Pharmacological Attributes of Hesperidin

Iqra      Subhan; Yasir   Hasan   Siddique
doi:10.2174/2215083810666230822113623
Abstract

Hesperidin is a major flavonoid in sweet oranges and lemons. Aglycone form of hesperidin i.e., hesperetin, and their various derivatives possess significant potential as therapeutic agents for a wide range of diseases and disorders. No signs of toxicity have been observed with the normal intake of hesperidin or related compounds. Hesperidin has been reported to possess a wide range of pharmacological properties, which includes antioxidant, anti-viral, anticancer, antidiabetic, analgesic, organ protective, neuroprotective, antihypertensive, and cardioprotective effects. This needs to be effectively studied at the clinical level so as to firmly establish the usefulness of these compounds in the treatment or prevention of disease in humans. This paper reviews various aspects of hesperidin, including their chemistry, biosynthesis, and bioactivity.
Keywords: Hesperidin, flavonoids, hepatoprotective, neuroprotective, antioxidant, radioprotective.
Graphical Abstract

[1]
Ganeshpurkar A, Saluja A. The pharmacological potential of hesperidin. Indian J Biochem Biophys  2019; 56(4): 287-300.

[2]
Kalpana KB, Devipriya N, Srinivasan M, Vishwanathan P, Kuppsamy T, Menon VP. Evaluating the radioprotective effect of hesperidin in the liver of Swiss albino mice. Eur J Pharmacol  2011; 658(2-3): 206-12.
 [http://dx.doi.org/10.1016/j.ejphar.2011.02.031] [PMID: 21371459]

[3]
Yahia EM, García-Solís P, Celis MEM. Contribution of fruits and vegetables to human nutrition and health. In: Postharvest physiology and biochemistry of fruits and vegetables.  Woodhead Publishing 2019; pp. 19-45.
 [http://dx.doi.org/10.1016/B978-0-12-813278-4.00002-6]

[4]
Kim J, Wie MB, Ahn M, Tanaka A, Matsuda H, Shin T. Benefits of hesperidin in central nervous system disorders: A review. Anat Cell Biol  2019; 52(4): 369-77.
 [http://dx.doi.org/10.5115/acb.19.119] [PMID: 31949974]

[5]
Tirkey N, Pilkhwal S, Kuhad A, Chopra K. Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetra-chloride in rat liver and kidney. BMC Pharmacol  2005; 5(1): 2.
 [http://dx.doi.org/10.1186/1471-2210-5-2] [PMID: 15683547]

[6]
Mas-Capdevila A, Teichenne J, Domenech-Coca C, et al. Effect of hesperidin on cardiovascular disease risk factors: The role of intestinal microbiota on hesperidin bioavailability. Nutrients  2020; 12(5): 1488.
 [http://dx.doi.org/10.3390/nu12051488] [PMID: 32443766]

[7]
Man MQ, Yang B, Elias PM. Benefits of hesperidin for cutaneous functions. Evid Based Complement Alternat Med  2019; 2019: 1-19.
 [http://dx.doi.org/10.1155/2019/2676307] [PMID: 31061668]

[8]
Li C, Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Crit Rev Food Sci Nutr  2017; 57(3): 613-31.
 [http://dx.doi.org/10.1080/10408398.2014.906382] [PMID: 25675136]

[9]
Haggag YA, El-Ashmawy NE, Okasha KM. Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection? Med Hypotheses  2020; 144: 109957.
 [http://dx.doi.org/10.1016/j.mehy.2020.109957] [PMID: 32531538]

[10]
Garg A, Garg S, Zaneveld LJD, Singla AK. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phyt Res  2000; 15(8): 655-69.

[11]
Fe SA, Ek B, D O, Jo A. Hesperidin-Sources, chemistry, extraction, measurement and biologic effects on reproduction in animals: A review.  Int J Vet Sci Anim Husb  2021; 6(4): 01-8.
 [http://dx.doi.org/10.22271/veterinary.2021.v6.i3a.360]

[12]
Horowitz RM, Gentili B. Flavonoids of citrus—VI. Tetrahedron  1963; 19(5): 773-82.
 [http://dx.doi.org/10.1016/S0040-4020(01)99211-7]

[13]
Kometani T, Nishimura T, Nakae T, Takii H, Okada S. Synthesis of neohesperidin glycosides and naringin glycosides by cyclodextrin glucanotransferase from an alkalophilic Bacillus species. Biosci Biotechnol Biochem  1996; 60(4): 645-9.
 [http://dx.doi.org/10.1271/bbb.60.645] [PMID: 8829532]

[14]
Devi KP, Rajavel T, Nabavi SF, et al. Hesperidin: A promising anticancer agent from nature. Ind Crops Prod  2015; 76: 582-9.
 [http://dx.doi.org/10.1016/j.indcrop.2015.07.051]

[15]
Fox DW, Savage WL, Wender SH. Hydrolysis of some flavonoid rhamnoglucosides to flavonoid glucosides. J Am Chem Soc  1953; 75(10): 2504-5.
 [http://dx.doi.org/10.1021/ja01106a507]

[16]
Wanner LA, Li G, Ware D, Somssich IE, Davis KR. The phenylalanine ammonialyase gene family in Arabidopsis thaliana. Plant Mol Biol  1995; 27(2): 327-38.
 [http://dx.doi.org/10.1007/BF00020187] [PMID: 7888622]

[17]
Mizutani M, Ohta D, Sato R. Isolation of a cDNA and a genomic clone encoding cinnamate 4-hydroxylase from Arabidopsis and its expression manner in planta. Plant Physiol  1997; 113(3): 755-63.
 [http://dx.doi.org/10.1104/pp.113.3.755] [PMID: 9085571]

[18]
Costa MA, Bedgar DL, Moinuddin SGA, et al. Characterization in vitro and in vivo of the putative multigene 4-coumarate:CoA ligase network in Arabidopsis: Syringyl lignin and sinapate/sinapyl alcohol derivative formation. Phytochemistry  2005; 66(17): 2072-91.
 [http://dx.doi.org/10.1016/j.phytochem.2005.06.022] [PMID: 16099486]

[19]
Jez JM, Noel JP. Reaction mechanism of chalcone isomerase. pH dependence, diffusion control, and product binding differences. J Biol Chem  2002; 277(2): 1361-9.
 [http://dx.doi.org/10.1074/jbc.M109224200] [PMID: 11698411]

[20]
Durren RL, McIntosh CA. Flavanone-7-O-glucosyltransferase activity from Petunia hybrida. Phytochemistry  1999; 52(5): 793-8.
 [http://dx.doi.org/10.1016/S0031-9422(99)00307-6] [PMID: 10626374]

[21]
Bar-Peled M, Lewinsohn E, Fluhr R, Gressel J. UDP-rhamnose:flavanone-7-O-glucoside-2“-O-rhamnosyltransferase. Purification and characterization of an enzyme catalyzing the production of bitter compounds in citrus. J Biol Chem  1991; 266(31): 20953-9.
 [http://dx.doi.org/10.1016/S0021-9258(18)54803-1] [PMID: 1939145]

[22]
Musa AE, Omyan G, Esmaely F, Shabeeb D. Radioprotective effect of hesperidin: A systematic review. Medicina  2019; 5(7): 370.
 [http://dx.doi.org/10.3390/medicina55070370]

[23]
Zanwar AA, Badole SL, Shende PS, Hegde MV, Bodhankar SL. Cardiovascular effects of hesperidin: A flavanone glycoside. In: Polyphenols in human health and disease.  Acad Press 2014; pp. 989-92.
 [http://dx.doi.org/10.1016/B978-0-12-398456-2.00076-1]

[24]
Sriset Y, Sukkasem N, Chatuphonprasert W, Jarukamjorn K. Nephroprotective effects of hesperidin and myricetin against high-fat diet plus ethanol-induced renal oxidative damage in mice. Rev Bras Farmacogn  2022; 32(4): 555-62.
 [http://dx.doi.org/10.1007/s43450-022-00275-5]

[25]
Ahmed OM, Mahmoud AM, Abdel-Moneim A, Ashour MB. Antidiabetic effects of hesperidin and naringin in type 2 diabetic rats. Diabetol Croat  2012; 41(2): 53-67.

[26]
Wei D, Ci X, Chu X, Wei M, Hua S, Deng X. Hesperidin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. Inflammation  2012; 35(1): 114-21.
 [http://dx.doi.org/10.1007/s10753-011-9295-7] [PMID: 21287361]

[27]
Panda S, Kar A. Antithyroid effects of naringin, hesperidin and rutin in l-T4 induced hyperthyroid rats: Possible mediation through 5′DI activity. Pharmacol Rep  2014; 66(6): 1092-9.
 [http://dx.doi.org/10.1016/j.pharep.2014.07.002] [PMID: 25443740]

[28]
Najm WI. Peptic ulcer disease. Primary Care. Prim Care  2011; 38(3): 383-94.
 [http://dx.doi.org/10.1016/j.pop.2011.05.001]

[29]
Araújo MB, Borini P, Guimarães RC. Etiopathogenesis of peptic ulcer: Back to the past? Arq Gastroenterol  2014; 51(2): 155-61.
 [http://dx.doi.org/10.1590/S0004-28032014000200016] [PMID: 25003270]

[30]
Graham DY. History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol  2014; 20(18): 5191-204.
 [http://dx.doi.org/10.3748/wjg.v20.i18.5191] [PMID: 24833849]

[31]
Fox RK, Muniraj T. Pharmacologic therapies in gastrointestinal diseases. Med Clin North Am  2016; 100(4): 827-50.
 [http://dx.doi.org/10.1016/j.mcna.2016.03.009] [PMID: 27235617]

[32]
Yu G, Torres J, Hu N, et al. Molecular characterization of the human stomach microbiota in gastric cancer patients. Front Cell Infect Microbiol  2017; 7: 302.
 [http://dx.doi.org/10.3389/fcimb.2017.00302] [PMID: 28730144]

[33]
Selmi S, Rtibi K, Grami D, Sebai H, Marzouki L. Protective effects of orange (Citrus sinensis L.) peel aqueous extract and hesperidin on oxidative stress and peptic ulcer induced by alcohol in rat. Lipids Health Dis  2017; 16(1): 152.
 [http://dx.doi.org/10.1186/s12944-017-0546-y] [PMID: 28806973]

[34]
Bigoniya P, Singh K. Ulcer protective potential of standardized hesperidin, a citrus flavonoid isolated from Citrus sinensis. Rev Bras Farmacogn  2014; 24(3): 330-40.
 [http://dx.doi.org/10.1016/j.bjp.2014.07.011]

[35]
da Silva LM, Pezzini BC, Somensi LB, et al. Hesperidin, a citrus flavanone glycoside, accelerates the gastric healing process of acetic acid-induced ulcer in rats. Chem Biol Interact  2019; 308: 45-50.
 [http://dx.doi.org/10.1016/j.cbi.2019.05.011] [PMID: 31095933]

[36]
Storz G, Imlayt JA. Oxidative stress. Curr Opin Microbiol  1999; 2(2): 188-94.
 [http://dx.doi.org/10.1016/S1369-5274(99)80033-2] [PMID: 10322176]

[37]
Burton GJ, Jauniaux E. Oxidative stress. Best practice & research. Clin Obs Gyn  2011; 25(3): 287-99.

[38]
Yoshikawa T, Naito Y. What is oxidative stress? Japan Med Assoc J  2002; 45(7): 271-6.

[39]
Sies H. What is oxidative stress?.  Springer US 2002; pp. 1-8.

[40]
Chen M, Gu H, Ye Y, et al. Protective effects of hesperidin against oxidative stress of tert-butyl hydroperoxide in human hepatocytes. Food Chem Toxicol  2010; 48(10): 2980-7.
 [http://dx.doi.org/10.1016/j.fct.2010.07.037] [PMID: 20678535]

[41]
Liu W, Liou SS, Hong TY, Liu IM. Protective effects of hesperidin (citrus flavonone) on high glucose induced oxidative stress and apoptosis in a cellular model for diabetic retinopathy. Nutrients  2017; 9(12): 1312.
 [http://dx.doi.org/10.3390/nu9121312] [PMID: 29207476]

[42]
Purves T, Middlemas A, Agthong S, et al. A role for mitogen‐activated protein kinases in the etiology of diabetic neuropathy. FASEB J  2001; 15(13): 2508-14.
 [http://dx.doi.org/10.1096/fj.01-0253hyp] [PMID: 11689477]

[43]
Estruel-Amades S, Massot-Cladera M, Pérez-Cano F, Franch À, Castell M, Camps-Bossacoma M. Hesperidin effects on gut microbiota and gut-associated lymphoid tissue in healthy rats. Nutrients  2019; 11(2): 324.
 [http://dx.doi.org/10.3390/nu11020324] [PMID: 30717392]

[44]
Adewusi EA, Afolayan AJ. A review of natural products with hepatoprotective activity. J Med Plants Res  2010; 4(13): 1318-34.

[45]
Nguyen P, Leray V, Diez M, et al. Liver lipid metabolism. J Anim Physiol Anim Nutr  2008; 92(3): 272-83.
 [http://dx.doi.org/10.1111/j.1439-0396.2007.00752.x] [PMID: 18477307]

[46]
Bondy PK, Bloom WL, Whitner VS, Farrar BW. Studies of the role of the liver in human carbohydrate metabolism by the venous catheter technic. II. Patients with diabetic ketosis, before and after the administration of insulin. J Clin Invest  1949; 28(5 Pt 2): 1126-33.
 [http://dx.doi.org/10.1172/JCI102146] [PMID: 16695784]

[47]
Charlton MR. Protein metabolism and liver disease. Baillieres Clin Endocrinol Metab  1996; 10(4): 617-35.
 [http://dx.doi.org/10.1016/S0950-351X(96)80771-3] [PMID: 9022955]

[48]
Apte U, Krishnamurthy P. Detoxification functions of the liver. Mol Pathol Liver Dis  2011; 147-63.

[49]
Mitra V, Metcalf J. Metabolic functions of the liver. Anaesth Intensive Care Med  2012; 13(2): 54-5.
 [http://dx.doi.org/10.1016/j.mpaic.2011.11.006]

[50]
Kumar CH, Ramesh A, Kumar JS, Ishaq BM. A review on hepatoprotective activity of medicinal plants. Int J Pharm Sci Res  2011; 2(3): 501.

[51]
Verma R. A review on hepatoprotective activity of medicinal plants. J Med Plants Stud  2018; 6(1): 188-90.

[52]
Mungole AJ, Awati R, Chaturvedi A, Zanwar P. Preliminary phytochemical screening of Ipomoea obscura (L): A hepatoprotective medicinal plant. Int J Pharm Tech Res  2010; 2(4): 2307-12.

[53]
Tabeshpour J, Hosseinzadeh H, Hashemzaei M, Karimi G. A review of the hepatoprotective effects of hesperidin, a flavanon glycoside in citrus fruits, against natural and chemical toxicities. Daru  2020; 28(1): 305-17.
 [http://dx.doi.org/10.1007/s40199-020-00344-x] [PMID: 32277430]

[54]
Zaghloul RA, Elsherbiny NM, Kenawy HI, El-Karef A, Eissa LA, El-Shishtawy MM. Hepatoprotective effect of hesperidin in hepatocellular carcinoma: Involvement of Wnt signaling pathways. Life Sci  2017; 185: 114-25.
 [http://dx.doi.org/10.1016/j.lfs.2017.07.026] [PMID: 28754618]

[55]
Akhtar T, Sheikh N. An overview of thioacetamide-induced hepatotoxicity. Toxicol Rev  2013; 32(3): 43-6.

[56]
Stringaris A. Editorial: What is depression? J Child Psychol Psychiatry  2017; 58(12): 1287-9.
 [http://dx.doi.org/10.1111/jcpp.12844] [PMID: 29148049]

[57]
Levinson DF. The genetics of depression: A review. Biol Psychiatry  2006; 60(2): 84-92.
 [http://dx.doi.org/10.1016/j.biopsych.2005.08.024] [PMID: 16300747]

[58]
Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci  2001; 2(5): 343-51.
 [http://dx.doi.org/10.1038/35072566] [PMID: 11331918]

[59]
El-Marasy SA, Abdallah HMI, El-Shenawy SM, El-Khatib AS, El-Shabrawy OA, Kenawy SA. Anti-depressant effect of hesperidin in diabetic rats. Can J Physiol Pharmacol  2014; 92(11): 945-52.
 [http://dx.doi.org/10.1139/cjpp-2014-0281] [PMID: 25358020]

[60]
Fu H, Liu L, Tong Y, et al. The antidepressant effects of hesperidin on chronic unpredictable mild stress-induced mice. Eur J Pharmacol  2019; 853: 236-46.
 [http://dx.doi.org/10.1016/j.ejphar.2019.03.035] [PMID: 30928632]

[61]
Zhu X, Liu H, Liu Y, Chen Y, Liu Y, Yin X. The antidepressant-like effects of hesperidin in streptozotocin‐induced diabetic rats by activating Nrf2/ARE/Glyoxalase 1 pathway. Front Pharmacol  2020; 11: 1325.
 [http://dx.doi.org/10.3389/fphar.2020.01325] [PMID: 32982741]

[62]
Donato F, de Gomes MG, Goes ATR, et al. Hesperidin exerts antidepressant-like effects in acute and chronic treatments in mice: Possible role of l-arginine-NO-cGMP pathway and BDNF levels. Brain Res Bull  2014; 104: 19-26.
 [http://dx.doi.org/10.1016/j.brainresbull.2014.03.004] [PMID: 24709058]

[63]
Hyman C, Hofer M, Barde YA, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature  1991; 350(6315): 230-2.
 [http://dx.doi.org/10.1038/350230a0] [PMID: 2005978]

[64]
Heiberg IL, Wegener G, Rosenberg R. Reduction of cGMP and nitric oxide has antidepressant-like effects in the forced swimming test in rats. Behav Brain Res  2002; 134(1-2): 479-84.
 [http://dx.doi.org/10.1016/S0166-4328(02)00084-0] [PMID: 12191834]

[65]
Riley PA. Free radicals in biology: Oxidative stress and the effects of ionizing radiation. Int J Radiat Biol  1994; 65(1): 27-33.
 [http://dx.doi.org/10.1080/09553009414550041] [PMID: 7905906]

[66]
Wang Y, Deng W, Li N, et al. Combining immunotherapy and radiotherapy for cancer treatment: Current challenges and future directions. Front Pharmacol  2018; 9: 185.
 [http://dx.doi.org/10.3389/fphar.2018.00185] [PMID: 29556198]

[67]
Gandhi NM, Nair CKK. Radiation protection by Terminalia chebula: Some mechanistic aspects. Mol Cell Biochem  2005; 277(1-2): 43-8.
 [http://dx.doi.org/10.1007/s11010-005-4819-9] [PMID: 16132713]

[68]
Hosseinimehr SJ, Nemati A. Radioprotective effects of hesperidin against gamma irradiation in mouse bone marrow cells. Br J Radiol  2006; 79(941): 415-8.
 [http://dx.doi.org/10.1259/bjr/40692384] [PMID: 16632622]

[69]
Najafi M, Rezaeyan A, Haddadi GH, Hosseinzadeh M, Moradi M. Radioprotective effects of hesperidin on oxidative damages and histopathological changes induced by X-irradiation in rats heart tissue. J Med Phys  2016; 41(3): 182-91.
 [http://dx.doi.org/10.4103/0971-6203.189482] [PMID: 27651565]

[70]
Hosseinimehr SJ, Mahmoudzadeh A, Ahmadi A, Mohamadifar S, Akhlaghpoor S. Radioprotective effects of hesperidin against genotoxi-city induced by -irradiation in human lymphocytes. Mutagenesis  2009; 24(3): 233-5.
 [http://dx.doi.org/10.1093/mutage/gep001] [PMID: 19193695]

[71]
Pradeep K, Ko KC, Choi MH, Kang JA, Chung YJ, Park SH. Protective effect of hesperidin, a citrus flavanoglycone, against γ-radiation-induced tissue damage in Sprague-Dawley rats. J Med Food  2012; 15(5): 419-27.
 [http://dx.doi.org/10.1089/jmf.2011.1737] [PMID: 22404572]

[72]
Dominguez C, Ed. Neurodegenerative diseases.  Springer Science & Business Media 2010; Vol. 6.
 [http://dx.doi.org/10.1007/978-3-642-16758-4]

[73]
Checkoway H, Lundin JI, Kelada SN. Neurodegenerative diseases. IARC Sci Publ  2011; (163): 407-19.
 [PMID: 22997874]

[74]
Siddique YH, Naz F, Mantasha I, Shahid M. Lemongrass extract alleviates oxidative stress and delayed the loss of climbing ability in transgenic drosophila model of parkinson’s disease. Lett Drug Des Discov  2021; 18(10): 987-97.
 [http://dx.doi.org/10.2174/1570180818666210413141434]

[75]
Naz F, Jyoti S, Siddique YH. Effect of kaempferol on the transgenic Drosophila model of Parkinson’s disease. Sci Rep  2020; 10(1): 1-14.
 [PMID: 31913322]

[76]
Fatima A, Khanam S, Rahul R, et al. Protective effect of tangeritin in transgenic Drosophila model of Parkinson’s disease. Front Biosci  2017; 9(1): 44-53.
 [PMID: 27814588]

[77]
Cho N, Choi JH, Yang H, et al. Neuroprotective and anti-inflammatory effects of flavonoids isolated from Rhus verniciflua in neuronal HT22 and microglial BV2 cell lines. Food Chem Toxicol  2012; 50(6): 1940-5.
 [http://dx.doi.org/10.1016/j.fct.2012.03.052] [PMID: 22465834]

[78]
Siddique YH, Naz F, Jyoti S, et al. Protective effect of Geraniol on the transgenic Drosophila model of Parkinson’s disease. Environ Toxicol Pharmacol  2016; 43: 225-31.
 [http://dx.doi.org/10.1016/j.etap.2016.03.018] [PMID: 27026137]

[79]
Auddy B, Ferreira M, Blasina F, et al. Screening of antioxidant activity of three Indian medicinal plants, traditionally used for the management of neurodegenerative diseases. J Ethnopharmacol  2003; 84(2-3): 131-8.
 [http://dx.doi.org/10.1016/S0378-8741(02)00322-7] [PMID: 12648805]

[80]
Siddique YH, Faisal M, Naz F, Jyoti S. Rahul. Role of Ocimum sanctum leaf extract on dietary supplementation in the transgenic Drosophila model of Parkinson’s disease. Chin J Nat Med  2014; 12(10): 777-81.
 [http://dx.doi.org/10.1016/S1875-5364(14)60118-7] [PMID: 25443371]

[81]
Karthika S, Kannappan N, Suriyaprakash TNK. Effect of Medicinal plants on amyloid β1–42 Intoxicated SH-SY5Y cell Lines -As Neuroprotective Evaluation. Res J Pharm Technol  2020; 13(7): 3351-5.
 [http://dx.doi.org/10.5958/0974-360X.2020.00595.8]

[82]
Walia V, Chaudhary SK, Kumar Sethiya N. Therapeutic potential of mangiferin in the treatment of various neuropsychiatric and neurodegenerative disorders. Neurochem Int  2021; 143: 104939.
 [http://dx.doi.org/10.1016/j.neuint.2020.104939] [PMID: 33346032]

[83]
Ali F, Rahul , Jyoti S, et al. Therapeutic potential of luteolin in transgenic Drosophila model of Alzheimer’s disease. Neurosci Lett  2019; 692: 90-9.
 [http://dx.doi.org/10.1016/j.neulet.2018.10.053] [PMID: 30420334]

[84]
Siddique YH, Naz F, Jyoti S, Ali F. Rahul. Effect of genistein on the transgenic drosophila model of parkinson’s disease. J Diet Suppl  2019; 16(5): 550-63.
 [http://dx.doi.org/10.1080/19390211.2018.1472706] [PMID: 29969325]

[85]
Hwang SL, Shih PH, Yen GC. Neuroprotective effects of citrus flavonoids. J Agric Food Chem  2012; 60(4): 877-85.
 [http://dx.doi.org/10.1021/jf204452y] [PMID: 22224368]

[86]
Hajialyani M, Hosein Farzaei M, Echeverría J, Nabavi S, Uriarte E, Sobarzo-Sánchez E. Hesperidin as a neuroprotective agent: A review of animal and clinical evidence. Molecules  2019; 24(3): 648.
 [http://dx.doi.org/10.3390/molecules24030648] [PMID: 30759833]

[87]
Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord  2015; 30(11): 1442-50.
 [http://dx.doi.org/10.1002/mds.26354] [PMID: 26208210]

[88]
Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet  2004; 363(9423): 1783-93.
 [http://dx.doi.org/10.1016/S0140-6736(04)16305-8] [PMID: 15172778]

[89]
Thomas B, Beal MF. Parkinson’s disease. Hum Mol Genet  2007; 16(R2): R183-94.
 [http://dx.doi.org/10.1093/hmg/ddm159] [PMID: 17911161]

[90]
Tamilselvam K, Braidy N, Manivasagam T, et al. Neuroprotective effects of hesperidin, a plant flavanone, on rotenone-induced oxida-tive stress and apoptosis in a cellular model for Parkinson’s disease. Oxid Med Cell Longev  2013; 2013: 102741.

[91]
Antunes MS, Goes ATR, Boeira SP, Prigol M, Jesse CR. Protective effect of hesperidin in a model of Parkinson’s disease induced by 6-hydroxydopamine in aged mice. Nutrition  2014; 30(11-12): 1415-22.
 [http://dx.doi.org/10.1016/j.nut.2014.03.024] [PMID: 25280422]

[92]
Poetini MR, Araujo SM, Trindade de Paula M, et al. Hesperidin attenuates iron-induced oxidative damage and dopamine depletion in Drosophila melanogaster model of Parkinson’s disease. Chem Biol Interact  2018; 279: 177-86.
 [http://dx.doi.org/10.1016/j.cbi.2017.11.018] [PMID: 29191452]

[93]
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease. Lancet  2011; 377(9770): 1019-31.
 [http://dx.doi.org/10.1016/S0140-6736(10)61349-9] [PMID: 21371747]

[94]
Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet  2006; 368(9533): 387-403.
 [http://dx.doi.org/10.1016/S0140-6736(06)69113-7] [PMID: 16876668]

[95]
Cam JA, Bu G. Modulation of β-amyloid precursor protein trafficking and processing by the low density lipoprotein receptor family. Mol Neurodegener  2006; 1(1): 8.
 [http://dx.doi.org/10.1186/1750-1326-1-8] [PMID: 16930455]

[96]
Scheltens P, Blennow K, Breteler MMB, et al. Alzheimer’s disease. Lancet  2016; 388(10043): 505-17.
 [http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]

[97]
Spencer B, Rockenstein E, Crews L, Marr R, Masliah E. Novel strategies for Alzheimer’s disease treatment. Expert Opin Biol Ther  2007; 7(12): 1853-67.
 [http://dx.doi.org/10.1517/14712598.7.12.1853] [PMID: 18034651]

[98]
Thenmozhi AJ, Raja TRW, Janakiraman U, Manivasagam T. Neuroprotective effect of hesperidin on aluminium chloride induced Alzheimer’s disease in Wistar rats. Neurochem Res  2015; 40(4): 767-76.
 [http://dx.doi.org/10.1007/s11064-015-1525-1] [PMID: 25630717]

[99]
Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging  2004; 21(7): 453-78.
 [http://dx.doi.org/10.2165/00002512-200421070-00004] [PMID: 15132713]

[100]
Nazari M, Ghorbani A, Hekmat-Doost A, Jeddi-Tehrani M, Zand H. Inactivation of Nuclear Factor-κB by citrus flavanone hesperidin contributes to apoptosis and chemo-sensitizing effect in Ramos cells. Eur J Pharmacol  2011; 650(2-3): 526-33.
 [http://dx.doi.org/10.1016/j.ejphar.2010.10.053] [PMID: 21044621]

[101]
Lee JH, Yang DS, Goulbourne CN, et al. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci  2022; 25(6): 688-701.
 [http://dx.doi.org/10.1038/s41593-022-01084-8] [PMID: 35654956]

[102]
Subhan I, Siddique YH. Modulation of huntington’s disease in drosophila. CNS Neurol Disord Drug Targets  2021; 20(10): 894-903.
 [http://dx.doi.org/10.2174/1871527320666210412155508] [PMID: 33845728]

[103]
Walker FO. Huntington’s disease. Lancet  2007; 369(9557): 218-28.
 [http://dx.doi.org/10.1016/S0140-6736(07)60111-1] [PMID: 17240289]

[104]
Finkbeiner S. Huntington’s Disease. Cold Spring Harb Perspect Biol  2011; 3(6): a007476.
 [http://dx.doi.org/10.1101/cshperspect.a007476] [PMID: 21441583]

[105]
Menze ET, Tadros MG, Abdel-Tawab AM, Khalifa AE. Potential neuroprotective effects of hesperidin on 3-nitropropionic acid-induced neurotoxicity in rats. Neurotoxicology  2012; 33(5): 1265-75.
 [http://dx.doi.org/10.1016/j.neuro.2012.07.007] [PMID: 22850463]

[106]
Ludolph AC, He F, Spencer PS, Hammerstad J, Sabri M. 3-Nitropropionic acid-exogenous animal neurotoxin and possible human striatal toxin. Can J Neurol Sci  1991; 18(4): 492-8.
 [http://dx.doi.org/10.1017/S0317167100032212] [PMID: 1782616]

[107]
Túnez I, Tasset I, Pérez-De LCV, Santamaría A. 3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington’s disease: past, present and future. Molecules  2010; 15(2): 878-916.
 [http://dx.doi.org/10.3390/molecules15020878] [PMID: 20335954]

[108]
Staessen JA, Wang J, Bianchi G, Birkenhäger WH. Essential hypertension. Lancet  2003; 361(9369): 1629-41.
 [http://dx.doi.org/10.1016/S0140-6736(03)13302-8] [PMID: 12747893]

[109]
Kulkarni S, O’Farrell I, Erasi M, Kochar MS. Stress and hypertension. WMJ  1998; 97(11): 34-8.
 [PMID: 9894438]

[110]
Messerli FH, Williams B, Ritz E. Essential hypertension. Lancet  2007; 370(9587): 591-603.
 [http://dx.doi.org/10.1016/S0140-6736(07)61299-9] [PMID: 17707755]

[111]
Ikemura M, Sasaki Y, Giddings JC, Yamamoto J. Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother Res  2012; 26(9): 1272-7.
 [http://dx.doi.org/10.1002/ptr.3724] [PMID: 22228501]

[112]
Wunpathe C, Potue P, Maneesai P, et al. Hesperidin suppresses renin-angiotensin system mediated NOX2 over-expression and sympa-thoexcitation in 2K-1C hypertensive rats. Am J Chin Med  2018; 46(4): 751-67.
 [http://dx.doi.org/10.1142/S0192415X18500398] [PMID: 29754503]

[113]
Dobiaš L, Petrová M, Vojtko R, Kristová V. Long‐term treatment with hesperidin improves endotheliumdependent vasodilation in fem-oral artery of spontaneously hypertensive rats: The involvement of NO‐synthase and Kv channels. Phytother Res  2016; 30(10): 1665-71.
 [http://dx.doi.org/10.1002/ptr.5670] [PMID: 27363952]

[114]
Cox RH. Changes in the expression and function of arterial potassium channels during hypertension. Vascul Pharmacol  2002; 38(1): 13-23.
 [http://dx.doi.org/10.1016/S1537-1891(02)00122-2] [PMID: 12378818]

[115]
Balakrishnan A, Menon VP. Protective effect of hesperidin on nicotine induced toxicity in rats. Indian J Exp Biol  2007; 45(2): 194-202.

[116]
Park HJ, Kim MJ, Ha E, Chung JH. Apoptotic effect of hesperidin through caspase3 activation in human colon cancer cells, SNU-C4. Phytomedicine  2008; 15(1-2): 147-51.
 [http://dx.doi.org/10.1016/j.phymed.2007.07.061] [PMID: 17897817]

[117]
Yamamoto M, Suzuki A, Jokura H, Yamamoto N, Hase T. Glucosyl hesperidin prevents endothelial dysfunction and oxidative stress in spontaneously hypertensive rats. Nutrition  2008; 24(5): 470-6.
 [http://dx.doi.org/10.1016/j.nut.2008.01.010] [PMID: 18329851]

[118]
Kalpana KB, Devipriya N, Srinivasan M, Menon VP. Investigation of the radioprotective efficacy of hesperidin against gamma-radiation induced cellular damage in cultured human peripheral blood lymphocytes.  Mut Res/Gen Tox Env Mut  2009; 676(1-2): 54-61.

[119]
Kamaraj S, Ramakrishnan G, Anandakumar P, Jagan S, Devaki T. Antioxidant and anticancer efficacy of hesperidin in benzo(a)pyrene induced lung carcinogenesis in mice. Invest New Drugs  2009; 27(3): 214-22.
 [http://dx.doi.org/10.1007/s10637-008-9159-7] [PMID: 18704264]

[120]
Xiaoting L, Xiangyun Z, Shumei L, Minghua D, Liang X. Effect of hesperidin on expression of inducible nitric oxide synthase in cultured rabbit retinal pigment epithelial cells. Adv Exp Med Biol  2010; 664: 193-201.

[121]
Selvaraj P, Pugalendi KV. Hesperidin, a flavanone glycoside, on lipid peroxidation and antioxidant status in experimental myocardial ischemic rats. Redox Rep  2010; 15(5): 217-23.
 [http://dx.doi.org/10.1179/135100010X12826446921509] [PMID: 21062537]

[122]
Wang X, Hasegawa J, Kitamura Y, et al. Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats. J Pharmacol Sci  2011; 117(3): 129-38.
 [http://dx.doi.org/10.1254/jphs.11097FP] [PMID: 21979313]

[123]
Hozayen WG, Abou Seif HS. Protective effects of rutin and hesperidin against doxorubicin-induced lipodystrophy and cardiotoxicity in albino rats. J Am Sci  2011; 7(12): 765-75.

[124]
Shi X, Liao S, Mi H, et al. Hesperidin prevents retinal and plasma abnormalities in streptozotocin-induced diabetic rats. Molecules  2012; 17(11): 12868-81.
 [http://dx.doi.org/10.3390/molecules171112868] [PMID: 23117428]

[125]
Anandan R, Subramanian P. Renal protective effect of hesperidin on gentamicin-induced acute nephrotoxicity in male Wistar albino rats. Redox Rep  2012; 17(5): 219-26.
 [http://dx.doi.org/10.1179/1351000212Y.0000000019] [PMID: 22889751]

[126]
Zaafan MA, Zaki HF, El-Brairy AI, Kenawy SA. Isoprenaline-induced myocardial infarction in rats: Protective effects of hesperidin. Egy J Basic and Clin Pharmacol  2012; 2(2): 13-22.

[127]
Kumar A, Lalitha S, Mishra J. Possible nitric oxide mechanism in the protective effect of hesperidin against pentylenetetrazole (PTZ)-induced kindling and associated cognitive dysfunction in mice. Epilepsy Behav  2013; 29(1): 103-11.
 [http://dx.doi.org/10.1016/j.yebeh.2013.06.007] [PMID: 23939034]

[128]
Souza LC, de Gomes MG, Goes ATR, et al. Evidence for the involvement of the serotonergic 5-HT1A receptors in the antidepressant-like effect caused by hesperidin in mice. Prog Neuropsychopharmacol Biol Psychiatry  2013; 40: 103-9.
 [http://dx.doi.org/10.1016/j.pnpbp.2012.09.003] [PMID: 22996046]

[129]
Agrawal YO, Sharma PK, Shrivastava B, et al. Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats. PLoS One  2014; 9(11): e111212.
 [http://dx.doi.org/10.1371/journal.pone.0111212] [PMID: 25369053]

[130]
Agrawal YO, Sharma PK, Shrivastava B, Arya DS, Goyal SN. Hesperidin blunts streptozotocin-isoproternol induced myocardial toxicity in rats by altering of PPAR-γ receptor. Chem Biol Interact  2014; 219: 211-20.
 [http://dx.doi.org/10.1016/j.cbi.2014.06.010] [PMID: 24954035]

[131]
Elshazly SM, Mahmoud AAA. Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats. Naunyn Schmiedebergs Arch Pharmacol  2014; 387(6): 559-67.
 [http://dx.doi.org/10.1007/s00210-014-0968-2] [PMID: 24627177]

[132]
Vijaya Bharathi B, Jaya Prakash G, Krishna KM, et al. Protective effect of alpha glucosyl hesperidin (G-hesperidin) on chronic vanadium induced testicular toxicity and sperm nuclear DNA damage in male Sprague Dawley rats. Andrologia  2015; 47(5): 568-78.
 [http://dx.doi.org/10.1111/and.12304] [PMID: 24909458]

[133]
Li G, Chen M, Wang C, et al. Protective effects of hesperidin on concanavalin A-induced hepatic injury in mice. Int Immunopharmacol  2014; 21(2): 406-11.
 [http://dx.doi.org/10.1016/j.intimp.2014.05.018] [PMID: 24867793]

[134]
Febriansah R, Dyaningtyas DPP. Sarmoko, Nurulita NA, Meiyanto E, Nugroho AE. Hesperidin as a preventive resistance agent in MCF–7 breast cancer cells line resistance to doxorubicin. Asian Pac J Trop Biomed  2014; 4(3): 228-33.
 [http://dx.doi.org/10.1016/S2221-1691(14)60236-7] [PMID: 25182442]

[135]
Fouad AA, Albuali WH, Jresat I. Protective effect of hesperidin against cyclophosphamide hepatotoxicity in rats. Int J Bioeng Life Scien  2014; 8(7): 730-3.

[136]
Allam G, Abuelsaad ASA. In vitro and in vivo effects of hesperidin treatment on adult worms of Schistosoma mansoni. J Helminthol  2014; 88(3): 362-70.
 [http://dx.doi.org/10.1017/S0022149X13000278] [PMID: 23656891]

[137]
Chang CY, Lin TY, Lu CW, et al. Hesperidin inhibits glutamate release and exerts neuroprotection against excitotoxicity induced by kainic acid in the hippocampus of rats. Neurotoxicology  2015; 50: 157-69.
 [http://dx.doi.org/10.1016/j.neuro.2015.08.014] [PMID: 26342684]

[138]
Lee H, Lee W, Chang S, Lee GY. Hesperidin, a popular antioxidant inhibits melanogenesis via Erk1/2 mediated MITF degradation. Int J Mol Sci  2015; 16(8): 18384-95.
 [http://dx.doi.org/10.3390/ijms160818384] [PMID: 26262610]

[139]
Vabeiryureilai M, Lalrinzuali K, Jagetia GC. Determination of anti-inflammatory and analgesic activities of a citrus bioflavanoid, hesperidin in mice. Immunochem Immunopathol  2015; 1(2): 2.
 [http://dx.doi.org/10.4172/2469-9756.1000107]

[140]
Khedr NF, Khalil RM. Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin. Tumour Biol  2015; 36(12): 9267-75.
 [http://dx.doi.org/10.1007/s13277-015-3655-0] [PMID: 26099723]

[141]
Li CF, Chen SM, Chen XM, et al. ERK-dependent brain-derived neurotrophic factor regulation by hesperidin in mice exposed to chronic mild stress. Brain Res Bull  2016; 124: 40-7.
 [http://dx.doi.org/10.1016/j.brainresbull.2016.03.016] [PMID: 27018164]

[142]
Peng H, Wei Z, Luo H, et al. Inhibition of fat accumulation by hesperidin in Caenorhabditis elegans. J Agric Food Chem  2016; 64(25): 5207-14.
 [http://dx.doi.org/10.1021/acs.jafc.6b02183] [PMID: 27267939]

[143]
Antunes MS, Jesse CR, Ruff JR, et al. Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity. Eur J Pharmacol  2016; 789: 411-20.
 [http://dx.doi.org/10.1016/j.ejphar.2016.07.042] [PMID: 27460180]

[144]
Rezaeyan A, Fardid R, Haddadi GH, et al. Evaluating radioprotective effect of hesperidin on acute radiation damage in the lung tissue of rats. J Biomed Phys Eng  2016; 6(3): 165-74.
 [PMID: 27853724]

[145]
Monfared AS, Karimi N, Haddadi G, et al. Radioprotective effect of hesperidin on reducing oxidative stress in the lens tissue of rats. Int J Pharm Investig  2017; 7(3): 149-54.
 [http://dx.doi.org/10.4103/jphi.JPHI_60_17] [PMID: 29184828]

[146]
Justin Thenmozhi A, William Raja TR, Manivasagam T, Janakiraman U, Essa MM. Hesperidin ameliorates cognitive dysfunction, oxida-tive stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease. Nutr Neurosci  2017; 20(6): 360-8.
 [http://dx.doi.org/10.1080/1028415X.2016.1144846] [PMID: 26878879]

[147]
Kosari-Nasab M, Shokouhi G, Ghorbanihaghjo A, Abbasi MM, Salari AA. Hesperidin attenuates depression-related symptoms in mice with mild traumatic brain injury. Life Sci  2018; 213: 198-205.
 [http://dx.doi.org/10.1016/j.lfs.2018.10.040] [PMID: 30352242]

[148]
Bhargava P, Verma VK, Malik S, Khan SI, Bhatia J, Arya DS. Hesperidin regresses cardiac hypertrophy by virtue of PPAR‐γ agonistic, anti‐inflammatory, antiapoptotic, and antioxidant properties. J Biochem Mol Toxicol  2019; 33(5): e22283.
 [http://dx.doi.org/10.1002/jbt.22283] [PMID: 30623541]

[149]
Turk E, Kandemir FM, Yildirim S, Caglayan C, Kucukler S, Kuzu M. Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biol Trace Elem Res  2019; 189(1): 95-108.
 [http://dx.doi.org/10.1007/s12011-018-1443-6] [PMID: 30066062]

[150]
Yuan X, Zhu J, Kang Q, He X, Guo D. Protective effect of hesperidin against sepsis-induced lung injury by inducing the heat-stable protein 70 (Hsp70)/toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88) pathway. Med Sci Monit  2019; 25: 107-14.
 [http://dx.doi.org/10.12659/MSM.912490]

[151]
Meng X, Wei M, Wang D, et al. The protective effect of hesperidin against renal ischemia-reperfusion injury involves the TLR-4/NF-κB/iNOS pathway in rats. Physiol Int  2020; 107(1): 82-91.
 [http://dx.doi.org/10.1556/2060.2020.00003] [PMID: 32491283]

[152]
Kwatra M, Ahmed S, Gawali B, Panda SR, Naidu VGM. Hesperidin alleviates chronic restraint stress and lipopolysaccharideinduced Hippocampus and Frontal cortex damage in mice: Role of TLR4/NF-κB, p38 MAPK/JNK, Nrf2/ARE signaling. Neurochem Int  2020; 140: 104835.
 [http://dx.doi.org/10.1016/j.neuint.2020.104835] [PMID: 32853749]

[153]
Xie L, Gu Z, Liu H, et al. The anti-depressive effects of hesperidin and the relative mechanisms based on the NLRP3 inflammatory signaling pathway. Front Pharmacol  2020; 11: 1251.
 [http://dx.doi.org/10.3389/fphar.2020.01251] [PMID: 32922291]

[154]
Rezaee R, Sheidary A, Jangjoo S, et al. Cardioprotective effects of hesperidin on carbon monoxide poisoned in rats. Drug Chem Toxicol  2021; 44(6): 668-73.
 [http://dx.doi.org/10.1080/01480545.2019.1650753] [PMID: 31412747]

[155]
Semis HS, Kandemir FM, Kaynar O, Dogan T, Arikan SM. The protective effects of hesperidin against paclitaxel-induced peripheral neuropathy in rats. Life Sci  2021; 287: 120104.
 [http://dx.doi.org/10.1016/j.lfs.2021.120104] [PMID: 34743946]

[156]
Gelen V, Şengül E, Yıldırım S, Senturk E, Tekin S, Kükürt A. The protective effects of hesperidin and curcumin on 5-fluorouracil–induced nephrotoxicity in mice. Environ Sci Pollut Res Int  2021; 28(34): 47046-55.
 [http://dx.doi.org/10.1007/s11356-021-13969-5] [PMID: 33886055]

[157]
Afzal SM, Vafa A, Rashid S, et al. Protective effect of hesperidin against N, N ′‐dimethylhydrazine induced oxidative stress, inflammation, and apoptotic response in the colon of Wistar rats. Environ Toxicol  2021; 36(4): 642-53.
 [http://dx.doi.org/10.1002/tox.23068] [PMID: 33289288]

[158]
Li S, Zhu J, Pan L, et al. Potential protective effect of hesperidin on hypoxia/reoxygenation-induced hepatocyte injury. Exp Ther Med  2021; 22(1): 764.
 [http://dx.doi.org/10.3892/etm.2021.10196]

[159]
Patel P, Shah J. Protective effects of hesperidin through attenuation of Ki67 expression against DMBA-induced breast cancer in female rats. Life Sci  2021; 285: 119957.
 [http://dx.doi.org/10.1016/j.lfs.2021.119957] [PMID: 34530017]

[160]
Lee B, Choi GM, Sur B. Antidepressant-like effects of hesperidin in animal model of post-traumatic stress disorder. Chin J Integr Med  2021; 27(1): 39-46.
 [http://dx.doi.org/10.1007/s11655-020-2724-4] [PMID: 32445019]

[161]
Noshy PA, Azouz RA. Neuroprotective effect of hesperidin against emamectin benzoate-induced neurobehavioral toxicity in rats. Neurotoxicol Teratol  2021; 86: 106981.
 [http://dx.doi.org/10.1016/j.ntt.2021.106981] [PMID: 33838246]

[162]
Herath HMUL, Piao MJ, Kang KA, et al. Hesperidin exhibits protective effects against PM2. 5-mediated mitochondrial damage, cell cycle arrest, and cellular senescence in human HaCaT Keratinocytes. Molecules  2022; 27(15): 4800.
 [http://dx.doi.org/10.3390/molecules27154800] [PMID: 35956749]

[163]
Mostafa OAA, Ibrahim F, Borai E. Protective effects of hesperidin in cyclophosphamide-induced parotid toxicity in rats. Sci Rep  2023; 13(1): 158.
 [http://dx.doi.org/10.1038/s41598-022-26881-w] [PMID: 36599902]
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DOI https://dx.doi.org/10.2174/2215083810666230822113623	Print ISSN 2215-0838
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Current Traditional Medicine

Pharmacological Attributes of Hesperidin

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Integrating Herbal Medicine into Modern Healthcare: An Evidence-Based Perspective

Current Traditional Medicine

Pharmacological Attributes of Hesperidin

Abstract

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Call for Papers in Thematic Issues

Integrating Herbal Medicine into Modern Healthcare: An Evidence-Based Perspective

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