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Volumn 53, Issue 8, 2012, Pages 1679-1689

Regulation of inflammatory and lipid metabolism genes by eicosapentaenoic acid-rich oil

Author keywords

Fatty acid desaturase; Nuclear receptor; Omega 3 polyunsaturated fatty acid; Peroxisome proliferator activated receptor; Steroyl coenzyme A desaturase

Indexed keywords

ACYL COENZYME A DESATURASE; ACYL COENZYME A DESATURASE 1; DOCOSAHEXAENOIC ACID; EICOSAPENTAENOIC ACID RICH OIL; FA DESATURASE 2; FARNESOID X RECEPTOR; LIVER X RECEPTOR; OIL; OLIVE OIL; OMEGA 3 FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; RETINOIC ACID RECEPTOR GAMMA; RETINOID X RECEPTOR; UNCLASSIFIED DRUG;

EID: 84863787484     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M022657     Document Type: Article
Times cited : (35)

References (51)
  • 1
    • 0034994339 scopus 로고    scopus 로고
    • Coronary heart disease: Dietary links and pathogenesis
    • Renaud, S., and D. Lanzmann-Petithory. 2001. Coronary heart disease: dietary links and pathogenesis. Public Health Nutr. 4: 459-474. (Pubitemid 32524568)
    • (2001) Public Health Nutrition , vol.4 , Issue.2 B , pp. 459-474
    • Renaud, S.1    Lanzmann-Petithory, D.2
  • 2
    • 34548803928 scopus 로고    scopus 로고
    • The role of dietary n-6 fatty acids in the prevention of cardiovascular disease
    • Willett, W. C. 2007. The role of dietary n-6 fatty acids in the prevention of cardiovascular disease. J. Cardiovasc. Med. (Hagerstown). 8 (Suppl.) : 42-45.
    • (2007) J. Cardiovasc. Med. (Hagerstown) , vol.8 , Issue.SUPPL. , pp. 42-45
    • Willett, W.C.1
  • 3
    • 0037184418 scopus 로고    scopus 로고
    • Optimal diets for prevention of coronary heart disease
    • DOI 10.1001/jama.288.20.2569
    • Hu, F. B., and W. C. Willett. 2002. Optimal diets for prevention of coronary heart disease. J. Am. Med. Assoc. 288: 2569-2578. (Pubitemid 35386892)
    • (2002) Journal of the American Medical Association , vol.288 , Issue.20 , pp. 2569-2578
    • Hu, F.B.1    Willett, W.C.2
  • 4
    • 0037971463 scopus 로고    scopus 로고
    • n-3 polyunsaturated fatty acids and inflammation: From molecular biology to the clinic
    • DOI 10.1007/s11745-003-1068-y
    • Calder, P. C. 2003. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids. 38: 343-352. (Pubitemid 36724290)
    • (2003) Lipids , vol.38 , Issue.4 , pp. 343-352
    • Calder, P.C.1
  • 5
    • 0036931477 scopus 로고    scopus 로고
    • Omega-3 fatty acids in inflammation and autoimmune diseases
    • Simopoulos, A. P. 2002. Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr. 21: 495-505. (Pubitemid 36026261)
    • (2002) Journal of the American College of Nutrition , vol.21 , Issue.6 , pp. 495-505
    • Simopoulos, A.P.1
  • 6
    • 54549108771 scopus 로고    scopus 로고
    • Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases
    • Calder, P. C. 2008. Polyunsaturated fatty acids, inflammatory processes and inflammatory bowel diseases. Mol. Nutr. Food Res. 52: 885-897.
    • (2008) Mol. Nutr. Food Res. , vol.52 , pp. 885-897
    • Calder, P.C.1
  • 7
    • 33846512302 scopus 로고    scopus 로고
    • Nutritional modulation of the inflammatory response in inflammatory bowel disease - From the molecular to the integrative to the clinical
    • Wild, G. E., L. Drozdowski, C. Tartaglia, M. T. Clandinin, and A. B. R. Thomson. 2007. Nutritional modulation of the inflammatory response in inflammatory bowel disease-from the molecular to the integrative to the clinical. World J. Gastroenterol. 13: 1-7. (Pubitemid 46165457)
    • (2007) World Journal of Gastroenterology , vol.13 , Issue.1 , pp. 1-7
    • Wild, G.E.1    Drozdowski, L.2    Tartaglia, C.3    Clandinin, M.T.4    Thomson, A.B.R.5
  • 8
    • 77957353557 scopus 로고    scopus 로고
    • Fish oil and rheumatoid arthritis: Past, present and future
    • James, M., S. Proudman, and L. Cleland. 2010. Fish oil and rheumatoid arthritis: past, present and future. Proc. Nutr. Soc. 69: 316-323.
    • (2010) Proc. Nutr. Soc. , vol.69 , pp. 316-323
    • James, M.1    Proudman, S.2    Cleland, L.3
  • 9
    • 78649325832 scopus 로고    scopus 로고
    • Nuclear receptors as drug targets for metabolic disease
    • Schulman, I. G. 2010. Nuclear receptors as drug targets for metabolic disease. Adv. Drug Deliv. Rev. 62: 1307-1315.
    • (2010) Adv. Drug Deliv. Rev. , vol.62 , pp. 1307-1315
    • Schulman, I.G.1
  • 10
    • 32944473282 scopus 로고    scopus 로고
    • Nuclear receptors in lipid metabolism: Targeting the heart of dyslipidemia
    • DOI 10.1146/annurev.med.57.121304.131428
    • Beaven, S. W., and P. Tontonoz. 2006. Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu. Rev. Med. 57: 313-329. (Pubitemid 43261994)
    • (2006) Annual Review of Medicine , vol.57 , pp. 313-329
    • Beaven, S.W.1    Tontonoz, P.2
  • 11
    • 23944435868 scopus 로고    scopus 로고
    • Polyunsaturated fatty acid regulation of genes of lipid metabolism
    • DOI 10.1146/annurev.nutr.25.051804.101917
    • Sampath, H., and J. M. Ntambi. 2005. Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu. Rev. Nutr. 25: 317-340. (Pubitemid 41209005)
    • (2005) Annual Review of Nutrition , vol.25 , pp. 317-340
    • Sampath, H.1    Ntambi, J.M.2
  • 12
    • 0038210248 scopus 로고    scopus 로고
    • Nuclear Receptors and the Control of Metabolism
    • DOI 10.1146/annurev.physiol.65.092101.142528
    • Francis, G. A., E. Fayard, F. Picard, and J. Auwerx. 2003. Nuclear receptors and the control of metabolism. Annu. Rev. Physiol. 65: 261-311. (Pubitemid 38249155)
    • (2003) Annual Review of Physiology , vol.65 , pp. 261-311
    • Francis, G.A.1    Fayard, E.2    Picard, F.3    Auwerx, J.4
  • 15
    • 77958459052 scopus 로고    scopus 로고
    • Direct assessment of plasma low density lipoprotein and high density lipoprotein cholesterol levels and coronary heart disease: Results from the Framingham Offspring Study
    • Otokozawa, S., M. Ai, B. F. Asztalos, C. C. White, S. Demissie-Banjaw, L. A. Cupples, K. Nakajima, P. W. F. Wilson, and E. J. Schaefer. 2010. Direct assessment of plasma low density lipoprotein and high density lipoprotein cholesterol levels and coronary heart disease: results from the Framingham Offspring Study. Atherosclerosis. 213: 251-255.
    • (2010) Atherosclerosis , vol.213 , pp. 251-255
    • Otokozawa, S.1    Ai, M.2    Asztalos, B.F.3    White, C.C.4    Demissie-Banjaw, S.5    Cupples, L.A.6    Nakajima, K.7    Wilson, P.W.F.8    Schaefer, E.J.9
  • 17
    • 0036288213 scopus 로고    scopus 로고
    • Cardiovascular disease risk factors and n-3 fatty acid status in the adult population of James Bay Cree
    • Dewailly, E., C. Blanchet, S. Gingras, S. Lemieux, and B. J. Holub. 2002. Cardiovascular disease risk factors and n-3 fatty acid status in the adult population of James Bay Cree. Am. J. Clin. Nutr. 76: 85-92. (Pubitemid 34686553)
    • (2002) American Journal of Clinical Nutrition , vol.76 , Issue.1 , pp. 85-92
    • Dewailly, E.1    Blanchet, C.2    Gingras, S.3    Lemieux, S.4    Holub, B.J.5
  • 18
    • 8344241096 scopus 로고    scopus 로고
    • High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study
    • DOI 10.1161/01.ATV.0000146325.93749.a8
    • Asztalos, B. F., L. A. Cupples, S. Demissie, K. V. Horvath, C. E. Cox, M. C. Batista, and E. J. Schaefer. 2004. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study. Arterioscler. Thromb. Vasc. Biol. 24: 2181-2187. (Pubitemid 39482449)
    • (2004) Arteriosclerosis, Thrombosis, and Vascular Biology , vol.24 , Issue.11 , pp. 2181-2187
    • Asztalos, B.F.1    Cupples, L.A.2    Demissie, S.3    Horvath, K.V.4    Cox, C.E.5    Batista, M.C.6    Schaefer, E.J.7
  • 23
    • 0035656180 scopus 로고    scopus 로고
    • Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells
    • Narayanan, B. A., N. K. Narayanan, and B. S. Reddy. 2001. Docosahexaenoic acid regulated genes and transcription factors inducing apoptosis in human colon cancer cells. Int. J. Oncol. 19: 1255-1262.
    • (2001) Int. J. Oncol. , vol.19 , pp. 1255-1262
    • Narayanan, B.A.1    Narayanan, N.K.2    Reddy, B.S.3
  • 24
    • 70350601103 scopus 로고    scopus 로고
    • Omega-3 poly-unsaturated fatty acid supplementation for the treatment of heart failure: Mechanisms and clinical potential
    • Duda, M. K., K. M. O'Shea, and W. C. Stanley. 2009. Omega-3 poly-unsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc. Res. 84: 33-41.
    • (2009) Cardiovasc. Res. , vol.84 , pp. 33-41
    • Duda, M.K.1    O'Shea, K.M.2    Stanley, W.C.3
  • 26
    • 39849099788 scopus 로고    scopus 로고
    • Effect of rapeseed oil and dietary n-3 fatty acids on triacylglycerol synthesis and secretion in Atlantic salmon hepatocytes
    • Kjaer, M. A., A. Vegusdal, T. Gjøen, A. C. Rustan, M. Todorcevi, and B. Ruyter. 2008. Effect of rapeseed oil and dietary n-3 fatty acids on triacylglycerol synthesis and secretion in Atlantic salmon hepatocytes. Biochim. Biophys. Acta. 1781: 112-122.
    • (2008) Biochim. Biophys. Acta , vol.1781 , pp. 112-122
    • Kjaer, M.A.1    Vegusdal, A.2    Gjøen, T.3    Rustan, A.C.4    Todorcevi, M.5    Ruyter, B.6
  • 27
    • 43049178118 scopus 로고    scopus 로고
    • Omega-3 fatty acid concentrates in the treatment of moderate hypertriglyceridemia
    • DOI 10.1517/14656566.9.7.1237
    • Skulas-Ray, A. C., S. G. West, M. H. Davidson, and P. M. Kris- Etherton. 2008. Omega-3 fatty acid concentrates in the treatment of moderate hypertriglyceridemia. Expert Opin. Pharmacother. 9: 1237-1248. (Pubitemid 351721760)
    • (2008) Expert Opinion on Pharmacotherapy , vol.9 , Issue.7 , pp. 1237-1248
    • Skulas-Ray, A.C.1    West, S.G.2    Davidson, M.H.3    Kris-Etherton, P.M.4
  • 28
    • 79251509572 scopus 로고    scopus 로고
    • Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia
    • Skulas-Ray, A. C., P. M. Kris-Etherton, W. S. Harris, J. P. Vanden Heuvel, P. R. Wagner, and S. G. West. 2011. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am. J. Clin. Nutr. 93: 243-252.
    • (2011) Am. J. Clin. Nutr. , vol.93 , pp. 243-252
    • Skulas-Ray, A.C.1    Kris-Etherton, P.M.2    Harris, W.S.3    Vanden Heuvel, J.P.4    Wagner, P.R.5    West, S.G.6
  • 29
    • 12744262842 scopus 로고    scopus 로고
    • Interaction of fish oil and conjugated linoleic acid in affecting hepatic activity of lipogenic enzymes and gene expression in liver and adipose tissue
    • Ide, T. 2005. Interaction of fish oil and conjugated linoleic acid in affecting hepatic activity of lipogenic enzymes and gene expression in liver and adipose tissue. Diabetes. 54: 412-423.
    • (2005) Diabetes , vol.54 , pp. 412-423
    • Ide, T.1
  • 30
    • 79956160797 scopus 로고    scopus 로고
    • Opposing effects of omega-3 and omega- 6 long chain polyunsaturated fatty acids on the expression of lipogenic genes in omental and retroperitoneal adipose depots in the rat
    • Epub ahead of print. August 5, 2010; doi:10.1155/2010/927836
    • Muhlhausler, B. S., R. Cook-Johnson, M. James, D. Miljkovic, E. Duthoit, and R. Gibson. Opposing effects of omega-3 and omega- 6 long chain polyunsaturated fatty acids on the expression of lipogenic genes in omental and retroperitoneal adipose depots in the rat. J. Nutr. Metab. Epub ahead of print. August 5, 2010; doi:10.1155/2010/927836.
    • J. Nutr. Metab.
    • Muhlhausler, B.S.1    Cook-Johnson, R.2    James, M.3    Miljkovic, D.4    Duthoit, E.5    Gibson, R.6
  • 31
    • 4444358045 scopus 로고    scopus 로고
    • Leptin and the control of metabolism: Role for stearoyl-CoA desaturase-1 (SCD-1)
    • Cohen, P., and J. M. Friedman. 2004. Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). J. Nutr. 134: 2455S-2463S. (Pubitemid 39201621)
    • (2004) Journal of Nutrition , vol.134 , Issue.9
    • Cohen, P.1    Friedman, J.M.2
  • 32
    • 68449089088 scopus 로고    scopus 로고
    • Regulation of human stearoyl-CoA desaturase by omega-3 and omega-6 fatty acids: Implications for the dietary management of elevated serum triglycerides
    • Velliquette, R. A., P. J. Gillies, P. M. Kris-Etherton, J. W. Green, G. Zhao, and J. P. Vanden Heuvel. 2009. Regulation of human stearoyl-CoA desaturase by omega-3 and omega-6 fatty acids: implications for the dietary management of elevated serum triglycerides. J. Clin. Lipidol. 3: 281-288.
    • (2009) J. Clin. Lipidol. , vol.3 , pp. 281-288
    • Velliquette, R.A.1    Gillies, P.J.2    Kris-Etherton, P.M.3    Green, J.W.4    Zhao, G.5    Vanden Heuvel, J.P.6
  • 33
    • 84858294016 scopus 로고    scopus 로고
    • Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: Evidence for a farnesoid-X-receptor mechanism of action
    • PubMed
    • Zhang, J., P. M. Kris-Etherton, J. T. Thompson, D. B. Hannon, P. J. Gillies, and J. P. Vanden Heuvel. 2012. Alpha-linolenic acid increases cholesterol efflux in macrophage-derived foam cells by decreasing stearoyl CoA desaturase 1 expression: evidence for a farnesoid-X-receptor mechanism of action. J. Nutr. Biochem. 23: 400-409. PubMed
    • (2012) J. Nutr. Biochem. , vol.23 , pp. 400-409
    • Zhang, J.1    Kris-Etherton, P.M.2    Thompson, J.T.3    Hannon, D.B.4    Gillies, P.J.5    Vanden Heuvel, J.P.6
  • 37
    • 33845972227 scopus 로고    scopus 로고
    • Reduction in 7,12-dimethylbenz[a]anthracene-induced hepatic cytochrome-P450 1A1 expression following soy consumption in female rats is mediated by degradation of the aryl hydrocarbon receptor
    • Singhal, R., T. M. Badger, and M. J. Ronis. 2007. Reduction in 7,12-dimethylbenz[a]anthracene-induced hepatic cytochrome- P450 1A1 expression following soy consumption in female rats is mediated by degradation of the aryl hydrocarbon receptor. J. Nutr. 137: 19-24. (Pubitemid 46052853)
    • (2007) Journal of Nutrition , vol.137 , Issue.1 , pp. 19-24
    • Singhal, R.1    Badger, T.M.2    Ronis, M.J.3
  • 38
    • 33746824712 scopus 로고    scopus 로고
    • N-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits
    • Gebauer, S. K., T. L. Psota, W. S. Harris, and P. M. Kris-Etherton. 2006. n-3 fatty acid dietary recommendations and food sources to achieve essentiality and cardiovascular benefits. Am. J. Clin. Nutr. 83 (Suppl.): 1526-1535.
    • (2006) Am. J. Clin. Nutr. , vol.83 , Issue.SUPPL. , pp. 1526-1535
    • Gebauer, S.K.1    Psota, T.L.2    Harris, W.S.3    Kris-Etherton, P.M.4
  • 39
    • 0036283121 scopus 로고    scopus 로고
    • PPARs: Transcriptional effectors of fatty acids and their derivatives
    • DOI 10.1007/s00018-002-8467-x
    • Hihi, A. K., L. Michalik, and W. Wahli. 2002. PPARs: transcriptional effectors of fatty acids and their derivatives. Cell. Mol. Life Sci. 59: 790-798. (Pubitemid 34628240)
    • (2002) Cellular and Molecular Life Sciences , vol.59 , Issue.5 , pp. 790-798
    • Hihi, A.K.1    Michalik, L.2    Wahli, W.3
  • 41
    • 0037160785 scopus 로고    scopus 로고
    • Peroxisome Proliferator-Activated Receptors (PPARS): From metabolic control to epidermal wound healing
    • Wahli, W. 2002. Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing. Swiss Med. Wkly. 132: 83-91. (Pubitemid 34492280)
    • (2002) Swiss Medical Weekly , vol.132 , Issue.7-8 , pp. 83-91
    • Wahli, W.1
  • 42
    • 0033625677 scopus 로고    scopus 로고
    • Growths, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta)
    • DOI 10.1128/MCB.20.14.5119-5128.2000
    • Peters, J. M., S. S. Lee, W. Li, J. M. Ward, O. Gavrilova, C. Everett, M. L. Reitman, L. D. Hudson, and F. J. Gonzalez. 2000. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol. Cell. Biol. 20: 5119-5128. (Pubitemid 30431565)
    • (2000) Molecular and Cellular Biology , vol.20 , Issue.14 , pp. 5119-5128
    • Peters, J.M.1    Lee, S.S.T.2    Li, W.3    Ward, J.M.4    Gavrilova, O.5    Everett, C.6    Reitman, M.L.7    Hudson, L.D.8    Gonzalez, F.J.9
  • 43
    • 0031589638 scopus 로고    scopus 로고
    • Peroxisome proliferator-activated receptor gamma: A key regulator of adipogenesis and systemic insulin sensitivity
    • Spiegelman, B. M. 1997. Peroxisome proliferator-activated receptor gamma: a key regulator of adipogenesis and systemic insulin sensitivity. Eur. J. Med. Res. 2: 457-464.
    • (1997) Eur. J. Med. Res. , vol.2 , pp. 457-464
    • Spiegelman, B.M.1
  • 44
    • 0030841936 scopus 로고    scopus 로고
    • Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism
    • DOI 10.1016/S0300-9084(97)81496-4
    • Latruffe, N., and J. Vamecq. 1997. Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism. Biochimie. 79: 81-94. (Pubitemid 27290347)
    • (1997) Biochimie , vol.79 , Issue.2-3 , pp. 81-94
    • Latruffe, N.1    Vamecq, J.2
  • 45
    • 0037144475 scopus 로고    scopus 로고
    • The CYP4A isoforms hydroxylate epoxyeicosatrienoic acids to form high affinity peroxisome proliferator-activated receptor ligands
    • Cowart, L. A., S. Wei, M-H. Hsu, E. F. Johnson, M. U. Krishna, J. R. Falck, and J. H. Capdevila. 2002. The CYP4A isoforms hydroxylate epoxyeicosatrienoic acids to form high affinity peroxisome proliferator- activated receptor ligands. J. Biol. Chem. 277: 35105-35112.
    • (2002) J. Biol. Chem. , vol.277 , pp. 35105-35112
    • Cowart, L.A.1    Wei, S.2    Hsu, M.-H.3    Johnson, E.F.4    Krishna, M.U.5    Falck, J.R.6    Capdevila, J.H.7
  • 46
    • 0030985318 scopus 로고    scopus 로고
    • Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay
    • DOI 10.1210/me.11.6.779
    • Krey, G., O. Braissant, F. L'Horset, E. Kalkhoven, M. Perroud, M. G. Parker, and W. Wahli. 1997. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol. Endocrinol. 11: 779-791. (Pubitemid 27225305)
    • (1997) Molecular Endocrinology , vol.11 , Issue.6 , pp. 779-791
    • Krey, G.1    Braissant, O.2    L'Horset, F.3    Kalkhoven, E.4    Perroud, M.5    Parker, M.G.6    Wahli, W.7
  • 48
    • 33947241783 scopus 로고    scopus 로고
    • The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta)
    • DOI 10.1016/j.freeradbiomed.2007.01.003, PII S089158490700010X
    • Coleman, J. D., K. S. Prabhu, J. T. Thompson, P. S. Reddy, J. M. Peters, B. R. Peterson, C. C. Reddy, and J. P. Vanden Heuvel. 2007. The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator- activated receptor-beta/delta (PPARbeta/delta). Free Radic. Biol. Med. 42: 1155-1164. (Pubitemid 46428510)
    • (2007) Free Radical Biology and Medicine , vol.42 , Issue.8 , pp. 1155-1164
    • Coleman, J.D.1    Prabhu, K.S.2    Thompson, J.T.3    Reddy, P.S.4    Peters, J.M.5    Peterson, B.R.6    Reddy, C.C.7    Vanden, H.J.P.8


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