Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action

Advances in Nutrition

Volumn 5, Issue 4, 2014, Pages 404-417

  Alam, M Ashraful ^a,b   Subhan, Nusrat ^c   Rahman, M Mahbubur ^a   Uddin, Shaikh J ^d   Reza, Hasan M ^b   Sarker, Satyajit D ^e  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b NORTH SOUTH UNIVERSITY   (Bangladesh)

^c CHARLES STURT UNIVERSITY   (Australia)

^d KHULNA UNIVERSITY   (Bangladesh)

^e LIVERPOOL JOHN MOORES UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTIOXIDANT; AURANTIIN; FLAVANONE DERIVATIVE; NARINGENIN; PLANT EXTRACT;

CHEMISTRY; CITRUS; DRUG EFFECTS; HUMAN; INFLAMMATION; LIPID METABOLISM; METABOLIC SYNDROME X; METABOLISM; OBESITY; OXIDATIVE STRESS; PHYTOTHERAPY;

ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; CITRUS; FLAVANONES; HUMANS; INFLAMMATION; LIPID METABOLISM; METABOLIC SYNDROME X; OBESITY; OXIDATIVE STRESS; PHYTOTHERAPY; PLANT EXTRACTS;

EID: 84909635530     PISSN: 21618313     EISSN: 21565376     Source Type: Journal    
DOI: 10.3945/an.113.005603     Document Type: Review

References (140)

1. Fogli-Cawley JJ, Dwyer JT, Saltzman E, McCullough ML, Troy LM, Meigs JB, Jacques PF. The 2005 Dietary Guidelines for Americans and risk of the metabolic syndrome. Am J Clin Nutr 2007;86:1193- 201.
2. Kesse-Guyot E, Fezeu L, Galan P, Hercberg S, Czernichow S, Castetbon K. Adherence to French nutritional guidelines is associated with lower risk of metabolic syndrome. J Nutr 2011;141:1134-9.
3. Yang Z-H, Miyahara H, Takeo J, Katayama M. Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice. Diabetol Metab Syndr 2012;4:32.
4. Bruce KD, Hanson MA. The developmental origins, mechanisms, and implications of metabolic syndrome. J Nutr 2010;140:648-52.
5. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006;444:881-7.
6. Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome-a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med 2006;23:469-80.
7. Russell RP. Side effects of calcium channel blockers. Hypertension 1988;11:II42-4.
8. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000;355:637-45.
9. Sowers JR, Epstein M. Diabetes mellitus and associated hypertension, vascular disease, and nephropathy. Hypertension 1995;26:869-79.
10. Estaquio C, Castetbon K, Kesse-Guyot E, Bertrais S, Deschamps V, Dauchet L, Péneau S, Galan P, Hercberg S. The French National Nutrition and Health Program Score is associated with nutritional status and risk of major chronic diseases. J Nutr 2008;138:946-53.
11. Liu S, Serdula M, Janket S-J, Cook NR, Sesso HD, Willett WC, Manson JE, Buring JE. A prospective study of fruit and vegetable intake and the risk of type 2 diabetes in women. Diabetes Care 2004;27: 2993-6.
12. Martin K, Appel C. Polyphenols as dietary supplements: A doubleedged sword. Nutrition and Dietary Supplements 2010, 2:1-12.
13. Tripoli E, Guardia ML, Giammanco S, Majo DD, Giammanco M. Citrus flavonoids: molecular structure, biological activity and nutritional properties: a review. Food Chem 2007;104:466-79.
14. Fuhr U, Kummert AL. The fate of naringin in humans: a key to grapefruit juice-drug interactions? Clin Pharmacol Ther 1995;58:365-73.
15. Ameer B, Weintraub RA. Drug interactions with grapefruit juice. Clin Pharmacokinet 1997;33:103-21.
16. Bailey DG. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br J Clin Pharmacol 2010;70:645-55.
17. Bailey DG, Dresser GK, Leake BF, Kim RB. Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther 2007;81: 495-502.
18. Dresser GK, Bailey D, Leake B, Schwarz U, Dawson P, Freeman D, Kim R. Fruit juices inhibit organic anion transporting polypeptide- mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther 2002;71:11-20.
19. Trombetta D, Cimino F, Cristani M, Mandalari G, Saija A, Ginestra G, Speciale A, Chirafisi J, Bisignano G, Waldron K, et al. In vitro protective effects of two extracts from bergamot peels on human endothelial cells exposed to tumor necrosis factor-a (TNF-a). J Agric Food Chem 2010;58:8430-6.
20. Chen Z-T, Chu H-L, Chyau C-C, Chu C-C, Duh P-D. Protective effects of sweet orange (Citrus sinensis) peel and their bioactive compounds on oxidative stress. Food Chem 2012;135:2119-27.
21. Sugiura M, Ohshima M, Ogawa K, Yano M. Chronic administration of Satsuma mandarin fruit (Citrus unshiu Marc.) improves oxidative stress in streptozotocin-induced diabetic rat liver. Biol Pharm Bull 2006;29:588-91.
22. Sugiura M, Ogawa K, Yano M. Effect of chronic administration of fruit extract (Citrus unshiu Marc.) on glucose tolerance in GK rats, a model of type 2 diabetes. Biosci Biotechnol Biochem 2006;70: 293-5.
23. Park H-J, Jung UJ, Cho S-J, Jung H-K, Shim S, Choi M-S. Citrus unshiu peel extract ameliorates hyperglycemia and hepatic steatosis by altering inflammation and hepatic glucose- and lipid-regulating enzymes in db/db mice. J Nutr Biochem 2013;24:419-27.
24. Kang SI, Shin HS, Kim HM, Hong YS, Yoon SA, Kang SW, Kim JH, Kim MH, Ko HC, Kim SJ. Immature Citrus sunki peel extract exhibits antiobesity effects by beta-oxidation and lipolysis in high-fat diet-induced obese mice. Biol Pharm Bull 2012;35:223-30.
25. Ramful D, Tarnus E, Rondeau P, Robert Da Silva C, Bahorun T, Bourdon E. Citrus fruit extracts reduce advanced glycation end products (AGEs) and H2O2-induced oxidative stress in human adipocytes. J Agric Food Chem 2010.
26. Fujioka K, Greenway F, Sheard J, Ying Y. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. J Med Food 2006;9:49-54.
27. Dallas C, Gerbi A, Tenca G, Juchaux F, Bernard F-X. Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes: mechanism of action by inhibition of cAMP-phosphodiesterase (PDE). Phytomedicine 2008;15: 783-92.
28. Cook NC, Samman S. Flavonoids-chemistry, metabolism, cardioprotective effects, and dietary sources. J Nutr Biochem 1996;7: 66-76.
29. Croft KD. The chemistry and biological effects of flavonoids and phenolic acids. Ann N Y Acad Sci 1998;854:435-42.
30. Peterson J, Dwyer J. Flavonoids: dietary occurrence and biochemical activity. Nutr Res 1998;18:1995-2018.
31. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002;22:19-34.
32. Renugadevi J, Prabu SM. Naringenin protects against cadmiuminduced oxidative renal dysfunction in rats. Toxicology 2009;256: 128-34.
33. Jung UJ, Kim HJ, Lee JS, Lee MK, Kim HO, Park EJ, Kim HK, Jeong TS, Choi MS. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin Nutr 2003;22:561-8.
34. Choudhury R, Chowrimootoo G, Srai K, Debnam E, Rice-Evans CA. Interactions of the flavonoid naringenin in the gastrointestinal tract and the influence of glycosylation. Biochem Biophys Res Commun 1999;265:410-5.
35. Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000;130 Suppl:2073S-85S.
36. Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 2003;133 Suppl:3248S-54S.
37. Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr 2007;137:1244-52.
38. Lyons-Wall P, Autenzio P, Lee E, Moss R, Samman S. Catechins are the major source of flavonoids in a group of Australian women. Asia Pac J Clin Nutr. 2004;13:S72.
39. Ishii K, Furuta T, Kasuya Y. Determination of naringin and naringenin in human urine by high-performance liquid chromatography utilizing solid-phase extraction. J Chromatogr B Biomed Sci Appl 1997;704: 299-305.
40. Lee YS, Reidenberg MM. A method for measuring naringenin in biological fluids and its disposition from grapefruit juice by man. Pharmacology 1998;56:314-7.
41. Wang M, Chao P, Hou Y, Hsiu S,Wen K, Tsai S. Pharmacokinetics and conjugation metabolism of naringin and naringenin in rats after single dose and multiple dose administrations. J Food Drug Anal. 2006;14: 247-53.
42. Ameer B, Weintraub RA, Johnson JV, Yost RA, Rouseff RL. Flavanone absorption after naringin, hesperidin, and citrus administration. Clin Pharmacol Ther 1996;60:34-40.
43. Lee MH, Yoon S, Moon JO. The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol Pharm Bull 2004;27: 72-6.
44. Ooghe WC, Ooghe SJ, Detavernier ClM, Huyghebaert A. Characterization of orange juice (Citrus sinensis) by flavanone glycosides. J Agric Food Chem 1994;42:2183-90.
45. Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. HL-60 differentiating activity and flavonoid content of the readily extractable fraction prepared from citrus juices. J Agric Food Chem 1999;47:128-35.
46. de Lourdes Mata Bilbao M, Andrés-Lacueva C, Jáuregui O, Lamuela-Raventós RM. Determination of flavonoids in a citrus fruit extract by LC-DAD and LC-MS. Food Chem 2007;101:1742-7.
47. Dhuique-Mayer C, Caris-Veyrat C, Ollitrault P, Curk F, Amiot MJ. Varietal and interspecific influence on micronutrient contents in citrus from the Mediterranean area. J Agric Food Chem 2005;53:2140-5.
48. Neveu V, Perez-Jimenez J, Vos F, Crespy V, du Chaffaut L, Mennen L, Knox C, Eisner R, Cruz J, Wishart D, et al. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database (Oxford). 2010;doi: 10.1093/database/bap024.
49. Rothwell JA, Urpi-Sarda M, Boto-Ordonez M, Knox C, Llorach R, Eisner R, Cruz J, Neveu V, Wishart D, Manach C, et al. Phenol-Explorer 2.0: a major update of the Phenol-Explorer database integrating data on polyphenol metabolism and pharmacokinetics in humans and experimental animals. Database (Oxford). 2015;doi: 10.1093/database/bas031.
50. Bhagwat S, Haytowitz D, Holden J. USDA database for the flavonoid content of selected foods. Release 3. USDA; 2011.
51. WHO. The World Health Report: reducing risks promoting healthy life. Geneva: WHO; 2002.
52. Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis A. The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health 2009;9:88.
53. Fukuchi Y, Hiramitsu M, Okada M, Hayashi S, Nabeno Y, Osawa T, Naito M. Lemon polyphenols suppress diet-induced obesity by upregulation of mRNA levels of the enzymes involved in beta-oxidation in mouse white adipose tissue. J Clin Biochem Nutr 2008;43:201-9.
54. Cho KW, Kim YO, Andrade JE, Burgess JR, Kim YC. Dietary naringenin increases hepatic peroxisome proliferators-activated receptor alpha protein expression and decreases plasma triglyceride and adiposity in rats. Eur J Nutr 2011;50:81-8.
55. Horiba T, Nishimura I, Nakai Y, Abe K, Sato R. Naringenin chalcone improves adipocyte functions by enhancing adiponectin production. Mol Cell Endocrinol 2010;323:208-14.
56. Hirai S, Takahashi N, Goto T, Lin S, Uemura T, Yu R, Kawada T. Functional food targeting the regulation of obesity-induced inflammatory responses and pathologies. Mediators Inflamm. 2010;2010: 367838.
57. Yu R, Kim C-S, Kwon B-S, Kawada T. Mesenteric adipose tissue-derived monocyte chemoattractant protein-1 plays a crucial role in adipose tissue macrophage migration and activation in obese mice. Obesity (Silver Spring) 2006;14:1353-62.
58. Hirai S, Kim, II Y, Goto T, Kang M-S, Yoshimura M, Obata A, Yu R, Kawada T. Inhibitory effect of naringenin chalcone on inflammatory changes in the interaction between adipocytes and macrophages. Life Sci 2007;81:1272-9.
59. Bravo L. Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 1998;56:317-33.
60. Pu P, Gao DM, Mohamed S, Chen J, Zhang J, Zhou XY, Zhou NJ, Xie J, Jiang H. Naringin ameliorates metabolic syndrome by activating AMP-activated protein kinase in mice fed a high-fat diet. Arch Biochem Biophys 2012;518:61-70.
61. Shin YW, Bok SH, Jeong TS, Bae KH, Jeoung NH, Choi MS, Lee SH, Park YB. Hypocholesterolemic effect of naringin associated with hepatic cholesterol regulating enzyme changes in rats. Int J Vitam Nutr Res 1999;69:341-7.
62. Li WL, Zheng HC, Bukuru J, De Kimpe N. Natural medicines used in the traditional Chinese medical system for therapy of diabetes mellitus. J Ethnopharmacol 2004;92:1-21.
63. Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, Markle JM, Hegele RA, Huff MW. Naringenin prevents dyslipidemia, apolipoprotein- B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes 2009;58:2198-210.
64. Alam MA, Kauter K, Brown L. Naringin improves diet-induced cardiovascular dysfunction and obesity in high carbohydrate, high fat dietfed rats. Nutrients. 2013;5:637-50.
65. Ikemura M, Sasaki Y, Giddings JC, Yamamoto J. Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother Res 2012;26:1272-7.
66. Fallahi F, Roghani M, Moghadami S. Citrus flavonoid naringenin improves aortic reactivity in streptozotocin-diabetic rats. Indian J Pharmacol 2012;44:382-6.
67. Saponara S, Testai L, Iozzi D, Martinotti E, Martelli A, Chericoni S, Sgaragli G, Fusi F, Calderone V. (+/2)-Naringenin as large conductance Ca2+-activated K+ (BKCa) channel opener in vascular smooth muscle cells. Br J Pharmacol 2006;149:1013-21.
68. Chen S, Ding Y, Tao W, Zhang W, Liang T, Liu C. Naringenin inhibits TNF-a induced VSMC proliferation and migration via induction of HO-1. Food Chem Toxicol 2012;50:3025-31.
69. Reshef N, Hayarib Y, Gorenb C, Boazc M, Madarb Z, Knoblera H. Antihypertensive effect of sweetie fruit in patients with stage I hypertension. Am J Hypertens 2005;18:1360-3.
70. Rajadurai M, Stanely Mainzen Prince P. Preventive effect of naringin on lipid peroxides and antioxidants in isoproterenol-induced cardiotoxicity in Wistar rats: biochemical and histopathological evidences. Toxicology 2006;228:259-68.
71. Reddy TK, Nagaraju I, Kumar KH, Lokanatha V, Reddy CD, Jagetia GC. Cardioprotective effect of naringin in mice treated with doxorubicin. Planta Med 2008;74:49.
72. Rajadurai M, Prince PS. Preventive effect of naringin on cardiac mitochondrial enzymes during isoproterenol-induced myocardial infarction in rats: a transmission electron microscopic study. J Biochem Mol Toxicol 2007;21:354-61.
73. Mojzisová G, Šarišský M, Mirossay L, Martinka P, Mojžiš J. Effect of flavonoids on daunorubicin-induced toxicity in H9c2 cardiomyoblasts. Phytother Res 2009;23:136-9.
74. Qin CX, Chen X, Hughes RA, Williams SJ, Woodman OL. Understanding the cardioprotective effects of flavonols: discovery of relaxant flavonols without antioxidant activity. J Med Chem 2008;51: 1874-84.
75. Panchal SK, Poudyal H, Iyer A, Nazer R, Alam MA, Diwan V, Kauter K, Sernia C, Campbell F, Ward L, et al. High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol 2011;57:611-24.
76. Chen Y, Nie Y-c, Luo Y-l, Lin F, Zheng Y-f, Cheng G-h,Wu H, Zhang K-j, Su W-w, Shen J-g, et al. Protective effects of naringin against paraquatinduced acute lung injury and pulmonary fibrosis in mice. Food Chem Toxicol 2013;58:133-40.
77. Huang H, Wu K, You Q, Huang R, Li S, Wu K. Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway. Int J Mol Med 2013;32:396-402.
78. Chen J, Guo R, Yan H, Tian L, You Q, Li S, Huang R, Wu K. Naringin inhibits ROS-activated MAPK pathway in high glucose-induced injuries in H9c2 cardiac cells. Basic Clin Pharmacol Toxicol 2014;114: 293-304.
79. Punithavathi VR, Anuthama R, Prince PSM. Combined treatment with naringin and vitamin C ameliorates streptozotocin-induced diabetes in male Wistar rats. J Appl Toxicol 2008;28:806-13.
80. Jung UJ, Lee M-K, Jeong K-S, Choi M-S. The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db Mice. J Nutr 2004;134:2499-503.
81. Annadurai T, Muralidharan AR, Joseph T, Hsu MJ, Thomas PA, Geraldine P. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats. J Physiol Biochem 2012;68:307-18.
82. Annadurai T, Thomas PA, Geraldine P. Ameliorative effect of naringenin on hyperglycemia-mediated inflammation in hepatic and pancreatic tissues of Wistar rats with streptozotocin- nicotinamide-induced experimental diabetes mellitus. Free Radic Res 2013;47:793-803.
83. Tsai S-J, Huang C-S, Mong M-C, Kam W-Y, Huang H-Y, Yin M-C. Anti-inflammatory and antifibrotic effects of naringenin in diabetic mice. J Agric Food Chem 2012;60:514-21.
84. Zygmunt K, Faubert B, MacNeil J, Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem Biophys Res Commun 2010;398:178-83.
85. Hotamisligil GS, Shargill N, Spiegelman B. Adipose expression of tumor necrosis factor-a: direct role in obesity-linked insulin resistance. Science 1993;259:87-91.
86. Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin-6, tumour necrosis factor a and blood cytokine production in type 2 diabetes. Life Sci 2000;67:291-300.
87. Kado S, Nagase T, Nagata N. Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetol 1999;36:67-72.
88. Krogh-Madsen R, Plomgaard P, Møller K, Mittendorfer B, Pedersen BK. Influence of TNF-a and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am J Physiol Endocrinol Metab 2006;291:E108-14.
89. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004;25:4-7.
90. Terra X, Montagut G, Bustos M, Llopiz N, Ardèvol A, Bladé C, Fernández-Larrea J, Pujadas G, Salvadó J, Arola L, et al. Grape-seed procyanidins prevent low-grade inflammation by modulating cytokine expression in rats fed a high-fat diet. J Nutr Biochem 2009;20:210-8.
91. Lee IS, Shin G, Choue R. Shifts in diet from high fat to high carbohydrate improved levels of adipokines and pro-inflammatory cytokines in mice fed a high-fat diet. Endocr J 2010;57:39-50.
92. Ali MM, El Kader MA. The influence of naringin on the oxidative state of rats with streptozotocin-induced acute hyperglycaemia. Z Naturforsch C 2004;59:726-33.
93. Pari L, Amudha K. Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats. Eur J Pharmacol 2011;650:364-70.
94. Renugadevi J, Prabu SM. Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin. Exp Toxicol Pathol 2010;62: 171-81.
95. Guan L-P, Nan J-X, Jin X-J, Jin Q-H, Kwak K, Chai K-y, Quan Z-S. Protective effects of chalcone derivatives for acute liver injury in mice. Arch Pharm Res 2005;28:81-6.
96. Kannappan S, Palanisamy N, Anuradha CV. Suppression of hepatic oxidative events and regulation of eNOS expression in the liver bynaringenin in fructose-administered rats. Eur J Pharmacol 2010;645: 177-84.
97. Bravo E, Palleschi S, Aspichueta P, Buque X, Rossi B, Cano A, Napolitano M, Ochoa B, Botham KM. High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway. Lipids Health Dis 2011;10:60.
98. Kawaguchi K, Kikuchi S, Hasegawa H, Maruyama H, Morita H, Kumazawa Y. Suppression of lipopolysaccharide-induced tumor necrosis factor-release and liver injury in mice by naringin. Eur J Pharmacol 1999;368:245-50.
99. Sharma AK, Bharti S, Ojha S, Bhatia J, Kumar N, Ray R, Kumari S, Arya DS. Up-regulation of PPARgamma, heat shock protein-27 and -72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br J Nutr 2011;106:1713-23.
100. St Clair RW, Yancey PG, Leight MA. Macrophage cholesterol balance: a potential site of genetic control of susceptibility to atherosclerosis. Ann N Y Acad Sci 1995;748:264-75.
101. Fuhrman B, Aviram M. Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol 2001;12:41-8.
102. Naderi GA, Asgary S, Sarraf-Zadegan N, Shirvany H. Anti-oxidant effect of flavonoids on the susceptibility of LDL oxidation. Mol Cell Biochem 2003;246:193-6.
103. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol 2012;32:2045-51.
104. Oak M-H, El Bedoui J, Schini-Kerth VB. Antiangiogenic properties of natural polyphenols from red wine and green tea. J Nutr Biochem 2005;16:1-8.
105. Choe S-C, Kim H-S, Jeong T-S, Bok S-H, Park Y-B. Naringin has an antiatherogenic effect with the inhibition of intercellular adhesion molecule-1 in hypercholesterolemic rabbits. J Cardiovasc Pharmacol 2001;38:947-55.
106. Lee C-H, Jeong T-S, Choi Y-K, Hyun B-H, Oh G-T, Kim E-H, Kim J-R, Han J-I, Bok S-H. Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun 2001;284:681-8.
107. Chanet A,Milenkovic D, Deval C, PotierM, Constans J,Mazur A, Bennetau-Pelissero C, Morand C, Bérard AM. Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. J Nutr Biochem 2012;23:469-77.
108. Merat S, Casanada F, Sutphin M, PalinskiW, Reaven PD. Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptordeficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. Arterioscler Thromb Vasc Biol 1999;19:1223-30.
109. Allister EM, Mulvihill EE, Barrett PHR, Edwards JY, Carter LP, Huff MW. Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor. J Lipid Res 2008;49:2218-29.
110. Borradaile NM, de Dreu LE, Huff MW. Inhibition of Net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes 2003;52:2554-61.
111. Mulvihill EE, Assini JM, Sutherland BG, DiMattia AS, Khami M, Koppes JB, Sawyez CG, Whitman SC, Huff MW. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat- fed low-density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol 2010;30:742-8.
112. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-808.
113. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-30.
114. Yu YH, Ginsberg HN. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circ Res 2005;96:1042-52.
115. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology 2007;132:2169-80.
116. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415-28.
117. Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 2004;15:2792-800.
118. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-a induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptormediated signal transduction. J Biol Chem. 1997;272:971-6.
119. Lin C-Y, Ni C-C, Yin M-C, Lii C-K. Flavonoids protect pancreatic beta-cells from cytokines mediated apoptosis through the activation of PI3-kinase pathway. Cytokine 2012;59:65-71.
120. García-Lafuente A, Guillamón E, Villares A, Rostagno M, Martínez J. Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm Res 2009;58:537-52.
121. Jain M, Parmar HS. Evaluation of antioxidative and anti-inflammatory potential of hesperidin and naringin on the rat air pouch model of inflammation. Inflamm Res 2011;60:483-91.
122. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kB. Nat Med 2005;11:183-90.
123. Lee E-J, Kim D-I, Kim W-J, Moon S-K. Naringin inhibits matrix metalloproteinase-9 expression and AKT phosphorylation in tumor necrosis factor-a-induced vascular smooth muscle cells. Mol Nutr Food Res 2009;53:1582-91.
124. Xiong Y, Wang GF, Zhang JY, Wu SY, Xu W, Zhang JJ, Wu SG, Rao JJ. Naringin inhibits monocyte adhesion to high glucose-induced human umbilical vein endothelial cells. Nan Fang Yi Ke Da Xue Xue Bao. 2010;30:321-5.
125. Gopinath K, Sudhandiran G. Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of Nrf2 signalling pathway. Neuroscience 2012;227:134-43.
126. Guimarães R, Barros L, Barreira JCM, Sousa MJ, Carvalho AM, Ferreira ICFR. Targeting excessive free radicals with peels and juices of citrus fruits: grapefruit, lemon, lime and orange. Food Chem Toxicol 2010;48:99-106.
127. Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, Ortega N, Perez-Mateos M, Muñiz P. Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric 2010;90:1238-44.
128. Russo A, Acquaviva R, Campisi A, Sorrenti V, Di Giacomo C, Virgata G, Barcellona ML, Vanella A. Bioflavonoids as antiradicals, antioxidants and DNA cleavage protectors. Cell Biol Toxicol 2000;16:91-8.
129. Jeon S-M, Bok S-H, Jang M-K, Kim Y-H, Nam K-T, Jeong T-S, Park YB, Choi M-S. Comparison of antioxidant effects of naringin and probucol in cholesterol-fed rabbits. Clin Chim Acta 2002;317:181-90.
130. Mollace V, Sacco I, Janda E, Malara C, Ventrice D, Colica C, Visalli V, Muscoli S, Ragusa S, Muscoli C, et al. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia 2011;82:309-16.
131. Dow CA, Going SB, Chow HH, Patil BS, Thomson CA. The effects of daily consumption of grapefruit on body weight, lipids, and blood pressure in healthy, overweight adults. Metabolism 2012;61:1026-35.
132. Aptekmann NP, Cesar T. Long-term orange juice consumption is associated with low LDL-cholesterol and apolipoprotein B in normal and moderately hypercholesterolemic subjects. Lipids Health Dis 2013;12:119.
133. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am J Clin Nutr 2000;72:1095-100.
134. Kaats GR, Miller H, Preuss HG, Stohs SJ. A 60 day double-blind, placebo-controlled safety study involving Citrus aurantium (bitter orange) extract. Food Chem Toxicol 2013;55:358-62.
135. Haramaki N, Stewart DB, Aggarwal S, Ikeda H, Reznick AZ, Packer L. Networking antioxidants in the isolated rat heart are selectively depleted by ischemia-reperfusion. Free Radic Biol Med 1998;25: 329-39.
136. Nagel E, Meyer zu Vilsendorf A, Bartels M, Pichlmayr R. Antioxidative vitamins in prevention of ischemia/reperfusion injury. Int J Vitam Nutr Res 1997;67:298-306.
137. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;293:1338-47.
138. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999;354:447-55.
139. Brown BG, Crowley J. Is there any hope for vitamin E? JAMA 2005; 293:1387-90.
140. Sesso HD, Buring JE, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Glynn RJ, Gaziano JM. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA 2008;300:2123-33.