https://doi.org/10.4081/jbr.2022.10313
Bioactive effects of citrus flavonoids and role in the prevention of atherosclerosis and cancer
Submitted: December 5, 2021
Accepted: January 8, 2022
Published: January 14, 2022
Accepted: January 8, 2022
Abstract Views: 2413
PDF: 707
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Citrus fruits are the main fruits of the Mediterranean diet and have been long recognized for their beneficial effects on human health. Observational studies have shown a significant association between dietary flavonoid intake and reduced risk of cardiovascular and malignant diseases. The beneficial effects of citrus fruits on human health appear to be due to their high content in vitamins, minerals and fibers. In particular, the antioxidant and anti-inflammatory activities have been indicated as some of the mechanisms through which citrus fruits may thwart the development of chronic degenerative diseases such as atherosclerosis and cancer. This review would critically examine the results from numerous experimental and clinical studies carried out in order assess the contribute of citrus flavonoids to the prevention of chronic pathological conditions including atherosclerosis and cancer.
Adefegha SA. Functional foods and nutraceuticals as dietary intervention in chronic diseases; novel perspectives for health promotion and disease prevention. J Diet Suppl 2018;15:977-1009.
DOI: https://doi.org/10.1080/19390211.2017.1401573
Gentile D, Fornai M, Pellegrini C, et al. Dietary flavonoids as a potential intervention to improve redox balance in obesity and related comorbidities: a review. Nutr Res Rev 2018;31:239-47.
DOI: https://doi.org/10.1017/S0954422418000082
Dillard CJ, German JB. Phytochemicals: nutraceuticals and human health. J Sci Food Agric 2000;80:1744-56.
DOI: https://doi.org/10.1002/1097-0010(20000915)80:12<1744::AID-JSFA725>3.0.CO;2-W
Keys A. Mediterranean diet and public health: Personal reflections. Am J Clin Nutr 1995;61:1321-3.
DOI: https://doi.org/10.1093/ajcn/61.6.1321S
Casas R, Sacanella E, Estruch R. The immune protective effect of the Mediterranean diet against chronic low grade inflammatory diseases. Endocr Metab Immune Disord Drug Targets 2016;14:245-54.
DOI: https://doi.org/10.2174/1871530314666140922153350
Tripoli E, La Guardia M, Giammanco S, et al. Citrus flavonoids: molecular structure, biological activity and nutritional properties: A review. Food Chem 2007;104:466-79.
Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002;13:572-84.
DOI: https://doi.org/10.1016/S0955-2863(02)00208-5
Mulvihill EE, Burke AC, Huff MW. Citrus flavonoids as regulators of lipoprotein metabo-lism and atherosclerosis. Annu Rev Nutr 2016;36:275-99.
DOI: https://doi.org/10.1146/annurev-nutr-071715-050718
Rodríguez-García C, Sánchez-Quesada C, Gaforio JJ. Dietary flavonoids as cancer chemo-preventive agents: an updated review of human studies. Antioxidants 2019;8:137.
DOI: https://doi.org/10.3390/antiox8050137
Xu H, Luo J, Huang J, Wen Q. Flavonoids intake and risk of type 2 diabetes mellitus. A meta-analysis of prospective cohort studies. Medicine 2018;97:e0686.
DOI: https://doi.org/10.1097/MD.0000000000010686
Hwang SL, Shih PH, Yen GC. Neuroprotective effects of citrus flavonoids. J Agric Food Chem 2012;60:877-85.
DOI: https://doi.org/10.1021/jf204452y
Hardcastle AC, Aucott L, Reid DM, Macdonald HM. Associations between dietary flavonoid intakes and bone health in a Scottish population. J Bone Miner Res 2011;26:941-7.
DOI: https://doi.org/10.1002/jbmr.285
Cassidy A, Rimm EB, O’Reilly EJ, et al. Dietary flavonoids and risk of stroke in women. Stroke 2012;43:946-51.
DOI: https://doi.org/10.1161/STROKEAHA.111.637835
Di Majo D, La Guardia M, Leto G, et al. Flavonols and flavan-3-ols as modulators of xanthine oxidase and manganese superoxide dismutase activity. Int J Food Sci Nutr 2014;65:886-89.
DOI: https://doi.org/10.3109/09637486.2014.931362
Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci 2016;5:1-15.
DOI: https://doi.org/10.1017/jns.2016.41
Croft KD. The chemistry and biological effects of flavonoids and phenolic acids. Ann NY Acad Sci 1998;854:435-42.
DOI: https://doi.org/10.1111/j.1749-6632.1998.tb09922.x
Yusof S, Ghazali HM, King GS. Naringin content in local citrus fruits. Food Chem 1990;37:113-12.
DOI: https://doi.org/10.1016/0308-8146(90)90085-I
Horowitz RM. Taste effects of flavonoids. Prog Clin Biol Res 1986;213:163-75.
Caristi C, Bellocco E, Gargiulli C, et al. Flavone-di-C-glycosides in citrus juices from Southern Italy. Food Chem 2006;95:431-437.
DOI: https://doi.org/10.1016/j.foodchem.2005.01.031
Tsiokanos E, Tsafantakis N, Termentzi A, et al. Phytochemical characteristics of bergamot oranges from the Ionian islands of Greece: A multianalytical approach with emphasis in the distribution of neohesperidose flavanones. Food Chem 2021;343:128400.
DOI: https://doi.org/10.1016/j.foodchem.2020.128400
Ooghe WC, Detavernier CM. Detection of the addition of Citrus reticulata and hybrids to Citrus sinensis by flavonoids. J Agric Food Chem 1997;45:1633-7.
DOI: https://doi.org/10.1021/jf9606262
Narayana KR, Reddy MS, Chaluvadi MR, Krishna DR. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian J Pharmacol 2001;33:2-16.
Verma ML, Sharma S, Saini R, et al. Chapter 3-Bioflavonoids: Synthesis, functions and biotechnological applications. Biotechnological Product Bioact Comp 2020;2020:69-105.
DOI: https://doi.org/10.1016/B978-0-444-64323-0.00003-5
Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Scient World J 2013;2013:162750.
DOI: https://doi.org/10.1155/2013/162750
Tripoli E, La Guardia M, Giammanco S, et al. Citrus flavonoids: molecular structure, biological activity and nutritional properties: A review. Food Chem 2007;104:466-79.
DOI: https://doi.org/10.1016/j.foodchem.2006.11.054
Feng X, Li Y, Brobbey M, et al. Insights into the intestinal bacterial metabolism of flavonoids and the bioactivities of their microbe derived ring cleavage metabolites. Drug Metab Rev 2018;50:343-56.
DOI: https://doi.org/10.1080/03602532.2018.1485691
Nielsen IL, Chee WS, Poulsen L, et al. Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans: a randomized, double-blind, crossover trial. J Nutr 2006;136:404-8.
DOI: https://doi.org/10.1093/jn/136.2.404
Kanaze FI, Bounartzi MI, Georgarakis M, Niopas, I. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur J Clin Nutr 2007;61:472-77.
DOI: https://doi.org/10.1038/sj.ejcn.1602543
Lin SP, Hou YC, Tsai SY, et al. Tissue distribution of naringenin conjugated metabolites following repeated dosing of naringin to rats. Biomedicine 2014;4:16.
DOI: https://doi.org/10.7603/s40681-014-0016-z
Ekalu A, Habila JH. Flavonoids: isolation, characterization, and health benefits. Beni Suef Univ J Basic Appl Sci 2020;9:45.
DOI: https://doi.org/10.1186/s43088-020-00065-9
Burda S, Oleszek W. Antioxidant and antiradical activities of flavonoids. J Agric Food Chem 2001;49:2774-9.
DOI: https://doi.org/10.1021/jf001413m
Di Majo D, Giammanco M, La Guardia M, et al. Flavanones in citrus fruit: structure antioxidant activity relationships. Food Res Int 2005;38:1161-6.
DOI: https://doi.org/10.1016/j.foodres.2005.05.001
Benavente-García O, Castillo J. Update on uses and properties of Citrus flavonoids: new findings in anticancer, cardiovascular, and antiinflammatory activity. J Agric Food Chem 2008;56:6185-6205.
DOI: https://doi.org/10.1021/jf8006568
Sichel G, Corsaro C, Scalia M, et al. In vitro scavenger activity of some flavonoids and melanins against O2•-. Free Radic Biol Med 1991;11:1-8.
DOI: https://doi.org/10.1016/0891-5849(91)90181-2
Di Majo D, La Neve L, La Guardia M, et al. The influence of two different pH levels on the antioxidant properties of flavonols, flavan-3-ols, phenolic acids and aldehyde compounds analysed in synthetic wine and in a phosphate buffer. J Food Compost Anal 2011;24:265-9.
DOI: https://doi.org/10.1016/j.jfca.2010.09.013
Cillard J, Cillard P. Composes phenoliques et radicaux libres. STP Pharma 1988;4:592-6.
Rapisarda P, Tomaino A, Lo Cascio R, et al. Effec-tiveness as influenced by phenolic content of fresh orange juices. J Agric Food Chem 1999;47:4718-23.
DOI: https://doi.org/10.1021/jf990111l
Di Majo D, La Guardia M, Crescimanno M, et al. In-fluence of flavonoids on the transmembrane electron transport: study ex vivo. 2015;88:59-60.
Di Majo D, La Guardia M, Di Sclafani E, et al. Influence of quercetin and luteolin on the activity of the catalase: Study ex vivo about erythrocytes in smokers and non-smokers. J Biol Res 2015;88:61-2.
Maleki SJ, Crespo JF, Cabanillas B. Anti-inflammatory effects of flavonoids. Food Chem 2019;299:124-5.
DOI: https://doi.org/10.1016/j.foodchem.2019.125124
Rathee P, Chaudhary H, Rathee S, et al. Mechanism of action of flavonoids as anti-inflammatory agents: a review. Inflamm. Allergy Drug Targets 2009, 8, 229-235. 10.2174/187152809788681029
DOI: https://doi.org/10.2174/187152809788681029
Manthey JA, Guthrie N, Grohmann K. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Curr Med Chem 2001;8:135-53.
DOI: https://doi.org/10.2174/0929867013373723
Da Silva EJA, Oliveira AS, Lapa AJ. Pharmacological evaluation of the antiinflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J Pharm Pharmacol 1994;46:118-22.
DOI: https://doi.org/10.1111/j.2042-7158.1994.tb03753.x
Sakata K, Hirose Y, Qiao Z, et al. Inhibition of inducible isoforms of cyclooxygenase and nitric oxide synthase by flavonoid hesperidin in mouse macrophage cell line. Cancer Lett 2003;199:139-45.
DOI: https://doi.org/10.1016/S0304-3835(03)00386-0
Lin N, Sato T, Takayama Y, et al. Novel anti inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem Pharmacol 2003;65:2065-71.
DOI: https://doi.org/10.1016/S0006-2952(03)00203-X
Huxley RR, Neil HAW. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur J Clin Nutr 2003;57:904-8.
DOI: https://doi.org/10.1038/sj.ejcn.1601624
Alam MA, Subhan N, Rahman MM, et al. Effect of citrus flavonoids, naringin and naringenin, on metabolic syndrome and their mechanisms of action. Adv Nutr 2014;5:404-17.
DOI: https://doi.org/10.3945/an.113.005603
Fuhrman B, Aviram M. Flavonoids protect LDL from oxidation and attenuate atherosclerosis. Curr Opin Lipidol 2001;12:41-8.
DOI: https://doi.org/10.1097/00041433-200102000-00008
Naderi GA, Asgary S, Sarraf-Zadegan GN, Shirvany H. Antioxidant effect of flavonoids on the susceptibility of LDL oxidation. Mol Cell Biochem 2003;246:193-6.
DOI: https://doi.org/10.1007/978-1-4615-0298-2_27
Mahmoud AM, Hernández Bautista RJ, Mansur A, et al. Beneficial effects of citrus flavonoids on cardiovascular and metabolic health. Oxid Med Cell Longev 2019;19:5484138.
DOI: https://doi.org/10.1155/2019/5484138
Kurowska EM, Borradaile NM, Spence JD, Carroll KK. Hypocholesterolemic effects of dietary citrus juices in rabbits. Nutr Res 2000;20:121-9.
DOI: https://doi.org/10.1016/S0271-5317(99)00144-X
Kim HK, Jeong TS, Lee MK, et al. Lipid lowering efficacy of hesperetin metabolites in high-cholesterol fed rats. Clin Chim Acta 2003;327:129-37.
DOI: https://doi.org/10.1016/S0009-8981(02)00344-3
Chtourou Y, Fetoui H, Jemai R, et al. Naringenin reduces cholesterol induced hepatic inflammation in rats by modulating matrix metalloproteinases-2, 9 via inhibition of nuclear factor κB pathway. Eur J Pharmacol 2015;746:96-105.
DOI: https://doi.org/10.1016/j.ejphar.2014.10.027
Kurowska EM, Manthey JA. Hypolipidemic effects and absorption of citrus polymethoxylated flavones in hamsters with diet induced hypercholesterolemia. J Agric Food Chem 2004;52:2879-86.
DOI: https://doi.org/10.1021/jf035354z
Park HJ, Jung UJ, Cho SJ, et al. Citrus unshiu peel extract ameliorates hyperglycemia and hepatic steatosis by altering inflammation and hepatic glucose- and lipid-regulating enzymes in db/db mice. J Nutr Biochem 2013;24:419-27.
DOI: https://doi.org/10.1016/j.jnutbio.2011.12.009
Lee S, Park YB, Bae KH, et al. Cholesterol lowering activity of naringenin via inhibition of 3- hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A: cholesterol acyltransferase in rats. Ann Nutr Metab 1999;43:173-80.
DOI: https://doi.org/10.1159/000012783
Lee MK, Moon SS, Lee SE, et al. Naringenin 7-O-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats. Bioorg Med Chem 2003;11:393-8.
DOI: https://doi.org/10.1016/S0968-0896(02)00441-8
Chanet A, Milenkovic D, Deval C, et al. Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. J Nutr Biochem 2012;23:469-77.
DOI: https://doi.org/10.1016/j.jnutbio.2011.02.001
Lee CH, Jeong TS, Choi YK, et al. 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. Biochem. Biophys Res Commun 2001;284:681-88.
DOI: https://doi.org/10.1006/bbrc.2001.5001
Lee S, Lee CH, Moon SS, et al. Naringenin derivatives as anti-atherogenic agents. Bioorg Med Chem Lett 2003;13:3901-3.
DOI: https://doi.org/10.1016/j.bmcl.2003.09.009
Mulvihill EE, Assini JM, Sutherland BG, et al. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high fat-fed low density lipoprotein receptor-null mice. Arterioscler Thromb Vasc Biol 2010;30:742-8.
DOI: https://doi.org/10.1161/ATVBAHA.109.201095
Oboh G, Bello FO, Ademosun AO. Hypocholesterolemic properties of grapefruit (Citrus paradisii) and shaddock (Citrus maxima) juices and inhibition of angiotensin-1-converting enzyme activity. J Food Drug Anal 2014;22:477-84.
DOI: https://doi.org/10.1016/j.jfda.2014.06.005
Angelone T, Pasqua T, Di Majo D, et al. Distinct signalling mechanisms are involved in the dissimilar myocardial and coronary effects elicited by quercetin and myricetin, two red wine flavonols. Nutr Metab Cardiovasc Dis 2011;21:362-71.
DOI: https://doi.org/10.1016/j.numecd.2009.10.011
Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr 2007;85;895-909.
DOI: https://doi.org/10.1093/ajcn/85.3.895
Aptekmann NP, Cesar TB. Long-term orange juice consumption is associated with low LDL-cholesterol and apolipoprotein B in normal and moderately hypercholesterolemic subjects. Lipids Health Dis 2013;12:119.
DOI: https://doi.org/10.1186/1476-511X-12-119
Yamada T, Hayasaka S, Shibata Y, et al. Frequency of citrus fruit intake is associated with the incidence of cardiovascular disease: the Jichi Medical School cohort study. J Epidemiol 2011;21:169-75.
DOI: https://doi.org/10.2188/jea.JE20100084
Gorinstein S, Caspi A, Libman I, et al. Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J Agr Food Chem 2006;54:1887-92.
DOI: https://doi.org/10.1021/jf058171g
Miwa Y, Yamada M, Sunayama T, et al. Effects of glucosyl hesperidin on serum lipids in hyperlipidemic subjects: preferential reduction in elevated serum triglyceride level. J Nutr Sci Vitaminol 2004;50:211-8.
DOI: https://doi.org/10.3177/jnsv.50.211
Miwa Y, Mitsuzumi H, Sunayama T, et al. Glucosyl hesperidin lowers serum triglyceride level in hypertriglyceridemic subjects through the improvement of very low density lipoprotein metabolic abnormality. J Nutr Sci Vitaminol 2005;51:460-70.
DOI: https://doi.org/10.3177/jnsv.51.460
Jung UJ, Kim HJ, Lee JS, et al. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin Nutr 2003;22:561-8.
DOI: https://doi.org/10.1016/S0261-5614(03)00059-1
Roza JM, Xian-Liu Z, Guthrie N. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects. Altern Ther Health Med 2007;13:44-8.
Reshef N, Hayari Y, Goren C, et al. Antihypertensive effect of sweetie fruit in patients with stage I hypertension. Am J Hypertens 2005;8:1360-63.
DOI: https://doi.org/10.1016/j.amjhyper.2005.05.021
Morand C, Dubray C, Milenkovic D, et al. Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers. Am J Clin Nutr 2011:93;73-80.
DOI: https://doi.org/10.3945/ajcn.110.004945
Rizza S, Muniyappa R, Iantorno M, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing in-flammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab 2011;96:782-92.
DOI: https://doi.org/10.1210/jc.2010-2879
Benavente-Garcìa O, Castillo J, Marin FR, et al. Uses and properties of citrus flavonoids. J Agric Food Chem 1997;45:4505-15.
DOI: https://doi.org/10.1021/jf970373s
Manach C, Regerat F, Texier O, et al. Bioavailability, metabolism and physiological impact of 4-oxo-flavonoids. Nutr Res 1996;16:517-44.
DOI: https://doi.org/10.1016/0271-5317(96)00032-2
Van Wauwe J, Goossens J. Effects of antioxidants on cyclooxygenase and lipoxygenase activities in intact human platelets: Comparison with indomethacin and ETYA. Prostaglandins 1983;26:725-30.
DOI: https://doi.org/10.1016/0090-6980(83)90057-6
Tzeng SH, Ko WC, Ko FN, Teng CM. Inhibition of platelet aggregation by some flavonoids. Thromb Res 1991;64:91-100.
DOI: https://doi.org/10.1016/0049-3848(91)90208-E
Alcaraz MJ, Ferrandiz ML. Modification of arachidonic metabolism by flavonoids. J Ethnopharmacol 1987;21:209-29.
DOI: https://doi.org/10.1016/0378-8741(87)90101-2
Reyes-Farias M, Carrasco-Pozo C. The anticancer effect of quercetin: Molecular implications in cancer metabolism. Int J Mol Sci 2019;20:3177.
DOI: https://doi.org/10.3390/ijms20133177
Aghajanpour M, Nazer MR, Obeidavi Z, et al. Functional foods and their role in cancer prevention and health promotion: a comprehensive review. Am J Cancer Res 2017;7:740-69.
Rawson NE, Ho CT, Li S. Efficacious anticancer property of flavonoids from citrus peels. Food Sci Human Wellness 2014;3:104-9.
DOI: https://doi.org/10.1016/j.fshw.2014.11.001
Shimoi K, Masuda S, Furogori M, et al. Radioprotective affect of antioxidative flavonoids in c-ray irradiated mice. Carcinogenesis 1994;15:2669-72.
DOI: https://doi.org/10.1093/carcin/15.11.2669
Jeon SM, Bok SH, Jang MK, et al. Antioxidative activity of naringin and lovastatin in high cholesterol-fed rabbits. Life Sci 2001;69:2855-66.
DOI: https://doi.org/10.1016/S0024-3205(01)01363-7
Heo HY, Lee SJ, Kwon CH, et al. Anticlastogenic effects of galangin against bleomycin-induced chromosomal aberrations in mouse spleen lymphocytes. Mut Res 1994;311:225-9.
DOI: https://doi.org/10.1016/0027-5107(94)90180-5
So FV, Guthrie N, Chambers AF, et al. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 1996;26:167-81.
Wesołowska O, Wisniewski J, Roda-Pomianek KS, et al. Multidrug resistance reversal and apoptosis induction in human colon cancer cells by some flavonoids present in citrus plants. J Nat Prod 2012;75:1896-902.
DOI: https://doi.org/10.1021/np3003468
Scambia G, Ranelletti FO, Benedetti-Panici P, et al. Quercetin potentiates the effect of adriamycin in a multidrug resistant MCF-7 human breast cancer cell line: P-glycoprotein as a possible target. Cancer Chemother Pharmacol 1994;34:459-64.
DOI: https://doi.org/10.1007/BF00685655
Manthey JA, Guthrie N. Antiproliferative activities of citrus flavonoids against six human cancer cell lines. J Agric Food Chem 2002;50:5837-43.
DOI: https://doi.org/10.1021/jf020121d
Larocca LM, Piantelli M, Leone G, et al. Type II oestrogen binding sites in acute lymphoid and myeloid leukaemias: Growth inhibitory effect of oestrogen and flavonoids. Br J Haematol 1990;75:489-95.
DOI: https://doi.org/10.1111/j.1365-2141.1990.tb07787.x
Yoshida M, Sakai T, Hosokawa N, et al. The effect of quercetin on cell cycle progression and growth of human gastric cancer cells. FEBS Lett 1990;260:10-3.
DOI: https://doi.org/10.1016/0014-5793(90)80053-L
Scambia G, Ranelletti FO, Benedetti-Panici P, et al. Inhibitory effect of quercetin on OVCA 433 cells and presence of type II oestrogen binding sites in primary ovariun tumors and cultured cells. Br J Cancer 1990;62:942-6.
DOI: https://doi.org/10.1038/bjc.1990.414
Feletto E, Yu XQ, Lew JB, et al. Trends in colon and rectal cancer incidence in Australia from 1982 to 2014: Analysis of data on over 375,000 cases. Cancer Epidemiol Biomarkers Prev 2019;28:83-90.
DOI: https://doi.org/10.1158/1055-9965.EPI-18-0523
Miyamoto S, Yasui Y, Tanaka T, et al. Suppressive effects of nobiletinon hyperleptinemia and colitis related colon carcinogenesis in male iCR mice. Carcinogenesis 2008;29:1057-63.
DOI: https://doi.org/10.1093/carcin/bgn080
Miyamoto S, Yasui Y, Ohigashi H, et al. Dietary flavonoids suppress azoxymethane-induced colonic preneoplastic lesions inmale C57BL/KsJ-db/db mice. Chem Biol Interact 2010;183:276-83.
DOI: https://doi.org/10.1016/j.cbi.2009.11.002
Lai CS, Li S, Liu CB, et al. Effective suppression of azoxymethane induced aberrant crypt foci formation in mice with citrus peel flavonoids. Mol Nutr Food Res 2013;57:551-5.
DOI: https://doi.org/10.1002/mnfr.201200606
Murthy KNC, Kim J, Vikram A, Patil BS. Differential inhibition of human colon cancer cells by structurally similar flavonoids of citrus. Food Chem 2012;132:27-34.
DOI: https://doi.org/10.1016/j.foodchem.2011.10.014
Au A, Li B, Wang W, et al. Effect of dietary apigenin on colonic ornithine decarboxylase activity, aberrant crypt foci formation, and tumorigenesis in different experimental models. Nutr Cancer 2006;54:243-51.
DOI: https://doi.org/10.1207/s15327914nc5402_11
Aranganathan S, Selvam JP, Nalini N. Effect of hesperetin, a citrus flavonoid, on bacterial enzymes and carcinogen-induced aberrant crypt foci in colon cancer rats: a dose dependent study. J Pharm Pharmacol 2008;60:1385-92.
DOI: https://doi.org/10.1211/jpp.60.10.0015
Leonardi T, Vanamala J, Taddeo SS, et al. Apigenin and naringenin suppress colon carcinogenesis through the aberrant crypt stage in azoxymethane-treated rats. Exp Biol Med 2010;235:710-7.
DOI: https://doi.org/10.1258/ebm.2010.009359
Hoensch H, Groh B, Edler L, Kirch W. Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence. World J Gastroenterol 2008;14:2187-93.
DOI: https://doi.org/10.3748/wjg.14.2187
Jaganathan SK, Vellayappan MV, Narasimhan G, Supriyanto E. Role of pomegranate and citrus fruit juices in colon cancer prevention. World J Gastroenterol 2014;20:4618-25.
DOI: https://doi.org/10.3748/wjg.v20.i16.4618
Torre LA, Siegel RL, Jemal A. Lung cancer statistics. In: Lung Cancer and Personalized Medicine. Adv Exp Med Biol 2016;893:1-19.
DOI: https://doi.org/10.1007/978-3-319-24223-1_1
Christensen KY, Naidu A, Parent ME, et al. The risk of lung cancer related to dietary intake of flavonoide. Nutr Cancer 2012;64:964-74.
DOI: https://doi.org/10.1080/01635581.2012.717677
Le Marchand L, Murphy SP, Hankin JH, et al. Intake of Flavonoids and Lung Cancer. J Natl Cancer Inst 2000;92:154-60.
DOI: https://doi.org/10.1093/jnci/92.2.154
Luo G, Guan X, Zhou L. Apoptotic effect of citrus fruit extract nobiletin on lung cancer cell line A549 in vitro and in vivo. Cancer Biol Ther 2008;7:966-73.
DOI: https://doi.org/10.4161/cbt.7.6.5967
Park KI, Park HS, Kim MK, et al. Flavonoids identified from Korean Citrus aurantium L. inhibit non small cell lung cancer growth in vivo and in vitro. J Funct Foods 2014;7:287-29.
DOI: https://doi.org/10.1016/j.jff.2014.01.032
Suntar I, Khan H, Patel S, Celano R, Rastrelli L. An Overview on Citrus aurantium L.: Its Functions as Food Ingredient and Therapeutic Agent. Oxid. Med. Cell. Longev. 2018, 2018, 7864269.
DOI: https://doi.org/10.1155/2018/7864269
Bruno A, Siena L, Gerbino S, et al. Apigenin affects leptin/leptin receptor pathway and induces cell apoptosis in lung adeno-carcinoma cell line. Eur J Cancer 2011;47:2042-51.
DOI: https://doi.org/10.1016/j.ejca.2011.03.034
Sak K. Epidemiological evidences on dietary flavonoids and breast cancer Risk: A narrative review. Asian Pac J Cancer Prev 2017;18:2309-28.
Hitomi T, Hiroyuki S, Shunsuke Y, Kayoko S. Breast cancer and flavonoids - A role in prevention. Curr Pharm Des 2013;19:6125-32.
DOI: https://doi.org/10.2174/1381612811319340006
La Guardia M, Giammanco M. Breast cancer and obesity. Panminerva Med 2001;43:123-33.
So FV, Guthrie N, Chambers AF, et al. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 1996;26:167-81.
DOI: https://doi.org/10.1080/01635589609514473
Martinez-Perez C, Ward C, Turnbull AK, et al. Antitumour activity of the novel flavonoid Oncamex in preclinical breast cancer models. Br J Cancer 2016;114:905-16.
DOI: https://doi.org/10.1038/bjc.2016.6
Sergeev IN, Ho CT, Li S, et al. Apoptosis inducing activity of hydroxylated polymethoxyflavones and polymethoxyflavones from orange peel in human breast cancer cells. Mol Nutr Food Res 2007;51:1478-84.
DOI: https://doi.org/10.1002/mnfr.200700136
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
DOI: https://doi.org/10.3322/caac.21492
Sepporta MV, Tumminello FM, Flandina C, et al. Follistatin as potential therapeutic target in prostate cancer. Targ Oncol 2013;8:215-22.
DOI: https://doi.org/10.1007/s11523-013-0268-7
Wang Y, Stevens VL, Shah R, et al. Dietary flavonoid and proanthocyanidin intakes and prostate cancer risk in a prospective cohort of US men. Am J Epidemiol 2014;179:974-86.
DOI: https://doi.org/10.1093/aje/kwu006
Haddad AQ, Venkateswaran V, Viswanathan L, et al. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer P D 2006;9:68-76.
DOI: https://doi.org/10.1038/sj.pcan.4500845
Gao K, Henning SM, Niu Y, et al. The citrus flavonoid naringenin stimulates DNA repair in prostate cancer cells. J Nutr Biochem 2006;17:89-95.
DOI: https://doi.org/10.1016/j.jnutbio.2005.05.009
Lee CJ, Wilson L, Jordan MA, et al. Hesperidin suppressed proliferations of both Human breast cancer and androgen‐dependent prostate cancer cells. Phytother Res 2010;24:15-9.
DOI: https://doi.org/10.1002/ptr.2856
Chen JA, Creed A, Chen AY, et al. Nobiletin suppresses cell viability through AKT Pathways in PC-3 and DU-145 prostate cancer cells. BMC Pharmacol Toxicol 2014;15:59.
DOI: https://doi.org/10.1186/2050-6511-15-59
Xu R, Zhang Y, Ye X, et al. Inhibition effects and induction of apoptosis of flavonoids on the prostate cancer cell line PC-3 in vitro. Food Chem 2013;138:48-53.
DOI: https://doi.org/10.1016/j.foodchem.2012.09.102
Lai CS, Li S, Miyauchi Y, et al. Potent anticancer effects of citrus peel flavonoids in human prostate xenograft tumors. Food Funct 2013;4:944-9.
DOI: https://doi.org/10.1039/c3fo60037h
Pellegriti G, Frasca F, Regalbuto C, et al. Worldwide increasing incidence of thyroid cancer: Update on epidemiology and risk factors. J Cancer Epidemiol 2013;10:965212.
DOI: https://doi.org/10.1155/2013/965212
Giammanco M, Di Gesù G, Massenti MF, et al. Role of color flow Doppler sonography in pre-operative diagnostics of the thyroid pathology. Minerva Endocrinol 2002;27:1-10.
Gonçalves CFL, de Freitas ML, Ferreira ACF. Flavonoids, thyroid iodide uptake and thyroid cancer-a review. Int J Mol Sci 2017;18:1247.
DOI: https://doi.org/10.3390/ijms18061247
Allegri L, Rosignolo F, Mio C, et al. Effects of nutraceuticals on anaplastic thyroid cancercells. J Cancer Res Clin Oncol 2018;144:285-94.
DOI: https://doi.org/10.1007/s00432-017-2555-7
Celano M, Maggisano V, De Rose F, et al. Flavonoid fraction of Citrus Reticulata juice reduces proliferation and migration of anaplastic thyroid carcinoma cells. Nutr Cancer 2015;67:1183-90.
DOI: https://doi.org/10.1080/01635581.2015.1073760
Patel PN, Yu XM, Jaskula-Sztul R, Chen H. Hesperetin activates the Notch1 signaling cascade, causes apoptosis, and induces cellular differentiation in anaplastic thyroid cancer. Ann Surg Oncol 2014;21:497-504.
DOI: https://doi.org/10.1245/s10434-013-3459-7
Ciumărnean L, Milaciu MV, Runcan O, et al. The effects of flavonoids in cardiovascular diseases. Molecules 2020;25:4320.
DOI: https://doi.org/10.3390/molecules25184320
Lafuente AG, Guillamón E, Villares A, et al. Flavonoids as antiinflammatory agents: implications in cancer and cardiovascular disease. Inflamm Res 2009;58:537-552.
DOI: https://doi.org/10.1007/s00011-009-0037-3
Salvamani S, Gunasekaran B, Shaharuddin NA, et al. Anti-artherosclerotic effects of plant flavonoids. Bio Med Res Int 2014;11:480258.
DOI: https://doi.org/10.1155/2014/480258
Park EJ, Pezzuto JM. Flavonoids in cancer prevention. Anti Cancer Agent 2012;12:836-51.
DOI: https://doi.org/10.2174/187152012802650075
Scarpa ES, Giammanco M, Magnani M. Gastrointestinal tumors: phytochemical and drug combinations targeting the hallmarks of cancer. Appl Sci 2021;11:10077.
DOI: https://doi.org/10.3390/app112110077
Cantarella CD, Ragusa D, Giammanco M, Tosi S. Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature. Genes Nutr 2017;12:14.
DOI: https://doi.org/10.1186/s12263-017-0560-8
Araujo F, Gouvinhas C, Fontes F, et al. Trends in cardiovascular diseases and cancer mortality in 45 countries from five continents (1980-2010). Eur J Prev Cardiol 2014;21:1004-17.
DOI: https://doi.org/10.1177/2047487313497864
How to Cite
Giammanco, M., Plescia, F. ., Giammanco, M. M. ., Leto, G. ., & Gentile, C. . (2022). Bioactive effects of citrus flavonoids and role in the prevention of atherosclerosis and cancer. Journal of Biological Research - Bollettino Della Società Italiana Di Biologia Sperimentale, 95(1). https://doi.org/10.4081/jbr.2022.10313
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.