-383.
53. Wolfram S., Raederstorff D., Preller M., Wang Y., Teixeira S.R., Riegger C., et al. Epigallocatechin gallate supplementation alleviates diabetes in rodents. J Nutr 2006, 136(10):2512-2518.
54. Jakobs S., Fridrich D., Hofem S., Pahlke G., Eisenbrand G. Natural flavonoids are potent inhibitors of glycogen phosphorylase. Mol Nutr Food Res 2006, 50(1):52-57.
55. Estrada O., Hasegawa M., Gonzalez-Mujica F., Motta N., Perdomo E., Solorzano A., et al. Evaluation of flavonoids from Bauhinia megalandra leaves as inhibitors of glucose-6-phosphatase system. Phytother Res 2005, 19(10):859-863.
56. Gonzalez-Mujica F., Motta N., Estrada O., Perdomo E., Mendez J., Hasegawa M. Inhibition of hepatic neoglucogenesis and glucose-6-phosphatase by quercetin 3-Oα(2″-galloyl)rhamnoside isolated from Bauhinia megalandra leaves. Phytother Res 2005, 19(7):624-627.
57. Kato A., Nasu N., Takebayashi K., Adachi I., Minami Y., Sanae F., et al. Structure-activity relationships of flavonoids as potential inhibitors of glycogen phosphorylase. J Agric Food Chem 2008, 56(12):4469-4473.
58. Liao Z., Chen X., Wu M. Antidiabetic effect of flavones from Cirsium japonicum DC in diabetic rats. Arch Pharm Res 2010, 33(3):353-362.
59. Parveen K., Khan M.R., Mujeeb M., Siddiqui W.A. Protective effects of pycnogenol on hyperglycemia-induced oxidative damage in the liver of type 2 diabetic rats. Chem Biol Interact 2010, 186(2):219-227.
60. Lee H.H., Kim K.J., Lee O.H., Lee B.Y. Effect of pycnogenol on glucose transport in mature 3T3-L1 adipocytes. Phytother Res 2010, 24(8):1242-1249.
61. 14C-glucose uptake in rat soleus muscle. Chem Biol Interact 2004, 149(2-3):89-96.
62. Ueda M., Nishiumi S., Nagayasu H., Fukuda I., Yoshida K., Ashida H. Epigallocatechin gallate promotes GLUT4 translocation in skeletal muscle. Biochem Biophys Res Commun 2008, 377(1):286-290.
63. Choi M.S., Jung U.J., Yeo J., Kim M.J., Lee M.K. Genistein and daidzein prevent diabetes onset by elevating insulin level and altering hepatic gluconeogenic and lipogenic enzyme activities in non-obese diabetic (NOD) mice. Diabetes Metab Res Rev 2008, 24(1):74-81.
64. Lee M.S., Kim C.H., Hoang D.M., Kim B.Y., Sohn C.B., Kim M.R., et al. Genistein-derivatives from Tetracera scandens stimulate glucose-uptake in L6 myotubes. Biol Pharm Bull 2009, 32(3):504-508.
65. Ong K.W., Hsu A., Song L., Huang D., Tan B.K. Polyphenols-rich Vernonia amygdalina shows anti-diabetic effects in streptozotocin-induced diabetic rats. J Ethnopharmacol 2011, 133(2):598-607.
66. Liu I.M., Liou S.S., Cheng J.T. Mediation of β-endorphin by myricetin to lower plasma glucose in streptozotocin-induced diabetic rats. J Ethnopharmacol 2006, 104(1-2):199-206.
67. Meezan E., Meezan E.M., Jones K., Moore R., Barnes S., Prasain J.K. Contrasting effects of puerarin and daidzin on glucose homeostasis in mice. J Agric Food Chem 2005, 53(22):8760-8767.
68. Wu L.Y., Juan C.C., Hwang L.S., Hsu Y.P., Ho P.H., Ho L.T. Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model. Eur J Nutr 2004, 43(2):116-124.
69. Ho L.-T., Kulkarni S., Lee J.-C. Development of sodium-dependent glucose co-transporter 2 inhibitors as potential anti-diabetic therapeutics. Curr Top Med Chem 2011, 11(12):1476-1512.
70. +-glucose cotransporter (SGLT) inhibitory flavonoids from the roots of Sophora flavescens. Bioorg Med Chem 2007, 15(10):3445-3449.
71. +-glucose cotransporter by naringenin. Int J Biochem Cell Biol 2006, 38(5-6):985-995.
72. Fernández M., Caballero J., Helguera A.M., Castro E.A., González M.P. Quantitative structure-activity relationship to predict differential inhibition of aldose reductase by flavonoid compounds. Bioorg Med Chem 2005, 13(9):3269-3277.
73. Wu C.H., Yen G.C. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem 2005, 53(8):3167-3173.
74. Sanchez M., Lodi F., Vera R., Villar I.C., Cogolludo A., Jimenez R., et al. Quercetin and isorhamnetin prevent endothelial dysfunction, superoxide production, and overexpression of p47phox induced by angiotensin II in rat aorta. J Nutr 2007, 137(4):910-915.
75. Costantino L., Rastelli G., Gamberini M.C., Vinson J.A., Bose P., Iannone A., et al. 1-benzopyran-4-one antioxidants as aldose reductase inhibitors. J Med Chem 1999, 42(11):1881-1893.
76. Costantino L., Del Corso A., Rastelli G., Petrash J.M., Mura U. 7-hydroxy-2-substituted-4-H-1-benzopyran-4-one derivatives as aldose reductase inhibitors: a SAR study. Eur J Med Chem 2001, 36(9):697-703.
77. Mao C.P., Gu Z.L. Puerarin reduces increased c-fos, c-jun, and type IV collagen expression caused by high glucose in glomerular mesangial cells. Acta Pharmacol Sin 2005, 26(8):982-986.
78. Yamabe N., Yokozawa T., Oya T., Kim M. Therapeutic potential of (-)-epigallocatechin 3-O-gallate on renal damage in diabetic nephropathy model rats. J Pharmacol Exp Ther 2006, 319(1):228-236.
79. Yokozawa T., Nakagawa T., Oya T., Okubo T., Juneja L.R. Green tea polyphenols and dietary fibre protect against kidney damage in rats with diabetic nephropathy. J Pharm Pharmacol 2005, 57(6):773-780.
80. Renno W.M., Abdeen S., Alkhalaf M., Asfar S. Effect of green tea on kidney tubules of diabetic rats. Br J Nutr 2008, 100(3):652-659.
81. Dong W., Shi H.B., Ma H., Miao Y.B., Liu T.J., Wang W. Homoisoflavanones from Polygonatum odoratum rhizomes inhibit advanced glycation end product formation. Arch Pharm Res 2010, 33(5):669-674.
82. Lu M., Xu L., Li B., Zhang W., Zhang C., Feng H., et al. Protective effects of grape seed proanthocyanidin extracts on cerebral cortex of streptozotocin-induced diabetic rats through modulating AGEs/RAGE/NFκB pathway. J Nutr Sci Vitaminol (Tokyo) 2010, 56(2):87-97.
83. Lixandru D., Mohora M., Coman A., Stoian I., van Gils C., Aerts P., et al. Diet and paraoxonase 1 enzymatic activity in diabetic foot patients from Romania and Belgium: favorable association of high flavonoid dietary intake with arylesterase activity. Ann Nutr Metab 2010, 56(4):294-301.
84. Yuan W.J., Jia F.Y., Meng J.Z. Effects of genistein on secretion of extracellular matrix components and transforming growth factor beta in high-glucose-cultured rat mesangial cells. J Artif Organs 2009, 12(4):242-246.
85. Dias A.S., Porawski M., Alonso M., Marroni N., Collado P.S., Gonzalez-Gallego J. Quercetin decreases oxidative stress, NFκB activation, and iNOS overexpression in liver of streptozotocin-induced diabetic rats. J Nutr 2005, 135(10):2299-2304.
86. Temme E.H., Van Hoydonck P.G., Schouten E.G., Kesteloot H. Effects of a plant sterol-enriched spread on serum lipids and lipoproteins in mildly hypercholesterolaemic subjects. Acta Cardiol 2002, 57(2):111-115.
87. Krishnamurthy G., Lakshman K., Pruthvi N., Chandrika P.U. Antihyperglycemic and hypolipidemic activity of methanolic extract of Amaranthus viridis leaves in experimental diabetes. Indian J Pharmacol 2011, 43(4):450-454.
88. Emanuela F., Grazia M., de Marco R., Maria Paola L., Giorgio F., Marco B. Inflammation as a link between obesity and metabolic syndrome. J Nutr Metab 2012, 2012:476380.
89. Pushparaj P.N., Low H.K., Manikandan J., Tan B.K., Tan C.H. Anti-diabetic effects of Cichorium intybus in streptozotocin-induced diabetic rats. J Ethnopharmacol 2007, 111(2):430-434.
90. Murali B., Upadhyaya U.M., Goyal R.K. Effect of chronic treatment with Enicostemma littorale in non-insulin-dependent diabetic (NIDDM) rats. J Ethnopharmacol 2002, 81(2):199-204.
91. al-Shamaony L., al-Khazraji S.M., Twaij H.A. Hypoglycaemic effect of Artemisia herba alba. II. Effect of a valuable extract on some blood parameters in diabetic animals. J Ethnopharmacol 1994, 43(3):167-171.
92. Kumar V., Khanna A.K., Khan M.M., Singh R., Singh S., Chander R., et al. Hypoglycemic, lipid lowering and antioxidant activities in root extract of Anthocephalus indicus in alloxan induced diabetic rats. Indian J Biochem 2009, 24:65-69.
93. Brunzell J.D., Hokanson J.E. Dyslipidemia of central obesity and insulin resistance. Diabetes Care 1999, 22(Suppl. 3):C10-13.
94. Bainton D., Miller N.E., Bolton C.H., Yarnell J.W., Sweetnam P.M., Baker I.A., et al. Plasma triglyceride and high density lipoprotein cholesterol as predictors of ischaemic heart disease in British men. The Caerphilly and Speedwell Collaborative Heart Disease Studies. Brit Heart J 1992, 68(1):60-66.
95. El-Hazmi M.A., Warsy A.S. Evaluation of serum cholesterol and triglyceride levels in 1-6-year-old Saudi children. J Trop Pediatr 2001, 47(3):181-185.
96. Steinberg D., Parthasarathy S., Carew T.E., Khoo J.C., Witztum J.L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. New Engl J Med 1989, 320(14):915-924.
97. Monforte M.T., Trovato A., Kirjavainen S., Forestieri A.M., Galati E.M., Lo Curto R.B. Biological effects of hesperidin, a citrus flavonoid. (note II): hypolipidemic activity on experimental hypercholesterolemia in rat. Farmaco 1995, 50(9):595-599.
98. Catapano A.L. Antioxidant effect of flavonoids. Angiology 1997, 48(1):39-44.
99. Mc Anlis G.T., Mc Eneny J., Pearce J., Young I.S. The effect of various dietary flavonoids on the susceptibility of low density lipoproteins to oxidation in vitro using both metallic and non-metallic oxidising agents. Biochem Soc Trans 1997, 25(1):142S.
100. Igarashi K., Ohmuma M. Effects of isorhamnetin, rhamnetin, and quercetin on the concentrations of cholesterol and lipoperoxide in the serum and liver and on the blood and liver antioxidative enzyme activities of rats. Biosci Biotechnol Biochem 1995, 59(4):595-601.
101. Fuhrman B., Lavy A., Aviram M. Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. Am J Clin Nutr 1995, 61(3):549-554.
102. Duchnowicz P., Broncel M., Podsedek A., Koter-Michalak M. Hypolipidemic and antioxidant effects of hydroxycinnamic acids, quercetin, and cyanidin 3-glucoside in hypercholesterolemic erythrocytes (in vitro study). Eur J Nutr 2012, 51(4):435-443.
103. Mulvihill E.E., Huff M.W. Protection from metabolic dysregulation, obesity, and atherosclerosis by citrus flavonoids: activation of hepatic PGC1α-mediated fatty acid oxidation. PPAR Res 2012, 2012:857142.
104. Goldwasser J., Cohen P.Y., Yang E., Balaguer P., Yarmush M.L., Nahmias Y. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARα, PPARγ and LXRα. PloS One 2010, 5(8):e12399.
105. Mezei O., Banz W.J., Steger R.W., Peluso M.R., Winters T.A., Shay N. Soy isoflavones exert antidiabetic and hypolipidemic effects through the PPAR pathways in obese Zucker rats and murine RAW 264.7 cells. J Nutr 2003, 133(5):1238-1243.
106. Wilcox L.J., Borradaile N.M., de Dreu L.E., Huff M.W. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J Lipid Res 2001, 42(5):725-734.
107. Chang T.Y., Li B.L., Chang C.C., Urano Y. Acyl-coenzyme A:cholesterol acyltransferases. Am J Physiol Endocrinol Metab 2009, 297(1):E1-9.
108. Cha J.Y., Cho Y.S., Kim I., Anno T., Rahman S.M., Yanagita T. Effect of hesperetin, a citrus flavonoid, on the liver triacylglycerol content and phosphatidate phosphohydrolase activity in orotic acid-fed rats. Plant Foods Hum Nutr 2001, 56(4):349-358.
109. Furuyashiki T., Nagayasu H., Aoki Y., Bessho H., Hashimoto T., Kanazawa K., et al. Tea catechin suppresses adipocyte differentiation accompanied by down-regulation of PPARγ2 and C/EBPα in 3T3-L1 cells. Biosci Biotechnol Biochem 2004, 68(11):2353-2359.
110. Yugarani T., Tan B.K., Teh M., Das N.P. Effects of polyphenolic natural products on the lipid profiles of rats fed high fat diets. Lipids 1992, 27(3):181-186.
111. Qureshi S.A., Nawaz A., Udani S.K., Azmi B. Hypoglycemic and hypolipidemic activities of Rauwolfia serpentina in alloxan-induced diabetic rats. Int J Pharmacol 2009, 5:323-326.
112. Rachh P.R., Rachh M.R., Ghadiya N.R., Modi D.C., Modi K.P., Patel N.M., et al. Antihyperlipidemic activity of Gymenma sylvestre R. Br. leaf extract on rats fed with high cholesterol diet. Int J Pharmacol 2010, 6(2):138-141.
113. Kim G.S., Park H.J., Woo J.H., Kim M.K., Koh P.O., Min W., et al. Citrus aurantium flavonoids inhibit adipogenesis through the Akt signaling pathway in 3T3-L1 cells. BMC Complement Altern Med 2012, 12:31.
114. Zhang H.H., Huang J., Duvel K., Boback B., Wu S., Squillace R.M., et al. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PloS One 2009, 4(7):e6189.
115. Grimes C.A., Jope R.S. The multifaceted roles of glycogen synthase kinase 3β in cellular signaling. Prog Neurobiol 2001, 65(4):391-426.
116. Verma P.R., Deshpande S.A., Kamtham Y.N., Vaidya L.B. Hypolipidemic and antihyperlipidemic effects from an aqueous extract of Pachyptera hymenaea (DC.) leaves in rats. Food Chem 2012, 132(3):1251-1257.
117. Chen W., Nishimura N., Oda H., Yokogoshi H. Effect of taurine on cholesterol degradation and bile acid pool in rats fed a high-cholesterol diet. Adv Exp Med Biol 2003, 526:261-267.
118. Koshy A.S., Anila L., Vijayalakshmi N.R. Flavonoids from Garcinia cambogia lower lipid levels in hypercholesterolemic rats. Food Chem 2001, 72(3):289-294.
119. Sykiotis G.P., Habeos I.G., Samuelson A.V., Bohmann D. The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation. Curr Opin Clin Nutr Metab Care 2011, 14(1):41-48.
120. Yuan M., Konstantopoulos N., Lee J., Hansen L., Li Z., Karin M., et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 2011, 293(5535):1673-1677.
121. Ozcan U., Cao Q., Yilmaz E., Lee A., Iwakoshi N., Ozdelen E., et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306(5695):457-461.
122. Morino K., Petersen K., Shulman G. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006, 55(Suppl. 2):S9-S15.
123. Yu Z.W., Li D., Ling W.H., Jin T.R. Role of nuclear factor (erythroid-derived 2)-like 2 in metabolic homeostasis and insulin action: a novel opportunity for diabetes treatment?. World J Diabetes 2012, 3(1):19-28.
124. Lee-Hilz Y.Y., Boerboom A.-M.J., Westphal A.H., Berkel W.J.H.v., Aarts J.M.M., Rietjens I.M.C. Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression. Chem Res Toxicol 2006, 19(11):1499-1505.
125. Shin S., Wakabayashi J., Yates M.S., Wakabayashi N., Dolan P.M., Aja S., et al. Role of Nrf2 in prevention of high-fat diet-induced obesity by synthetic triterpenoid CDDO-imidazolide. Eur J Pharmacol 2009, 620(1-3):138-144.
126. Aleksunes L.M., Reisman S.A., Yeager R.L., Goedken M.J., Klaassen C.D. Nuclear factor erythroid 2-related factor 2 deletion impairs glucose tolerance and exacerbates hyperglycemia in type 1 diabetic mice. J Pharmacol Exp Ther 2010, 333(1):140-151.
127. Jiang T., Huang Z., Lin Y., Zhang Z., Fang D., Zhang D.D. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy. Diabetes 2010, 59(4):850-860.
128. Yoh K., Hirayama A., Ishizaki K., Yamada A., Takeuchi M., Yamagishi S., et al. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells 2008, 13(11):1159-1170.
129. Kwak M.K., Wakabayashi N., Itoh K., Motohashi H., Yamamoto M., Kensler T.W. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 2003, 278(10):8135-8145.
130. de Haan J.B. Nrf2 activators as attractive therapeutics for diabetic nephropathy. Diabetes 2011, 60(11):2683-2684.
131. Zheng H., Whitman S.A., Wu W., Wondrak G.T., Wong P.K., Fang D., et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 2011, 60(11):3055-3066.
132. Habeos I.G., Ziros P.G., Chartoumpekis D., Psyrogiannis A., Kyriazopoulou V., Papavassiliou A.G. Simvastatin activates Keap1/Nrf2 signaling in rat liver. J Mol Med (Berl) 2008, 86(11):1279-1285.
133. Song M., Kim E., Moon W., Park J., Kim H., So H., et al. Sulforaphane protects against cytokine- and streptozotocin-induced β-cell damage by suppressing the NFκB pathway. Toxicol Appl Pharmacol 2009, 235(1):57-67.
134. He X., Kan H., Cai L., Ma Q. Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J Mol Cell Cardiol 2009, 46(1):47-58.
135. Xue M., Qian Q., Adaikalakoteswari A., Rabbani N., Babaei-Jadidi R., Thornalley P. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes 2008, 57(10):2809-2817.
136. Negi G., Kumar A., Joshi R., Sharma S. Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: old perspective with a new angle. Biochem Biophys Res Commun 2011, 408(1):1-5.
137. Pi J., Leung L., Xue P., Wang W., Hou Y., Liu D., et al. Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J Biol Chem 2010, 285(12):9292-9300.
138. Ferreira J.F.S., Luthria D.L., Sasaki T., Heyerick A. Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules 2010, 15(5):3135-3170.
139. Procházková D., Boušová I., Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011, 82(4):512-523.
140. Hur W., Gray N.S. Small molecule modulators of antioxidant response pathway. Curr Opin Chem Biol 2011, 15(1):162-173.
141. Leopoldini M., Russo N., Chiodo S., Toscano M. Iron chelation by the powerful antioxidant flavonoid quercetin. J Agric Food Chem 2006, 54(17):6343-6351.
142. Molina M., Sanchez-Reus I., Iglesias I., Benedi J. Quercetin a flavonoid antioxidant, prevents and protects against ethanol-induced oxidative stress in mouse liver. Biol Pharm Bull 2003, 26(10):1398-1402.
143. Vargas A.J., Burdnure R. Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev 2010, 68(7):418-428.
144. Magalhães P., Carvalho D., Cruz J., Guido L., Barros A. Fundamentals and health benefits of xanthohumol, a natural product derived from hops and beer. Nat Prod Commun 2009, 4(5):591-610.
145. Miranda C., Stevens J., Ivanov V., Mc Call M., Frei B., Deinzer M., et al. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J Agric Food Chem 2000, 48(9):3876-3884.
146. Borrás C., Gambini J., Gómez-Cabrera M.C., Sastre J., Pallardó F.V., Mann G.E., et al. Genistein, a soy isoflavone, up-regulates expression of antioxidant genes: involvement of estrogen receptors, ERK1/2, and NFκB. FASEB J 2006, 20(12):E1476-E1481.
147. Jeon S.M., Kim H.K., Kim H.J., Do G.M., Jeong T.S., Park Y.B., et al. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats. Transl Res 2007, 149(1):15-21.
148. Ekambaram G., Rajendran P., Magesh V., Sakthisekaran D. Naringenin reduces tumor size and weight lost in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Nutr Res 2008, 28(2):106-112.
149. Kong J.M., Chia L.S., Goh N.K., Chia T.F., Brouillard R. Analysis and biological activities of anthocyanins. Phytochemistry 2003, 64(5):923-933.
150. Galvano F., La Fauci L., Lazzarino G., Fogliano V., Ritieni A., Ciappellano S., et al. Cyanidins: metabolism and biological properties. J Nutr Biochem 2004, 15(1):2-11.
151. Noda Y., Kaneyuki T., Igarashi K., Mori A., Packer L. Antioxidant activity of nasunin, an anthocyanin in eggplant. Res Commun Mol Pathol Pharmacol 1998, 102(2):175-187.
152. Nijveldt R.J., Nood E.v., Hoorn D.E.v., Boelens P.G., Norren K.v., Leeuwen P.A.v. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 2001, 74:418-425.
153. Halliwell B. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies?. Arch Biochem Biophys 2008, 476(2):107-112.
154. Manach C., Donovan J.L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic Res 2004, 38(8):771-785.
155. Williamson G., Barron D., Shimoi K., Terao J. In vitro biological properties of flavonoid conjugates found in vivo. Free Radic Res 2005, 39(5):457-469.
156. Rechner A.R., Kuhnle G., Bremner P., Hubbard G.P., Moore K.P., Rice-Evans C.A. The metabolic fate of dietary polyphenols in humans. Free Radic Biol Med 2002, 33(2):220-235.
157. Myhrstad M.C.W., Carlsen H., Nordström O., Blomhoff R., Moskaug J.O. Flavonoids increase the intracellular glutathione level by transactivation of the γ-glutamylcysteine synthetase catalytical subunit promoter. Free Rad Biol Med 2002, 32(5):386-393.
158. Münzel T., Gori T., Bruno R.M., Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease?. Eur Heart J 2010, 31(22):2741-2749.
159. 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(1):65-72.
160. Hu M.-L. Dietary polyphenols as antioxidants and anticancer agents: more questions than answers. Chang Gung Med J 2011, 34(5):449-460.
161. Calabrese V., Cornelius C., Mancuso C., Pennisi G., Calafato S., Bellia F., et al. Cellular stress response: a novel target for chemoprevention and nutritional neuroprotection in aging, neurodegenerative disorders and longevity. Neurochem Res 2008, 33(12):2444-2471.
162. Rahman I., Biswas S., Kirkham P. Regulation of inflammation and redox signaling by dietary polyphenols. Biochem Pharmacol 2006, 72(12):1439-1452.
163. Surh Y.J., Kundu J.K., Na H.K., Lee J.S. Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. J Nutri 2005, 135(12 Suppl):2993S-3001S.
164. Nakamura Y., Miyoshi N. Electrophiles in foods: the current status of isothiocyanates and their chemical biology. Biosci Biotechnol Biochem 2010, 74(2):242-255.
165. Na H.K., Surh Y.J. Modulation of Nrf2-mediated antioxidant and detoxifying enzyme induction by the green tea polyphenol EGCG. Food Chem Toxicol 2008, 46(4):1271-1278.
166. Surh Y.J. NFκB and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities. Asia Pac J Clin Nutr 2008, 17(Suppl. 1):269-272.
167. Surh Y.J., Kundu J.K., Na H.K. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008, 74(13):1526-1539.
168. Surh Y.J., Na H.K. NFκB and Nrf2 as prime molecular targets for chemoprevention and cytoprotection with anti-inflammatory and antioxidant phytochemicals. Genes Nutr 2008, 2(4):313-317.
169. Zhang Y., Gordon G. A strategy for cancer prevention: stimulation of the Nrf2-ARE signalling pathway. Mol Cancer Ther 2004, 3(7):885-893.
170. Kimura M., Yamamoto T., Zhang J., Itoh K., Kyo M., Kamiya T., et al. Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer. J Biol Chem 2007, 282(46):33681-33690.
171. Kensler T.W., Wakabayashi N., Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007, 47:89-116.
172. Lu J., Papp L.V., Fang J., Rodriguez-Nieto S., Zhivotovsky B., Holmgren A. Inhibition of mammalian thioredoxin reductase by some flavonoids: implications for myricetin and quercetin anticancer activity. Cancer Res 2006, 66(8):4410-4418.
173. Dal Piaz F., Braca A., Belisario M., De Tommasi N. Thioredoxin system modulation by plant and fungal secondary metabolites. Curr Med Chem 2010, 17(5):479-494.
174. Meyer Y., Verdoucq L., Vignols F. Plant thioredoxins and glutaredoxins: identity and putative roles. Trends Plant Sci 1999, 4(10):388-394.
175. Tanigawa S., Fujii M., Hou D.X. Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 2007, 42(11):1690-1703.
176. 2-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages. Biochem Pharmacol 2005, 69(12):1839-1851.
177. Panchal S.K., Poudyal H., Brown L. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. J Nutr 2012, 142(6):1026-1032.
178. Xi Y., Yu H., Ding J., Ma W., Yuan L., Feng J., et al. Flavonoids protect cerebrovascular endothelial cells through Nrf2 and PI3K from β-amyloid peptide-induced oxidative damage. Curr Neurovasc Res 2012, 9(1):32-41.
179. Hirose E, Matsushima M, Takagi K, Ota Y, Ishigami K, Hirayama T, et al. Involvement of heme oxygenase-1 in kaempferol-induced anti-allergic actions in RBL-2H3 cells. Inflammation 2009;32(2):99-108.
180. De Nicola G.M., Karreth F.A., Humpton T.J., Gopinathan A., Wei C., Frese K., et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 2011, 475(7354):106-109.
181. Barajas B., Che N., Yin F., Rowshanrad A., Orozco L.D., Gong K.W., et al. NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection. Arterioscler Thromb Vasc Biol 2011, 31(1):58-66.
182. Lee K., Won H.Y., Bae M.A., Hong J.-H., Hwang E.S. Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells. Proc Natl Acad Sci USA 2011, 108(23):9548-9553.
183. Bashan N., Kovsan J., Kachko I., Ovadia H., Rudich A. Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 2009, 89(1):27-71.
184. Moskaug J.Ø., Carlsen H., Myhrstad M.C., Blomhoff R. Polyphenols and glutathione synthesis regulation. Am J Clin Nutr 2005, 81(1 Suppl):277S-283S.
185. Song Y., Manson J.E., Buring J.E., Sesso H.D., Liu S. Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis. J Am Coll Nutr 2005, 24(5):376-384.
186. Curtis P.J., Sampson M., Potter J., Dhatariya K., Kroon P.A., Cassidy A. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care 2012, 35(2):226-232.
187. Rietveld A., Wiseman S. Antioxidant effects of tea: evidence from human clinical trials. J Nutr 2003, 133(10):3285S-3292S.
188. Lean M.E., Noroozi M., Kelly I., Burns J., Talwar D., Sattar N., et al. Dietary flavonols protect diabetic human lymphocytes against oxidative damage to DNA. Diabetes 1999, 48(1):176-181.
189. Hooper L., Kroon P.A., Rimm E.B., Cohn J.S., Harvey I., Le Cornu K.A., et al. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2008, 88(1):38-50.
190. Arai Y., Watanabe S., Kimira M., Shimoi K., Mochizuki R., Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 2000, 130(9):2243-2250.
191. Jung U.J., Kim H.J., Lee J.S., Lee M.K., Kim H.O., Park E.J., et al. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin Nutr 2003, 22(6):561-568.
192. Huffman F.G., Vaccaro J.A., Zarini G.G., Dixon Z. Dietary intake of flavonoids and HDL- and LDL-cholesterol in two black ethnicities with and without type 2 diabetes. Internet J Cardiovasc Res 2012, 7(2). doi:10.5580/2b01.
193. Azoulay L., Yin H., Filion K.B., Assayag J., Majdan A., Pollak M.N., et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. Brit Med J 2012, 344:e3645.
194. Wang H.X., Ng T.B. Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and antithrombotic activities. Life Sci 1999, 65(25):2663-2677.
195. Pollak M., Gonzalez-Angulo A.M. Metformin and hepatic carcinogenesis. Cancer Prev Res (Phila) 2012, 5(4):500-502.