Abstract
Introduction: Diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) have become some of the most urgent and prevalent health problems in recent decades, side by side with the growing obesity crisis. The close relationship between T2DM and CVD has become clear: endothelial dysfunction caused by oxidative stress and inflammation resulting from hyperglycaemia are the key factors in the development of vascular complications of T2DM, leading to CVD. Coenzyme Q10 (CoQ10) is a great candidate for the treatment of these diseases, acting precisely at the intersection between T2DM and CVD that is oxidative stress, due to its strong antioxidant activity and fundamental physiological role in mitochondrial bioenergetics. CoQ10 is a biologically active liposoluble compound comprising a quinone group and a side chain of 10 isoprenoid units, which is synthesized endogenously in the body from tyrosine and mevalonic acid. The main biochemical action of CoQ10 is as a cofactor in the electron transport chain that synthesizes adenosine triphosphate (ATP). As most cellular functions depend on an adequate supply of ATP, CoQ10 is essential for the health of virtually all human tissues and organs. CoQ10 supplementation has been used as an intensifier of mitochondrial function and an antioxidant with the aim of palliating or reducing oxidative damage that can worsen the physiological outcome of a wide range of diseases including T2DM and CVDs.
Conclusion: Although there is not enough evidence to conclude it is effective for different therapeutic indications, CoQ10 supplementation is probably safe and well-tolerated, with few drug interactions and minor side effects. Many valuable advances have been made in the use of CoQ10 in clinical practice for patients with T2DM and a high risk of CVD. However, further research is needed to assess the real safety and benefit to indicate CoQ10 supplementation in patients with T2DM.
Keywords: Cardiovascular, diabetes, ubiquinol, ubiquinone, CoQ10, oxidative stress.
[1]
Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: Results from Q-SYMBIO: A randomized double-blind trial. JACC Heart Fail 2014; 2(6): 641-9.
[http://dx.doi.org/10.1016/j.jchf.2014.06.008] [PMID: 25282031]
[http://dx.doi.org/10.1016/j.jchf.2014.06.008] [PMID: 25282031]
[2]
Mortensen AL, Rosenfeldt F, Filipiak KJ. Effect of coenzyme Q10 in Europeans with chronic heart failure: A sub-group analysis of the Q-SYMBIO randomized double-blind trial. Cardiol J 2019; 26(2): 147-56.
[http://dx.doi.org/10.5603/CJ.a2019.0022] [PMID: 30835327]
[http://dx.doi.org/10.5603/CJ.a2019.0022] [PMID: 30835327]
[3]
Zhao Q, Kebbati AH, Zhang Y, Tang Y, Okello E, Huang C. Effect of coenzyme Q10 on the incidence of atrial fibrillation in patients with heart failure. J Investig Med 2015; 63(5): 735-9.
[http://dx.doi.org/10.1097/JIM.0000000000000202] [PMID: 25919281]
[http://dx.doi.org/10.1097/JIM.0000000000000202] [PMID: 25919281]
[4]
Chew GT, Watts GF. Coenzyme Q10 and diabetic endotheliopathy: Oxidative stress and the ‘recoupling hypothesis’. QJM 2004; 97(8): 537-48.
[http://dx.doi.org/10.1093/qjmed/hch089] [PMID: 15256611]
[http://dx.doi.org/10.1093/qjmed/hch089] [PMID: 15256611]
[5]
Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: A report from the American Heart Association. Circulation 2018; 137(12): e67-e492.
[http://dx.doi.org/10.1161/CIR.0000000000000558] [PMID: 29386200]
[http://dx.doi.org/10.1161/CIR.0000000000000558] [PMID: 29386200]
[6]
Festenstein GN, Heaton FW, Lowe JS, Morton RA. A constituent of the unsaponifiable portion of animal tissue lipids (lambda max. 272 m mu). Biochem J 1955; 59(4): 558-66.
[http://dx.doi.org/10.1042/bj0590558] [PMID: 14363147]
[http://dx.doi.org/10.1042/bj0590558] [PMID: 14363147]
[7]
Crane FL, Hatefi Y, Lester RL, Widmer C. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 1957; 25(1): 220-1.
[http://dx.doi.org/10.1016/0006-3002(57)90457-2]
[http://dx.doi.org/10.1016/0006-3002(57)90457-2]
[8]
Saini R. Coenzyme Q10: The essential nutrient. J Pharm Bioallied Sci 2011; 3(3): 466-7.
[http://dx.doi.org/10.4103/0975-7406.84471] [PMID: 21966175]
[http://dx.doi.org/10.4103/0975-7406.84471] [PMID: 21966175]
[9]
Zhang Y, Aberg F, Appelkvist EL, Dallner G, Ernster L. Uptake of dietary coenzyme Q supplement is limited in rats. J Nutr 1995; 125(3): 446-53.
[http://dx.doi.org/10.1093/jn/125.3.446] [PMID: 7876919]
[http://dx.doi.org/10.1093/jn/125.3.446] [PMID: 7876919]
[10]
Bentinger M, Brismar K, Dallner G. The antioxidant role of coenzyme Q. Mitochondrion 2007; 7: S41-50.
[http://dx.doi.org/10.1016/j.mito.2007.02.006]
[http://dx.doi.org/10.1016/j.mito.2007.02.006]
[11]
Gutierrez-Mariscal FM, Arenas-de Larriva AP, Limia-Perez L, Romero-Cabrera JL, Yubero-Serrano EM, López-Miranda J. Coenzyme Q10 supplementation for the reduction of oxidative stress: Clinical implications in the treatment of chronic diseases. Int J Mol Sci 2020; 21(21): 7870.
[http://dx.doi.org/10.3390/ijms21217870] [PMID: 33114148]
[http://dx.doi.org/10.3390/ijms21217870] [PMID: 33114148]
[12]
Gutierrez-Mariscal FM, Yubero-Serrano EM, Villalba JM, Lopez-Miranda J. Coenzyme Q10: From bench to clinic in aging diseases, a translational review. Crit Rev Food Sci Nutr 2019; 59(14): 2240-57.
[http://dx.doi.org/10.1080/10408398.2018.1442316] [PMID: 29451807]
[http://dx.doi.org/10.1080/10408398.2018.1442316] [PMID: 29451807]
[13]
Martelli A, Testai L, Colletti A, Cicero AFG. Coenzyme Q10: Clinical applications in cardiovascular diseases. Antioxidants 2020; 9(4): 341.
[http://dx.doi.org/10.3390/antiox9040341] [PMID: 32331285]
[http://dx.doi.org/10.3390/antiox9040341] [PMID: 32331285]
[14]
Milwidsky A, Maor E, Kivity S, et al. Impaired fasting glucose and left ventricular diastolic dysfunction in middle-age adults: A retrospective cross-sectional analysis of 2971 subjects. Cardiovasc Diabetol 2015; 14(1): 119.
[http://dx.doi.org/10.1186/s12933-015-0282-4] [PMID: 26369690]
[http://dx.doi.org/10.1186/s12933-015-0282-4] [PMID: 26369690]
[15]
Cai L, Wang Y, Zhou G, et al. Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol 2006; 48(8): 1688-97.
[http://dx.doi.org/10.1016/j.jacc.2006.07.022] [PMID: 17045908]
[http://dx.doi.org/10.1016/j.jacc.2006.07.022] [PMID: 17045908]
[16]
Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972; 30(6): 595-602.
[http://dx.doi.org/10.1016/0002-9149(72)90595-4] [PMID: 4263660]
[http://dx.doi.org/10.1016/0002-9149(72)90595-4] [PMID: 4263660]
[17]
Fontes-Carvalho R, Ladeiras-Lopes R, Bettencourt P, Leite-Moreira A, Azevedo A. Diastolic dysfunction in the diabetic continuum: Association with insulin resistance, metabolic syndrome and type 2 diabetes. Cardiovasc Diabetol 2015; 14(1): 4.
[http://dx.doi.org/10.1186/s12933-014-0168-x] [PMID: 25582424]
[http://dx.doi.org/10.1186/s12933-014-0168-x] [PMID: 25582424]
[18]
Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: A two faced disease with restrictive and dilated phenotypes. Eur Heart J 2015; 36: 1718-27.
[http://dx.doi.org/10.1093/eurheartj/ehv134]
[http://dx.doi.org/10.1093/eurheartj/ehv134]
[19]
Lorenzo-Almorós A, Tuñón J, Orejas M, Cortés M, Egido J, Lorenzo Ó. Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol 2017; 16(1): 28.
[http://dx.doi.org/10.1186/s12933-017-0506-x] [PMID: 28231848]
[http://dx.doi.org/10.1186/s12933-017-0506-x] [PMID: 28231848]
[20]
Saraiva JFK, Franco D. Oral GLP-1 analogue: Perspectives and impact on atherosclerosis in type 2 diabetic patients. Cardiovasc Diabetol 2021; 20(1): 235.
[http://dx.doi.org/10.1186/s12933-021-01417-0] [PMID: 34911560]
[http://dx.doi.org/10.1186/s12933-021-01417-0] [PMID: 34911560]
[21]
World Health Organization. Obesity and overweight fact sheet. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight Assessed 8 May 2021.
[22]
Wilson PW, D’Agostino RB, Sullivan L, Parise H, Kannel WB. Overweight and obesity as determinants of cardiovascular risk: The Framingham experience. Arch Intern Med 2002; 162(16): 1867-72.
[http://dx.doi.org/10.1001/archinte.162.16.1867] [PMID: 12196085]
[http://dx.doi.org/10.1001/archinte.162.16.1867] [PMID: 12196085]
[23]
Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006; 17(1): 4-12.
[PMID: 16613757]
[PMID: 16613757]
[24]
Lee SY, Chang HJ, Sung J, et al. The impact of obesity on subclinical coronary atherosclerosis according to the risk of cardiovascular disease. Obesity (Silver Spring) 2014; 22(7): 1762-8.
[http://dx.doi.org/10.1002/oby.20760] [PMID: 24719352]
[http://dx.doi.org/10.1002/oby.20760] [PMID: 24719352]
[25]
Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): An open-label, cluster-randomised trial. Lancet 2018; 391(10120): 541-51.
[http://dx.doi.org/10.1016/S0140-6736(17)33102-1] [PMID: 29221645]
[http://dx.doi.org/10.1016/S0140-6736(17)33102-1] [PMID: 29221645]
[26]
Wing RR, Bolin P, Brancati FL, et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369(2): 145-54.
[http://dx.doi.org/10.1056/NEJMoa1212914] [PMID: 23796131]
[http://dx.doi.org/10.1056/NEJMoa1212914] [PMID: 23796131]
[27]
Gregg EW, Jakicic JM, Blackburn G, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: A post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol 2016; 4(11): 913-21.
[http://dx.doi.org/10.1016/S2213-8587(16)30162-0] [PMID: 27595918]
[http://dx.doi.org/10.1016/S2213-8587(16)30162-0] [PMID: 27595918]
[28]
Ghosh-Swaby OR, Goodman SG, Leiter LA, et al. Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: An updated systematic review and meta-analysis of randomised cardiovascular outcome trials. Lancet Diabetes Endocrinol 2020; 8(5): 418-35.
[http://dx.doi.org/10.1016/S2213-8587(20)30038-3] [PMID: 32333878]
[http://dx.doi.org/10.1016/S2213-8587(20)30038-3] [PMID: 32333878]
[29]
Paglialunga S, Ludzki A, Root-McCaig J, Holloway GP. In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice. Diabetologia 2015; 58(5): 1071-80.
[http://dx.doi.org/10.1007/s00125-015-3531-x] [PMID: 25754553]
[http://dx.doi.org/10.1007/s00125-015-3531-x] [PMID: 25754553]
[30]
Anderson EJ, Lustig ME, Boyle KE, et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 2009; 119(3): 573-81.
[http://dx.doi.org/10.1172/JCI37048] [PMID: 19188683]
[http://dx.doi.org/10.1172/JCI37048] [PMID: 19188683]
[31]
Fazakerley DJ, Chaudhuri R, Yang P, et al. Mitochondrial CoQ deficiency is a common driver of mitochondrial oxidants and insulin resistance. eLife 2018; 7: e32111.
[http://dx.doi.org/10.7554/eLife.32111] [PMID: 29402381]
[http://dx.doi.org/10.7554/eLife.32111] [PMID: 29402381]
[32]
Raygan F, Rezavandi Z, Dadkhah Tehrani S, Farrokhian A, Asemi Z. The effects of coenzyme Q10 administration on glucose homeostasis parameters, lipid profiles, biomarkers of inflammation and oxidative stress in patients with metabolic syndrome. Eur J Nutr 2016; 55(8): 2357-64.
[http://dx.doi.org/10.1007/s00394-015-1042-7] [PMID: 26385228]
[http://dx.doi.org/10.1007/s00394-015-1042-7] [PMID: 26385228]
[33]
Saboori S, Rad EY, Mardani M, Khosroshahi MZ, Nouri Y, Falahi E. Effect of Q10 supplementation on body weight and body mass index: A systematic review and meta-analysis of randomized controlled clinical trials. Diabetes Metab Syndr 2019; 13(2): 1179-85.
[http://dx.doi.org/10.1016/j.dsx.2019.01.047] [PMID: 31336462]
[http://dx.doi.org/10.1016/j.dsx.2019.01.047] [PMID: 31336462]
[34]
Chen K, Chen X, Xue H, et al. Coenzyme Q10 attenuates high-fat diet-induced non-alcoholic fatty liver disease through activation of the AMPK pathway. Food Funct 2019; 10(2): 814-23.
[http://dx.doi.org/10.1039/C8FO01236A] [PMID: 30675881]
[http://dx.doi.org/10.1039/C8FO01236A] [PMID: 30675881]
[35]
Ates O, Bilen H, Keles S, et al. Plasma coenzyme Q10 levels in type 2 diabetic patients with retinopathy. Int J Ophthalmol 2013; 6(5): 675-9.
[http://dx.doi.org/10.3980/j.issn.2222-3959.2013.05.24] [PMID: 24195048]
[http://dx.doi.org/10.3980/j.issn.2222-3959.2013.05.24] [PMID: 24195048]
[36]
El-ghoroury EA, Raslan HM, Badawy EA, et al. Malondialdehyde and coenzyme Q10 in platelets and serum in type 2 diabetes mellitus: Correlation with glycemic control. Blood Coagul Fibrinolysis 2009; 20(4): 248-51.
[http://dx.doi.org/10.1097/MBC.0b013e3283254549] [PMID: 19530339]
[http://dx.doi.org/10.1097/MBC.0b013e3283254549] [PMID: 19530339]
[37]
Yamashita S, Yamamoto Y. Simultaneous detection of ubiquinol and ubiquinone in human plasma as a marker of oxidative stress. Anal Biochem 1997; 250(1): 66-73.
[http://dx.doi.org/10.1006/abio.1997.2187] [PMID: 9234900]
[http://dx.doi.org/10.1006/abio.1997.2187] [PMID: 9234900]
[38]
Hasegawa G, Yamamoto Y, Zhi JG, et al. Daily profile of plasma %CoQ10 level, a biomarker of oxidative stress, in patients with diabetes manifesting postprandial hyperglycaemia. Acta Diabetol 2005; 42(4): 179-81.
[http://dx.doi.org/10.1007/s00592-005-0199-6] [PMID: 16382305]
[http://dx.doi.org/10.1007/s00592-005-0199-6] [PMID: 16382305]
[39]
Huang H, Chi H, Liao D, Zou Y. Effects of coenzyme Q10 on cardiovascular and metabolic biomarkers in overweight and obese patients with type 2 diabetes mellitus: A pooled analysis. Diabetes Metab Syndr Obes 2018; 11: 875-86.
[http://dx.doi.org/10.2147/DMSO.S184301] [PMID: 30568475]
[http://dx.doi.org/10.2147/DMSO.S184301] [PMID: 30568475]
[40]
Folkers K, Vadhanavikit S, Mortensen SA. Biochemical rationale and myocardial tissue data on the effective therapy of cardiomyopathy with coenzyme Q10. Proc Natl Acad Sci USA 1985; 82(3): 901-4.
[http://dx.doi.org/10.1073/pnas.82.3.901] [PMID: 3856239]
[http://dx.doi.org/10.1073/pnas.82.3.901] [PMID: 3856239]
[41]
Judy WV, Stogsdill WW, Folkers K. Myocardial preservation by therapy with coenzyme Q10 during heart surgery. Clin Investig 1993; 71(8) (Suppl.): S155-61.
[http://dx.doi.org/10.1007/BF00226859] [PMID: 8241702]
[http://dx.doi.org/10.1007/BF00226859] [PMID: 8241702]
[42]
Weber C, Bysted A, Hłlmer G. The coenzyme Q10 content of the average Danish diet. Int J Vitam Nutr Res 1997; 67(2): 123-9.
[PMID: 9129255]
[PMID: 9129255]
[43]
Onur S, Niklowitz P, Jacobs G, Lieb W, Menke T, Döring F. Association between serum level of ubiquinol and NT-proBNP, a marker for chronic heart failure, in healthy elderly subjects. Biofactors 2015; 41(1): 35-43.
[http://dx.doi.org/10.1002/biof.1198] [PMID: 25728634]
[http://dx.doi.org/10.1002/biof.1198] [PMID: 25728634]
[44]
Belardinelli R, Muçaj A, Lacalaprice F, et al. Coenzyme Q10 improves contractility of dysfunctional myocardium in chronic heart failure. Biofactors 2005; 25(1-4): 137-45.
[http://dx.doi.org/10.1002/biof.5520250115] [PMID: 16873938]
[http://dx.doi.org/10.1002/biof.5520250115] [PMID: 16873938]
[45]
Munkholm H, Hansen HH, Rasmussen K. Coenzyme Q10 treatment in serious heart failure. Biofactors 1999; 9(2-4): 285-9.
[http://dx.doi.org/10.1002/biof.5520090225] [PMID: 10416042]
[http://dx.doi.org/10.1002/biof.5520090225] [PMID: 10416042]
[46]
Keogh A, Fenton S, Leslie C, et al. Randomised double-blind, placebo-controlled trial of coenzyme Q, therapy in class II and III systolic heart failure. Heart Lung Circ 2003; 12(3): 135-41.
[http://dx.doi.org/10.1046/j.1443-9506.2003.00189.x] [PMID: 18705154]
[http://dx.doi.org/10.1046/j.1443-9506.2003.00189.x] [PMID: 18705154]
[47]
Cirilli I, Damiani E, Dludla PV, et al. Role of coenzyme Q10 in health and disease: An update on the last 10 years (2010-2020). Antioxidants 2021; 10(8): 1325.
[http://dx.doi.org/10.3390/antiox10081325] [PMID: 34439573]
[http://dx.doi.org/10.3390/antiox10081325] [PMID: 34439573]
[48]
Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 2004; 15(8): 1983-92.
[http://dx.doi.org/10.1097/01.ASN.0000132474.50966.DA] [PMID: 15284284]
[http://dx.doi.org/10.1097/01.ASN.0000132474.50966.DA] [PMID: 15284284]
[49]
Dai YL, Luk TH, Yiu KH, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: A randomized controlled trial. Atherosclerosis 2011; 216(2): 395-401.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.02.013] [PMID: 21388622]
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.02.013] [PMID: 21388622]
[50]
Kawashima C, Matsuzawa Y, Konishi M, et al. Ubiquinol improves endothelial function in patients with heart failure with reduced ejection fraction: A single-center, randomized double-blind placebo-controlled crossover pilot study. Am J Cardiovasc Drugs 2020; 20(4): 363-72.
[http://dx.doi.org/10.1007/s40256-019-00384-y] [PMID: 31713723]
[http://dx.doi.org/10.1007/s40256-019-00384-y] [PMID: 31713723]
[51]
Gutierrez-Mariscal FM, de la Cruz-Ares S, Torres-Peña JD, Alcalá-Diaz JF, Yubero-Serrano EM, López-Miranda J. Coenzyme Q10 and cardiovascular diseases. Antioxidants 2021; 10(6): 906.
[http://dx.doi.org/10.3390/antiox10060906] [PMID: 34205085]
[http://dx.doi.org/10.3390/antiox10060906] [PMID: 34205085]
[52]
Bhagavan HN, Chopra RK. Plasma coenzyme Q10 response to oral ingestion of coenzyme Q10 formulations. Mitochondrion 2007; 7: S78-88.
[http://dx.doi.org/10.1016/j.mito.2007.03.003]
[http://dx.doi.org/10.1016/j.mito.2007.03.003]
[53]
Beg S, Javed S, Kohli K. Bioavailability enhancement of coenzyme Q10: An extensive review of patents. Recent Pat Drug Deliv Formul 2010; 4(3): 245-55.
[http://dx.doi.org/10.2174/187221110793237565] [PMID: 20863275]
[http://dx.doi.org/10.2174/187221110793237565] [PMID: 20863275]
[54]
Wajda R, Zirkel J, Schaffer T. Increase of bioavailability of coenzyme Q(10) and vitamin E. J Med Food 2007; 10(4): 731-4.
[http://dx.doi.org/10.1089/jmf.2006.254] [PMID: 18158850]
[http://dx.doi.org/10.1089/jmf.2006.254] [PMID: 18158850]
[55]
Hidaka T, Fujii K, Funahashi I, Fukutomi N, Hosoe K. Safety assessment of coenzyme Q10 (CoQ10). Biofactors 2008; 32(1-4): 199-208.
[http://dx.doi.org/10.1002/biof.5520320124] [PMID: 19096117]
[http://dx.doi.org/10.1002/biof.5520320124] [PMID: 19096117]
[56]
Pravst I, Žmitek K, Žmitek J. Coenzyme Q10 contents in foods and fortification strategies. Crit Rev Food Sci Nutr 2010; 50(4): 269-80.
[http://dx.doi.org/10.1080/10408390902773037] [PMID: 20301015]
[http://dx.doi.org/10.1080/10408390902773037] [PMID: 20301015]
[57]
Bentinger M, Dallner G, Chojnacki T, Swiezewska E. Distribution and breakdown of labeled coenzyme Q10 in rat. Free Radic Biol Med 2003; 34(5): 563-75.
[http://dx.doi.org/10.1016/S0891-5849(02)01357-6] [PMID: 12614845]
[http://dx.doi.org/10.1016/S0891-5849(02)01357-6] [PMID: 12614845]
[58]
Pastor-Maldonado CJ, Suárez-Rivero JM, Povea-Cabello S, et al. Coenzyme Q10: Novel formulations and medical trends. Int J Mol Sci 2020; 21(22): 8432.
[http://dx.doi.org/10.3390/ijms21228432] [PMID: 33182646]
[http://dx.doi.org/10.3390/ijms21228432] [PMID: 33182646]
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