What is naringenin?

Abstract

Flavonoids are a broad class of phytonutrients, commonly observed in most vegetables and herbs. Flavonoids are important natural compounds with various biological activities. Citrus flavonoids form an important series of flavonoids. Citrus flavonoids are found in citrus fruits such as grapefruit, lemons, tangerines, limes, oranges and are a class of therapeutically important flavonoids. Citrus nutritional components are a group of bioactive flavonoids, commonly referred to as Vitamin P, and include naringenin, naringin, quercetin, diosmetin, narirutin, diosmin, nobiletin, neohesperidin, rutin, hesperidin, tangeritin, etc. includes. Naringenin (5,7,4'-trihydroxyflavanone) belongs to the class of flavonoids called flavanones. Naringenin is associated with beneficial effects in osteoporosis, cancer, and cardiovascular disease. The main effects of naringenin include inhibition of pro-oxidant enzymes such as xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, lipoxygenase and cyclooxygenase; metal ion chelation and, most importantly, scavenging of free radicals.

Keywords

• Naringenin
• Vitamin P.
• flavanone

Naringenin Nedir?

Abstract

Flavonoidler, sebze ve bitkilerin çoğunda yaygın olarak gözlenen geniş bir kapsamı olan bitki besinleri sınıfıdır. Flavonoidler, çeşitli biyolojik aktiviteleri olan önemli doğal bileşiklerdir. Narenciye flavonoidleri önemli bir flavonoid serisini oluşturur. Narenciye flavonoidleri, greyfurt, limon, mandalina, misket limonu, portakal gibi turunçgillerde bulunmaktadır ve terapötik açıdan önemli bir flavanoid sınıfıdır. Narenciye besin bileşenleri, yaygın olarak Vitamin P olarak adlandırılan bir grup biyoaktif flavonoiddir ve naringenin, naringin, quercetin, diosmetin, narirutin, diosmin, nobiletin, neohesperidin, rutin, hesperidin, tangeritin vb. içerir. Naringenin (5,7,4'-trihidroksiflavanon) flavanonlar adı verilen flavonoidler sınıfına aittir. Naringenin, osteoporoz, kanser ve kardiyovasküler hastalıklarda faydalı etkilerle ilişkilidir. Naringenin'in başlıca etkileri arasında ksantin oksidaz, nikotinamid adenin dinükleotid fosfat oksidaz, lipoksijenaz ve siklooksijenaz gibi pro-oksidan enzimlerin inhibisyonu; metal iyon şelasyonu ve en önemlisi serbest radikallerin temizlenmesi yer alır.

Keywords

• Naringenin
• Vitamin P.
• flavanon

References

1. Aherne, S.A. ve O’Brien, N.M., 2002, Dietary flavonols: Chemistry, food content, and metabolism, Nutrition, 18(1), 75-81. https://doi.org/10.1016/S0899-9007(01)00695-5.
2. Alam, M.A., Subhan, N., Rahman, M.M., Uddin, S.J., Reza, H.M. ve Sarker, S.D., 2014, Effect of citrus flavonoids, naringin and naringenin on metabolic syndrome and their mechanisms of action, Advances and Nutrition, 5(4), 404-17. https://doi.org/10.3945/an.113.005603.
3. Alberca, R.W., Teixeira, F.M.E., Beserra, D.R., de Oliveira, E.A., de Andrade, M.M.S., Pietrobon, A.J. ve Sato, M.N., 2020, Perspective: the potential effects of naringenin in COVID-19, Frontiers in Immunology, (2020) 11, 1.
4. Bolli, A., Marino, M., Rimbach, G., Fanali, G., Fasano, M. ve Ascenzi, P., 2010, Flavonoid binding to human serum albümin, Biochemical and Biophysical Research Communications, 398, 444-449. PMID: 20599706 DOI: 10.1016/j.bbrc.2010.06.096.
5. Bourian, M., Runkel, M., Krisp, A., Tegtmeier, M., Freudenstein, J. ve Legrum, W., 1999, Naringenin and interindividual variability in interaction of coumarin with grapefruit juice, Experimental and Toxicologic Pathology, (1999) 51, 289–93. doi: 10.1016/S0940-2993(99)80008-6.
6. Breinholt, V.M., Svendsen, G.W., Dragsted, L.O. ve Hossaini, A., 2008, The citrus-derived flavonoid naringenin exerts uterotrophic effects in female mice at human relevant doses, Basic and Clinical Pharmacology and Toxicology, (2008) 94, 30–6. doi: 10.1111/ j.1742-7843.2004.pto_940106.x.
7. Cavia‐Saiz, M., Busto, M.D., Pilar‐Izquierdo, M.C., Ortega, N., Perez‐Mateos, M. ve Muñiz, P., 2010, Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study, Journal of the Science of Food and Agriculture, 90(7), 1238-44. https://doi.org/10.1002/jsfa.3959.
8. Chabane, M.N., Ahmad, A.A., Peluso, J., Muller, C.D. ve Ubeaud‐Séquier, G., 2009, Quercetin and naringenin transport across human intestinal Caco‐2 cells, Journal of Pharmacy and Pharmacology, 61(11), 1473-83. https://doi.org/10.1211/jpp/61.11.0006.

9. Chao, C.L., Weng, C.S., Chang, N. C., Lin, J.S., Kao, S.T. ve Ho, F.M., 2010, Naringenin more effectively inhibits inducible nitric oxide synthase and cyclooxygenase-2 expression in macrophages than in microglia, Nutrition Research, 30, 858–864.
10. Chen, G., Wu, D., Guo, W., Cao, Y., Huang, D., Wang, H., vd., 2020, Clinical and immunologic features in severe and moderate forms of Coronavirus disease 2019, medRxiv[Preprint] (2020). doi: 10.1101/2020.02.16.2002 3903.
11. Chen, H. ve Du, Q., 2020, Potential natural compounds for preventing SARS-CoV- 2 (2019-nCoV) infection, Preprints. doi: 10.20944/preprints202001. 0358.v3.
12. Cheng, L., Zheng, W., Li, M., Huang, J., Bao, S., Xu, Q., Ma, Z., 2020, Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2, Preprints. doi: 10.20944/preprints202002.0313.v1.
13. Choudhury, R., Chowrimootoo, G., Srai, K., Debnam, E. ve Rice-Evans, C.A., 1999, Interactions of the flavonoid naringenin in the gastrointestinal tract and the influence of glycosylation, Biochemical and Biophysical Research Communications, 265, 410-415. PMID: 10558881 DOI: 10.1006/bbrc.1999.1695.
14. Chousterman, B.G, Swirski, F.K. ve Weber, G.F., 2017, Cytokine storm and sepsis disease pathogenesis, Semin Immunopathol, (2017) 39, 517–28. doi: 10.1007/s00281- 017-0639-8.
15. Chtourou, Y., Slima, A.B., Makni, M., Gdoura, R. ve Fetoui, H., 2015, Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats, Pharmacological Reports, 67, 1090–1097.
16. Da Pozzo, E., Costa, B., Cavallini, C., Testai, L., Martelli, A., Calderone, V. ve Martini, C., 2017, The citrus flavanone naringenin protects myocardial cells against age-associated damage, Oxidative Medicine and Cellular Longevity, (2017) 9536148. doi: 10.1155/2017/9536148.
17. Day, A. J., Du, Pont, M.S., Ridley, S., Rhodes, M., Rhodes, M.J., Morgan, M.R. ve Williamson, G., 1998, Deglycosylation of flavonoid and isoflavonoid glycosides by human small intestine and liver β‐glucosidase activity, FEBS Letters, 436(1), 71-5. https://doi.org/10.1016/S0014-5793(98)01101-6.
18. Diaz, J.H., 2020, Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19, Journal of Travel Medicine, (2020) 27, 1–2. doi: 10.1093/jtm/taaa041.
19. Djuric, Z., Chen, G., Doerge, D.R., Heilbrun, L.K. ve Kucuk, O., 2001, Effect of soy isoflavone supplementation on markers of oxidative stress in men and women, Cancer Letters, 172(1), 1-6. https://doi.org/10.1016/S0304-3835(01)00627-9.
20. El Mohsen, M.A., Marks, J., Kuhnle, G., Rice-Evans, C., Moore K., Gibson, G., Debnam, E., Srai, S.K., 2004, The differential tissue distribution of the citrus flavanone naringenin following gastric instillation, Free Radical Research, 38, 1329-1340. PMID: 15763957 DOI:10.1080/10715760400017293.
21. Erdogdu, Y., Unsalan, O., Gulluoglu, M.T., 2009, Vibrational analysis of flavone, Turkish Journal of Physics, 33, 249-259.
22. Erlund, I., Meririnne, E., Alfthan, G. ve Aro, A., 2001, Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice, The Journal of Nutrition, (2001) 131, 235–41. doi: 10.1093/jn/131.2.235.
23. Felgines, C., Texier, O., Morand, C., Manach, C., Scalbert, A., Régerat, F. ve Rémésy, C., 2000, Bioavailability of the flavanone naringenin and its glycosides in rats, The American Journal of Physiology-Gastrointestinal and Liver Physiology, 279(6), 1148-54. https://doi.org/10.1152/ajpgi.2000.279.6.G1148.
24. Feng, J., Luo, J., Deng, L., Zhong, Y., Wen, X., Cai, Y. ve Li, J., 2019, Naringenin-induced HO-1 ameliorates high glucose or free fatty acids-associated apoptosis via PI3K and JNK/Nrf2 pathways in human umbilical vein endothelial cells, International Immunopharmacology, 75, 105769.
25. Fuhr, U. ve Kummert, A.L., 1995, The fate of naringin in humans: a key to grapefruit juice-drug interactions?, Clinical Pharmacology & Therapeutics, 58, 365–73. doi: 10. 1016/0009-9236(95)90048-9.
26. Galluzzo, P., Ascenzi, P., Bulzomi, P. ve Marino, M., 2008, The nutritional fl avanone naringenin triggers antiestrogenic effects by regulating estrogen receptor α-palmitoylation, Endocrinology, 149, 2567-2575. https://doi.org/10.1210/en.2007-1173.
27. Gao, Y., Wang, Z., Zhang, Y., Liu, Y., Wang, S., Sun, W., Guo, J., Yu, C., Wang, Y., Kong, W. ve Zheng, J., 2018, Naringenin inhibits N(G)-nitro-l-arginine methyl ester-induced hypertensive left ventricular hypertrophy by decreasing angiotensin-converting enzyme 1 expression, Experimental and Therapeutic Medicine, 16, 867–873.
28. Garg, A., Garg, S., Zaneveld, L.J. ve Singla, A.K., 2001, Chemistry and pharmacology of the citrus bioflavonoid hesperidin, Phytotherapy Research, 15(8), 655-69. https://doi.org/10.1002/ptr.1074.
29. Gattinoni, L., Coppola, S., Cressoni, M., Busana, M. ve Chiumello, D., 2020, Covid-19 does not lead to a “Typical” acute respiratory distress syndrome, American Journal of Respiratory and Critical Care Medicine, (2020) 201, 1299–300. doi: 10.1164/rccm.202003-0817LE.
30. Gera, S., Talluri, S., Rangaraj, N. ve Sampathi, S., 2017, Formulation and evaluation of naringenin nanosuspensions for bioavailability enhancement, AAPS PharmSciTech, (2017) 18, 3151–62. doi: 10.1208/s12249-017-0790-5.
31. Goldwasser, J., Cohen, P.Y., Lin, W., Kitsberg, D., Balaguer, P., Polyak, S.J. Chung, R.T., Yarmush, M.L. ve Nahmias, Y., 2011, Naringenin inhibits the assembly and long-term production of infectious hepatitis C virus particles through a PPAR-mediated mechanism, Journal of Hepatology, (2011) 55, 963–71. doi: 10.1016/j.jhep.2011.02.011.
32. Gonçalves, D., Lima, C., Ferreira, P., Costa, P., Costa, A., Figueiredo, W. ve Cesar, T., 2017, Orange juice as dietary source of antioxidants for patients with hepatitis C under antiviral therapy, Food & Nutrition Research, (2017) 61, 1296675. doi: 10.1080/16546628. 2017.1296675.
33. Graf, B. A., Milbury, P. E. ve Blumberg, J. B., 2005, Flavonols, flavones, flavanones, and human health: epidemiological evidence, Journal of Medicinal Food, 8(3), 281-90. https://doi.org/10.1089/jmf.2005.8.281.
34. Habauzit, V., Verny, M.A., Milenkovic, D., Barber-Chamoux, N., Mazur, A., Dubray, C. ve Morand C., 2015, Flavanones protect from arterial stiffness in postmenopausal women consuming grapefruit juice for 6 mo: a randomized, controlled, crossover trial, The American Journal of Clinical Nutrition, (2015) 102, 66–74. doi: 10.3945/ajcn.114.104646.
35. Heim, K.E., Tagliaferro, A.R. ve Bobilya, D.J., 2002, Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships, Journal of Nutritional Biochemistry, 13, 572-584. PMID: 12550068 DOI: 10.1016/ S0955-2863(02)00208-5.
36. Hernández-Aquino, E. ve Muriel, P., 2018, Beneficial effects of naringenin in liver diseases: Molecular Mechanisms, World Journal of Gastroenterology, (2018 April 28) 24(16), 1679-1707. DOI: 10.3748/wjg.v24.i16.1679, ISSN 1007-9327 (print).
37. Hollman, P.C. ve Arts, I.C., 2000, Flavonols, flavones and flavanols–nature, occurrence and dietary burden, Journal of the Science of Food and Agriculture, 80(7), 1081-93. https://doi.org/10.1002/(SICI)1097-0010(20000515)80:7<1081::AID-JSFA566>3.0.CO;2-G.
38. Hu, Y.J., Wang, Y., Ou-Yang, Y., Zhou, J. ve Liu, Y., 2010, Characterize the interaction between naringenin and bovine serum albumin using spectroscopic approach, Journal of Luminescence, 130, 1394-1399. DOI:10.1016/j.jlumin.2010.02.053.
39. Hughes, L.A., Arts, I.C., Ambergen, T., Brants, H.A., Dagnelie, P.C., Goldbohm, R.A. van den Brandt, P.A., Weijenberg, M.P., Study, N.C., 2008, Higher dietary flavone, flavonol, and catechin intakes are associated with less of an increase in BMI over time in women: a longitudinal analysis from the Netherlands Cohort Study, The American Journal of Clinical Nutrition, 88, 1341-1352.
40. Imai, Y., Kuba, K., Rao S., Huan, Y., Guo, F., Guan, B., Yang, P., Sarao, R., Wada, T., Leong-Poi, H., Crackower, M.A., Fukamizu, A., Hui, C.C., Hein, L., Uhlig, S., Slutsky, A.S., Jiang, C. ve Penninger, J.M., 2005, Angiotensin-converting enzyme 2 protects from severe acute lung failure, Nature, (2005) 436, 112–6. doi: 10.1038/nature03712.
41. Joshi, R., Kulkarni, Y.A. ve Wairkar, S., 2018, Pharmacokinetic, pharmacodynamic and formulations aspects of Naringenin: An update, Lfs (Life Sciences). https://doi.org/10.1016/j.lfs.2018.10.066.
42. Jung, U.J., Kim, H.J., Lee, J. S., Lee, M.K., Kim, H.O., Park, E.J., Kim, H.K., Jeong, T.S. ve Choi, M.S., 2003, Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects, Clinical Nutrition, 22, 561–8.
43. Justesen, U., Knuthsen, P. ve Leth, T., 1998, Quantitative analysis of flavonols, flavones, and flavanones in fruits, vegetables and beverages by high-performance liquid chromatography with photo-diode array and mass spectrometric detection, Journal of Chromatography A, 799(1), 101-10. https://doi.org/10.1016/S0021-9673(97)01061-3.
44. Kanaze, F.I., Bounartzi, M.I., Georgarakis, M. ve Niopas, I., 2007, Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects, European Journal of Clinical Nutrition, (2007) 61, 472–7. doi: 10.1038/sj.ejcn.1602543.
45. Khaerunnisa, S., Kurniawan, H., Awaluddin, R. ve Suhartati, S., 2020, Potential inhibitor of COVID-19 main protease (M pro) from several medicinal plant compounds by molecular docking study, Preprints. doi: 10.20944/preprints202003.0226.v1.
46. Khan, A.W., Kotta, S., Ansari, S.H., Sharma, R.K. ve Ali, J., 2015, Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design, characterization, in vitro and in vivo evaluation, Drug Delivery, 22, 552–61. doi: 10.3109/10717544.2013.878003.
47. Khan, M.K., Rakotomanomana, N., Dufour, C. ve Dangles, O., 2011, Binding of citrus flavanones and their glucuronides and chalcones to human serum albümin, Food and Function, 2, 617-626. PMID: 21952533 DOI: 10.1039/c1fo10077g.
48. Kim, J.H. ve Lee, J.K., 2015, Naringenin enhances NK cell lysis activity by increasing the expression of NKG2D ligands on Burkitt's lymphoma cells, Archives of Pharmaceutical Research, 38, 2042-8.
49. Kulkarni, Y.A., Garud, M.S., Oza, M.J., Barve, K.H. ve Gaikwad, A.B., 2016, Diabetes, diabetic complications, and flavonoids, In: R. R.Watson, V. R. Preedy (Eds.), Fruits, Vegetables, and Herbs, Academic Press, London, 77-104.
50. Kumar, R.P. ve Abraham, A., 2016, PVP- coated naringenin nanoparticles for biomedical applications – in vivo toxicological evaluations, Chemico-Biological Interactions, (2016) 257, 110–8. doi: 10.1016/j.cbi.2016.07.012.
51. Lee, C.H., Jeong, T.S., Choi, Y.K., Hyun, B.H., Oh, G.T., Kim, E.H., Kim, J.R., Han, J.I. ve Bok, S.H., 2001, Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits, Biochemical and Biophysical Research Communications, 284, 681-688.
52. Lee, M.H., Yoon, S. ve Moon, J.O., 2004, The flavonoid naringenin inhibits dimethylnitrosamine- induced liver damage in rats, Biological and Pharmaceutical Bulletin, 27, 72–6.
53. Lee, Y.S. ve Reidenberg, M.M., 1998, A method for measuring naringenin in biological fluids and its disposition from grapefruit juice by man, Pharmacology, 56, 314-317. doi: 10.1159/000028215.
54. Lu, W.J., Ferlito, V., Xu, C., Flockhart, D.A. ve Caccamese, S., 2011, Enantiomers of naringenin as pleiotropic, stereoselective inhibitors of cytochrome P450 isoforms, Chirality, (2011) 23, 891–6. doi: 10.1002/chir.21005.
55. Middleton, E. ve Kandaswami, C., 1992, Effects of flavonoids on immune and inflammatory cell functions, Merck Index., 43:1167-1179, Biochem Pharmacol, 1992 Mar 17, 43(6), 1167-79. doi: 10.1016/0006-2952(92)90489-6.
56. Moghaddam, R.H., Samimi, Z., Moradi, S.Z., Little, P.J., Xu, S. ve Farzaei, M.H., 2020, Naringenin and naringin in cardiovascular disease prevention: A preclinical review, European Journal of Pharmacology, 887-173535.
57. Mu, L., Hu, G., Liu, J., Chen, Y., Cui, W. ve Qiao, L., 2019, Protective effects of naringenin in a rat model of sepsis-triggered acute kidney injury via activation of antioxidant enzymes and reduction in urinary angiotensinogen, Medical Science Monitor, 25, 5986–91. doi: 10.12659/MSM.916400.
58. Mulvihill, E.E., Allister, E.M., Sutherland, B.G., Telford, D.E., Sawyez, C.G. ve Edwards, J.Y., 2009, Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance, Diabetes, 58:2198-2210.
59. Nagy, E., Papay, V., Litkei, G., Dinya, Z., 1985, Investigation of the chemical constituents, particularly the flavonoid components, of propolis and populi gemma by the GC/MS method, Elsevier, 223-232.
60. Nielsen, I.L.F., Chee, W.S.S., Poulsen, L., Offord-Cavin, E, Rasmussen, S.E., Frederiksen, H., Enslen, M., Barron, D., Horcajada, M.N. ve Williamson, G., 2006, Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans: a randomized, doubleblind, crossover trial, Journal of Nutrition, 136, 404–8. doi: 10.1093/jn/136. 2.404.
61. Orrego-Lagarón, N., Martínez-Huélamo, M., Vallverdú-Queralt, A., Lamuela-Raventos, R.M. ve Escribano-Ferrer, E., 2015, High gastrointestinal permeability and local metabolism of naringenin: influence of antibiotic treatment on absorption and metabolism, British Journal of Nutrition, 114 (2), 169-80. https://doi.org/10.1017/S0007114515001671.
62. Ortiz-Andrade, R.R., Sanchez-Salgado, J.C., Navarrete-Vazquez, G., Webster, S.P., Binnie, M., García-Jiménez, S., León-Rivera, I., Cigarroa-Vázquez, P., Villalobos-Molina, R. ve Estrada-Soto, S., 2008, Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation, Diabetes, Obesity and Metabolism, 10, 1097–1104.
63. Pari, L. ve Amudha, K., 2011, Hepatoprotective role of naringin on nickel-induced toxicity in male wistar rats, European Journal of Pharmacology, 650, 364–70.
64. Patel D.K., Laloo, D., Kumar, R. ve Hemalatha, S., 2011, Pedalium murex Linn—an overview of its phytopharmacological aspects, Asian Pacific Journal of Tropical Medicine, 4, 748-755.
65. Patel, D.K., Kumar, R, Prasad, S.K. ve Hemalatha, S., 2011, Pharmacologically screened aphrodisiac plant—a review of current scientific literatüre, Asian Pacific Journal of Tropical Biomedicine, 1, 131-138.
66. Patel, D.K., Prasad, S.K., Kumar, R. ve Hemalatha, S., 2011, Cataract: a major secondary complication of diabetes, its epidemiology and an overview on major medicinal plants screened for anticatract activity, Asian Pacific Journal of Tropical Disease, 1, 323-329.
67. Patel, K., Singh, G.K. ve Patel, D.K., 2014, A review on pharmacological and analytical aspects of naringenin, Chinese Journal of Integrative Medicine, 1-13. https://doi.org/10.1007/s11655-014-1960-x.
68. Qin, W., Ren, B., Wang, S., Liang, S., He, B., Shi, X., Wang, L., Liang, J. ve Wu, F., 2016, Apigenin and naringenin ameliorate PKCbetaII-associated endothelial dysfunction via regulating ROS/caspase-3 and NO pathway in endothelial cells exposed to high glucose, Vascular Pharmacology, 85, 39–49.
69. Rani, N., Bharti, S., Krishnamurthy, B., Bhatia, J., Sharma, C., Kamal, M. A., Ojha, S. ve Arya D. S., 2016, Pharmacological properties and therapeutic potential of naringenin: a citrus flavonoid of pharmaceutical promise, Current Pharmaceutical Design, 22(28), 4341-59. https://doi.org/10.2174/1381612822666160530150936.
70. Recourt, K., van Brussel, A.A., Driessen, A.J. ve Lugtenberg, B.J., 1989, Accumulation of a nod gene inducer, the flavonoid naringenin, in the cytoplasmic membrane of Rhizobium leguminosarum biovar viciae is caused by the pH-dependent hydrophobicity of naringenin, Journal of Bacteriology, 171, 4370–7. doi: 10.1128/ jb.171.8.4370-4377.1989.
71. Renaud, S.D. ve de Lorgeril, M., 1992, Wine, alcohol, platelets, and the French paradox for coronary heart disease, The Lancet, 339(8808), 1523-6. https://doi.org/10.1016/0140-6736 (92)91277-F.
72. Renugadevi, J. ve Prabu, S.M., 2009, Naringenin protects against cadmiuminduced oxidative renal dysfunction in rats, Toxicology, 256, 128–34.
73. Renugadevi, J. ve Prabu, S.M., 2010, Cadmium-induced hepatotoxicity in rats and the protective effect of naringenin, Experimental and Toxicologic Pathology, 62, 171–81.
74. Rice-Evans, C.A., Miller, N.J. ve Paganga, G., 1996, Structure-antioxidant activity relationships of flavonoids and phenolic acids, Free Radical Biology and Medicine, 20, 933-956. PMID: 8743980 DOI: 10.1016/0891-5849(95)02227-9. Rice-Evans, C.A., Miller, N.J., Bolwell, P.G., Bramley, P.M. ve Pridham, J.B., 1995, The relative antioxidant activities of plant-derived polyphenolic flavonoids, Free Radical Research, 22(4), 375-83. https://doi.org/10.3109/10715769509145649.
75. Romaszko, E., Marzec-Wróblewska, U., Badura, A. ve Buci´nski, A., 2017, Does consumption of red grapefruit juice alter naringenin concentrations in milk produced by breastfeeding mothers?, Plos One, 12, e0185954. doi: 10.1371/journal.pone.0185954.
76. Salehi, B., Fokou, P.V.T., Sharifi-Rad, M., Zucca, P., Pezzani, R., Martins, N. ve Sharifi-Rad, J., 2019, The therapeutic potential of naringenin: a review of clinical trials, Pharmaceuticals, 12, 11. doi: 10.3390/ph12010011.
77. Salehi, B., Valere, P., Fokou, T., Sharifi-Rad, M., Zucca, P., Pezzani, R., Martins, N. ve Sharifi-Rad, J., 2019, The therapeutic potential of naringenin: A review of clinical trials, Pharmaceuticals, 12, 11, 1-18.
78. Setchell, K.D. ve Cassidy, A., 1999, Dietary isoflavones: biological effects and relevance to human health, Journal of Nutrition, 129(3), 758-67. https://doi.org/10.1093/jn/129.3.758S.
79. Simons, A.L., Renouf , M., Murphy, P.A. ve Hendrich, S., 2010, Greater apparent absorption of flavonoids is associated with lesser human fecal flavonoid disappearance rates, Journal of Agricultural and Food Chemistry, 58, 141-147 [PMID: 19921837 DOI: 10.1021/jf902284u].
80. Spencer, J. ve Crozier, A., 2012, Flavonoids and Related Compounds: Bioavailability and Function, CRC Press, New York.
81. Tapas, A.R., Sakarkar, D. M. ve Kakde, R.B., 2008, Flavonoids as nutraceuticals: a review, Tropical Journal of Pharmaceutical Research, 7(3), 1089-99. http://dx.doi.org/10.4314/ tjpr.v7i3.14693.
82. Treutter, D., 2006, Significance of flavonoids in plant resistance: a review, Environmental Chemistry Letters, 4(3), 147. https://doi.org/10.1055/s-2005-873009.
83. Tripoli, E., La Guardia, M., Giammanco, S., Di Majo, D. ve Giammanco, M., 2007, Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review, Food Chemistry, 104(2), 466-79. https://doi.org/10.1016/j.foodchem.2006.11.054.
84. Van Acker, F.A.A., Schouten, O., Haenen, G.R.M.M., van der Vijgh, W.J.F. ve Bast, A., 2000, Flavonoids can replace [alpha]-tocopherol as an antioxidant, FEBS Lett, 473, 145–148.
85. Venkateswara Rao, P., Kiran, S.D.V.S., Rohini, P. and Bhagyasree, P., 2017, Flavonoid: A review on Naringenin, Journal of Pharmacognosy and Phytochemistry, 6(5): 2778-2783.
86. Verbeek, R., Plomp, A.C., van Tol, E.A. ve van Noort, J.M., 2004, The flavones luteolin and apigenin inhibit in vitro antigenspecific proliferation and interferongamma production by murine and human autoimmune T cells, Biochemical Pharmacology , 68, 621-629.
87. Wang, M.J., Chao, P.D., Hou, Y.C. ve Hsiu, S.L., 2006, Pharmacokinetics and conjugation metabolism of naringin and naringenin in rats after single dose and multiple dose administrations, Journal of Food and Drug Analysis, 14(3), 247-253.
88. Wang, N., Li, D., Lu, N.H., Yi, L., Huang, X.W. ve Gao, Z.H., 2010, Peroxynitrite and hemoglobinmediated nitrative/oxidative modification of human plasma protein: effects of some flavonoids, Journal of Asian Natural Products Research, 12(4), 257-64. https://doi.org/10.1080/10286021003620226.
89. Wang, Y., Wang, S., Firempong, C.K., Zhang, H., Wang, M., Zhang, Y., Zhu, Y., Yu, J., Xu, X., 2017, Enhanced solubility and bioavailability o fnaringenin via liposomal nanoformulation: preparation and in vitro and in vivo evaluations, AAPS PharmSciTech, (2017) 18, 586–94. doi: 10.1208/s12249-016-0537-8.
90. Wang, Z., Wang, S., Zhao, J., Yu, C., Hu, Y., Tu, Y., Yang, Z., Zheng, J., Wang, Y., Gao, Y., 2019, Naringenin ameliorates renovascular hypertensive renal damage by normalizing the balance of reninangiotensin system components in rats, International Journal of Medical Sciences, 16, 644–53. doi: 10.7150/ijms.31075.
91. Wilcox, L.J., Borradaile, N.M. ve Huff, M.W., 1999, Antiatherogenic properties of naringenin, a citrus flavonoid, Cardiovascular Drug Reviews,17:160-178.
92. Yao, L.H., Jiang, Y.M., Shi, J., Tomas-Barberan, F.A., Datta N., Singanusong, R., Chen, S. S., 2004, Flavonoids in food and their health benefits, Plant Foods for Human Nutrition, 59(3), 113-22. https://doi.org/10.1007/s11130-004-0049-7.
93. Ye, Q., Wang, B. ve Mao, J., 2020, Cytokine storm in COVID-19 and treatment, Journal of Infection, (2020) 80, 607–13. doi: 10.1016/j.jinf.2020.03.037.
94. Yoshida, H., Takamura, N., Shuto, T., Ogata, K., Tokunaga, J. ve Kawai, K., 2010, The citrus flavonoids hesperetin and naringenin block the lipolytic actions of TNF-α in mouse adipocytes, Biochemical and Biophysical Research Communications, 394, 728-732.
95. Zeng, W., Jin, L., Zhang, F., Zhang, C. ve Liang, W., 2018, Naringenin as a potential immunomodulator in therapeutics, Pharmacological Research, 135 (2018), 122–126.
96. Zhang, J.J., Dong, X., Cao, Y.Y., Yuan, Y. D., Yang, Y.B., Yan, Y.Q., vd., 2020, Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China, Allergy, 75, 1730–41. doi: 10.1111/all. 14238.
97. Zhang, L., Song, L., Zhang, P., Liu, T., Zhou, L., Yang, G., Lin, R. ve Zhang, J., 2015, Solubilities of naringin and naringenin in different solvents and dissociation constants of naringenin, Journal of Chemical & Engineering Data, 60(3), 932-40. https://doi.org/10.1021/je501004g.
98. Zhao, M., Li, C., Shen, F., Wang, M., Jia, N. ve Wang, C., 2017, Naringenin ameliorates LPSinduced acute lung injury through its anti-oxidative and anti-inflammatory activity and by inhibition of the PI3K/AKT pathway, Experimental and Therapeutic Medicine, 14, 2228–34. doi: 10.3892/etm.2017.4772.
99. Zou, W., Yang, C., Liu, M. ve Su, W., 2012, Tissue distribution study of naringin in rats by liquid chromatography-tandem mass spectrometry, Arzneimittelforschung, 62, 181-186. PMID: 22270844 DOI: 10.1055/s-0031-1299746.