Health-promoting effects of the citrus flavanone hesperidin

Critical Reviews in Food Science and Nutrition

Volumn 57, Issue 3, 2017, Pages 613-631

  Li, Chaoyun ^a   Schluesener, Hermann ^a  

^a UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

Hesperidin; hesperitin; pharmacokinetics; pharmacology

Indexed keywords

MEDICAL APPLICATIONS; PHARMACOKINETICS;

CARDIO-VASCULAR DISEASE; HESPERIDIN; HESPERITIN; NEUROLOGICAL DISORDERS; PHARMACOLOGICAL ACTIVITY; PHARMACOLOGY; PRECLINICAL STUDIES; PSYCHIATRIC DISORDERS;

FLAVONOIDS;

ANTIINFLAMMATORY AGENT; ANTIOXIDANT; HESPERETIN; HESPERIDIN;

CARCINOMA; CARDIOVASCULAR DISEASE; CHEMISTRY; CITRUS; DRUG COMBINATION; HUMAN; NEUROLOGIC DISEASE; RANDOMIZED CONTROLLED TRIAL (TOPIC);

ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; CARCINOMA; CARDIOVASCULAR DISEASES; CITRUS; DRUG COMBINATIONS; HESPERIDIN; HUMANS; NERVOUS SYSTEM DISEASES; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 84992738230     PISSN: 10408398     EISSN: 15497852     Source Type: Journal    
DOI: 10.1080/10408398.2014.906382     Document Type: Article

References (160)

1. A.S.Abuelsaad, I.Mohamed, G.Allam, and A.A.Al-Solumani, (2013). Antimicrobial and immunomodulating activities of hesperidin and ellagic acid against diarrheic Aeromonas hydrophila in a murine model. Life Sci. 93:714–722.
2. S.T.Ahmad, W.Arjumand, S.Nafees, A.Seth, N.Ali, S.Rashid, and S.Sultana, (2012). Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation. Toxicol. Lett. 208:149–161.
3. A.Ahmadi, S.J.Hosseinimehr, F.Naghshvar, E.Hajir, and M.Ghahremani, (2008). Chemoprotective effects of hesperidin against genotoxicity induced by cyclophosphamide in mice bone marrow cells. Arch. Pharm. Res. 31:794–797.
4. S.Akiyama, S.Katsumata, K.Suzuki, Y.Ishimi, J.Wu, and M.Uehara, (2010). Dietary hesperidin exerts hypoglycemic and hypolipidemic effects in streptozotocin-induced marginal type 1 diabetic rats. J. Clin. Biochem. Nutr. 46:87–92.
5. S.Akiyama, S.Katsumata, K.Suzuki, Y.Nakaya, Y.Ishimi, and M.Uehara, (2009). Hypoglycemic and hypolipidemic effects of hesperidin and cyclodextrin-clathrated hesperetin in Goto-Kakizaki rats with type 2 diabetes. Biosci. Biotechnol. Biochem. 73:2779–2782.
6. C.Allegra, M.Bartolo, Jr., B.Carioti, and D.Cassiani, (1995). An original microhaemorheological approach to the pharmacological effects of Daflon 500 mg in severe chronic venous insufficiency. Int. J. Microcirc. Clin. Exp. 15(Suppl. 1):50–54.
7. C.Amato, (1994). Advantage of a micronized flavonoidic fraction (Daflon 500 mg) in comparison with a nonmicronized diosmin. Angiology. 45:531–536.
8. A.American Diabetes,. (2011). Diagnosis and classification of diabetes mellitus. Diabetes Care. 34(Suppl. 1):S62–S69.
9. R.Anandan, and P.Subramanian, (2012). Renal protective effect of hesperidin on gentamicin-induced acute nephrotoxicity in male Wistar albino rats. Redox. Rep. 17:219–226.
10. R.Andriantsitohaina, L.Duluc, J.C.Garcia-Rodriguez, L.Gil-del Valle, M.Guevara-Garcia, G.Simard, R.Soleti, D.F.Su, L.Velasquez-Perez, J.X.Wilson, and I.Laher, (2012). Systems biology of antioxidants. Clin. Sci. 123:173–192.
11. M.Arai, T.Matsumura, N.Tsuchiya, C.Sadakane, R.Inami, T.Suzuki, M.Yoshikawa, F.Imazeki, and O.Yokosuka, (2012). Rikkunshito improves the symptoms in patients with functional dyspepsia, accompanied by an increase in the level of plasma ghrelin. Hepato-Gastroenterology. 59:62–66.
12. I.C.Arts, and P.C.Hollman, (2005). Polyphenols and disease risk in epidemiologic studies. Am. J. Clin. Nutr. 81:317S–325S.
13. M.G.Baker, R.Kale, and M.Menken, (2002). The wall between neurology and psychiatry. Bmj. 324:1468–1469.
14. A.Balakrishnan, and V.P.Menon, (2007a). Antioxidant properties of hesperidin in nicotine-induced lung toxicity. Fundam. Clin. Pharmacol. 21:535–546.
15. A.Balakrishnan, and V.P.Menon, (2007b). Effect of hesperidin on matrix metalloproteinases and antioxidant status during nicotine-induced toxicity. Toxicology. 238:90–98.
16. A.Balakrishnan, and V.P.Menon, (2007c). Effect of hesperidin on nicotine toxicity and histopathological studies. Toxicol. Mech. Methods. 17:233–239.
17. A.Balakrishnan, and V.P.Menon, (2007d). Protective effect of hesperidin on nicotine induced toxicity in rats. Indian J. Exp. Biol. 45:194–202.
18. P.Bannasch, D.Mayer, and H.J.Hacker, (1980). Hepatocellular glycogenosis and hepatocarcinogenesis. Biochim. Biophys. Acta. 605:217–245.
19. A.Behar, G.Lagrue, F.Cohen-Boulakia, and J.Baillet, (1988). Study of capillary filtration by double labelling I131-albumin and Tc99m red cells. Application to the pharmacodynamic activity of Daflon 500 mg. Int. Angiol. 7:35–38.
20. M.A.Berhow, (1998). Flavonoid accumulation in tissue and cell culture. Studies in Citrus and other plant species. Adv. Exp. Med. Biol. 439:67–84.
21. H.Cai, and D.G.Harrison, (2000). Endothelial dysfunction in cardiovascular diseases:The role of oxidant stress. Circ. Res. 87:840–844.
22. S.T.Carmichael, (2005). Rodent models of focal stroke:Size, mechanism, and purpose. Neuro Rx. 2:396–409.
23. A.Chanet, D.Milenkovic, C.Manach, A.Mazur, and C.Morand, (2012). Citrus flavanones:What is their role in cardiovascular protection? J. Agric. Food Chem. 60:8809–8822.
24. M.Chen, H.Gu, Y.Ye, B.Lin, L.Sun, W.Deng, J.Zhang, and J.Liu, (2010a). Protective effects of hesperidin against oxidative stress of tert-butyl hydroperoxide in human hepatocytes. Food Chem. Toxicol. 48:2980–2987.
25. M.C.Chen, Y.Y.Ye, G.Ji, and J.W.Liu, (2010b). Hesperidin upregulates heme oxygenase-1 to attenuate hydrogen peroxide-induced cell damage in hepatic L02 cells. J. Agric. Food Chem. 58:3330–3335.
26. H.Chiba, H.Kim, A.Matsumoto, S.Akiyama, Y.Ishimi, K.Suzuki, and M.Uehara, (2013). Hesperidin prevents androgen deficiency-induced bone loss in male mice. Phytother Res.
27. H.Chiba, M.Uehara, J.Wu, X.Wang, R.Masuyama, K.Suzuki, K.Kanazawa, and Y.Ishimi, (2003). Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice. J. Nutr. 133:1892–1897.
28. M.Cospite, (1994). Double-blind, placebo-controlled evaluation of clinical activity and safety of Daflon 500 mg in the treatment of acute hemorrhoids. Angiology. 45:566–573.
29. D.Darr, and I.Fridovich, (1994). Free radicals in cutaneous biology. J. Invest. Dermatol. 102:671–675.
30. J.E.Deanfield, J.P.Halcox, and T.J.Rabelink, (2007). Endothelial function and dysfunction:Testing and clinical relevance. Circulation. 115:1285–1295.
31. B.M.Demaerschalk, H.M.Hwang, and G.Leung, (2010). US cost burden of ischemic stroke:A systematic literature review. Am. J. Manag. Care. 16:525–533.
32. I.Demonty, Y.Lin, Y.E.Zebregs, M.A.Vermeer, H.C.van der Knaap, M.Jakel, and E.A.Trautwein, (2010). The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and women. J. Nutr. 140:1615–1620.
33. E.E.Devore, J.H.Kang, M.M.Breteler, and F.Grodstein, (2012). Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann. Neurol. 72:135–143.
34. P.Duchene Marullaz, M.Amiel, and R.Barbe, (1988). Evaluation of the clinical pharmacological activity of a phlebotonic agent. Application to the study of Daflon 500 mg. Int. Angiol. 7:25–32.
35. S.M.El-Sayed el, O.M.Abo-Salem, M.F.Abd-Ellah, and G.M.Abd-Alla, (2008). Hesperidin, an antioxidant flavonoid, prevents acrylonitrile-induced oxidative stress in rat brain. J. Biochem. Mol. Toxicol. 22:268–273.
36. J.Elavarasan, P.Velusamy, T.Ganesan, S.K.Ramakrishnan, D.Rajasekaran, and K.Periandavan, (2012). Hesperidin-mediated expression of Nrf2 and upregulation of antioxidant status in senescent rat heart. J. Pharm. Pharmacol. 64:1472–1482.
37. C.B.Filho, Del L.Fabbro, M.G.de Gomes, A.T.Goes, L.C.Souza, S.P.Boeira, and C.R.Jesse, (2013). Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test. Eur. J. Pharmacol. 698:286–291.
38. C.Gandhi, A.Upaganalawar, and R.Balaraman, (2009). Protection against in vivo focal myocardial ischemia/reperfusion injury-induced arrhythmias and apoptosis by hesperidin. Free Radic. Res. 43:817–827.
39. X.Gao, A.Cassidy, M.A.Schwarzschild, E.B.Rimm, and A.Ascherio, (2012). Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology. 78:1138–1145.
40. A.Garg, S.Garg, L.J.Zaneveld, and A.K.Singla, (2001). Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother. Res. 15:655–669.
41. V.Gaur, A.Aggarwal, and A.Kumar, (2011). Possible nitric oxide mechanism in the protective effect of hesperidin against ischemic reperfusion cerebral injury in rats. Indian J. Exp. Biol. 49:609–618.
42. V.Gaur, and A.Kumar, (2010). Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol. Rep. 62:635–648.
43. G.Geroulakos, and A.N.Nicolaides, (1994). Controlled studies of Daflon 500 mg in chronic venous insufficiency. Angiology. 45:549–553.
44. A.Ghorbani, M.Nazari, M.Jeddi-Tehrani, and H.Zand, (2012). The citrus flavonoid hesperidin induces p53 and inhibits NF-kappaB activation in order to trigger apoptosis in NALM-6 cells:Involvement of PPARgamma-dependent mechanism. Eur. J. Nutr. 51:39–46.
45. P.Godeberge, (1994). Daflon 500 mg in the treatment of hemorrhoidal disease:A demonstrated efficacy in comparison with placebo. Angiology. 45:574–578.
46. R.Gonzalez-Barrio, L.M.Trindade, P.Manzanares, L.H.de Graaff, F.A.Tomas-Barberan, and J.C.Espin, (2004). Production of bioavailable flavonoid glucosides in fruit juices and green tea by use of fungal alpha-L-rhamnosidases. J. Agric. Food Chem. 52:6136–6142.
47. T.Guardia, A.E.Rotelli, A.O.Juarez, and L.E.Pelzer, (2001). Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco. 56:683–687.
48. J.J.Guex, Enriquez D.M.Vega, L.Avril, S.Boussetta, and C.Taieb, (2009). Assessment of quality of life in Mexican patients suffering from chronic venous disorder:Impact of oral Ruscus aculeatus-hesperidin-methyl-chalcone-ascorbic acid treatment—‘QUALITY Study’. Phlebology. 24:157–165.
49. J.J.Guilhou, O.Dereure, L.Marzin, P.Ouvry, F.Zuccarelli, C.Debure, Van H.Landuyt, M.N.Gillet-Terver, B.Guillot, H.Levesque, J.Mignot, G.Pillion, B.Fevrier, and D.Dubeaux, (1997). Efficacy of Daflon 500 mg in venous leg ulcer healing:A double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology. 48:77–85.
50. E.Ho, Karimi K.Galougahi, C.C.Liu, R.Bhindi, and G.A.Figtree, (2013). Biological markers of oxidative stress:Applications to cardiovascular research and practice. Redox. Biology. 1:483–491.
51. M.N.Horcajada, V.Habauzit, A.Trzeciakiewicz, C.Morand, A.Gil-Izquierdo, J.Mardon, P.Lebecque, M.J.Davicco, W.S.Chee, V.Coxam, and E.Offord, (2008). Hesperidin inhibits ovariectomized-induced osteopenia and shows differential effects on bone mass and strength in young and adult intact rats. J. Appl. Physiol. (1985). 104:648–654.
52. S.J.Hosseinimehr, A.Ahmadi, D.Beiki, E.Habibi, and A.Mahmoudzadeh, (2009a). Protective effects of hesperidin against genotoxicity induced by (99m)Tc-MIBI in human cultured lymphocyte cells. Nucl. Med. Biol. 36:863–867.
53. S.J.Hosseinimehr, A.Mahmoudzadeh, A.Ahmadi, S.Mohamadifar, and S.Akhlaghpoor, (2009b). Radioprotective effects of hesperidin against genotoxicity induced by gamma-irradiation in human lymphocytes. Mutagenesis. 24:233–235.
54. S.M.Huang, S.Y.Tsai, J.A.Lin, C.H.Wu, and G.C.Yen, (2012). Cytoprotective effects of hesperetin and hesperidin against amyloid beta-induced impairment of glucose transport through downregulation of neuronal autophagy. Mol. Nutr. Food Res. 56:601–609.
55. S.L.Hwang, J.A.Lin, P.H.Shih, C.T.Yeh, and G.C.Yen, (2012). Pro-cellular survival and neuroprotection of citrus flavonoid:The actions of hesperetin in PC12 cells. Food Funct. 3:1082–1090.
56. S.L.Hwang, and G.C.Yen, (2011). Effect of hesperetin against oxidative stress via ER- and TrkA-mediated actions in PC12 cells. J. Agric. Food Chem. 59:5779–5785.
57. V.Ibegbuna, A.N.Nicolaides, O.Sowade, M.Leon, and G.Geroulakos, (1997). Venous elasticity after treatment with Daflon 500 mg. Angiology. 48:45–49.
58. M.Ikemura, Y.Sasaki, J.C.Giddings, and J.Yamamoto, (2012). Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother. Res. 26:1272–1277.
59. M.J.Jin, U.Kim, I.S.Kim, Y.Kim, D.H.Kim, S.B.Han, D.H.Kim, O.S.Kwon, and H.H.Yoo, (2010). Effects of gut microflora on pharmacokinetics of hesperidin:A study on non-antibiotic and pseudo-germ-free rats. J. Toxicol. Environ. Health A. 73:1441–1450.
60. S.Jin, B.Zhou, and D.Luo, (2011). Hesperidin promotes cyclobutane pyrimidine dimer repair in UVB-exposed mice epidermis. Ir. J. Med. Sci. 180:709–714.
61. U.J.Jung, M.K.Lee, K.S.Jeong, and M.S.Choi, (2004). The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J. Nutr. 134:2499–2503.
62. K.B.Kalpana, N.Devipriya, M.Srinivasan, and V.P.Menon, (2009). Investigation of the radioprotective efficacy of hesperidin against gamma-radiation induced cellular damage in cultured human peripheral blood lymphocytes. Mutat. Res. 676:54–61.
63. S.Kamaraj, P.Anandakumar, S.Jagan, G.Ramakrishnan, and T.Devaki, (2010). Modulatory effect of hesperidin on benzo(a)pyrene induced experimental lung carcinogenesis with reference to COX-2, MMP-2 and MMP-9. Eur. J. Pharmacol. 649:320–327.
64. S.Kamaraj, P.Anandakumar, S.Jagan, G.Ramakrishnan, and T.Devaki, (2011). Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice. Fundam. Clin. Pharmacol. 25:91–98.
65. S.Kamaraj, G.Ramakrishnan, P.Anandakumar, S.Jagan, and T.Devaki, (2009). Antioxidant and anticancer efficacy of hesperidin in benzo(a)pyrene induced lung carcinogenesis in mice. Invest. New Drugs. 27:214–222.
66. S.Kamisli, O.Ciftci, K.Kaya, A.Cetin, O.Kamisli, and C.Ozcan, (2013). Hesperidin protects brain and sciatic nerve tissues against cisplatin-induced oxidative, histological and electromyographical side effects in rats. Toxicol. Ind. Health.
67. G.Kaur, N.Tirkey, and K.Chopra, (2006). Beneficial effect of hesperidin on lipopolysaccharide-induced hepatotoxicity. Toxicology. 226:152–160.
68. M.Kim, T.Kometani, S.Okada, and M.Shimuzu, (1999). Permeation of hesperidin glycosides across Caco-2 cell monolayers via the paracellular pathway. Biosci. Biotechnol. Biochem. 63:2183–2188.
69. S.H.Kim, B.K.Kim, and Y.C.Lee, (2011). Antiasthmatic effects of hesperidin, a potential Th2 cytokine antagonist, in a mouse model of allergic asthma. Mediators Inflamm. 2011:485402.
70. P.Knekt, J.Kumpulainen, R.Jarvinen, H.Rissanen, M.Heliovaara, A.Reunanen, T.Hakulinen, and A.Aromaa, (2002). Flavonoid intake and risk of chronic diseases. Am. J. Clin. Nutr. 76:560–568.
71. S.Kobayashi, S.Tanabe, M.Sugiyama, and Y.Konishi, (2008). Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers. Biochim. Biophys. Acta. 1778:33–41.
72. B.Kremer, P.Goldberg, S.E.Andrew, J.Theilmann, H.Telenius, J.Zeisler, F.Squitieri, B.Lin, A.Bassett, E.Almqvist, et al. (1994). A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N. Engl. J. Med. 330:1401–1406.
73. B.Kumar, S.K.Gupta, B.P.Srinivasan, T.C.Nag, S.Srivastava, R.Saxena, and K.A.Jha, (2013b). Hesperetin rescues retinal oxidative stress, neuroinflammation and apoptosis in diabetic rats. Microvasc. Res. 87:65–74.
74. P.Kumar, and A.Kumar, (2010). Protective effect of hesperidin and naringin against 3-nitropropionic acid induced Huntington's like symptoms in rats:Possible role of nitric oxide. Behav. Brain Res. 206:38–46.
75. A.Kumar, S.Lalitha, and J.Mishra, (2013a). Possible nitric oxide mechanism in the protective effect of hesperidin against pentylenetetrazole (PTZ)-induced kindling and associated cognitive dysfunction in mice. Epilepsy. Behav. 29:103–111.
76. E.M.Kurowska, J.D.Spence, J.Jordan, S.Wetmore, D.J.Freeman, L.A.Piche, and P.Serratore, (2000). HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am. J. Clin. Nutr. 72:1095–1100.
77. H.Kusunoki, K.Haruma, J.Hata, M.Ishii, T.Kamada, N.Yamashita, K.Honda, K.Inoue, H.Imamura, N.Manabe, A.Shiotani, and T.Tsunoda, (2010). Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Int. Med. 49:2195–2202.
78. M.C.Lai, and S.N.Yang, (2011). Perinatal hypoxic-ischemic encephalopathy. J. Biomed. Biotechnol. 2011:609813.
79. R.Laurent, R.Gilly, and C.Frileux, (1988). Clinical evaluation of a venotropic drug in man. Example of Daflon 500 mg. Int. Angiol. 7:39–43.
80. C.Le Devehat, T.Khodabandehlou, M.Vimeux, and C.Kempf, (1997). Evaluation of haemorheological and microcirculatory disturbances in chronic venous insufficiency:Activity of Daflon 500 mg. Int. J. Microcirc. Clin. Exp. 17(Suppl. 1):27–33.
81. C.J.Lee, L.Wilson, M.A.Jordan, V.Nguyen, J.Tang, and G.Smiyun, (2010a). Hesperidin suppressed proliferations of both human breast cancer and androgen-dependent prostate cancer cells. Phytother. Res. 24(Suppl. 1):S15–S19.
82. K.A.Lee, S.H.Lee, Y.J.Lee, S.M.Baeg, and J.H.Shim, (2012). Hesperidin Induces Apoptosis by Inhibiting Sp1 and Its Regulatory Protein in MSTO-211H Cells. Biomol. Ther. (Seoul). 20:273–279.
83. K.H.Lee, M.H.Yeh, S.T.Kao, C.M.Hung, C.J.Liu, Y.Y.Huang, and C.C.Yeh, (2010b). The inhibitory effect of hesperidin on tumor cell invasiveness occurs via suppression of activator protein 1 and nuclear factor-kappaB in human hepatocellular carcinoma cells. Toxicol. Lett. 194:42–49.
84. Y.R.Lee, J.H.Jung, and H.S.Kim, (2011). Hesperidin partially restores impaired immune and nutritional function in irradiated mice. J. Med. Food. 14:475–482.
85. R.Li, L.Cai, X.F.Xie, F.Yang, and J.Li, (2010). Hesperidin suppresses adjuvant arthritis in rats by inhibiting synoviocyte activity. Phytother. Res. 24(Suppl 1):S71–S76.
86. C.Li, A.Ebrahimi, and H.Schluesener, (2013a). Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease. Ageing Res. Rev. 12:116–140.
87. R.Li, J.Li, L.Cai, C.M.Hu, and L.Zhang, (2008a). Suppression of adjuvant arthritis by hesperidin in rats and its mechanisms. J. Pharm. Pharmacol. 60:221–228.
88. Y.M.Li, X.M.Li, G.M.Li, W.C.Du, J.Zhang, W.X.Li, J.Xu, M.Hu, and Z.Zhu, (2008b). In vivo pharmacokinetics of hesperidin are affected by treatment with glucosidase-like BglA protein isolated from yeasts. J. Agric. Food Chem. 56:5550–5557.
89. C.Li, K.Yuan, and H.Schluesener, (2013b). Impact of minocycline on neurodegenerative diseases in rodents:A meta-analysis. Rev. Neurosci. 24:553–562.
90. A.M.Mahmoud, M.B.Ashour, A.Abdel-Moneim, and O.M.Ahmed, (2012). Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat ed/streptozotocin-induced type 2 diabetic rats. J. Diab. Complicat. 26:483–490.
91. C.Manach, C.Morand, A.Gil-Izquierdo, C.Bouteloup-Demange, and C.Remesy, (2003). Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. Eur. J. Clin. Nutr. 57:235–242.
92. J.A.Manthey, and K.Grohmann, (1998). Flavonoids of the orange subfamily Aurantioideae. Adv. Exp. Med. Biol. 439:85–101.
93. M.C.Martinez, S.P.Fernandez, L.M.Loscalzo, C.Wasowski, A.C.Paladini, M.Marder, J.H.Medina, and H.Viola, (2009). Hesperidin, a flavonoid glycoside with sedative effect, decreases brain pERK1/2 levels in mice. Pharmacol. Biochem. Behav. 92:291–296.
94. E.T.Menze, M.G.Tadros, A.M.Abdel-Tawab, and A.E.Khalifa, (2012). Potential neuroprotective effects of hesperidin on 3-nitropropionic acid-induced neurotoxicity in rats. Neurotoxicology. 33:1265–1275.
95. A.W.Meshikhes, (2002). Efficacy of Daflon in the treatment of hemorrhoids. Saudi Medical Journal. 23:1496–1498.
96. A.W.Meshikhes, (2004). Daflon for haemorrhoids:A prospective, multi-centre observational study. Surg. J. R. Coll. Surg. E. I. 2:335–338, 361.
97. D.Milenkovic, C.Deval, C.Dubray, A.Mazur, and C.Morand, (2011). Hesperidin displays relevant role in the nutrigenomic effect of orange juice on blood leukocytes in human volunteers:A randomized controlled cross-over study. PLoS One. 6:e26669.
98. Y.Miwa, M.Yamada, T.Sunayama, H.Mitsuzumi, Y.Tsuzaki, H.Chaen, Y.Mishima, and M.Kibata, (2004). Effects of glucosyl hesperidin on serum lipids in hyperlipidemic subjects:Preferential reduction in elevated serum triglyceride level. J. Nutr. Sci. Vitaminol (Tokyo). 50:211–218.
99. M.F.Molina-Jimenez, M.I.Sanchez-Reus, D.Andres, M.Cascales, and J.Benedi, (2004). Neuroprotective effect of fraxetin and myricetin against rotenone-induced apoptosis in neuroblastoma cells. Brain Res. 1009:9–16.
100. P.D.Moon, and H.M.Kim, (2012). Antiinflammatory effects of traditional Korean medicine, JinPi-tang and its active ingredient, hesperidin in HaCaT cells. Phytother. Res. 26:657–662.
101. C.Morand, C.Dubray, D.Milenkovic, D.Lioger, J.F.Martin, A.Scalbert, and A.Mazur, (2011). Hesperidin contributes to the vascular protective effects of orange juice:A randomized crossover study in healthy volunteers. Am. J. Clin. Nutr. 93:73–80.
102. S.E.Moss, R.Klein, and B.E.Klein, (1998). The 14-year incidence of visual loss in a diabetic population. Ophthalmology. 105:998–1003.
103. C.F.Mueller, K.Laude, J.S.McNally, and D.G.Harrison, (2005). ATVB in focus:Redox mechanisms in blood vessels. Arterioscler. Thromb. Vasc. Biol. 25:274–278.
104. N.Nandakumar, and M.P.Balasubramanian, (2011). Hesperidin protects renal and hepatic tissues against free radical-mediated oxidative stress during DMBA-induced experimental breast cancer. J. Environ. Pathol. Toxicol. Oncol. 30:283–300.
105. N.Nandakumar, and M.P.Balasubramanian, (2012). Hesperidin a citrus bioflavonoid modulates hepatic biotransformation enzymes and enhances intrinsic antioxidants in experimental breast cancer rats challenged with 7, 12-dimethylbenz (a) anthracene. J. Exp. Ther. Oncol. 9:321–335.
106. N.Nandakumar, R.Jayaprakash, and M.P.Balasubramanian, (2012). Influence of hesperidin on renal cell surface glycoprotein content, nucleic acids, lysosomal enzymes and macromolecules against 7, 12-dimethylbenz [a] anthracene induced experimental breast carcinoma. J. Exp. Ther. Oncol. 9:265–280.
107. N.Nandakumar, T.Rengarajan, A.Balamurugan, and M.Balasubramanian, (2013). Modulating effects of hesperidin on key carbohydrate-metabolizing enzymes, lipid profile, and membrane-bound adenosine triphosphatases against 7,12-dimethylbenz(a)anthracene-induced breast carcinogenesis. Hum. Exp. Toxicol.
108. I.L.Nielsen, W.S.Chee, L.Poulsen, E.Offord-Cavin, S.E.Rasmussen, H.Frederiksen, M.Enslen, D.Barron, M.N.Horcajada, and G.Williamson, (2006). Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans:A randomized, double-blind, crossover trial. J. Nutr. 136:404–408.
109. J.Nones, T.C.Spohr, and F.C.Gomes, (2011). Hesperidin, a flavone glycoside, as mediator of neuronal survival. Neurochem. Res. 36:1776–1784.
110. J.Nones, T.C.Spohr, and F.C.Gomes, (2012). Effects of the flavonoid hesperidin in cerebral cortical progenitors in vitro:Indirect action through astrocytes. Int. J. Dev. Neurosci. 30:303–313.
111. K.Ohtsuki, A.Abe, H.Mitsuzuwi, M.Kondo, K.Uemura, Y.Iwasaki, and Y.Kondo, (2002). Effects of long-term administration of hesperidin and glucosyl hesperidin to spontaneously hypertensive rats. J. Nutr. Sci. Vitaminol. (Tokyo). 48:420–422.
112. K.Ohtsuki, A.Abe, H.Mitsuzumi, M.Kondo, K.Uemura, Y.Iwasaki, and Y.Kondo, (2003). Glucosyl hesperidin improves serum cholesterol composition and inhibits hypertrophy in vasculature. J. Nutr. Sci. Vitaminol. (Tokyo). 49:447–450.
113. S.Okuno, K.Hirayama, J.Inoue, K.Yamasaki, R.Kawahara, T.Yokoi, N.Saeki, and T.Funato, (2008). [Effects of rikkunshito on the postoperative nausea and vomiting (PONV) after laparoscopic gynecological surgery]. Masui. Jpn J. Anesthesiol. 57:1502–1509.
114. A.D.Ortega, M.Sanchez-Arago, D.Giner-Sanchez, L.Sanchez-Cenizo, I.Willers, and J.M.Cuezva, (2009). Glucose avidity of carcinomas. Cancer Lett. 276:125–135.
115. H.J.Park, M.J.Kim, E.Ha, and J.H.Chung, (2008). Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine. 15:147–151.
116. A.P.Pecking, (1995). Evaluation by lymphoscintigraphy of the effect of a micronized flavonoid fraction (Daflon 500 mg) in the treatment of upper limb lymphedema. Int. Angiol. 14:39–43.
117. A.P.Pecking, B.Fevrier, C.Wargon, and G.Pillion, (1997). Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Angiology. 48:93–98.
118. J.J.Peterson, J.T.Dwyer, G.R.Beecher, S.A.Bhagwat, S.E.Gebhardt, D.B.Haytowitz, and J.M.Holden, (2006). Flavanones in oranges, tangerines (mandarins), tangors, and tangelos:A compilation and review of the data from the analytical literature. J. Food Composit. Anal. 19:S66–S73.
119. A.Petrova, L.M.Davids, F.Rautenbach, and J.L.Marnewick, (2011). Photoprotection by honeybush extracts, hesperidin and mangiferin against UVB-induced skin damage in SKH-1 mice. J. Photochem. Photobiol. B. 103:126–139.
120. K.Pradeep, K.C.Ko, M.H.Choi, J.A.Kang, Y.J.Chung, and S.H.Park, (2012). Protective effect of hesperidin, a citrus flavanoglycone, against gamma-radiation-induced tissue damage in Sprague–Dawley rats. J. Med. Food. 15:419–427.
121. K.Pradeep, S.H.Park, and K.C.Ko, (2008). Hesperidin a flavanoglycone protects against gamma-irradiation induced hepatocellular damage and oxidative stress in Sprague–Dawley rats. Eur. J. Pharmacol. 587:273–280.
122. K.Radad, W.D.Rausch, and G.Gille, (2006). Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem. Int. 49:379–386.
123. S.S.Raza, M.M.Khan, A.Ahmad, M.Ashafaq, G.Khuwaja, R.Tabassum, H.Javed, M.S.Siddiqui, M.M.Safhi, and F.Islam, (2011). Hesperidin ameliorates functional and histological outcome and reduces neuroinflammation in experimental stroke. Brain Res. 1420:93–105.
124. S.Rizza, R.Muniyappa, M.Iantorno, J.A.Kim, H.Chen, P.Pullikotil, N.Senese, M.Tesauro, D.Lauro, C.Cardillo, and M.J.Quon, (2011). Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J. Clin. Endocrinol. Metab. 96:E782–E792.
125. Z.Rong, R.Pan, Y.Xu, C.Zhang, Y.Cao, and D.Liu, (2013). Hesperidin pretreatment protects hypoxia-ischemic brain injury in neonatal rat. Neuroscience. 255:292–299.
126. K.Roztocil, V.Stvrtinova, and J.Strejcek, (2003). Efficacy of a 6-month treatment with Daflon 500 mg in patients with venous leg ulcers associated with chronic venous insufficiency. Int. Angiol. 22:24–31.
127. R.K.Saha, T.Takahashi, and T.Suzuki, (2009). Glucosyl hesperidin prevents influenza a virus replication in vitro by inhibition of viral sialidase. Biol. Pharm. Bull. 32:1188–1192.
128. B.D.Sahu, M.Kuncha, G.J.Sindhura, and R.Sistla, (2013). Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. Phytomedicine. 20:453–460.
129. U.Z.Said, H.N.Saada, M.S.Abd-Alla, M.E.Elsayed, and A.M.Amin, (2012). Hesperidin attenuates brain biochemical changes of irradiated rats. Int. J. Radiat. Biol. 88:613–618.
130. G.Saiprasad, P.Chitra, R.Manikandan, and G.Sudhandiran, (2013). Hesperidin alleviates oxidative stress and downregulates the expressions of proliferative and inflammatory markers in azoxymethane-induced experimental colon carcinogenesis in mice. Inflamm. Res. 62:425–440.
131. P.Selvaraj, and K.V.Pugalendi, (2010). Hesperidin, a flavanone glycoside, on lipid peroxidation and antioxidant status in experimental myocardial ischemic rats. Redox. Rep. 15:217–223.
132. P.Selvaraj, and K.V.Pugalendi, (2012). Efficacy of hesperidin on plasma, heart and liver tissue lipids in rats subjected to isoproterenol-induced cardiotoxicity. Exp. Toxicol. Pathol. 64:449–452.
133. X.Shi, S.Liao, H.Mi, C.Guo, D.Qi, F.Li, C.Zhang, and Z.Yang, (2012). Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Molecules. 17:12868–12881.
134. M.Shiratori, T.Shoji, M.Kanazawa, M.Hongo, and S.Fukudo, (2011). Effect of rikkunshito on gastric sensorimotor function under distention. Neurogastroenterol. Motil. 23:323–329, e155–e326.
135. N.A.Simonian, and J.T.Coyle, (1996). Oxidative stress in neurodegenerative diseases. Ann. Rev. Pharmacol. Toxicol. 36:83–106.
136. M.Simsek, F.Burak, and O.Taskin, (2007). Effects of micronized purified flavonoid fraction (Daflon) on pelvic pain in women with laparoscopically diagnosed pelvic congestion syndrome:A randomized crossover trial. Clin. Exp. Obstet. Gynecol. 34:96–98.
137. G.D.Smith, M.J.Shipley, M.G.Marmot, and G.Rose, (1992). Plasma cholesterol concentration and mortality. The whitehall study. JAMA. 267:70–76.
138. V.C.Sonntag, (1987). The Chemical Basis of Radiation Biology. London:Taylor and Francis.
139. L.C.Souza, M.G.de Gomes, A.T.Goes, Del L.Fabbro, C.B.Filho, S.P.Boeira, and C.R.Jesse, (2013). Evidence for the involvement of the serotonergic 5-HT(1A) receptors in the antidepressant-like effect caused by hesperidin in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry. 40:103–109.
140. T.Takahashi, S.Endo, K.Nakajima, Y.Souma, and T.Nishida, (2009). Effect of rikkunshito, a chinese herbal medicine, on stasis in patients after pylorus-preserving gastrectomy. World J Surg. 33:296–302.
141. S.Takiguchi, Y.Hiura, T.Takahashi, Y.Kurokawa, M.Yamasaki, K.Nakajima, H.Miyata, M.Mori, H.Hosoda, K.Kangawa, and Y.Doki, (2013). Effect of rikkunshito, a Japanese herbal medicine, on gastrointestinal symptoms and ghrelin levels in gastric cancer patients after gastrectomy. Gastric Cancer. 16:167–174.
142. K.Tamilselvam, N.Braidy, T.Manivasagam, M.Essa, N.R.Prasad, S.Karthikeyan, A.J.Thenmozhi, S.Selvaraju, and G.J.Guillemin, (2013). Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxidative stress and apoptosis in a cellular model for Parkinson's disease. Oxid. Med. Cell. Longev.2013:102741.
143. T.Tanaka, H.Makita, K.Kawabata, H.Mori, M.Kakumoto, K.Satoh, A.Hara, T.Sumida, and H.Ogawa, (1997). Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin. Carcinogenesis. 18:957–965.
144. W.Thanapongsathorn, and T.Vajrabukka, (1992). Clinical trial of oral diosmin (Daflon) in the treatment of hemorrhoids. Dis Colon. Rectum. 35:1085–1088.
145. K.Tominaga, R.Iwakiri, K.Fujimoto, Y.Fujiwara, M.Tanaka, Y.Shimoyama, E.Umegaki, K.Higuchi, M.Kusano, T.Arakawa, and G.S.Group, (2012). Rikkunshito improves symptoms in PPI-refractory GERD patients:A prospective, randomized, multicenter trial in Japan. J. Gastroenterol. 47:284–292.
146. E.C.Tsimoyiannis, G.Floras, N.Antoniou, N.Papanikolaou, P.Siakas, and A.Tassis, (1996). Low-molecular-weight heparins and Daflon for prevention of postoperative thromboembolism. World J Surg. 20:968–971; discussion 972.
147. S.Umar, A.Kumar, M.Sajad, J.Zargan, M.Ansari, S.Ahmad, C.K.Katiyar, and H.A.Khan, (2013). Hesperidin inhibits collagen-induced arthritis possibly through suppression of free radical load and reduction in neutrophil activation and infiltration. Rheumatol. Int. 33:657–663.
148. G.L.Viswanatha, H.Shylaja, Sandeep K.S.Rao, Santhosh V.R.Kumar, and M.Jagadeesh, (2012). Hesperidin ameliorates immobilization-stress-induced behavioral and biochemical alterations and mitochondrial dysfunction in mice by modulating nitrergic pathway. ISRN Pharmacol. 2012:479570.
149. X.Wang, J.Hasegawa, Y.Kitamura, Z.Wang, A.Matsuda, W.Shinoda, N.Miura, and K.Kimura, (2011). Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats. J. Pharmacol. Sci. 117:129–138.
150. D.M.Wang, S.Q.Li, X.Y.Zhu, Y.Wang, W.L.Wu, and X.J.Zhang, (2013). Protective effects of hesperidin against amyloid-beta (Abeta) induced neurotoxicity through the voltage dependent anion channel 1 (VDAC1)-mediated mitochondrial apoptotic pathway in PC12 cells. Neurochem. Res. 38:1034–1044.
151. C.Wasowski, L.M.Loscalzo, J.Higgs, and M.Marder, (2012). Chronic intraperitoneal and oral treatments with hesperidin induce central nervous system effects in mice. Phytother. Res. 26:308–312.
152. D.Wei, X.Ci, X.Chu, M.Wei, S.Hua, and X.Deng, (2012). Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. Inflammation. 35:114–121.
153. L.Xu, Z.L.Yang, P.Li, and Y.Q.Zhou, (2009). Modulating effect of Hesperidin on experimental murine colitis induced by dextran sulfate sodium. Phytomedicine. 16:989–995.
154. M.Yamada, F.Tanabe, N.Arai, H.Mitsuzumi, Y.Miwa, M.Kubota, H.Chaen, and M.Kibata, (2006). Bioavailability of glucosyl hesperidin in rats. Biosci. Biotechnol. Biochem. 70:1386–1394.
155. M.Yamamoto, H.Jokura, K.Hashizume, H.Ominami, Y.Shibuya, A.Suzuki, T.Hase, and A.Shimotoyodome, (2013). Hesperidin metabolite hesperetin-7-O-glucuronide, but not hesperetin-3′-O-glucuronide, exerts hypotensive, vasodilatory, and anti-inflammatory activities. Food Funct. 4:1346–1351.
156. M.Yamamoto, A.Suzuki, H.Jokura, N.Yamamoto, and T.Hase, (2008b). Glucosyl hesperidin prevents endothelial dysfunction and oxidative stress in spontaneously hypertensive rats. Nutrition. 24:470–476.
157. M.Yamamoto, A.Suzuki, and T.Hase, (2008a). Short-term effects of glucosyl hesperidin and hesperetin on blood pressure and vascular endothelial function in spontaneously hypertensive rats. J. Nutr. Sci. Vitaminol. (Tokyo). 54:95–98.
158. M.H.Yeh, S.T.Kao, C.M.Hung, C.J.Liu, K.H.Lee, and C.C.Yeh, (2009). Hesperidin inhibited acetaldehyde-induced matrix metalloproteinase-9 gene expression in human hepatocellular carcinoma cells. Toxicol. Lett. 184:204–210.
159. C.C.Yeh, S.J.Kao, C.C.Lin, S.D.Wang, C.J.Liu, and S.T.Kao, (2007). The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro. Life Sci. 80:1821–1831.
160. K.A.Youdim, M.S.Dobbie, G.Kuhnle, A.R.Proteggente, N.J.Abbott, and C.Rice-Evans, (2003). Interaction between flavonoids and the blood-brain barrier:In vitro studies. J. Neurochem. 85:180–192.