Saffron (Crocus sativus L.) Supplements Modulate Circulating MicroRNA (miR-21) in Atherosclerosis Patients; A Randomized, Double-Blind, Placebo-Controlled Trial (original) (raw)

Abstract

Background: microRNAs (miRNAs) are endogenous gene expression regulators, which are involved in the physiopathology of diseases, and potentially make biomarkers in diseases, such as Cardiovascular Disease (CVD). Objectives: Since miR-21 is a robust regulator in plaque formation, this study aimed at identifying the effect of saffron as a functional food and traditional food additive antioxidant in fighting against the progress of atherosclerosis, by modulation of miR-21, as a new circulating marker of inflammation. Methods: In this randomized, double-blind clinical trial, 63 subjects with atherosclerosis were recruited from Emam Sajjad Hospital, Valiasr Hospital, and Zafaranieyh Clinic in Tehran, Iran, and divided randomly to two groups. They received 100 mg/d saffron or a placebo capsule for six weeks. The expression levels of miR-21 were quantified by real-time quantitative-PCR (RT-qPCR) in the blood of patients. Furthermore, fasting blood sugar, lipid profile, and anthropometric index of participants were evaluated before and after the intervention. Results: Statistical analysis showed significant differences in the expression level of miR-21 between atherosclerosis patients, who received placebo, and those, who consumed saffron (P value = 0.02). Moreover, a significant decrease was seen in hip circumference after saffron supplementation (P = 0.049, P = 0.006). Nevertheless, consumption of saffron did not significantly influence other anthropometric indexes and blood biochemical parameters, such as FBS and lipid profile. Conclusions: In the present study, different expression levels of miR-21 were observed between patients with atherosclerosis, who received saffron supplements and placebo; thus saffron may be considered as a novel therapeutic target in cardiovascular disease management.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (47)

  1. Barja G. Updating the mitochondrial free radical theory of aging: An integrated view, key aspects, and confounding concepts. Antioxid Re- dox Signal. 2013;19(12):1420-45. doi: 10.1089/ars.2012.5148. [PubMed: 23642158]. [PubMed Central: PMC3791058].
  2. Torres N, Guevara-Cruz M, Velazquez-Villegas LA, Tovar AR. Nu- trition and atherosclerosis. Arch Med Res. 2015;46(5):408-26. doi: 10.1016/j.arcmed.2015.05.010. [PubMed: 26031780].
  3. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med. 1979;90(1):85-91. doi: 10.7326/0003-4819-90-1-85. [PubMed: 217290].
  4. McGill HC, Jr, McMahan CA, Herderick EE, Zieske AW, Malcom GT, Tracy RE, et al. Obesity accelerates the progression of coronary atherosclerosis in young men. Circulation. 2002;105(23):2712-8. doi: 10.1161/01.CIR.0000018121.67607.CE. [PubMed: 12057983].
  5. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Cir- culation. 2002;105(9):1135-43. doi: 10.1161/hc0902.104353. [PubMed: 11877368].
  6. Hedin U, Hansson GK. Atherosclerosis-disease mechanisms and clin- ical consequences. In: Thompson M, editor. Oxford Textbook of Vascular Surgery. Oxford University Press; 2016. 3 p.
  7. Alissa EM, Ferns GA. Dietary fruits and vegetables and cardiovas- cular diseases risk. Crit Rev Food Sci Nutr. 2017;57(9):1950-62. doi: 10.1080/10408398.2015.1040487. [PubMed: 26192884].
  8. Bekkering S, Joosten LA, van der Meer JW, Netea MG, Riksen NP. The epigenetic memory of monocytes and macrophages as a novel drug target in atherosclerosis. Clin Ther. 2015;37(4):914-23. doi: 10.1016/j.clinthera.2015.01.008. [PubMed: 25704108].
  9. 9. Rafieian-Kopaei M, Setorki M, Doudi M, Baradaran A, Nasri H. Atherosclerosis: Process, indicators, risk factors and new hopes. Int J Prev Med. 2014;5(8):927-46. [PubMed: 25489440]. [PubMed Central: PMC4258672].
  10. Gong F, Liu Z, Liu J, Zhou P, Liu Y, Lu X. The paradoxical role of IL-17 in atherosclerosis. Cell Immunol. 2015;297(1):33-9. doi: 10.1016/j.cellimm.2015.05.007. [PubMed: 26077826].
  11. Wang S, Zhang X, Liu M, Luan H, Ji Y, Guo P, et al. Chrysin in- hibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages. Pharm Biol. 2015;53(10):1481-7. doi: 10.3109/13880209.2014.986688. [PubMed: 25857322].
  12. Yuan M, Fu H, Ren L, Wang H, Guo W. Soluble CD40 ligand pro- motes macrophage foam cell formation in the etiology of atheroscle- rosis. Cardiology. 2015;131(1):1-12. doi: 10.1159/000374105. [PubMed: 25825037].
  13. Fang L, Moore XL, Dart AM, Wang LM. Systemic inflammatory re- sponse following acute myocardial infarction. J Geriatr Cardiol. 2015;12(3):305-12. doi: 10.11909/j.issn.1671-5411.2015.03.020. [PubMed: 26089856]. [PubMed Central: PMC4460175].
  14. Salvayre R, Negre-Salvayre A, Camare C. Oxidative theory of atherosclerosis and antioxidants. Biochimie. 2016;125:281-96. doi: 10.1016/j.biochi.2015.12.014. [PubMed: 26717905].
  15. Dorighello GG, Paim BA, Leite ACR, Vercesi AE, Oliveira HCF. Spon- taneous experimental atherosclerosis in hypercholesterolemic mice advances with ageing and correlates with mitochon- drial reactive oxygen species. Exp Gerontol. 2018;109:47-50. doi: 10.1016/j.exger.2017.02.010. [PubMed: 28213051].
  16. Griffiths K, Aggarwal BB, Singh RB, Buttar HS, Wilson D, De Meester F. Food antioxidants and their anti-inflammatory properties: A po- tential role in cardiovascular diseases and cancer prevention. Dis- eases. 2016;4(3). doi: 10.3390/diseases4030028. [PubMed: 28933408]. [PubMed Central: PMC5456284].
  17. Kussmann M, Stover P. Nutrigenomics and proteomics in health and dis- ease: Towards a systems-level understanding of gene-diet interactions. 2nd ed. Oxford: John Wiley & Sons; 2017.
  18. Barzegari A, Pavon-Djavid G. Carotenoids as signaling molecules in cardiovascular biology. Bioimpacts. 2014;4(3):111-2. doi: 10.15171/bi.2014.002. [PubMed: 25337462]. [PubMed Central: PMC4204034].
  19. Rahaiee S, Moini S, Hashemi M, Shojaosadati SA. Evaluation of an- tioxidant activities of bioactive compounds and various extracts ob- tained from saffron (Crocus sativus L.): A review. J Food Sci Technol. 2015;52(4):1881-8. doi: 10.1007/s13197-013-1238-x. [PubMed: 25829569]. [PubMed Central: PMC4375186].
  20. Milajerdi A, Mahmoudi M. [Review on the effects of saffron extract and its constituents on factors related to nervous system, cardiovas- cular and gastrointestinal diseases].
  21. J Clin Excellence. 2014;3(1):108-27. Persian.
  22. Sheedy FJ. Turning 21: Induction of miR-21 as a key switch in the inflammatory response. Front Immunol. 2015;6:19. doi: 10.3389/fimmu.2015.00019. [PubMed: 25688245]. [PubMed Central: PMC4310327].
  23. Xu X, Kriegel AJ, Jiao X, Liu H, Bai X, Olson J, et al. miR-21 in is- chemia/reperfusion injury: A double-edged sword? Physiol Ge- nomics. 2014;46(21):789-97. doi: 10.1152/physiolgenomics.00020.2014. [PubMed: 25159851]. [PubMed Central: PMC4280148].
  24. Kumar S, Kim CW, Simmons RD, Jo H. Role of flow-sensitive microR- NAs in endothelial dysfunction and atherosclerosis: Mechanosen- sitive athero-miRs. Arterioscler Thromb Vasc Biol. 2014;34(10):2206-16. doi: 10.1161/ATVBAHA.114.303425. [PubMed: 25012134]. [PubMed Cen- tral: PMC4169332].
  25. Rodriguez-Ruiz V, Barzegari A, Zuluaga M, Zunooni-Vahed S, Rahbar- Saadat Y, Letourneur D, et al. Potential of aqueous extract of saffron ( Crocus sativus L.) in blocking the oxidative stress by modulation of signal transduction in human vascular endothelial cells. J Function Food. 2016;26:123-34. doi: 10.1016/j.jff.2016.07.003.
  26. Olivieri F, Spazzafumo L, Santini G, Lazzarini R, Albertini MC, Rippo MR, et al. Age-related differences in the expression of circulating mi- croRNAs: miR-21 as a new circulating marker of inflammaging. Mech Ageing Dev. 2012;133(11-12):675-85. doi: 10.1016/j.mad.2012.09.004. [PubMed: 23041385].
  27. Fadai F, Mousavi B, Ashtari Z, Ali beigi N, Farhang S, Hashempour S, et al. Saffron aqueous extract prevents metabolic syndrome in patients with schizophrenia on olanzapine treatment: A randomized triple blind placebo controlled study. Pharmacopsychiatry. 2014;47(4-5):156- 61. doi: 10.1055/s-0034-1382001. [PubMed: 24955550].
  28. Schmidt M, Betti G, Hensel A. Saffron in phytotherapy: Pharmacol- ogy and clinical uses. Wien Med Wochenschr. 2007;157(13-14):315-9. doi: 10.1007/s10354-007-0428-4. [PubMed: 17704979].
  29. Verma SK, Bordia A. Antioxidant property of Saffron in man. Indian J Med Sci. 1998;52(5):205-7. [PubMed: 9808914].
  30. Bourges C. Use of saffron and/or safranal and/or crocin and/or picro- crocin and/or derivatives thereof as a sateity agent for treatment of obesity. Google Patents. 2017.
  31. Milajerdi A, Jazayeri S, Hashemzadeh N, Shirzadi E, Derakhshan Z, Djazayeri A, et al. The effect of saffron (Crocus sativus L.) hydroal- coholic extract on metabolic control in type 2 diabetes mellitus: A triple-blinded randomized clinical trial. J Res Med Sci. 2018;23:16. doi: 10.4103/jrms.JRMS_286_17. [PubMed: 29531568]. [PubMed Cen- tral: PMC5842443].
  32. Azimi P, Ghiasvand R, Feizi A, Hariri M, Abbasi B. Effects of cin- namon, cardamom, saffron, and ginger consumption on markers of glycemic control, lipid profile, oxidative stress, and inflamma- tion in type 2 diabetes patients. Rev Diabet Stud. 2014;11(3-4):258-66. doi: 10.1900/RDS.2014.11.258. [PubMed: 26177486]. [PubMed Central: PMC5397291].
  33. Fan X, Wang E, Wang X, Cong X, Chen X. MicroRNA-21 is a unique sig- nature associated with coronary plaque instability in humans by reg- ulating matrix metalloproteinase-9 via reversion-inducing cysteine- rich protein with Kazal motifs. Exp Mol Pathol. 2014;96(2):242-9. doi: 10.1016/j.yexmp.2014.02.009. [PubMed: 24594117].
  34. Jiang Y, Wang HY, Li Y, Guo SH, Zhang L, Cai JH. Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases. Sci Rep. 2014;4:5026. doi: 10.1038/srep05026. [PubMed: 24848278]. [PubMed Central: PMC4052773].
  35. Jin H, Li DY, Chernogubova E, Sun C, Busch A, Eken SM, et al. Local de- livery of miR-21 stabilizes fibrous caps in vulnerable atherosclerotic lesions. Mol Ther. 2018;26(4):1040-55. doi: 10.1016/j.ymthe.2018.01.011. [PubMed: 29503197]. [PubMed Central: PMC6080193].
  36. Barwari T, Rienks M, Mayr M. MicroRNA-21 and the Vulnerabil- ity of Atherosclerotic Plaques. Mol Ther. 2018;26(4):938-40. doi: 10.1016/j.ymthe.2018.03.005. [PubMed: 29571964]. [PubMed Central: PMC6080134].
  37. Schober A, Nazari-Jahantigh M, Weber C. MicroRNA-mediated mech- anisms of the cellular stress response in atherosclerosis. Nat Rev Cardiol. 2015;12(6):361-74. doi: 10.1038/nrcardio.2015.38. [PubMed: 25855604].
  38. Davis CD, Ross SA. Evidence for dietary regulation of microRNA ex- pression in cancer cells. Nutr Rev. 2008;66(8):477-82. doi: 10.1111/j.1753- 4887.2008.00080.x. [PubMed: 18667010].
  39. Hosseinzadeh H, Abootorabi A, Sadeghnia HR. Protective effect of Crocus sativus stigma extract and crocin (trans-crocin 4) on methyl methanesulfonate-induced DNA damage in mice organs. DNA Cell Biol. 2008;27(12):657-64. doi: 10.1089/dna.2008.0767. [PubMed: 18788978].
  40. Premkumar K, Abraham SK, Santhiya ST, Gopinath PM, Ramesh A. In- hibition of genotoxicity by saffron (Crocus sativus L.) in mice. Drug Chem Toxicol. 2001;24(4):421-8. doi: 10.1081/DCT-100106266. [PubMed: 11665650].
  41. Premkumar K, Thirunavukkarasu C, Abraham SK, Santhiya ST, Ramesh A. Protective effect of saffron (Crocus sativus L.) aqueous ex- tract against genetic damage induced by anti-tumor agents in mice. Hum Exp Toxicol. 2006;25(2):79-84. doi: 10.1191/0960327106ht589oa. [PubMed: 16539212].
  42. Naghshineh A, Dadras A, Ghalandari B, Riazi GH, Modaresi SM, Afrasi- abi A, et al. Safranal as a novel anti-tubulin binding agent with po- tential use in cancer therapy: An in vitro study. Chem Biol Interact. 2015;238:151-60. doi: 10.1016/j.cbi.2015.06.023. [PubMed: 26102007].
  43. Mehdizadeh R, Parizadeh MR, Khooei AR, Mehri S, Hosseinzadeh H. Cardioprotective effect of saffron extract and safranal in isoproterenol-induced myocardial infarction in wistar rats. Iran J Basic Med Sci. 2013;16(1):56-63. [PubMed: 23638293]. [PubMed Central: PMC3637905].
  44. Guleria P, Goswami D, Yadav K. Computational identification of miRNAs and their targets from Crocus sativus L. Arch Biolog Sci. 2012;64(1):65-70. doi: 10.2298/abs1201065g.
  45. Economou EK, Oikonomou E, Siasos G, Papageorgiou N, Tsalamandris S, Mourouzis K, et al. The role of microRNAs in coronary artery dis- ease: From pathophysiology to diagnosis and treatment. Atheroscle- rosis. 2015;241(2):624-33. doi: 10.1016/j.atherosclerosis.2015.06.037. [PubMed: 26117399].
  46. Gao Y, Peng J, Ren Z, He NY, Li Q, Zhao XS, et al. Functional regulatory roles of microRNAs in atherosclerosis. Clin Chim Acta. 2016;460:164-71. doi: 10.1016/j.cca.2016.06.044. [PubMed: 27384386].
  47. Canfran-Duque A, Rotllan N, Zhang X, Fernandez-Fuertes M, Ramirez-Hidalgo C, Araldi E, et al. Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflamma- tion during atherogenesis. EMBO Mol Med. 2017;9(9):1244-62. doi: 10.15252/emmm.201607492. [PubMed: 28674080]. [PubMed Central: PMC5582411].