Oxidative stress: New insights on the association of nonalcoholic fatty liver disease and atherosclerosis

World Journal of Hepatology

Volumn 7, Issue 10, 2015, Pages 1325-1336

  Polimeni, Licia ^a   del Ben, Maria ^b   Baratta, Francesco ^b   Perri, Ludovica ^b   Albanese, Fabiana ^b   Pastori, Daniele ^b   Violi, Francesco ^b   Angelico, Francesco ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

Atherosclerosis; Cardiovascular disease; Non alcoholic fatty liver disease; Nonalcoholic steatohepatitis; Oxidative stress

Indexed keywords

EID: 84930398528     PISSN: None     EISSN: 19485182     Source Type: Journal    
DOI: 10.4254/wjh.v7.i10.1325     Document Type: Review

References (134)

1. Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34: 274-285 [PMID: 21623852 DOI: 10.1111/j.1365-2036.2011.04724.x].
2. Kemmer N, Neff GW, Franco E, Osman-Mohammed H, Leone J, Parkinson E, Cece E, Alsina A. Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation. Transplantation 2013; 96: 860-862 [PMID: 24247899 DOI: 10.1097/01.TP.0000436723.59879.01].
3. Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol 2013; 48: 434-441 [PMID: 23397118 DOI: 10.1007/s00535-013-0 758-5].
4. Del Ben M, Baratta F, Polimeni L, Angelico F. Non-alcoholic fatty liver disease and cardiovascular disease: epidemiological, clinical and pathophysiological evidences. Intern Emerg Med 2012; 7 Suppl 3: S291-S296 [PMID: 23073870 DOI: 10.1007/s11739-012-0819-4].
5. Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Fiorello S, Cavallo MG, Zalunardo B, Lirussi F, Alessandri C, Violi F. Insulin resistance, the metabolic syndrome, and nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2005; 90: 1578-1582 [PMID: 15598693 DOI: 10.1210/jc.2004-1024].
6. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Spertus JA, Costa F. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005; 112: 2735-2752 [PMID: 16157765 DOI: 10.1161/CIRCULATIONAHA. 105.169404].
7. Angelico F, Del Ben M, Conti R, Francioso S, Feole K, Maccioni D, Antonini TM, Alessandri C. Non-alcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases. J Gastroenterol Hepatol 2003; 18: 588-594 [PMID: 12702052 DOI: 10.1046/j.1440-1746.2003.02958.x].
8. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231 [PMID: 11961152 DOI: 10.1056/NEJMra011775].
9. Del Ben M, Polimeni L, Brancorsini M, Di Costanzo A, D'Erasmo L, Baratta F, Loffredo L, Pastori D, Pignatelli P, Violi F, Arca M, Angelico F. Non-alcoholic fatty liver disease, metabolic syndrome and patatin-like phospholipase domain-containing protein3 gene variants. Eur J Intern Med 2014; 25: 566-570 [PMID: 24947770 DOI: 10.1016/j.ejim.2014.05.012].
10. Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16: 663-678 [PMID: 12406438 DOI: 10.1053/bega.2002.0333].
11. Gambino R, Musso G, Cassader M. Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities. Antioxid Redox Signal 2011; 15: 1325-1365 [PMID: 20969475 DOI: 10.1089/ars.2009.3058].
12. Söderberg C, Stål P, Askling J, Glaumann H, Lindberg G, Marmur J, Hultcrantz R. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51: 595-602 [PMID: 20014114 DOI: 10.1002/hep.23314].
13. Ballestri S, Lonardo A, Bonapace S, Byrne CD, Loria P, Targher G. Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J Gastroenterol 2014; 20: 1724-1745 [PMID: 24587651 DOI: 10.3748/wjg.v20.i7.1724].
14. Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 2012; 10: 646-650 [PMID: 22245962 DOI: 10.1016/j.cgh.2011.12.039].
15. Hamaguchi M, Kojima T, Takeda N, Nagata C, Takeda J, Sarui H, Kawahito Y, Yoshida N, Suetsugu A, Kato T, Okuda J, Ida K, Yoshikawa T. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13: 1579-1584 [PMID: 17461452 DOI: 10.3748/wjg.v13.i10.1579].
16. Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. Hepatology 2010; 52: 1156-1161 [PMID: 20658466 DOI: 10.1002/hep.23789].
17. Bieghs V, Rensen PC, Hofker MH, Shiri-Sverdlov R. NASH and atherosclerosis are two aspects of a shared disease: central role for macrophages. Atherosclerosis 2012; 220: 287-293 [PMID: 21930273 DOI: 10.1016/j.atherosclerosis.2011.08.041].
18. Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, Kechagias S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-873 [PMID: 17006923 DOI: 10.1002/hep.21327].
19. Wong VW, Wong GL, Yip GW, Lo AO, Limquiaco J, Chu WC, Chim AM, Yu CM, Yu J, Chan FK, Sung JJ, Chan HL. Coronary artery disease and cardiovascular outcomes in patients with nonalcoholic fatty liver disease. Gut 2011; 60: 1721-1727 [PMID: 21602530 DOI: 10.1136/gut.2011.242016].
20. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008; 49: 600-607 [PMID: 18672311 DOI: 10.1016/j.jhep.2008.06.012].
21. Pacifico L, Cantisani V, Ricci P, Osborn JF, Schiavo E, Anania C, Ferrara E, Dvisic G, Chiesa C. Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Pediatr Res 2008; 63: 423-427 [PMID: 18356751 DOI: 10.1203/PDR.0b013e318165b8e7].
22. Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. Hyperuricaemia and non-alcoholic fatty liver disease (NAFLD): a relationship with implications for vascular risk?. Curr Vasc Pharmacol 2011; 9: 698-705 [PMID: 21388346 DOI: 10.2174/157 016111797484152].
23. Mohammadi A, Sedani HH, Ghasemi-Rad M. Evaluation of carotid intima-media thickness and flow-mediated dilatation in middle-aged patients with nonalcoholic fatty liver disease. Vasc Health Risk Manag 2011; 7: 661-665 [PMID: 22140316 DOI: 10.2147/VHRM.S26011].
24. Volzke H, Robinson DM, Kleine V, Deutscher R, Hoffmann W, Ludemann J, Schminke U, Kessler C, John U. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol 2005; 11: 1848-1853 [PMID: 15793879 DOI: 10.3748/wjg.v11.i12.1848].
25. Kim HC, Kim DJ, Huh KB. Association between nonalcoholic fatty liver disease and carotid intima-media thickness according to the presence of metabolic syndrome. Atherosclerosis 2009; 204: 521-525 [PMID: 18947828 DOI: 10.1016/j.atherosclerosis.2008.0 9.012].
26. Vlachopoulos C, Manesis E, Baou K, Papatheodoridis G, Koskinas J, Tiniakos D, Aznaouridis K, Archimandritis A, Stefanadis C. Increased arterial stiffness and impaired endothelial function in nonalcoholic Fatty liver disease: a pilot study. Am J Hypertens 2010; 23: 1183-1189 [PMID: 20634799 DOI: 10.1038/ajh.2010.144].
27. Brea A, Mosquera D, Martín E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol 2005; 25: 1045-1050 [PMID: 15731489 DOI: 10.1161/01. ATV.0000160613.57985.18].
28. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, Cigolini M, Falezza G, Arcaro G. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006; 29: 1325-1330 [PMID: 16732016 DOI: 10.2337/dc06-0135].
29. Al-Qaisi M, Kharbanda RK, Mittal TK, Donald AE. Measurement of endothelial function and its clinical utility for cardiovascular risk. Vasc Health Risk Manag 2008; 4: 647-652 [PMID: 18827914].
30. Thakur ML, Sharma S, Kumar A, Bhatt SP, Luthra K, Guleria R, Pandey RM, Vikram NK. Nonalcoholic fatty liver disease is associated with subclinical atherosclerosis independent of obesity and metabolic syndrome in Asian Indians. Atherosclerosis 2012; 223: 507-511 [PMID: 22748277 DOI: 10.1016/j.atherosclerosis.20 12.06.005].
31. Villanova N, Moscatiello S, Ramilli S, Bugianesi E, Magalotti D, Vanni E, Zoli M, Marchesini G. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005; 42: 473-480 [PMID: 15981216 DOI: 10.1002/hep.20781].
32. Pacifico L, Anania C, Martino F, Cantisani V, Pascone R, Marcantonio A, Chiesa C. Functional and morphological vascular changes in pediatric nonalcoholic fatty liver disease. Hepatology 2010; 52: 1643-1651 [PMID: 20890890 DOI: 10.1002/hep.23890].
33. Perri L, Pastori D, Pignatelli P, Violi F, Loffredo L. Flow-mediated dilation is associated with cardiovascular events in non-valvular atrial fibrillation patients. Int J Cardiol 2015; 179: 139-143 [PMID: 25464433 DOI: 10.1016/j.ijcard.2014.10.039].
34. Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?. Eur Heart J 2012; 33: 1190-1200 [PMID: 22408036 DOI: 10.1093/eurheartj/ehr453].
35. Targher G. Non-alcoholic fatty liver disease, the metabolic syndrome and the risk of cardiovascular disease: the plot thickens. Diabet Med 2007; 24: 1-6 [PMID: 17227317 DOI: 10.1111/j. 1464-5491.2007.02025.x].
36. Sookoian S, Castaño GO, Burgueño AL, Rosselli MS, Gianotti TF, Mallardi P, Martino JS, Pirola CJ. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 2010; 209: 585-591 [PMID: 19896127 DOI: 10.1016/j.atherosclerosis.2009.1 0.011].
37. Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?. Diabetologia 2008; 51: 1947-1953 [PMID: 18762907 DOI: 10.1007/s00125-008-1135-4].
38. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37: 917-923 [PMID: 12668987 DOI: 10.1053/jhep.2003.50161].
39. Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middleaged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140: 124-131 [PMID: 20858492 DOI: 10.1053/j.gastro.2010.09.038].
40. Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, Sasso F, Cristanini G, Tiribelli C. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000; 132: 112-117 [PMID: 10644271 DOI: 10.7326/0003-4819-132-2-200001180-00 004].
41. Pagadala M, Zein CO, McCullough AJ. Predictors of steatohepatitis and advanced fibrosis in non-alcoholic fatty liver disease. Clin Liver Dis 2009; 13: 591-606 [PMID: 19818307 DOI: 10.1016/j.cld.2009.07.011].
42. van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 2008; 48: 449-457 [PMID: 18627003 DOI: 10.1002/hep.22350].
43. Hsiao TJ, Chen JC, Wang JD. Insulin resistance and ferritin as major determinants of nonalcoholic fatty liver disease in apparently healthy obese patients. Int J Obes Relat Metab Disord 2004; 28: 167-172 [PMID: 14610526 DOI: 10.1038/sj.ijo.0802519].
44. Thamer C, Machann J, Haap M, Stefan N, Heller E, Schnödt B, Stumvoll M, Claussen C, Fritsche A, Schick F, Häring H. Intrahepatic lipids are predicted by visceral adipose tissue mass in healthy subjects. Diabetes Care 2004; 27: 2726-2729 [PMID: 15505012 DOI: 10.2337/diacare.27.11.2726].
45. Mårin P, Andersson B, Ottosson M, Olbe L, Chowdhury B, Kvist H, Holm G, Sjöström L, Björntorp P. The morphology and metabolism of intraabdominal adipose tissue in men. Metabolism 1992; 41: 1242-1248 [PMID: 1435298].
46. Kabir M, Catalano KJ, Ananthnarayan S, Kim SP, Van Citters GW, Dea MK, Bergman RN. Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance. Am J Physiol Endocrinol Metab 2005; 288: E454-E461 [PMID: 15522994 DOI: 10.1152/ajpendo.00203.2004].
47. Wajchenberg BL, Giannella-Neto D, da Silva ME, Santos RF. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Horm Metab Res 2002; 34: 616-621 [PMID: 12660870 DOI: 10.1055/s-2002-38256].
48. Rankinen T, Kim SY, Pérusse L, Després JP, Bouchard C. The prediction of abdominal visceral fat level from body composition and anthropometry: ROC analysis. Int J Obes Relat Metab Disord 1999; 23: 801-809 [PMID: 10490780].
49. Kral JG, Schaffner F, Pierson RN, Wang J. Body fat topography as an independent predictor of fatty liver. Metabolism 1993; 42: 548-551 [PMID: 8492707].
50. Stranges S, Dorn JM, Muti P, Freudenheim JL, Farinaro E, Russell M, Nochajski TH, Trevisan M. Body fat distribution, relative weight, and liver enzyme levels: a population-based study. Hepatology 2004; 39: 754-763 [PMID: 14999694 DOI: 10.1002/hep.20149].
51. Nseir W, Shalata A, Marmor A, Assy N. Mechanisms linking nonalcoholic fatty liver disease with coronary artery disease. Dig Dis Sci 2011; 56: 3439-3449 [PMID: 21655948 DOI: 10.1007/s10620-011-1767-y].
52. Mangge H, Becker K, Fuchs D, Gostner JM. Antioxidants, inflammation and cardiovascular disease. World J Cardiol 2014; 6: 462-477 [PMID: 24976919 DOI: 10.4330/wjc.v6.i6.462].
53. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 1497-1502 [PMID: 15307867 DOI: 10.1111/j. 1572-0241.2004.301 59.x].
54. Yesilova Z, Yaman H, Oktenli C, Ozcan A, Uygun A, Cakir E, Sanisoglu SY, Erdil A, Ates Y, Aslan M, Musabak U, Erbil MK, Karaeren N, Dagalp K. Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol 2005; 100: 850-855 [PMID: 15784031 DOI: 10.1111/j.1572-0241.2005.41500.x].
55. Narasimhan S, Gokulakrishnan K, Sampathkumar R, Farooq S, Ravikumar R, Mohan V, Balasubramanyam M. Oxidative stress is independently associated with non-alcoholic fatty liver disease (NAFLD) in subjects with and without type 2 diabetes. Clin Biochem 2010; 43: 815-821 [PMID: 20398645 DOI: 10.1016/j.clin biochem.2010.04.003].
56. Nobili V, Parola M, Alisi A, Marra F, Piemonte F, Mombello C, Sutti S, Povero D, Maina V, Novo E, Albano E. Oxidative stress parameters in paediatric non-alcoholic fatty liver disease. Int J Mol Med 2010; 26: 471-476 [PMID: 20818484 DOI: 10.3892/ijmm_00000487].
57. Irie M, Sohda T, Iwata K, Kunimoto H, Fukunaga A, Kuno S, Yotsumoto K, Sakurai K, Iwashita H, Hirano G, Ueda SI, Yokoyama K, Morihara D, Nishizawa S, Anan A, Takeyama Y, Sakamoto M, Shakado S, Sakisaka S. Levels of the oxidative stress marker γ-glutamyltranspeptidase at different stages of nonalcoholic fatty liver disease. J Int Med Res 2012; 40: 924-933 [PMID: 22906265].
58. Pirgon Ö, Bilgin H, Çekmez F, Kurku H, Dündar BN. Association between insulin resistance and oxidative stress parameters in obese adolescents with non-alcoholic fatty liver disease. J Clin Res Pediatr Endocrinol 2013; 5: 33-39 [PMID: 23367495 DOI: 10.4274/Jcrpe.825].
59. Gaens KH, Niessen PM, Rensen SS, Buurman WA, Greve JW, Driessen A, Wolfs MG, Hofker MH, Bloemen JG, Dejong CH, Stehouwer CD, Schalkwijk CG. Endogenous formation of Ne-(carboxymethyl)lysine is increased in fatty livers and induces inflammatory markers in an in vitro model of hepatic steatosis. J Hepatol 2012; 56: 647-655 [PMID: 21907687 DOI: 10.1016/j.jhep.2011.07.028].
60. Del Ben M, Polimeni L, Baratta F, Bartimoccia S, Carnevale R, Loffredo L, Pignatelli P, Violi F, Angelico F. Serum Cytokeratin-18 Is Associated with NOX2-Generated Oxidative Stress in Patients with Nonalcoholic Fatty Liver. Int J Hepatol 2014; 2014: 784985 [PMID: 24678423 DOI: 10.1155/2014/784985].
61. Del Ben M, Polimeni L, Carnevale R, Bartimoccia S, Nocella C, Baratta F, Loffredo L, Pignatelli P, Violi F, Angelico F. NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2014; 14: 81 [PMID: 24758604 DOI: 10.1186/1471-230X-14-81].
62. Fam SS, Morrow JD. The isoprostanes: unique products of arachidonic acid oxidation-a review. Curr Med Chem 2003; 10: 1723-1740 [PMID: 12871112].
63. Violi F, Pignatelli P, Pignata C, Plebani A, Rossi P, Sanguigni V, Carnevale R, Soresina A, Finocchi A, Cirillo E, Catasca E, Angelico F, Loffredo L. Reduced atherosclerotic burden in subjects with genetically determined low oxidative stress. Arterioscler Thromb Vasc Biol 2013; 33: 406-412 [PMID: 23288160 DOI: 10.1161/ATVBAHA.112.300438].
64. Basili S, Raparelli V, Napoleone L, Del Ben M, Merli M, Riggio O, Nocella C, Carnevale R, Pignatelli P, Violi F. Polyunsaturated fatty acids balance affects platelet NOX2 activity in patients with liver cirrhosis. Dig Liver Dis 2014; 46: 632-638 [PMID: 24703705 DOI: 10.1016/j.dld.2014.02.021].
65. Carnevale R, Iuliano L, Nocella C, Bartimoccia S, Trapè S, Russo R, Gentile MC, Cangemi R, Loffredo L, Pignatelli P, Violi F. Relationship between platelet and urinary 8-Iso-PGF2a levels in subjects with different degrees of NOX2 regulation. J Am Heart Assoc 2013; 2: e000198 [PMID: 23770972 DOI: 10.1161/JAHA.113.000198].
66. Hummel SL, Seymour EM, Brook RD, Kolias TJ, Sheth SS, Rosenblum HR, Wells JM, Weder AB. Low-sodium dietary approaches to stop hypertension diet reduces blood pressure, arterial stiffness, and oxidative stress in hypertensive heart failure with preserved ejection fraction. Hypertension 2012; 60: 1200-1206 [PMID: 23033371 DOI: 10.1161/HYPERTENSIONA HA.112.202705].
67. Loffredo L, Martino F, Carnevale R, Pignatelli P, Catasca E, Perri L, Calabrese CM, Palumbo MM, Baratta F, Del Ben M, Angelico F, Violi F. Obesity and hypercholesterolemia are associated with NOX2 generated oxidative stress and arterial dysfunction. J Pediatr 2012; 161: 1004-1009 [PMID: 22727869 DOI: 10.1016/j.jpeds.2012.05.042].
68. Davì G, Chiarelli F, Santilli F, Pomilio M, Vigneri S, Falco A, Basili S, Ciabattoni G, Patrono C. Enhanced lipid peroxidation and platelet activation in the early phase of type 1 diabetes mellitus: role of interleukin-6 and disease duration. Circulation 2003; 107: 3199-3203 [PMID: 12810609 DOI: 10.1161/01.CIR.0000074205.17807.D0].
69. Angelico F, Loffredo L, Pignatelli P, Augelletti T, Carnevale R, Pacella A, Albanese F, Mancini I, Di Santo S, Del Ben M, Violi F. Weight loss is associated with improved endothelial dysfunction via NOX2-generated oxidative stress down-regulation in patients with the metabolic syndrome. Intern Emerg Med 2012; 7: 219-227 [PMID: 21512794 DOI: 10.1007/s11739-011-0591-x].
70. Loffredo L, Carnevale R, Perri L, Catasca E, Augelletti T, Cangemi R, Albanese F, Piccheri C, Nocella C, Pignatelli P, Violi F. NOX2-mediated arterial dysfunction in smokers: acute effect of dark chocolate. Heart 2011; 97: 1776-1781 [PMID: 21807659 DOI: 10.1136/heartjnl-2011-300304].
71. Pignatelli P, Pastori D, Carnevale R, Farcomeni A, Cangemi R, Nocella C, Bartimoccia S, Vicario T, Saliola M, Lip GY, Violi F. Serum NOX2 and urinary isoprostanes predict vascular events in patients with atrial fibrillation. Thromb Haemost 2015; 113: 617-624 [PMID: 25392853 DOI: 10.1160/TH14-07-0571].
72. Davies SS, Roberts LJ. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med 2011; 50: 559-566 [PMID: 21126576 DOI: 10.1016/j.freeradbiomed.2010.11. 023].
73. Puccetti L, Santilli F, Pasqui AL, Lattanzio S, Liani R, Ciani F, Ferrante E, Ciabattoni G, Scarpini F, Ghezzi A, Auteri A, Davì G. Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia. Atherosclerosis 2011; 214: 122-128 [PMID: 21056418 DOI: 10.1016/j.atherosclerosis.2010.10.006].
74. Del Ben M, Angelico F, Cangemi R, Loffredo L, Carnevale R, Augelletti T, Baratta F, Polimeni L, Pignatelli P, Violi F. Moderate weight loss decreases oxidative stress and increases antioxidant status in patients with metabolic syndrome. ISRN Obes 2012; 2012: 960427 [PMID: 24533215 DOI: 10.5402/2012/960427].
75. Del Ben M, Fabiani M, Loffredo L, Polimeni L, Carnevale R, Baratta F, Brunori M, Albanese F, Augelletti T, Violi F, Angelico F. Oxidative stress mediated arterial dysfunction in patients with obstructive sleep apnoea and the effect of continuous positive airway pressure treatment. BMC Pulm Med 2012; 12: 36 [PMID: 22824065 DOI: 10.1186/1471-2466-12-36].
76. Violi F, Sanguigni V, Carnevale R, Plebani A, Rossi P, Finocchi A, Pignata C, De Mattia D, Martire B, Pietrogrande MC, Martino S, Gambineri E, Soresina AR, Pignatelli P, Martino F, Basili S, Loffredo L. Hereditary deficiency of gp91(phox) is associated with enhanced arterial dilatation: results of a multicenter study. Circulation 2009; 120: 1616-1622 [PMID: 19805647].
77. Violi F, Sanguigni V, Loffredo L, Carnevale R, Buchetti B, Finocchi A, Tesauro M, Rossi P, Pignatelli P. Nox2 is determinant for ischemia-induced oxidative stress and arterial vasodilatation: a pilot study in patients with hereditary Nox2 deficiency. Arterioscler Thromb Vasc Biol 2006; 26: e131-e132 [PMID: 16857955 DOI: 10.1161/01.ATV.0000229710.13054.2d].
78. Hirase T, Node K. Endothelial dysfunction as a cellular mechanism for vascular failure. Am J Physiol Heart Circ Physiol 2012; 302: H499-H505 [PMID: 22081698 DOI: 10.1152/ajpheart. 00325.2011].
79. Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999; 340: 115-126 [PMID: 9887164].
80. Vita JA, Keaney JF. Endothelial function: a barometer for cardiovascular risk?. Circulation 2002; 106: 640-642 [PMID: 12163419].
81. Muiesan ML, Salvetti M, Paini A, Monteduro C, Galbassini G, Poisa P, Porteri E, Agabiti-Rosei C, Paderno V, Belotti E, Rizzoni D, Castellano M, Agabiti-Rosei E. Prognostic role of flowmediated dilatation of the brachial artery in hypertensive patients. J Hypertens 2008; 26: 1612-1618 [PMID: 18622240 DOI: 10.1097/HJH.0b013e328304b083].
82. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to anklebrachial pressure index. Circulation 2003; 108: 2093-2098 [PMID: 14530195 DOI: 10.1161/01.CIR.0000095273.92468.D9].
83. Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, Yasskiy A. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 2005; 111: 310-314 [PMID: 15655134 DOI: 10.1161/01.CIR.0000153349.77489. CF].
84. Gokce N, Keaney JF, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003; 41: 1769-1775 [PMID: 12767663].
85. Colak Y, Senates E, Yesil A, Yilmaz Y, Ozturk O, Doganay L, Coskunpinar E, Kahraman OT, Mesci B, Ulasoglu C, Tuncer I. Assessment of endothelial function in patients with nonalcoholic fatty liver disease. Endocrine 2013; 43: 100-107 [PMID: 22661277 DOI: 10.1007/s12020-012-9712-1].
86. Münzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease?. Eur Heart J 2010; 31: 2741-2748 [PMID: 20974801 DOI: 10.1093/eurheartj/ehq396].
87. Violi F, Pignatelli P. Platelet NOX, a novel target for antithrombotic treatment. Thromb Haemost 2014; 111: 817-823 [PMID: 24402688 DOI: 10.1160/TH13-10-0818].
88. Lirussi F, Azzalini L, Orando S, Orlando R, Angelico F. Antioxidant supplements for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev 2007; (1): CD004996 [PMID: 17253535 DOI: 10.1002/14651858.CD004996.pub3].
89. Erhardt A, Stahl W, Sies H, Lirussi F, Donner A, Häussinger D. Plasma levels of vitamin E and carotenoids are decreased in patients with Nonalcoholic Steatohepatitis (NASH). Eur J Med Res 2011; 16: 76-78 [PMID: 21463986].
90. Nan YM, Wu WJ, Fu N, Liang BL, Wang RQ, Li LX, Zhao SX, Zhao JM, Yu J. Antioxidants vitamin E and 1-aminobenzotriazole prevent experimental non-alcoholic steatohepatitis in mice. Scand J Gastroenterol 2009; 44: 1121-1131 [PMID: 19606393 DOI: 10.1080/00365520903114912].
91. Phung N, Pera N, Farrell G, Leclercq I, Hou JY, George J. Prooxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis. Int J Mol Med 2009; 24: 171-180 [PMID: 19578790].
92. Pacana T, Sanyal AJ. Vitamin E and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 2012; 15: 641-648 [PMID: 23075940 DOI: 10.1097/MCO.0b013e328357f747].
93. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675-1685 [PMID: 20427778 DOI: 10.1056/NEJMoa0907929].
94. Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2003; 98: 2485-2490 [PMID: 14638353 DOI: 10.1111/j. 1572-0241.2003.086 99.x].
95. Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2006; 4: 1537-1543 [PMID: 17162245 DOI: 10.1016/j.cgh.2006.09.025].
96. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Ünalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011; 305: 1659-1668 [PMID: 21521847 DOI: 10.1001/jama.2011.520].
97. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55: 2005-2023 [PMID: 22488764 DOI: 10.1002/hep.25762].
98. Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ 2010; 341: c5702 [PMID: 21051774 DOI: 10.1136/bmj.c5702].
99. Klein EA, Thompson IM, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE, Meyskens FL, Baker LH. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011; 306: 1549-1556 [PMID: 21990298 DOI: 10.1001/jama.2011.1437].
100. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and metaanalysis. JAMA 2007; 297: 842-857 [PMID: 17327526 DOI: 10.1001/jama.297.8.842].
101. Berry D, Wathen JK, Newell M. Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality. Clin Trials 2009; 6: 28-41 [PMID: 19254931 DOI: 10.1177/174077450 8101279].
102. Gerss J, Köpcke W. The questionable association of vitamin E supplementation and mortality-inconsistent results of different meta-analytic approaches. Cell Mol Biol (Noisy-le-grand) 2009; 55 Suppl: OL1111-OL1120 [PMID: 19267994].
103. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006; 5: 493-506 [PMID: 16732220 DOI: 10.1038/nrd2060].
104. Frémont L. Biological effects of resveratrol. Life Sci 2000; 66: 663-673 [PMID: 10680575].
105. Gnoni GV, Paglialonga G. Resveratrol inhibits fatty acid and triacylglycerol synthesis in rat hepatocytes. Eur J Clin Invest 2009; 39: 211-218 [PMID: 19260951 DOI: 10.1111/j. 1365-2362.2008.02 077.x].
106. Wang GL, Fu YC, Xu WC, Feng YQ, Fang SR, Zhou XH. Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem Biophys Res Commun 2009; 380: 644-649 [PMID: 19285015 DOI: 10.1016/j.bbrc.2009.01.163].
107. Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 2006; 55: 2180-2191 [PMID: 16873680 DOI: 10.2337/db05-1188].
108. Shang J, Chen LL, Xiao FX, Sun H, Ding HC, Xiao H. Resveratrol improves non-alcoholic fatty liver disease by activating AMPactivated protein kinase. Acta Pharmacol Sin 2008; 29: 698-706 [PMID: 18501116 DOI: 10.1111/j.1745-7254.2008.00807.x].
109. Bujanda L, Hijona E, Larzabal M, Beraza M, Aldazabal P, García-Urkia N, Sarasqueta C, Cosme A, Irastorza B, González A, Arenas JI. Resveratrol inhibits nonalcoholic fatty liver disease in rats. BMC Gastroenterol 2008; 8: 40 [PMID: 18782455 DOI: 10.1186/1471-230X-8-40].
110. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14: 612-622 [PMID: 22055504 DOI: 10.1016/j.cmet.2011.10.002].
111. Tomé-Carneiro J, Gonzálvez M, Larrosa M, Yáñez-Gascón MJ, García-Almagro FJ, Ruiz-Ros JA, Tomás-Barberán FA, García-Conesa MT, Espín JC. Resveratrol in primary and secondary prevention of cardiovascular disease: a dietary and clinical perspective. Ann N Y Acad Sci 2013; 1290: 37-51 [PMID: 23855464 DOI: 10.1111/nyas.12150].
112. Pietrangelo A, Borella F, Casalgrandi G, Montosi G, Ceccarelli D, Gallesi D, Giovannini F, Gasparetto A, Masini A. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroenterology 1995; 109: 1941-1949 [PMID: 7498660].
113. Crocenzi FA, Sánchez Pozzi EJ, Pellegrino JM, Favre CO, Rodríguez Garay EA, Mottino AD, Coleman R, Roma MG. Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: a study in vivo and in isolated hepatocyte couplets. Hepatology 2001; 34: 329-339 [PMID: 11481618 DOI: 10.1053/jhep. 2001.26520].
114. Schümann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G. Silibinin protects mice from T cell-dependent liver injury. J Hepatol 2003; 39: 333-340 [PMID: 12927918].
115. Salamone F, Galvano F, Marino Gammazza A, Paternostro C, Tibullo D, Bucchieri F, Mangiameli A, Parola M, Bugianesi E, Li Volti G. Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis. Dig Liver Dis 2012; 44: 334-342 [PMID: 22197629 DOI: 10.1016/j.dld.2011.11.010].
116. Cacciapuoti F, Scognamiglio A, Palumbo R, Forte R, Cacciapuoti F. Silymarin in non alcoholic fatty liver disease. World J Hepatol 2013; 5: 109-113 [PMID: 23556042 DOI: 10.4254/wjh.v5.i3.109].
117. Loguercio C, Festi D. Silybin and the liver: from basic research to clinical practice. World J Gastroenterol 2011; 17: 2288-2301 [PMID: 21633595 DOI: 10.3748/wjg.v17.i18.2288].
118. Loguercio C, Andreone P, Brisc C, Brisc MC, Bugianesi E, Chiaramonte M, Cursaro C, Danila M, de Sio I, Floreani A, Freni MA, Grieco A, Groppo M, Lazzari R, Lobello S, Lorefice E, Margotti M, Miele L, Milani S, Okolicsanyi L, Palasciano G, Portincasa P, Saltarelli P, Smedile A, Somalvico F, Spadaro A, Sporea I, Sorrentino P, Vecchione R, Tuccillo C, Del Vecchio Blanco C, Federico A. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med 2012; 52: 1658-1665 [PMID: 22343419 DOI: 10.1016/j.freeradbiomed.2012. 02.008].
119. Gülçin I. Antioxidant and antiradical activities of L-carnitine. Life Sci 2006; 78: 803-811 [PMID: 16253281 DOI: 10.1016/j.lfs.2005.05.103].
120. Cuturic M, Abramson RK, Moran RR, Hardin JW, Frank EM, Sellers AA. Serum carnitine levels and levocarnitine supplementation in institutionalized Huntington's disease patients. Neurol Sci 2013; 34: 93-98 [PMID: 22294053 DOI: 10.1007/s10072-012-0952-x].
121. Malaguarnera M, Gargante MP, Russo C, Antic T, Vacante M, Malaguarnera M, Avitabile T, Li Volti G, Galvano F. L-carnitine supplementation to diet: a new tool in treatment of nonalcoholic steatohepatitis-a randomized and controlled clinical trial. Am J Gastroenterol 2010; 105: 1338-1345 [PMID: 20068559 DOI: 10.1038/ajg.2009.719].
122. Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherardi G, Orisio S, Remuzzi G. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension 2009; 54: 567-574 [PMID: 19620516 DOI: 10.1161/HYPERTENSIONAHA. 109.132522].
123. Capaldo B, Napoli R, Di Bonito P, Albano G, Saccà L. Carnitine improves peripheral glucose disposal in non-insulin-dependent diabetic patients. Diabetes Res Clin Pract 1991; 14: 191-195 [PMID: 1778112].
124. Malaguarnera M, Vacante M, Motta M, Malaguarnera M, Li Volti G, Galvano F. Effect of L-carnitine on the size of low-density lipoprotein particles in type 2 diabetes mellitus patients treated with simvastatin. Metabolism 2009; 58: 1618-1623 [PMID: 19604523 DOI: 10.1016/j.metabol.2009.05.014].
125. Johri AM, Heyland DK, Hétu MF, Crawford B, Spence JD. Carnitine therapy for the treatment of metabolic syndrome and cardiovascular disease: evidence and controversies. Nutr Metab Cardiovasc Dis 2014; 24: 808-814 [PMID: 24837277 DOI: 10.1016/j.numecd.2014.03.007].
126. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013; 19: 576-585 [PMID: 23563705 DOI: 10.1038/nm.3145].
127. Takaki A, Kawai D, Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH). Int J Mol Sci 2013; 14: 20704-20728 [PMID: 24132155 DOI: 10.3390/ijms141020704].
128. Sliwa K, Woodiwiss A, Kone VN, Candy G, Badenhorst D, Norton G, Zambakides C, Peters F, Essop R. Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study. Circulation 2004; 109: 750-755 [PMID: 14970111 DOI: 10.1161/01.CIR.0000112568.48837.60].
129. Sliwa K, Skudicky D, Candy G, Wisenbaugh T, Sareli P. Randomised investigation of effects of pentoxifylline on left-ventricular performance in idiopathic dilated cardiomyopathy. Lancet 1998; 351: 1091-1093 [PMID: 9660578 DOI: 10.1016/S0140-6736(97)09338-0].
130. Skudicky D, Sliwa K, Bergemann A, Candy G, Sareli P. Reduction in Fas/APO-1 plasma concentrations correlates with improvement in left ventricular function in patients with idiopathic dilated cardiomyopathy treated with pentoxifylline. Heart 2000; 84: 438-439 [PMID: 10995419].
131. Skudicky D, Bergemann A, Sliwa K, Candy G, Sareli P. Beneficial effects of pentoxifylline in patients with idiopathic dilated cardiomyopathy treated with angiotensin-converting enzyme inhibitors and carvedilol: results of a randomized study. Circulation 2001; 103: 1083-1088 [PMID: 11222470].
132. Zein CO, Lopez R, Fu X, Kirwan JP, Yerian LM, McCullough AJ, Hazen SL, Feldstein AE. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism. Hepatology 2012; 56: 1291-1299 [PMID: 22505276 DOI: 10.1002/hep.25778].
133. Zein CO, Yerian LM, Gogate P, Lopez R, Kirwan JP, Feldstein AE, McCullough AJ. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011; 54: 1610-1619 [PMID: 21748765 DOI: 10.1002/hep.24544].
134. Schindhelm RK, Dekker JM, Nijpels G, Bouter LM, Stehouwer CD, Heine RJ, Diamant M. Alanine aminotransferase predicts coronary heart disease events: a 10-year follow-up of the Hoorn Study. Atherosclerosis 2007; 191: 391-396 [PMID: 16682043 DOI: 10.1016/j.atherosclerosis.2006.04.006].