Flavonols in the Prevention of Diabetes-induced Vascular Dysfunction

Journal of Cardiovascular Pharmacology

Volumn 65, Issue 6, 2015, Pages 532-544

  Leo, Chen Huei ^a   Woodman, Owen L ^b  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b RMIT UNIVERSITY   (Australia)

Author keywords

diabetes; endothelial dysfunction; flavonols

Indexed keywords

FLAVONOL DERIVATIVE; PHOSPHOTRANSFERASE; ANTIDIABETIC AGENT; ANTIINFLAMMATORY AGENT; ANTIOXIDANT; CARDIOVASCULAR AGENT; PROTEIN KINASE INHIBITOR; VASODILATOR AGENT;

ANTIOXIDANT ACTIVITY; CARDIOVASCULAR DISEASE; CONFERENCE PAPER; DIABETIC ANGIOPATHY; DRUG TARGETING; ENDOTHELIAL DYSFUNCTION; FRUIT; GLUCOSE BLOOD LEVEL; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; VASODILATATION; ANIMAL; DIABETES MELLITUS; DIABETIC ANGIOPATHIES; DISEASE MODEL; DRUG EFFECTS; METABOLISM; OXIDATIVE STRESS; PATHOPHYSIOLOGY; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIUM;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; CARDIOVASCULAR AGENTS; DIABETES MELLITUS; DIABETIC ANGIOPATHIES; DISEASE MODELS, ANIMAL; ENDOTHELIUM, VASCULAR; FLAVONOLS; HUMANS; HYPOGLYCEMIC AGENTS; OXIDATIVE STRESS; PROTEIN KINASE INHIBITORS; SIGNAL TRANSDUCTION; VASODILATION; VASODILATOR AGENTS;

EID: 84931568645     PISSN: 01602446     EISSN: 15334023     Source Type: Journal    
DOI: 10.1097/FJC.0000000000000180     Document Type: Conference Paper

References (127)

1. He FJ, Nowson CA, Lucas M, et al. Increased consumption of fruit and vegetables is related to a reduced risk of coronary heart disease: meta-analysis of cohort studies. J Hum Hypertens. 2007;21:717-728.
2. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet. 2006;367:320-326.
3. Hertog MG, Feskens EJ, Hollman PC, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993;342:1007-1011.
4. Hertog MG, Feskens EJ, Kromhout D. Antioxidant flavonols and coronary heart disease risk. Lancet. 1997;349:699.
5. Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007;85:895-909.
6. Knekt P, Jarvinen R, Reunanen A, et al. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312:478-481.
7. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013;93:137-188.
8. Holman RR, Paul SK, Bethel A, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
9. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653.
10. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-820.
11. De Vriese AS, Verbeuren TJ, Van de Voorde J, et al. Endothelial dysfunction in diabetes. Br J Pharmacol. 2000;130:963-974.
12. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404:787-790.
13. Chan EC, Pannangpetch P, Woodman OL. Relaxation to flavones and flavonols in rat isolated thoracic aorta: mechanism of action and structure-activity relationships. J Cardiovasc Pharmacol. 2000;35:326-333.
14. Woodman OL, Chan ECH. Vascular and anti-oxidant actions of flavonols and flavones. Clin Exp Pharmacol Physiol. 2004;31:786-790.
15. Yap S, Qin CX, Woodman OL. Effects of resveratrol and flavonols on cardiovascular function: physiological mechanisms. Biofactors. 2010; 36:350-359.
16. Dauchet L, Amouyel P, Dallongeville J. Fruits, vegetables and coronary heart disease. Nat Rev Cardiol. 2009;6:599-608.
17. Duarte J, Pérez-Palencia R, Vargas F, et al. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol. 2001;133:117-124.
18. Perez-Vizcaino F, Duarte J, Jimenez R, et al. Antihypertensive effects of the flavonoid quercetin. Pharmacol Rep. 2009;61:67-75.
19. Galindo P, Rodriguez-Gómez I, González-Manzano S, et al. Glucuronidated quercetin lowers blood pressure in spontaneously hypertensive rats via deconjugation. PLoS One. 2012;3:e32673.
20. Pérez-Vizcaíno F, Ibarra M, Cogolludo AL, et al. Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries. J Pharmacol Exp Ther. 2002;302:66-72.
21. Duarte J, Pérez-Vizcaíno F, Zarzuelo A, et al. Vasodilator effects of quercetin in isolated rat vascular smooth muscle. Eur J Pharmacol. 1993;239:1-7.
22. Ibarra M, Pérez-Vizcaíno F, Cogolludo A, et al. Cardiovascular effects of isorhamnetin and quercetin in isolated rat and porcine vascular smooth muscle and isolated rat atria. Planta Med. 2002;68:307-310.
23. Duarte J, Pérez Vizcaíno F, Utrilla P, et al. Vasodilatory effects of flavonoids in rat aortic smooth muscle. Structure-activity relationships. Gen Pharmacol. 1993;24:857-862.
24. Qin CX, Chen XQ, Hughes RA, et al. Understanding the cardioprotective effects of flavonols: discovery of relaxant flavonols without antioxidant activity. J Med Chem. 2008;51:1847-1884.
25. Perez A, Gonzalez-Manzano S, Jimenez R, et al. The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: correlation with beta-glucuronidase activity. Pharmacol Res. 2014. In press. DOI: 10.1016/j.phrs.2014.07.005.
26. Andriambeloson E, Kleschyov AL, Muller B, et al. Nitric oxide production and endothelium-dependent vasorelaxation induced by wine polyphenols in rat aorta. Br J Pharmacol. 1997;120:1053-1058.
27. Fitzpatrick DF, Hirschfield SL, Coffey RG. Endothelium-dependent vasorelaxing activity of wine and other grape products. Am J Physiol. 1993;265:H774-H778.
28. Loke WM, Hodgson JM, Proudfoot JM, et al. Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. Am J Clin Nutr. 2008;88:1018-1025.
29. Anter E, Thomas SR, Schulz E, et al. Activation of endothelial nitricoxide synthase by the p38 MAPK in response to black tea polyphenols. J Biol Chem. 2004;279:46637-46643.
30. Ko FN, Huang TF, Teng CM. Vasodilatory action mechanisms of apigenin isolated from Apium graveolens in rat thoracic aorta. Biochim Biophys Acta. 1991;1115:69-74.
31. 2+ desensitization in permeabilized rat mesenteric artery. Naunyn Schmiedebergs Arch Pharmacol. 2012;385:191-202.
32. Herrera MD, Zarzuelo A, Jiménez J, et al. Effects of flavonoids on rat aortic smooth muscle contractility: structure-activity relationships. Gen Pharmacol. 1996;27:273-277.
33. Song MJ, Baek I, Seo M, et al. Effects of 3',4'-dihydroxyflavonol on vascular contractions of rat aortic rings. Clin Exp Pharmacol Physiol. 2010;37:803-810.
34. 2. Role in vasodilatation. Cardiovasc Res. 2007;73:424-431.
35. Chan EC, Drummond GR, Woodman OL. 3',4'-Dihydroxyflavonol enhances nitric oxide bioavailability and improves vascular function after ischemia and reperfusion injury in the rat. J Cardiovasc Pharmacol. 2003;42:727-735.
36. Yap S, Loft KJ, Woodman OL, et al. Discovery of water-soluble antioxidant flavonols without vasorelaxant activity. ChemMedChem. 2008; 3:1572-1579.
37. Wang S, Dusting GJ, May CN, et al. 3',4'-Dihydroxyflavonol reduces infarct size and injury associated with myocardial ischaemia and reperfusion in sheep. Br J Pharmacol. 2004;142:443-452.
38. Wang S, Thomas CJ, Dusting GJ, et al. 3',4'-Dihydroxyflavonol improves post-ischaemic coronary endothelial function following 7 days reperfusion in sheep. Eur J Pharmacol. 2009;624:31-37.
39. Qin CX, Williams SJ, Woodman OL. Antioxidant activity contributes to flavonol cardioprotection during reperfusion of rat hearts. Free Radic Biol Med. 2011;51:1437-1444.
40. Haenen GR, Paquay JB, Korthouwer RE, et al. Peroxynitrite scavenging by flavonoids. Biochem Biophys Res Commun. 1997;236:591-593.
41. Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Rad Biol Med. 2004;36:838-849.
42. Mahn K, Borrás C, Knock GA, et al. Dietary soy isoflavone induced increases in antioxidant and eNOS gene expression lead to improved endothelial function and reduced blood pressure in vivo. FASEB J. 2005;19:1755-1757.
43. Arredondo F, Echeverry C, Abin-Carriquiry JA, et al. After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult. Free Rad Biol Med. 2010;49:738-747.
44. Mann GE, Rowlands DJ, Li FYL, et al. Activation of endothelial nitric oxide synthase by dietary isoflavones: role of NO in Nrf2-mediated antioxidant gene expression. Cardiovasc Res. 2007;75:261-274.
45. Khong FL, Zhang Y, Edgley AJ, et al. 3',4'-Dihydroxyflavonol antioxidant attenuates diastolic dysfunction and cardiac remodeling in streptozotocin-induced diabetic m(Ren2)27 rats. PLoS One. 2011;6: e22777.
46. Drummond GR, Selemidis S, Griendling KK, et al. Combating oxidative stress in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov. 2011;10:453-471.
47. Jiang F, Guo N, Dusting GJ. Modulation of nicotinamide adenine dinucleotide phosphate oxidase expression and function by 3',4'-dihydroxyflavonol in phagocytic and vascular cells. J Pharmacol Exp Ther. 2008;324:261-269.
48. Sanchez M, Galisteo M, Vera R, et al. Quercetin downregulates NADPH oxidase, increases eNOS activity and prevents endothelial dysfunction in spontaneously hypertensive rats. J Hypertens. 2006;24:75-84.
49. phox induced by angiotensin II in rat aorta. JNutr.2007;137:910-915.
50. Romero M, Jiménez R, Sánchez M, et al. Quercetin inhibits vascular superoxide production induced by endothelin-1: role of NADPH oxidase, uncoupled eNOS and PKC. Arteriosclerosis. 2009;202:58-67.
51. Laughton MJ, Evans PJ, Moroney MA, et al. Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability. Biochem Pharmacol. 1991;42:1673-1681.
52. Hong J, Smith TJ, Ho CT, et al. Effects of purified green and black tea polyphenols on cyclooxygenase- and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Biochem Pharmacol. 2001;62:1175-1183.
53. Nagao A, Seki M, Kobayashi H. Inhibition of xanthine oxidase by flavonoids. Biosci Biotechnol Biochem. 1999;63:1787-1790.
54. Cos P, Ying L, Calomme M, et al. Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers. J Nat Prod. 1998;61:71-76.
55. Hua S. Targeting sites of inflammation: intercellular adhesion molecule-1 as a target for novel inflammatory therapies. Front Pharmacol. 2013; 4:127.
56. Kobuchi H, Roy S, Sen CK, et al. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol. 1999;277:C403-C411.
57. Chen CC, Chow MP, Huang WC, et al. Flavonoids inhibit tumor necrosis factor-alpha-induced up-regulation of intercellular adhesion molecule-1 (ICAM-1) in respiratory epithelial cells through activator protein-1 and nuclear factor-kappaB: structure-activity relationships. Mol Pharmacol. 2004;66:683-693.
58. Ying B, Yang T, Song X, et al. Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. Mol Biol Rep. 2009;36:1825-1832.
59. Crespo I, García-Mediavilla MV, Gutiérrez B, et al. A comparison of the effects of kaempferol and quercetin on cytokine-induced pro-inflammatory status of cultured human endothelial cells. Br J Nutr. 2008;100: 968-976.
60. Hämäläinen M, Nieminen R, Vuorela P, et al. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm. 2007;2007:45673.
61. García-Mediavilla V, Crespo I, Collado PS, et al. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and downregulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol. 2007;557:221-229.
62. Kim EK, Kwon KB, Song MY, et al. Flavonoids protect against cytokine-induced pancreatic beta-cell damage through suppression of nuclear factor kappaB activation. Pancreas. 2007;35:e1-e9.
63. Comalada M, Ballester I, Bailón E, et al. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. Biochem Pharmacol. 2006;72:1010-1021.
64. Kempuraj D, Madhappan B, Christodoulou S, et al. 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.
65. Jiang F, Guo N, Dusting GJ. 3',4'-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling. Br J Pharmacol. 2009;157:597-606.
66. Stewart LK, Soileau JL, Ribnicky D, et al. Quercetin transiently increases energy expenditure but persistently decreases circulating markers of inflammation in C57BL/6J mice fed a high-fat diet. Metabolism. 2008;57:S39-S46.
67. Thomas CJ, Ng DC, Patsikatheodorou N, et al. Cardioprotection from ischaemia-reperfusion injury by a novel flavonol that reduces activation of p38 MAPK. Eur J Pharmacol. 2011;658:160-167.
68. Song Y, Liu J, Zhang F, et al. Antioxidant effect of quercetin against acute spinal cord injury in rats and its correlation with the p38MAPK/ iNOS signaling pathway. Life Sci. 2013;92:1215-1221.
69. Arumugam S, Thandavarayan RA, Arozal W, et al. Quercetin offers cardioprotection against progression of experimental autoimmune myocarditis by suppression of oxidative and endoplasmic reticulum stress via endothelin-1/MAPK signalling. Free Radic Res. 2012;46: 154-163.
70. Liu CM, Zheng GH, Ming QL, et al. Protective effect of quercetin on lead-induced oxidative stress and endoplasmic reticulum stress in rat liver via the IRE1/JNK and PI3K/Akt pathway. Free Radic Res. 2013; 47:192-201.
71. Chen HJ, Lin CM, Lee CY, et al. Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells. Oncol Rep. 2013;30:925-932.
72. Lee KM, Lee KW, Jung SK, et al. Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity. Biochem Pharmacol. 2010;80:2042-2049.
73. Chen X, Yang X, Liu T, et al. Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int Immunopharmacol. 2012;14:209-216.
74. Lim NR, Thomas CJ, Silva LS, et al. Cardioprotective 3',4'-dihydroxyflavonol attenuation of JNK and p38(MAPK) signalling involves CaMKII inhibition. Biochem J. 2013;456:149-161.
75. Zhang Y, Liu D. Flavonol kaempferol improves chronic hyperglycemia-impaired pancreatic beta-cell viability and insulin secretory function. Eur J Pharmacol. 2011;670:325-332.
76. Zhang Y, Zhen W, Maechler P, et al. Small molecule kaempferol modulates PDX-1 protein expression and subsequently promotes pancreatic β-cell survival and function via CREB. J Nutr Biochem. 2013;24: 638-646.
77. Li JM, Wang W, Fan CY, et al. Quercetin preserves β-cell mass and function in fructose-induced hyperinsulinemia through modulating pancreatic Akt/FoxO1 activation. Evid Based Complement Alternat Med. 2013:303902.
78. Youl E, Bardy G, Magous R, et al. Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway. Br J Pharmacol. 2010;161:799-814.
79. Dai X, Ding Y, Zhang Z, et al. Quercetin and quercitrin protect against cytokine-induced injuries in RINm5F β-cells via the mitochondrial pathway and NF-κB signaling. Int J Mol Med. 2013;31: 265-271.
80. Eid HM, Martineau LC, Saleem A, et al. Stimulation of AMP-activated protein kinase and enhancement of basal glucose uptake in muscle cells by quercetin and quercetin glycosides, active principles of the antidiabetic medicinal plant Vaccinium vitis-idaea. Mol Nutr Food Res. 2010; 54:991-1003.
81. Dai X, Ding Y, Zhang Z, et al. Quercetin but not quercitrin ameliorates tumor necrosis factor-alpha-induced insulin resistance in C2C12 skeletal muscle cells. Biol Pharm Bull. 2013;36:788-795.
82. Anhê GF, Okamoto MM, Kinote A, et al. Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes. Eur J Pharmacol. 2012;689:285-293.
83. Coskun O, Kanter M, Korkmaz A, et al. Quercetin, a flavonoid antioxidant, prevents and protects streptozotocin-induced oxidative stress and beta-cell damage in rat pancreas. Pharmacol Res. 2005;51:117-123.
84. Vessal M, Hemmati M, Vasei M. Antidiabetic effects of quercetin in streptozocin-induced diabetic rats. Comp Biochem Physiol C Toxicol Pharmacol. 2003;135C:357-364.
85. Kobori M, Masumoto S, Akimoto Y, et al. Dietary quercetin alleviates diabetic symptoms and reduces streptozotocin-induced disturbance of hepatic gene expression in mice. Mol Nutr Food Res. 2009;53:859-868.
86. Prasath GS, Subramanian SP. Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2011;668:492-496.
87. Prasath GS, Subramanian SP. Fisetin, a tetra hydroxy flavone recuperates antioxidant status and protects hepatocellular ultrastructure from hyperglycemia mediated oxidative stress in streptozotocin induced experimental diabetes in rats. Food Chem Toxicol. 2013;59:249-255.
88. Prasath GS, Sundaram CS, Subramanian SP. Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats. Endocrine. 2013;44:359-368.
89. Jeong SM, Kang MJ, Choi HN, et al. Quercetin ameliorates hyperglycemia and dyslipidemia and improves antioxidant status in type 2 diabetic db/db mice. Nutr Res Pract. 2012;6:201-207.
90. Rivera L, Morón R, Sánchez M, et al. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity. 2008;16:2081-2087.
91. Wang Y, Xin X, Jin Z, et al. Anti-diabetic effects of pentamethylquercetin in neonatally streptozotocin-induced diabetic rats. Eur J Pharmacol. 2011;668:347-353.
92. Henagan TM, Lenard NR, Gettys TW, et al. Dietary quercetin supplementation in mice increases skeletal muscle PGC1α expression, improves mitochondrial function and attenuates insulin resistance in a time-specific manner. PLoS One. 2014;9:e89365.
93. Arias N, Macarulla MT, Aguirre L, et al. Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation. Genes Nutr. 2014;9:361.
94. Fang XK, Gao J, Zhu DN. Kaempferol and quercetin isolated from Euonymus alatus improve glucose uptake of 3T3-L1 cells without adipogenesis activity. Life Sci. 2008;82:615-622.
95. Chen L, He T, Han Y, et al. Pentamethylquercetin improves adiponectin expression in differentiated 3T3-L1 cells via a mechanism that implicates PPARγ together with TNF-α and IL-6. Molecules. 2011;16: 5754-5768.
96. Torres-Piedra M, Ortiz-Andrade R, Villalobos-Molina R, et al. A comparative study of flavonoid analogues on streptozotocin-nicotinamide induced diabetic rats: quercetin as a potential antidiabetic agent acting via 11beta-hydroxysteroid dehydrogenase type 1 inhibition. Eur J Med Chem. 2010;45:2606-2612.
97. Leo CH, Hart JL, Woodman OL. 3',4'-Dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries. PLoS One. 2011;6:e20813.
98. Mosawy S, Jackson DE, Woodman OL, et al. The flavonols quercetin and 3',4'-dihydroxyflavonol reduce platelet function and delay thrombus formation in a model of type 1 diabetes. Diab Vasc Dis Res. 2014; 11:174-181.
99. Woodman OL, Malakul W. 3',4'-Dihydroxyflavonol prevents diabetesinduced endothelial dysfunction in rat aorta. Life Sci. 2009;85:54-59.
100. Mahmoud MF, Hassan NA, El Bassossy HM, et al. Quercetin protects against diabetes-induced exaggerated vasoconstriction in rats: effect on low grade inflammation. PLoS One. 2013;8:e63784.
101. Maher P, Dargusch R, Ehren JL, et al. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One. 2011;6:e21226.
102. Bast A, Wolf G, Oberbäumer I, et al. Oxidative and nitrosative stress induces peroxiredoxins in pancreatic beta cells. Diabetologia. 2002;45: 867-876.
103. Coughlan KA, Valentine RJ, Ruderman NB, et al. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. 2014;24:241-253.
104. Anderson A, Walker BR. 11β-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease. Drugs. 2013;73:1385-1393.
105. Knekt P, Kumpulainen J, Järvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;76:560-568.
106. Jacques PF, Cassidy A, Rogers G, et al. Higher dietary flavonol intake is associated with lower incidence of type 2 diabetes. J Nutr. 2013;143: 1474-1480.
107. Zamora-Ros R, Forouhi NG, Sharp SJ, et al. The association between dietary flavonoid and lignan intakes and incident type 2 diabetes in European populations: the EPIC-InterAct study. Diabetes Care. 2013; 36:3961-3970.
108. Zamora-Ros R, Forouhi NG, Sharp SJ, et al. Dietary intakes of individual flavanols and flavonols are inversely associated with incident type 2 diabetes in European populations. J Nutr. 2014;144:335-343.
109. Nettleton JA, Harnack LJ, Scrafford CG, et al. Dietary flavonoids and flavonoid-rich foods are not associated with risk of type 2 diabetes in postmenopausal women. J Nutr. 2006;136:3039-3045.
110. Song Y, Manson JE, Buring JE, et al. Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and crosssectional analysis. J Am Coll Nutr. 2005;24:376-384.
111. Zahedi M, Ghiasvand R, Feizi A, et al. Does quercetin improve cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes: a double-blind randomized controlled clinical trial. Int J Prev Med. 2013;4:777-785.
112. Ding H, Triggle CR. Endothelial dysfunction in diabetes: multiple targets for treatment. Pflugers Arch. 2010;459:977-994.
113. Leo CH, Hart JL, Woodman OL. Impairment of both nitric oxidemediated and EDHF-type relaxation in small mesenteric arteries from rats with streptozotocin-induced diabetes. Br J Pharmacol. 2011;162: 365-377.
114. Leo CH, Joshi A, Hart JL, et al. Endothelium-dependent nitroxylmediated relaxation is resistant to superoxide anion scavenging and preserved in diabetic rat aorta. Pharmacol Res. 2012;66:383-391.
115. Leo CH, Joshi A, Woodman OL. Short term type 1 diabetes alters the mechanism of endothelium-dependent relaxation in the rat carotid artery. Am J Physiol Heart Circ Physiol. 2010;299:H502-H511.
116. Shi Y, So KF, Man RY, et al. Oxygen-derived free radicals mediate endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes. Br J Pharmacol. 2007;152: 1033-1041.
117. Shi Y, Vanhoutte PM. Oxidative stress and COX cause hyperresponsiveness in vascular smooth muscle of the femoral artery from diabetic rats. Br J Pharmacol. 2008;154:639-651.
118. Vanhoutte PM, Shimokawa H, Tang EHC, et al. Endothelial dysfunction and vascular disease. Acta Physiol. 2009;196:193-222.
119. Roberts AC, Porter KE. Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res. 2013;10: 472-482.
120. Wong WT, Tian XY, Huang Y. Endothelial dysfunction in diabetes and hypertension: cross talk in RAS, BMP4, and ROS-dependent COX-2-derived prostanoids. J Cardiovasc Pharmacol. 2013;61:204-214.
121. Ajay M, Achike FI, Mustafa AM, et al. Effect of quercetin on altered vascular reactivity in aortas isolated from streptozotocin-induced diabetic rats. Diabetes Res Clin Pract. 2007;73:1-7.
122. Machha A, Achike FI, Mustafa AM, et al. Quercetin, a flavonoid, modulates endothelium-derived nitric oxide bioavailability in diabetic rat aortas. Nitric Oxide. 2007;16:441-447.
123. Panicker SR, Sreenivas P, Babu MS, et al. Quercetin attenuates monocyte chemoattractant protein-1 gene expression in glucose primed aortic endothelial cells through NF-kappaB and AP-1. Pharmacol Res. 2010; 62:328-336.
124. Chao CL, Hou YC, Chao PD, et al. The antioxidant effects of quercetin metabolites on the prevention of high glucose-induced apoptosis of human umbilical vein endothelial cells. Br J Nutr. 2009;101: 1165-1170.
125. Leo CH, Hart JL, Woodman OL. 3',4'-Dihydroxyflavonol restores endothelium dependent relaxation in small mesenteric artery from rats with type 1 and type 2 diabetes. Eur J Pharmacol. 2011;659: 193-198.
126. Mosawy S, Jackson DE, Woodman OL, et al. Treatment with quercetin and 3',4'-dihydroxyflavonol inhibits platelet function and reduces thrombus formation in vivo. J Thromb Thrombolysis. 2013; 36:50-57.
127. Mosawy S, Jackson DE, Woodman OL, et al. Inhibition of plateletmediated arterial thrombosis and platelet granule exocytosis by 3',4'-dihydroxyflavonol and quercetin. Platelets. 2013;24:594-604.