Bergamot (citrus bergamia risso) flavonoids and their potential benefits in human hyperlipidemia and atherosclerosis: An overview

Mini-Reviews in Medicinal Chemistry

Volumn 16, Issue 8, 2016, Pages 619-629

  Cappello, A R ^a   Dolce, V ^a   Iacopetta, D ^a   Martello, M ^a   Fiorillo, M ^a   Curcio, R ^a   Muto, L ^a   Dhanyalayam, D ^a  

^a UNIVERSITY OF CALABRIA   (Italy)

Author keywords

3 hydroxy 3 methylglutaryl CoA reductase enzyme; Atherosclerosis; Bergamot fruit; Flavonoids; Hyperlipidemia

Indexed keywords

ABC TRANSPORTER; APIGENIN; AURANTIIN; BRUTIERIDIN; CHOLESTEROL; ERIOCITRIN; ERIODICTYOL MONO RHAMNOSIDE; FLAVONOID; HESPERETIN MONO RHAMNOSIDE; HESPERIDIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LIVER X RECEPTOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MELITIDIN; MICRORNA; MICRORNA 33A; NARINGENIN MONO RHAMNOSIDE; NARINGIN DI OXALATE; NARIRUTIN; NEOERIOCITRIN; NEOERIOCITRIN DI OXALATE; NEOHESPERIDIN; NEOHESPERIDIN DI OXALATE; NEOPONCIRIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PLANT MEDICINAL PRODUCT; PONCIRIN; STEROL REGULATORY ELEMENT BINDING PROTEIN; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ARTICLE; ATHEROSCLEROSIS; CARDIOVASCULAR RISK; CITRUS; CITRUS BERGAMIA RISSO; CORONARY ARTERY DISEASE; DOWN REGULATION; FRUIT; HUMAN; HYPERLIPIDEMIA; HYPOCHOLESTEROLEMIA; LIPID PEROXIDATION; PROTEIN EXPRESSION; UPREGULATION; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; HYPERLIPIDEMIAS; ISOLATION AND PURIFICATION;

ANIMALS; ATHEROSCLEROSIS; CITRUS; FLAVONOIDS; HUMANS; HYPERLIPIDEMIAS; MOLECULAR STRUCTURE;

EID: 84961613997     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/1389557515666150709110222     Document Type: Article

References (91)

1. Balbisi, E.A. Management of hyperlipidemia: new LDL-C targets for persons at high-risk for cardiovascular events. Med. Sci. Monit., 2006, 12(2), RA34-39.
2. Maxfield, F.R. Tabas, I. Role of cholesterol and lipid organization in disease. Nature, 2005, 438(7068), 612-621.
3. Gielen, S.; Sandri, M.; Schuler, G.; Teupser, D. Risk factor management: antiatherogenic therapies. Eur. J. Cardiovasc. Prev. Rehabil., 2009, 16 Suppl 2 S29-36.
4. Stamler, J.; Neaton, J.D.; Cohen, J.D.; Cutler, J.; Eberly, L.; Grandits, G.; Kuller, L.H.; Ockene, J.; Prineas, R.; Group, M.R. Multiple risk factor intervention trial revisited: a new perspective based on nonfatal and fatal composite endpoints, coronary and cardiovascular, during the trial. J. Am. Heart Assoc., 2012, 1(5), e003640.
5. Stamler, J. Neaton, J.D. The Multiple Risk Factor Intervention Trial (MRFIT)--importance then and now. JAMA, 2008, 300(11), 1343-1345.
6. Baigent, C.; Keech, A.; Kearney, P.M.; Blackwell, L.; Buck, G.; Pollicino, C.; Kirby, A.; Sourjina, T.; Peto, R.; Collins, R.; Simes, R. Cholesterol Treatment Trialists, C. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet, 2005, 366(9493), 1267-1278.
7. Boekholdt, S.M.; Hovingh, G.K.; Mora, S.; Arsenault, B.J.; Amarenco, P.; Pedersen, T.R.; LaRosa, J.C.; Waters, D.D.; DeMicco, D.A.; Simes, R.J.; Keech, A.C.; Colquhoun, D.; Hitman, G.A.; Betteridge, D.J.; Clearfield, M.B.; Downs, J.R.; Colhoun, H.M.; Gotto, A.M., Jr.; Ridker, P.M.; Grundy, S.M. Kastelein, J.J. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J. Am. Coll. Cardiol., 2014, 64(5), 485-494.
8. Boekholdt, S.M.; Arsenault, B.J.; Mora, S.; Pedersen, T.R.; LaRosa, J.C.; Nestel, P.J.; Simes, R.J.; Durrington, P.; Hitman, G.A.; Welch, K.M.; DeMicco, D.A.; Zwinderman, A.H.; Clearfield, M.B.; Downs, J.R.; Tonkin, A.M.; Colhoun, H.M.; Gotto, A.M., Jr.; Ridker, P.M. Kastelein, J.J. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA, 2012, 307(12), 1302-1309.
9. Goldstein, J.L. Brown, M.S. Regulation of the mevalonate pathway. Nature, 1990, 343(6257), 425-430.
10. Ross, S.D.; Allen, I.E.; Connelly, J.E.; Korenblat, B.M.; Smith, M.E.; Bishop, D. Luo, D. Clinical outcomes in statin treatment trials: a meta-analysis. Arch. Intern. Med., 1999, 159(15), 1793-1802.
11. Scharnagl, H.; Schinker, R.; Gierens, H.; Nauck, M.; Wieland, H. Marz, W. Effect of atorvastatin, simvastatin, and lovastatin on the metabolism of cholesterol and triacylglycerides in HepG2 cells. Biochem. Pharmacol., 2001, 62(11), 1545-1555.
12. Stone, N.J.; Robinson, J.G.; Lichtenstein, A.H.; Bairey Merz, C.N.; Blum, C.B.; Eckel, R.H.; Goldberg, A.C.; Gordon, D.; Levy, D.; Lloyd-Jones, D.M.; McBride, P.; Schwartz, J.S.; Shero, S.T.; Smith, S.C., Jr.; Watson, K.; Wilson, P.W.; Eddleman, K.M.; Jarrett, N.M.; LaBresh, K.; Nevo, L.; Wnek, J.; Anderson, J.L.; Halperin, J.L.; Albert, N.M.; Bozkurt, B.; Brindis, R.G.; Curtis, L.H.; DeMets, D.; Hochman, J.S.; Kovacs, R.J.; Ohman, E.M.; Pressler, S.J.; Sellke, F.W.; Shen, W.K.; Smith, S.C., Jr.; Tomaselli, G.F. American College of Cardiology/American Heart Association Task Force on Practice, G. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation, 2014, 129(25 Suppl 2), S1-45.
13. Assini, J.M.; Mulvihill, E.E.; Huff, M.W. Citrus flavonoids and lipid metabolism. Curr. Opin. Lipidol., 2013, 24(1), 34-40.
14. Gorinstein, S.; Leontowicz, H.; Leontowicz, M.; Krzeminski, R.; Gralak, M.; Martin-Belloso, O.; Delgado-Licon, E.; Haruenkit, R.; Katrich, E.; Park, Y.S.; Jung, S.T. Trakhtenberg, S. Fresh Israeli Jaffa blond (Shamouti) orange and Israeli Jaffa red Star Ruby (Sunrise) grapefruit juices affect plasma lipid metabolism and antioxidant capacity in rats fed added cholesterol. J. Agric. Food Chem., 2004, 52(15), 4853-4859.
15. Gorinstein, S.; Leontowicz, H.; Leontowicz, M.; Krzeminski, R.; Gralak, M.; Delgado-Licon, E.; Martinez Ayala, A.L.; Katrich, E. Trakhtenberg, S. Changes in plasma lipid and antioxidant activity in rats as a result of naringin and red grapefruit supplementation. J. Agric. Food Chem., 2005, 53(8), 3223-3228.
16. 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.
17. Srinivasan, S. Pani, L. Antihyperlipidemic effect of diosmin: A citrus flavonoid on lipid metabolism in experimental diabetic rats. Journal of Functional Foods, 2013, 5(1), 484-492.
18. Marounek, M.; Volek, Z.; Synytsya, A. Copikova, J. Effect of pectin and amidated pectin on cholesterol homeostasis and cecal metabolism in rats fed a high-cholesterol diet. Physiol. Res., 2007, 56(4), 433-442.
19. Lappano, R.; Rosano, C.; Madeo, A.; Albanito, L.; Plastina, P.; Gabriele, B.; Forti, L.; Stivala, L.A.; Iacopetta, D.; Dolce, V.; Ando, S.; Pezzi, V.; Maggiolini, M. Structure-activity relationships of resveratrol and derivatives in breast cancer cells. Mol. Nutr. Food Res., 2009, 53(7), 845-858.
20. Burda, S.; Oleszek, W. Antioxidant and antiradical activities of flavonoids. J. Agric. Food Chem., 2001, 49(6), 2774-2779.
21. Peterson, J.J.; Dwyer, J.T.; Jacques, P.F.; McCullough, M.L. Associations between flavonoids and cardiovascular disease incidence or mortality in European and US populations. Nutr. Rev., 2012, 70(9), 491-508.
22. Garcia-Lafuente, A.; Guillamon, E.; Villares, A.; Rostagno, M.A. Martinez, J.A. Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm. Res., 2009, 58(9), 537-552.
23. Kim, H.P.; Son, K.H.; Chang, H.W.; Kang, S.S. Anti-inflammatory plant flavonoids and cellular action mechanisms. J. Pharmacol. Sci., 2004, 96(3), 229-245.
24. Yin, D.; Li, J.; Lei, X.; Liu, Y.; Yang, Z.; Chen, K. Antiviral Activity of Total Flavonoid Extracts from Selaginella moellendorffii Hieron against Coxsackie Virus B3 In Vitro and In Vivo. Evid. Based Complement Alternat. Med., 2014, 2014, 950-817.
25. Mandalari, G.; Bennett, R.N.; Bisignano, G.; Trombetta, D.; Saija, A.; Faulds, C.B.; Gasson, M.J. Narbad, A. Antimicrobial activity of flavonoids extracted from bergamot (Citrus bergamia Risso) peel, a byproduct of the essential oil industry. J. Appl. Microbiol., 2007, 103(6), 2056-2064.
26. Tijburg, L.B.; Mattern, T.; Folts, J.D.; Weisgerber, U.M. Katan, M.B. Tea flavonoids and cardiovascular disease: a review. Crit. Rev. Food Sci. Nutr., 1997, 37(8), 771-785.
27. Peluso, I.; Miglio, C.; Morabito, G.; Ioannone, F. Serafini, M. Flavonoids and immune function in human: a systematic review. Crit. Rev. Food Sci. Nutr., 2015, 55(3), 383-395.
28. Matsuo, M. ATP-binding cassette proteins involved in glucose and lipid homeostasis. Biosci. Biotechnol. Biochem., 2010, 74(5), 899-907.
29. Jia, L.; Betters, J.L.; Yu, L. Niemann-pick C1-like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annu. Rev. Physiol., 2011, 73 239-259.
30. Attie, A.D. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis. Trends Biochem. Sci., 2007, 32(4), 172-179.
31. Sampath, H.; Ntambi, J.M. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu. Rev. Nutr., 2005, 25 317-340.
32. Santolla, M.F.; Lappano, R.; De Marco, P.; Pupo, M.; Vivacqua, A.; Sisci, D.; Abonante, S.; Iacopetta, D.; Cappello, A.R.; Dolce, V.; Maggiolini, M. G protein-coupled estrogen receptor mediates the up-regulation of fatty acid synthase induced by 17beta-estradiol in cancer cells and cancer-associated fibroblasts. J. Biol. Chem., 2012, 287(52), 43234-43245.
33. Dolce, V.; Capobianco, L. Cappello, A.R. Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants. IUBMB Life, 2014, 66(7), 462-671.
34. Dolce, V.; Cappello, A.R.; Lappano, R. Maggiolini, M. Glycerophospholipid synthesis as a novel drug target against cancer. Curr. Mol. Pharmacol., 2011, 4(3), 167-175.
35. Cappello, A.R.; Guido, C.; Santoro, A.; Santoro, M.; Capobianco, L.; Montanaro, D.; Madeo, M.; Ando, S.; Dolce, V. Aquila, S. The mitochondrial citrate carrier (CIC) is present and regulates insulin secretion by human male gamete. Endocrinology, 2012, 153(4), 1743-1754.
36. Goldstein, J.L.; Brown, M.S. The LDL receptor. Arterioscler. Thromb. Vasc. Biol., 2009, 29(4), 431-438.
37. Steinberg, G.R.; Kemp, B.E. AMPK in Health and Disease. Physiol. Rev., 2009, 89(3), 1025-1078.
38. Steck, T.L. Lange, Y. Cell cholesterol homeostasis: mediation by active cholesterol. Trends Cell Biol., 2010, 20(11), 680-687.
39. Desvergne, B. Wahli, W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev., 1999, 20(5), 649-688.
40. Braissant, O.; Foufelle, F.; Scotto, C.; Dauca, M. Wahli, W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and - gamma in the adult rat. Endocrinology, 1996, 137(1), 354-366.
41. Bensinger, S.J. Tontonoz, P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature, 2008, 454(7203), 470-477.
42. Chawla, A.; Repa, J.J.; Evans, R.M. Mangelsdorf, D.J. Nuclear receptors and lipid physiology: opening the X-files. Science, 2001, 294(5548), 1866-1870.
43. Bonofiglio, D.; Santoro, A.; Martello, E.; Vizza, D.; Rovito, D.; Cappello, A.R.; Barone, I.; Giordano, C.; Panza, S.; Catalano, S.; Iacobazzi, V.; Dolce, V.; Ando, S. Mechanisms of divergent effects of activated peroxisome proliferator-activated receptor-gamma on mitochondrial citrate carrier expression in 3T3-L1 fibroblasts and mature adipocytes. Biochim. Biophys. Acta, 2013, 1831(6), 1027-1036.
44. Francis, G.A.; Fayard, E.; Picard, F.; Auwerx, J. Nuclear receptors and the control of metabolism. Annu. Rev. Physiol., 2003, 65 261-311.
45. Toh, S.A.; Millar, J.S.; Billheimer, J.; Fuki, I.; Naik, S.U.; Macphee, C.; Walker, M. Rader, D.J. PPARgamma activation redirects macrophage cholesterol from fecal excretion to adipose tissue uptake in mice via SR-BI. Biochem. Pharmacol., 2011, 81(7), 934-941.
46. Vrins, C.L.; van der Velde, A.E.; van den Oever, K.; Levels, J.H.; Huet, S.; Oude Elferink, R.P.; Kuipers, F.; Groen, A.K. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux. J. Lipid Res., 2009, 50(10), 2046-2054.
47. Kennedy, M.A.; Venkateswaran, A.; Tarr, P.T.; Xenarios, I.; Kudoh, J.; Shimizu, N. Edwards, P.A. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J. Biol. Chem., 2001, 276(42), 39438-39447.
48. Wagner, B.L.; Valledor, A.F.; Shao, G.; Daige, C.L.; Bischoff, E.D.; Petrowski, M.; Jepsen, K.; Baek, S.H.; Heyman, R.A.; Rosenfeld, M.G.; Schulman, I.G.; Glass, C.K. Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Mol. Cell Biol., 2003, 23(16), 5780-5789.
49. Laffitte, B.A.; Repa, J.J.; Joseph, S.B.; Wilpitz, D.C.; Kast, H.R.; Mangelsdorf, D.J.; Tontonoz, P. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci. U S A, 2001, 98(2), 507-512.
50. Repa, J.J.; Berge, K.E.; Pomajzl, C.; Richardson, J.A.; Hobbs, H. Mangelsdorf, D.J. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol. Chem., 2002, 277(21), 18793-18800.
51. Peet, D.J.; Turley, S.D.; Ma, W.; Janowski, B.A.; Lobaccaro, J.M.; Hammer, R.E. Mangelsdorf, D.J. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell, 1998, 93(5), 693-704.
52. Shukla, G.C.; Singh, J. Barik, S. MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. Mol. Cell Pharmacol., 2011, 3(3), 83-92.
53. Najafi-Shoushtari, S.H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen, D.E.; Gerszten, R.E. Naar, A.M. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science, 2010, 328(5985), 1566-1569.
54. Rayner, K.J.; Suarez, Y.; Davalos, A.; Parathath, S.; Fitzgerald, M.L.; Tamehiro, N.; Fisher, E.A.; Moore, K.J. Fernandez- Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science, 2010, 328(5985), 1570-1573.
55. Harborne, J.B. Williams, C.A. Advances in flavonoid research since 1992. Phytochemistry, 2000, 55(6), 481-504.
56. Vogt, T. Phenylpropanoid biosynthesis. Mol. Plant, 2010, 3(1), 2-20.
57. Benavente-Garcia, O. Castillo, J. Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J. Agric. Food Chem., 2008, 56(15), 6185-6205.
58. Gattuso, G.; Barreca, D.; Gargiulli, C.; Leuzzi, U. Caristi, C. Flavonoid composition of Citrus juices. Molecules, 2007, 12(8), 1641-1673.
59. Nogata, Y.; Sakamoto, K.; Shiratsuchi, H.; Ishii, T.; Yano, M. Ohta, H. Flavonoid composition of fruit tissues of citrus species. Biosci. Biotechnol. Biochem., 2006, 70(1), 178-192.
60. Di Donna, L.; De Luca, G.; Mazzotti, F.; Napoli, A.; Salerno, R.; Taverna, D. Sindona, G. Statin-like principles of bergamot fruit (Citrus bergamia): isolation of 3-hydroxymethylglutaryl flavonoid glycosides. J. Nat. Prod., 2009, 72(7), 1352-1354.
61. Di Donna, L.; Iacopetta, D.; Cappello, A.R.; Gallucci, G.; Martello, E.; Fiorillo, M.; Dolce, V. Sindona, G. Hypocholesterolaemic activity of 3-hydroxy-3- methyl-glutaryl flavanones enriched fraction from bergamot fruit (Citrus bergamia): "In vivo" studies. J. Funct. Foods, 2014, 7, 558-568.
62. Sindona, G.; Di Donna, L.; Dolce, V. Natural molecules extracted from bergamot tissues, extraction process and pharmaceutical use., April 15, 2010, WO/2010/041290 A1(WO/2010/041290 A1).
63. Gardana, C.; Nalin, F.; Simonetti, P. Evaluation of flavonoids and furanocoumarins from Citrus bergamia (Bergamot) juice and identification of new compounds. Molecules, 2008, 13(9), 2220-2228.
64. Mandalari, G.; Bennett, R.N.; Bisignano, G.; Saija, A.; Dugo, G.; Lo Curto, R.B.; Faulds, C.B.; Waldron, K.W. Characterization of flavonoids and pectins from bergamot (Citrus bergamia Risso) peel, a major byproduct of essential oil extraction. J. Agric. Food Chem., 2006, 54(1), 197-203.
65. Dugo, P.; Presti, M.L.; Ohman, M.; Fazio, A.; Dugo, G. Mondello, L. Determination of flavonoids in citrus juices by micro-HPLCESI/ MS. J. Sep. Sci., 2005, 28(11), 1149-1156.
66. Gattuso, G.; Barreca, D.; Caristi, C.; Gargiulli, C.; Leuzzi, U. Distribution of flavonoids and furocoumarins in juices from cultivars of Citrus bergamia Risso. J. Agric. Food Chem., 2007, 55(24), 9921-9927.
67. Gattuso, G.; Caristi, C.; Gargiulli, C.; Bellocco, E.; Toscano, G. Leuzzi, U. Flavonoid glycosides in bergamot juice (Citrus bergamia Risso). J. Agric. Food Chem., 2006, 54(11), 3929-3935.
68. Caristi, C.; Bellocco, E.; Gargiulli, C.; Toscano, G. Leuzzi, U. Flavone-di-C-glycosides in citrus juices from Southern Italy. Food Chem., 2006, 95(3), 431-437.
69. Dugo, P.; Mondello, L.; Dugo, L.; Stancanelli, R. Dugo, G. LC-MS for the identification of oxygen heterocyclic compounds in citrus essential oils. J. Pharm. Biomed. Anal., 2000, 24(1), 147-154.
70. Barreca, D.; Bellocco, E.; Caristi, C.; Leuzzi, U.; Gattuso, G. Flavonoid composition and antioxidant activity of juices from Chinotto (Citrus x myrtifolia Raf.) fruits at different ripening stages. J. Agric. Food Chem., 2010, 58(5), 3031-3036.
71. Morin, B.; Nichols, L.A.; Zalasky, K.M.; Davis, J.W.; Manthey, J.A.; Holland, L.J. The citrus flavonoids hesperetin and nobiletin differentially regulate low density lipoprotein receptor gene transcription in HepG2 liver cells. J. Nutr., 2008, 138(7), 1274-1281.
72. Kou, M.C.; Fu, S.H.; Yen, J.H.; Weng, C.Y.; Li, S.; Ho, C.T.; Wu, M.J. Effects of citrus flavonoids, 5-hydroxy-3,6,7,8,3',4'- hexamethoxyflavone and 3,5,6,7,8,3',4'-heptamethoxyflavone, on the activities of macrophage scavenger receptors and the hepatic LDL receptor. Food Funct., 2013, 4(4), 602-609.
73. 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(6), 947-955.
74. Yu, J.; Wang, L.; Walzem, R.L.; Miller, E.G.; Pike, L.M.; Patil, B.S. Antioxidant activity of citrus limonoids, flavonoids, and coumarins. J. Agric. Food Chem., 2005, 53(6), 2009-2014.
75. Miceli, N.; Mondello, M.R.; Monforte, M.T.; Sdrafkakis, V.; Dugo, P.; Crupi, M.L.; Taviano, M.F.; De Pasquale, R. Trovato, A. Hypolipidemic effects of Citrus bergamia Risso et Poiteau juice in rats fed a hypercholesterolemic diet. J. Agric. Food Chem., 2007, 55(26), 10671-10677.
76. Paine, M.F.; Criss, A.B. Watkins, P.B. Two major grapefruit juice components differ in time to onset of intestinal CYP3A4 inhibition. J. Pharmacol. Exp. Ther., 2005, 312(3), 1151-1160.
77. Mollace, V.; Sacco, I.; Janda, E.; Malara, C.; Ventrice, D.; Colica, C.; Visalli, V.; Muscoli, S.; Ragusa, S.; Muscoli, C.; Rotiroti, D. Romeo, F. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia, 2011, 82(3), 309-316.
78. Gliozzi, M.; Walker, R.; Muscoli, S.; Vitale, C.; Gratteri, S.; Carresi, C.; Musolino, V.; Russo, V.; Janda, E.; Ragusa, S.; Aloe, A.; Palma, E.; Muscoli, C.; Romeo, F.; Mollace, V. Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia. Int. J. Cardiol., 2013, 170(2), 140-145.
79. Di Donna, L.; Iacopetta, D.; Cappello, A.R.; Gallucci, G.; Martello, E.; Fiorillo, M.; Dolce, V. Sindona, G. Hypocholesterolaemic activity of 3-hydroxy-3- methyl-glutaryl flavanones enriched fraction from bergamot fruit (Citrus bergamia): ‘‘In vivo’’ studies. J. Funct. Foods, 2014, 7, 558-568.
80. Kong, W.J.; Wei, J.; Zuo, Z.Y.; Wang, Y.M.; Song, D.Q.; You, X.F.; Zhao, L.X.; Pan, H.N. Jiang, J.D. Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism, 2008, 57(8), 1029-1037.
81. Lee, S.; Birukov, K.G.; Romanoski, C.E.; Springstead, J.R.; Lusis, A.J. Berliner, J.A. Role of phospholipid oxidation products in atherosclerosis. Circ. Res., 2012, 111(6), 778-799.
82. Bochkov, V.N.; Oskolkova, O.V.; Birukov, K.G.; Levonen, A.L.; Binder, C.J.; Stockl, J. Generation and biological activities of oxidized phospholipids. Antioxid. Redox Signal, 2010, 12(8), 1009-1059.
83. Berliner, J.A.; Leitinger, N.; Tsimikas, S. The role of oxidized phospholipids in atherosclerosis. J. Lipid Res., 2009, 50 Suppl S207-212.
84. Trombetta, D.; Cimino, F.; Cristani, M.; Mandalari, G.; Saija, A.; Ginestra, G.; Speciale, A.; Chirafisi, J.; Bisignano, G.; Waldron, K.; Narbad, A. Faulds, C.B. In vitro protective effects of two extracts from bergamot peels on human endothelial cells exposed to tumor necrosis factor-alpha (TNF-alpha). J. Agric. Food Chem., 2010, 58(14), 8430-8436.
85. Kim, Y.S.; Ahn, Y.; Hong, M.H.; Joo, S.Y.; Kim, K.H.; Sohn, I.S.; Park, H.W.; Hong, Y.J.; Kim, J.H.; Kim, W.; Jeong, M.H.; Cho, J.G.; Park, J.C. Kang, J.C. Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells. J. Cardiovasc. Pharmacol., 2007, 50(1), 41-49.
86. Scheuer, H.; Gwinner, W.; Hohbach, J.; Grone, E.F.; Brandes, R.P.; Malle, E.; Olbricht, C.J.; Walli, A.K. Grone, H.J. Oxidant stress in hyperlipidemia-induced renal damage. Am. J. Physiol. Renal Physiol., 2000, 278(1), F63-74.
87. Chade, A.R.; Rodriguez-Porcel, M.; Grande, J.P.; Krier, J.D.; Lerman, A.; Romero, J.C.; Napoli, C. Lerman, L.O. Distinct renal injury in early atherosclerosis and renovascular disease. Circulation, 2002, 106(9), 1165-1171.
88. Stulak, J.M.; Lerman, A.; Porcel, M.R.; Caccitolo, J.A.; Romero, J.C.; Schaff, H.V.; Napoli, C. Lerman, L.O. Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation. J. Am. Soc. Nephrol., 2001, 12(9), 1882-1891.
89. Trovato, A.; Taviano, M.F.; Pergolizzi, S.; Campolo, L.; De Pasquale, R. Miceli, N. Citrus bergamia Risso & Poiteau juice protects against renal injury of diet-induced hypercholesterolemia in rats. Phytother. Res., 2010, 24(4), 514-519.
90. Jones, P.H. Expert perspective: reducing cardiovascular risk in metabolic syndrome and type 2 diabetes mellitus beyond lowdensity lipoprotein cholesterol lowering. Am. J. Cardiol., 2008, 102(12A), 41L-47L.
91. Joy, T.R. Hegele, R.A. Narrative review: statin-related myopathy. Ann. Intern. Med., 2009, 150(12), 858-868.