Pharmacological, medicinal and biological properties of flavonoids: A comprehensive review

Year 2025, Volume: 29 Issue: 2, 561 - 584

Oruc Yunusoğlu , İlknur Ayaz Ebru Havva Dovankaya

https://doi.org/10.12991/jrespharm.1661054

Abstract

Plant-based phytochemicals are currently being used to prevent and treat several diseases. Flavonoids are plant-based compounds that are widely found in the plant kingdom, which contain the benzopyrone ring, and possess various biological activities. To date, approximately more than 6000 different flavonoids have been identified and classified as flavones, flavanones, flavanols, isoflavones, anthocyanidins, and catechins. Many in vitro and in vivo experimental studies were published on the use of flavonoids in different conditions. Antioxidant, antiinflammatory, antibacterial, antifungal, antiviral, antihypertensive, antihyperlipidemic, antithrombotic, antiasthma, antiallergic, antidiabetic, antiobesity, antiarthritis, antiulcer, hepatoprotective, osteoprotective, immunomodulation, anticancer, antiaging, neuroprotective, antiaddictive, antiparkinsonian, antiepileptic, anxiolytics and antidepressant are among the primary pharmacological properties of these compounds. Despite a wide range of the ongoing research on the potential health benefits of flavonoids, the U.S. FDA (and similar organizations) has not approved any flavonoid compounds for therapeutic use. However, these compounds are available as nutritional supplements in various dosage forms. In this review, we used the databases like PubMed, Web of Science, ScienceDirect, Scopus, ResearchGate and Google Scholar to find the best-matched information about flavonoids’ pharmacological, medicinal and biological properties to elucidate the therapeutic potential as well as their side effects. A comprehensive systematic literature review was carried out to achieve the main goal of this study.

Keywords

Flavonoids, polyphenols, pharmacological activity, therapeutic potential, systematic review

References

• [1] Wen K, Fang X, Yang J, Yao Y, Nandakumar KS, Salem ML, Cheng K. Recent research on flavonoids and their biomedical applications. Curr Med Chem. 2021; 28(5): 1042-1066. http://dx.doi.org/10.2174/0929867327666200713184138.
• [2] Calis Z, Mogulkoc R, Baltaci A. The roles of flavonols/flavonoids in neurodegeneration and neuroinflammation. Mini Rev Med Chem. 2020; 20 (15): 1475-1488. http://dx.doi.org/10.2174/1389557519666190617150051.
• [3] Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, Lucarini M, Santini A, Souto E, Novellino E, Antolak E, Azzini E, Setzer W, Martins N. The therapeutic potential of apigenin. Int J Mol Sci. 2019; 20 (6): 1305. https://doi.org/10.3390/ijms20061305.
• [4] Jayaprakasha G, Jagan M, Sakariah K. Chemistry and biological activities of C. longa. Trends Food Sci Technol. 2005; 16 (12): 533-548. https://doi.org/10.1016/j.tifs.2005.08.006.
• [5] Acker S, Tromp M, Griffioen D, Bennekom W, Vijgh W, Bast A. Structural aspects of antioxidant activity of flavonoids. Free Radic Biol Med. 1996; 20 (3): 331-342. http://dx.doi.org/https://doi.org/10.1016/0891- 5849(95)02047-0.
• [6] Jucá MM, Cysne Filho FMS, de Almeida JC, Mesquita DDS, Barriga JRM, Dias KCF, Barbosa TM, Vasconcelos LC, Leal LKAM, Ribeiro JE, Vasconcelos SMM. Flavonoids: biological activities and therapeutic potential. Nat Prod Res. 2020; 34(5): 692-705. https://doi.org/10.1080/14786419.2018.1493588.
• [7] Yalniz Y, Yunusoğlu O, Berköz M, Demirel ME. Effects of fisetin on ethanol-induced rewarding properties in mice. Am J Drug Alcohol Abuse. 2024; 2;50(1): 75-83. http://dx.doi.org/DOI:10.1080/00952990.2023.2292976.
• [8] Yunusoğlu O. Resveratrol inhibits nicotine-induced conditioned place preference in mice. Braz J Pharm Sci. 2023; 59: e20883. http://dx.doi.org/DOI:10.1590/s2175-97902023e20883.
• [9] Tasdemir D, Kaiser M, Brun R, Yardley V, Schmidt T, Tosun F, Rüedi P. Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies. Antimicrob Agents Chemother. 2006; 50 (4): 1352-1364. https://doi.org/10.1128/aac.50.4.1352-1364.2006.
• [10] Alamgir A. Cultivation of herbal drugs, biotechnology, and in vitro production of secondary metabolites, highvalue medicinal plants, herbal wealth, and herbal trade. Therapeutic Use of Medicinal Plants and Their Extracts. 2017; 1: 379-452. https://doi.org/10.1007/978-3-319-63862-1_9.
• [11] Kurt AH, Olutas EB, Avcioglu F, Karakuş H, Sungur MA, Oztabag CK, Yıldırım M. Quercetin-and caffeic acidfunctionalized chitosan-capped colloidal silver nanoparticles: one-pot synthesis, characterization, and anticancer and antibacterial activities. Beilstein J Nanotechnol. 2023; 14: 362-376. https://doi.org/10.3762/bjnano.14.31.
• [12] Ahmet A, Hakan KA, Derya K, Mustafa C, Cansu OK, Adem D. Protective effects of quercetin in combination with donepezil against H2O2-induced oxidative stress in glioblastoma cells. Pharm Chem J. 2023; 56(12): 1577-1586. https://doi.org/10.1007/s11094-023-02830-3.
• [13] Abuse S. Key substance use and mental health indicators in the United States: results from the 2019 National Survey on Drug Use and Health. 2020, Publication Number PEP20-07-01-001
• [14] Berköz M, Ünal S, Karayakar F, Yunusoğlu O, Özkan-Yılmaz F, Özlüer-Hunt A, Aslan A. Prophylactic effect of myricetin and apigenin against lipopolysaccharide-induced acute liver injury. Mol Biol Rep. 2021; 48(9): 6363-6373. https://doi.org/10.1007/s11033-021-06637-x.
• [15] Berköz M, Allahverdiyev O. Punicalagin isolated from Punica granatum husk can decrease the inflammatory response in RAW 264.7 macrophages. East J Med. 2017; 22(2): 57-64. https://dx.doi.org/10.5505/ejm.2017.08760.
• [16] Berkoz M, Yildirim M, Arvas G, Turkmen O, Allahyerdiyev O. Effect of capsaicin on transcription factors in 3T3-L1 cell line. East J Med. 2015; 20(1): 34-45. https://doi.org/10.1021/jf062912b.
• [17] Berköz M, Allahverdiyev O, Yıldırım M. Investigation of the effect of hyperforin and hypericin on inflammatory response in RAW 264.7 macrophages. Van Med J. 2018; 25(2): 124-131. http://dx.doi.org/10.5505/vtd.2018.07769.
• [18] Akünal Türel C, Yunusoğlu O. Oleanolic acid suppresses pentylenetetrazole-induced seizure in vivo. Int J Environ Health Res. 2023; 33(5): 529-540. https://doi.org/10.1080/09603123.2023.2167947.
• [19] Berköz M, Yıldırım M, Yalın S, İlhan M, Yunusoğlu O. Myricetin inhibits angiotensin converting enzyme and induces nitric oxide production in HUVEC cell line. Gen Physiol Biophys. 2020; 39(3): 249-258. https://doi.org/10.4149/gpb_2020007.
• [20] Yunusoglu O, Türkmen Ö, Berkoz M, Yıldırım M, Yalın S. In vitro anti-obesity effect of Aloe vera extract through transcription factors and lipolysis-associated genes. East J Med. 2022; 27(4): 519-528. http://doi.org/10.5505/ejm.2022.13285.
• [21] Berköz M, Yunusoğlu O, Aslan A, Bozkurt A. Investigation of antiepileptic potentials of usnic acid and some lichen species on the behavioral and biochemical levels in pentylenetetrazole-induced kindling model of epilepsy. J Res Pharm. 2024; 28(5): 1378-1390. http://dx.doi.org/10.29228/jrp.816
• [22] Pan SY, Litscher G, Chan K, Yu ZL, Chen HQ, Ko KM. Traditional medicines in the world: where to go next. Evid Based Complement Alternat Med. 2014; 2014: 739895. https://doi.org/10.1155/2014/739895.
• [23] Van BE. A review of commercially important African medicinal plants. J Ethnopharmacol. 2015; 176: 118-134. http://dx.doi.org/https://doi.org/10.1016/j.jep.2015.10.031.
• [24] Tauchen J, Huml L, Rimpelova S, Jurášek M. Flavonoids and related members of the aromatic polyketide group in human health and disease: do they really work? Molecules. 2020; 25(17): 3846. https://doi.org/10.3390/molecules25173846.
• [25] Ferraz CR, Carvalho TT, Manchope MF, Artero NA, Rasquel-Oliveira FS, Fattori V, Casagrande R, Verri WA Jr. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules. 2020; 25(3): 762. https://doi.org/10.3390%2Fmolecules25030762.
• [26] Lautie E, Russo O, Ducrot P, Boutin J. Unraveling plant natural chemical diversity for drug discovery purposes. Front Pharmacol. 2020; 11: 397. https://doi.org/10.3389/fphar.2020.00397.
• [27] Allahverdiyev O, Nurten A, Enginar N. Assessment of rewarding and reinforcing properties of biperiden in conditioned place preference in rats. Behav Brain Res. 2011; 225(2): 642-645. http://dx.doi.org/10.1016/j.bbr.2011.07.050.
• [28] Allahverdiyev O, Türkmen AZ, Nurten A, Sehirli I, Enginar N. Spontaneous withdrawal in intermittent morphine administration in rats and mice: effect of clonidine coadministration and sex-related differences. Turk J Med Sci. 2015; 45(6): 1380-1389. https://doi.org/10.3906/sag-1408-137.
• [29] Büget B, Türkmen AZ, Allahverdiyev O, Enginar N. Antimuscarinic-induced convulsions in fasted animals after food intake: evaluation of the effects of levetiracetam, topiramate and different doses of atropine. Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(1): 57-62. https://doi.org/10.1007/s00210-015-1175-5.
• [30] Dzhafar S, Dalar A, Mükemre M, Ekin S, Yildiz D, Yunusoğlu O. Phytochemical profile and in vitro and in vivo anticonvulsant and antioxidant activities of Epilobium hirsutum. IJSM. 2020; 7(2): 63-76. https://doi.org/10.21448/ijsm.669451.
• [31] Wang X, Yang Y, An Y, Fang G. The mechanism of anticancer action and potential clinical use of kaempferol in the treatment of breast cancer. Biomed Pharmacother. 2019; 117: 109086. https://doi.org/10.1016/j.biopha.2019.109086.
• [32] Yunusoğlu O. Evaluation of the effects of quercetin on the rewarding property of ethanol in mice. Neurosci Lett. 2022; 768: 136383. http://dx.doi.org/10.1016/j.neulet.2021.136383.
• [33] Jafarinia M, Hosseini M, Kasiri N, Fazel N, Fathi F, Hakemi M, Eskandari N. Quercetin with the potential effect on allergic diseases. Allergy Asthma Clin Immunol. 2020; 16: 36. https://doi.org/10.1186/s13223-020-00434-0.
• [34] Kandemir K, Tomas M, McClements DJ, Capanoglu E. Recent advances on the improvement of quercetin bioavailability. Trends Food Sci Technol. 2022; 119: 192-200. https://doi.org/10.1016/j.tifs.2021.11.032.
• [35] Yang Y, Zhang X, Xu M, Wu X, Zhao F, Zhao C. Quercetin attenuates collagen-induced arthritis by restoration of Th17/Treg balance and activation of Heme Oxygenase 1-mediated anti-inflammatory effect. Int Immunopharmacol. 2018; 54: 153-162. https://doi.org/10.1016/j.intimp.2017.11.013.
• [36] Zhu J, Wen L, Zhong W, Xiong L, Liang J, Wang H. Quercetin, kaempferol and isorhamnetin in Elaeagnus pungens Thunb. Leaf: Pharmacological activities and quantitative determination studies. Chem Biodivers. 2018; 15(8): e1800129. https://doi.org/10.1002/cbdv.201800129.
• [37] Sozmen S, Karaman M, Micili S, Isik S, Bagriyanik A, Ayyildiz Z, Uzuner N, Anal O, Karaman O. Effects of quercetin treatment on epithelium-derived cytokines and epithelial cell apoptosis in allergic airway inflammation mice model. Iran J Allergy Asthma Immunol. 2016; 15(6): 487-497.
• [38] Zhu S, Wang H, Zhang J, Yu C, Liu C, Sun H, Wu Y, Wang Y, Lin X. Antiasthmatic activity of quercetin glycosides in neonatal asthmatic rats. 3 Biotech. 2019; 9(5): 189. https://doi.org/10.1007%2Fs13205-019-1618-7.
• [39] Luo X, Xue L, Xu H, Zhao QY, Wang Q, She YS, Zang DA, Shen J, Peng YB, Zhao P, Yu MF, Chen W, Ma LQ, Chen S, Chen S, Fu X, Hu S, Nie X, Shen C, Zou C, Qin G, Dai J, Ji G, Su Y, Hu S, Chen J, Liu QH. Polygonum aviculare L. extract and quercetin attenuate contraction in airway smooth muscle. Sci Rep. 2018; 8(1): 3114. https://doi.org/10.1038/s41598-018-20409-x.
• [40] Jaisinghani R. Antibacterial properties of quercetin. Microbiol Res. 2017; 8(1): 6877. http://dx.doi.org/10.4081/mr.2017.6877.
• [41] Wang S, Yao J, Zhou B, Yang J, Chaudry M, Wang M, Xiao F, Li Y, Yin W. Bacteriostatic effect of quercetin as an antibiotic alternative in vivo and its antibacterial mechanism in vitro. J Food Prot. 2018; 81(1): 68-78. https://doi.org/10.4315/0362-028X.JFP-17-214.
• [42] Akan Z, Garip A. Antioxidants may protect cancer cells from apoptosis signals and enhance cell viability. Asian Pac J Cancer Prev. 2013; 14(8): 4611-4614. https://doi.org/10.7314/apjcp.2013.14.8.4611.
• [43] Vásquez V, Arellanes J, García R, Aparicio D, Villa S. Inhibition of reactive oxygen species and pre-neoplastic lesions by quercetin through an antioxidant defense mechanism. Free Radic Res. 2009; 43(2): 128-137. https://doi.org/10.1080/10715760802626535.
• [44] Cruz M, Shoskes D, Sanchez P, Zhao R, Hylind L, Wexner S, Giardiello F. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006; 4(8): 1035-1038. https://doi.org/10.1016/j.cgh.2006.03.020.
• [45] Pratheeshkumar P, Son Y, Divya S, Wang L, Turcios L, Roy R, Hitron J, Kim D, Dai J, Asha P. Quercetin inhibits Cr (VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway. Oncotarget. 2017; 8(32): 52118-52131. https://doi.org/10.18632%2Foncotarget.10130.
• [46] Han M, Song Y, Zhang X. Quercetin suppresses the migration and invasion in human colon cancer Caco-2 cells through regulating toll-like receptor 4/nuclear factor-kappa B pathway. Pharmacogn Mag. 2016; 12(2): 237-244. https://doi.org/10.4103%2F0973-1296.182154.
• [47] Yang F, Song L, Wang H, Wang J, Xu Z, Xing N. Quercetin in prostate cancer: Chemotherapeutic and chemopreventive effects, mechanisms and clinical application potential. Oncol Rep. 2015; 33(6): 2659-2668. https://doi.org/10.3892/or.2015.3886.
• [48] Shi GJ, Li Y, Cao QH, Wu HX, Tang XY, Gao XH, Yu JQ, Chen Z, Yang Y. In vitro and in vivo evidence that quercetin protects against diabetes and its complications: A systematic review of the literature. Biomed Pharmacother. 2019; 109: 1085-1099. https://doi.org/10.1016/j.biopha.2018.10.130.
• [49] Oboh G, Ademosun A, Ayeni P, Omojokun O, Bello F. Comparative effect of quercetin and rutin on α-amylase, α- glucosidase, and some pro-oxidant-induced lipid peroxidation in rat pancreas. Comp Clin Path. 2015; 24: 1103-1110. http://dx.doi.org/10.1007/s00580-014-2040-5.
• [50] Oboh G, Ademosun A, Ogunsuyi O. Quercetin and its role in chronic diseases. Adv Exp Med Biol. 2016; 929: 377- 387. https://doi.org/10.1007/978-3-319-41342-6_17.
• [51] Hemmati M, Mostafavi S, Zarban A, Hoshyar R. Protective effects of quercetin on hyperglycemia and stress proteins expression in rats with streptozocin-induced diabetes. Mod Care J. 2018; 15(2): e64964. http://dx.doi.org/10.5812/modernc.64964.
• [52] Oliveira VM, Carraro E, Auler ME, Khalil NM. Quercetin and rutin as potential agents antifungal against Cryptococcus spp. Braz J Biol. 2016; 76(4): 1029-1034. https://doi.org/10.1590/1519-6984.07415.
• [53] Tempesti T, Alvarez MG, Araújo M, Catunda Júnior FEA, Carvalho MG, Durantini E. Antifungal activity of a novel quercetin derivative bearing a trifluoromethyl group on Candida albicans. Med Chem Res. 2012; 21: 2217-2222. http://dx.doi.org/10.1007/s00044-011-9750-x.
• [54] Gao M, Wang H, Zhu L. Quercetin assists fluconazole to inhibit biofilm formations of fluconazole-resistant Candida albicans in in vitro and in vivo antifungal managements of vulvovaginal candidiasis. Cell Physiol Biochem. 2016; 40(3-4): 727-742. https://doi.org/10.1159/000453134.
• [55] Dhawan V, Bakshi C, Rather R. Molecular targets and novel therapeutics to target oxidative stress in cardiovascular diseases. Oxidative Stress in Heart Diseases. 2019, pp. 59-82. http://dx.doi.org/10.1007/978-981-13-8273-4_4.
• [56] Taïlé J, Arcambal A, Clerc P, Gauvin-Bialecki A, Gonthier M. Medicinal plant polyphenols attenuate oxidative stress and improve inflammatory and vasoactive markers in cerebral endothelial cells during hyperglycemic condition. J Antioxidants. 2020; 9(7): 573. https://doi.org/10.3390/antiox9070573.
• [57] Patel R, Mistry B, Shinde S, Syed R, Singh V, Shin H. Therapeutic potential of quercetin as a cardiovascular agent. Eur J Med Chem. 2018; 155: 889-904. https://doi.org/10.1016/j.ejmech.2018.06.053.
• [58] Xiao X, Shi D, Liu L, Wang J, Xie X, Kang T, Deng W. Quercetin suppresses cyclooxygenase-2 expression and angiogenesis through inactivation of P300 signaling. PLoS One. 2011; 6(8): e22934. https://doi.org/10.1371/journal.pone.0022934.
• [59] Oyagbemi AA, Omobowale TO, Ola-Davies OE, Asenuga ER, Ajibade TO, Adejumobi OA, Arojojoye OA, Afolabi JM, Ogunpolu BS, Falayi OO, Hassan FO, Ochigbo GO, Saba AB, Adedapo AA, Yakubu MA. Quercetin attenuates hypertension induced by sodium fluoride via reduction in oxidative stress and modulation of HSP 70/ERK/PPARγ signaling pathways. Biofactors. 2018; 44(5): 465-479. https://doi.org/10.1002/biof.1445.
• [60] Sato S, Mukai Y. Modulation of chronic inflammation by quercetin: The beneficial effects on obesity. J Inflamm Res. 2020; 13: 421-431. https://doi.org/10.2147/jir.s228361.
• [61] Warren C, Paulhill K, Davidson L, Lupton J, Taddeo S, Hong M, Carroll R, Chapkin R, Turner N. Quercetin may suppress rat aberrant crypt foci formation by suppressing inflammatory mediators that influence proliferation and apoptosis. J Nutr. 2009; 139(1): 101-105. https://doi.org/10.3945%2Fjn.108.096271.
• [62] Chun OK, Chung SJ, Claycombe KJ, Song WO. Serum C-reactive protein concentrations are inversely associated with dietary flavonoid intake in US adults. J Nutr. 2008; 138(4): 753-760. https://doi.org/10.1093/jn/138.4.753.
• [63] Mediavilla V, Crespo I, Collado PS, Esteller A, Sánchez-Campos S, Tuñón MJ, González-Gallego J. The antiinflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol. 2007; 557(2-3): 221-229. https://doi.org/10.1016/j.ejphar.2006.11.014.
• [64] Kaneider NC, Mosheimer B, Reinisch N, Patsch JR, Wiedermann CJ. Inhibition of thrombin-induced signaling by resveratrol and quercetin: effects on adenosine nucleotide metabolism in endothelial cells and platelet–neutrophil interactions. Thromb Res. 2004; 114(3): 185-194. https://doi.org/10.1016/j.thromres.2004.06.020.
• [65] Hosoda S, Kawazoe Y, Shiba T, Numazawa S, Manabe A. Anti-obesity effect of ginkgo vinegar, a fermented product of ginkgo seed coat, in mice fed a high-fat diet and 3T3-L1 preadipocyte cells. Nutrients. 2020; 12(1): 230. https://doi.org/10.3390/nu12010230.
• [66] Pei Y, Otieno D, Gu I, Lee S-O, Parks JS, Schimmel K, Kang HW. Effect of quercetin on nonshivering thermogenesis of brown adipose tissue in high-fat diet-induced obese mice. J Nutr Biochem. 2021; 88: 108532. https://doi.org/10.1016/j.jnutbio.2020.108532.
• [67] Ahmed HH, Kotob SE, Abd-Rabou AA, Aglan HA, Elmegeed GA, Mohawed OA. Pre-clinical evidence for the antiobesity potential of quercetin and curcumin loaded chitosan/PEG blended PLGA nanoparticles. Biomed Pharm J. 2021; 14(4): 1731-1759. https://dx.doi.org/10.13005/bpj/2274.
• [68] Nabavi SF, Russo GL, Daglia M, Nabavi SM. Role of quercetin as an alternative for obesity treatment: you are what you eat. Food Chem. 2015; 179: 305-310. https://doi.org/10.1016/j.foodchem.2015.02.006.
• [69] Lakhanpal P, Rai DK. Quercetin: a versatile flavonoid. IJMU. 2007; 2(2): 22-37. http://dx.doi.org/10.4314/ijmu.v2i2.39851.
• [70] Begum AN, Terao J. Protective effect of quercetin against cigarette tar extract-induced impairment of erythrocyte deformability. J Nutr Biochem. 2002; 13(5): 265-272. https://doi.org/10.1016/s0955-2863(01)00219-4.
• [71] Rojas Á, Del Campo JA, Clement S, Lemasson M, García-Valdecasas M, Gil-Gómez A, Ranchal I, Bartosch B, Bautista JD, Rosenberg AR, Negro F, Romero-Gómez M. Effect of quercetin on hepatitis C virus life cycle: from viral to host targets. Sci Rep. 2016; 6: 31777. https://doi.org/10.1038%2Fsrep31777.
• [72] Petrillo AD, Orrù G, Fais A, Fantini MC. Quercetin and its derivates as antiviral potentials: A comprehensive review. Phytother Res. 2022; 36(1): 266-278. https://doi.org/10.1002/ptr.7309.
• [73] Edwards RL, Lyon T, Litwin SE, Rabovsky A, Symons JD, Jalili T. Quercetin reduces blood pressure in hypertensive subjects. J Nutr. 2007; 137(11): 2405-2411. https://doi.org/10.1093/jn/137.11.2405.
• [74] Chopra M, Fitzsimons PE, Strain JJ, Thurnham DI, Howard AN. Nonalcoholic red wine extract and quercetin inhibit LDL oxidation without affecting plasma antioxidant vitamin and carotenoid concentrations. Clin Chem. 2000; 46(8): 1162-1170.
• [75] Egert S, Bosy-Westphal A, Seiberl J, Kürbitz C, Settler U, Plachta-Danielzik S, Wagner AE, Frank J, Schrezenmeir J, Rimbach G, Wolffram S, Müller MF. Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a doubleblinded, placebo-controlled cross-over study. Br J Nutr. 2009; 102(7): 1065-1074. https://doi.org/10.1017/s0007114509359127.
• [76] Ahmad B, Serpell CJ, Fong IL, Wong EH. Molecular mechanisms of adipogenesis: the anti-adipogenic role of AMPactivated protein kinase. Front Mol Biosci. 2020; 7: 76. https://doi.org/10.3389/fmolb.2020.00076.
• [77] Park HJ, Yang J-Y, Ambati S, Della-Fera MA, Hausman DB, Rayalam S, Baile CA. Combined effects of genistein, quercetin, and resveratrol in human and 3T3-L1 adipocytes. J Med Food. 2008; 11(4): 773-783. https://doi.org/10.1089/jmf.2008.0077.
• [78] Strobel P, Allard C, Perez-Acle T, Calderon R, Aldunate R, Leighton F. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes. Biochem J. 2005; 386(3): 471-478. https://doi.org/10.1042/bj20040703.
• [79] Huxley RR, Neil HAW. The relation between dietary flavonol intake and coronary heart disease mortality: a metaanalysis of prospective cohort studies. Eur J Clin Nutr. 2003; 57(8): 904-908. https://doi.org/10.1038/sj.ejcn.1601624.
• [80] Pereira MA, O'Reilly E, Augustsson K, Fraser GE, Goldbourt U, Heitmann BL, Hallmans G, Knekt P, Liu S, Pietinen P, Spiegelman D, Stevens J, Virtamo J, Willett WC, Ascherio A. Dietary fiber and risk of coronary heart disease: a pooled analysis of cohort studies. Arch Intern Med. 2004; 164(4):370-376. https://doi.org/10.1001/archinte.164.4.370.
• [81] Naidu PS, Singh A, Joshi D, Kulkarni SK. Possible mechanisms of action in quercetin reversal of morphine tolerance and dependence. Addict Biol. 2003; 8(3): 327-336. http://dx.doi.org/10.1080/13556210310001602248.
• [82] Chen F, Sun J, Chen C, Zhang Y, Zou L, Zhang Z, Chen M, Wu H, Tian W, Liu Y, Xu Y, Luo H, Zhu M, Yu J, Wang Q, Wang K. Quercetin mitigates methamphetamine-induced anxiety-like behavior through ameliorating mitochondrial dysfunction and neuroinflammation. Front Mol Neurosci. 2022; 15: 829886. http://dx.doi.org/10.3389/fnmol.2022.829886.
• [83] ElShebiney S, Elgohary R, El-Shamarka M, Mowaad N, Abulseoud OA. Natural polyphenols-resveratrol, quercetin, magnolol, and β-catechin-block certain aspects of heroin addiction and modulate striatal IL-6 and TNF-α. Toxics. 2023; 11(4): 379. http://dx.doi.org/10.3390/toxics11040379.
• [84] Imran M, Salehi B, Sharifi-Rad J, Aslam Gondal T, Saeed F, Imran A, Shahbaz M, Tsouh Fokou PV, Umair Arshad M, Khan H, Guerreiro SG, Martins N, Estevinho LM. Kaempferol: A key emphasis to its anticancer potential. Molecules. 2019; 24(12): 2277. https://doi.org/10.3390%2Fmolecules24122277.
• [85] Calderon-Montano JM, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M. A review on the dietary flavonoid kaempferol. Mini Rev Med Chem. 2011; 11(4): 298-344. https://doi.org/10.2174/138955711795305335.
• [86] Barve A, Chen C, Hebbar V, Desiderio J, Saw CLL, Kong AN. Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats. Biopharm Drug Dispos. 2009; 30(7): 356-365. https://doi.org/10.1002%2Fbdd.677.
• [87] Kashafi E, Moradzadeh M, Mohamadkhani A, Erfanian S. Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/AKT and telomerase pathways. Biomed Pharmacother. 2017; 89: 573-577. https://doi.org/10.1016/j.biopha.2017.02.061.
• [88] Kashyap D, Sharma A, Tuli HS, Sak K, Punia S, Mukherjee TK. Kaempferol–A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements. J Funct Foods. 2017; 30: 203-219. https://doi.org/10.1016/j.jff.2017.01.022.
• [89] Yang Y, Chen Z, Zhao X, Xie H, Du L, Gao H, Xie C. Mechanisms of Kaempferol in the treatment of diabetes: A comprehensive and latest review. Front Endocrinol (Lausanne). 2022; 13: 990299. https://doi.org/10.3389/fendo.2022.990299.
• [90] Silva Dos Santos J, Gonçalves Cirino JP, de Oliveira Carvalho P, Ortega MM. The pharmacological action of kaempferol in central nervous system diseases: A Review. Front Pharmacol. 2020; 11: 565700. http://dx.doi.org/10.3389/fphar.2020.565700
• [91] Jin S, Zhang L, Wang L. Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine. Biomed Pharmacother. 2023; 165: 115215. http://dx.doi.org/10.1016/j.biopha.2023.115215.
• [92] Yang S, Liu W, Lu S, Tian YZ, Wang WY, Ling TJ, Liu RT. A novel multifunctional compound camellikaempferoside B decreases Aβ production, interferes with Aβ aggregation, and prohibits Aβ-mediated neurotoxicity and neuroinflammation. ACS Chem Neurosci. 2016; 7(4): 505-518. http://dx.doi.org/10.1021/acschemneuro.6b00091.
• [93] Azlan UK, Khairul Annuar NA, Mediani A, Aizat WM, Damanhuri HA, Tong X, Yanagisawa D, Tooyama I, Wan Ngah WZ, Jantan I, Hamezah HS. An insight into the neuroprotective and anti-neuroinflammatory effects and mechanisms of Moringa oleifera. Front Pharmacol. 2023; 13: 1035220. https://doi.org/10.3389/fphar.2022.1035220.
• [94] Lin CW, Shen SC, Chien CC, Yang LY, Shia LT, Chen YC. 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced invasion/migration of glioblastoma cells through activating PKCα/ERK/NF‐κB‐dependent MMP‐9 expression. J Cell Physiol. 2010; 225(2): 472-481. https://doi.org/10.1002/jcp.22226.
• [95] Habauzit V, Nielsen IL, Gil-Izquierdo A, Trzeciakiewicz A, Morand C, Chee W, Barron D, Lebecque P, Davicco MJ, Williamson G, Offord E, Coxam V, Horcajada MN. Increased bioavailability of hesperetin-7-glucoside compared with hesperidin results in more efficient prevention of bone loss in adult ovariectomised rats. Br J Nutr. 2009; 102(7): 976-984. https://doi.org/10.1017/s0007114509338830.
• [96] Wong SK, Chin K-Y, Ima-Nirwana S. The osteoprotective effects of kaempferol: the evidence from in vivo and in vitro studies. Drug Des Devel Ther. 2019; 13: 3497-3514. https://doi.org/10.2147%2FDDDT.S227738.
• [97] Man MQ, Yang B, Elias PM. Benefits of hesperidin for cutaneous functions. Evid Based Complement Alternat Med. 2019; 2019: 2676307. http://dx.doi.org/10.1155/2019/2676307.
• [98] 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(4): 472-477. http://dx.doi.org/10.1038/sj.ejcn.1602543.
• [99] Lee N-K, Choi S-H, Park S-H, Park E-K, Kim D-H. Antiallergic activity of hesperidin is activated by intestinal microflora. Pharmacology. 2004; 71(4): 174-180. https://doi.org/10.1159/000078083.
• [100] Kim S-H, Kim B-K, Lee Y-C. Antiasthmatic effects of hesperidin, a potential Th2 cytokine antagonist, in a mouse model of allergic asthma. Mediators Inflamm. 2011; 2011: 485402. https://doi.org/10.1155/2011/485402.
• [101] Pandey P, Khan F. A mechanistic review of the anticancer potential of hesperidin, a natural flavonoid from citrus fruits. Nutr Res. 2021; 92: 21-31. http://dx.doi.org/10.1016/j.nutres.2021.05.011.
• [102] Roohbakhsh A, Parhiz H, Soltani F, Rezaee R, Iranshahi M. Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases. Life Sci. 2015; 124: 64-74. https://doi.org/10.1016/j.lfs.2014.12.030.
• [103] Jin Y-R, Han X-H, Zhang Y-H, Lee J-J, Lim Y, Chung J-H, Yun Y-P. Antiplatelet activity of hesperetin, a bioflavonoid, is mainly mediated by inhibition of PLC-γ2 phosphorylation and cyclooxygenase-1 activity. Atherosclerosis. 2007; 194(1): 144-152. https://doi.org/10.1016/j.atherosclerosis.2006.10.011.
• [104] Sasaki Y, Hyodo K, Hoshino A, Kisa E, Matsuda K, Horikawa Y, Giddings JC. Myricetin and Hesperidin inhibit cerebral thrombogenesis and atherogenesis in Apoe-/-and Ldlr-/-mice. Food Nutr Sci. 2018; 9(1): 20-31. https://doi.org/10.4236/fns.2018.91002.
• [105] 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): 1272-1277. https://doi.org/10.1002/ptr.3724.
• [106] Hajialyani M, Hosein Farzaei M, Echeverría J, Nabavi SM, Uriarte E, Sobarzo-Sánchez E. Hesperidin as a neuroprotective agent: a review of animal and clinical evidence. Molecules. 2019; 24(3): 648. https://doi.org/10.3390/molecules24030648.
• [107] Nones J, Spohr T, Gomes F. Hesperidin, a flavone glycoside, as mediator of neuronal survival. Neurochem Res. 2011; 36: 1776-1784. https://doi.org/10.1007/s11064-011-0493-3. [108] Hu HY, Zhang ZZ, Jiang XY, Duan TH, Feng W, Wang XG. Hesperidin anti-osteoporosis by regulating estrogen signaling pathways. Molecules. 2023; 28(19): 6987. http://dx.doi.org/10.3390/molecules28196987.
• [109] Alshehri SM, Shakeel F, Ibrahim MA, Elzayat EM, Altamimi M, Mohsin K, Almeanazel OT, Alkholief M, Alshetaili A, Alsulays B, Alanazi FK, Alsarra IA. Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepared by different techniques. Saudi Pharm J. 2019; 27(2): 264-273. https://doi.org/10.1016/j.jsps.2018.11.008.
• [110] Elhennawy MG, Lin H-S. Dose-and time-dependent pharmacokinetics of apigenin trimethyl ether. Eur J Pharm Sci. 2018; 118: 96-102. https://doi.org/10.1016/j.ejps.2018.03.022.
• [111] Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, Lucarini M, Santini A, Souto EB, Novellino E, Antolak H, Azzini E, Setzer WN, Martins N. The therapeutic potential of apigenin. Int J Mol Sci. 2019; 20(6): 1305. https://doi.org/10.3390/ijms20061305.
• [112] Zhang K, Song W, Li D, Jin XJE, Medicine T. Apigenin in the regulation of cholesterol metabolism and protection of blood vessels. Exp Ther Med. 2017; 13(5): 1719-1724. https://doi.org/10.3892/etm.2017.4165.
• [113] Zhao L, Wang J-L, Liu R, Li X-X, Li J-F, Zhang L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer’s disease mouse model. Molecules. 2013; 18(8): 9949-9965. https://doi.org/10.3390/molecules18089949.
• [114] Shilpa VS, Shams R, Dash KK, Pandey VK, Dar AH, Ayaz Mukarram S, Harsányi E, Kovács B. Phytochemical properties, extraction, and pharmacological benefits of naringin: A Review. Molecules. 2023; 28(15): 5623. http://dx.doi.org/10.3390/molecules28155623.
• [115] Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J. Naringin and naringenin: Their mechanisms of action and the potential anticancer activities. Biomedicines. 2022; 10(7): 1686. https://doi.org/10.3390/biomedicines10071686.
• [116] Aroui S, Najlaoui F, Chtourou Y, Meunier AC, Laajimi A, Kenani A, Fetoui H. Naringin inhibits the invasion and migration of human glioblastoma cell via downregulation of MMP-2 and MMP-9 expression and inactivation of p38 signaling pathway. Tumour Biol. 2016; 37(3): 3831-3839. https://doi.org/10.1007/s13277-015-4230-4.
• [117] Memariani Z, Abbas SQ, Ul Hassan SS, Ahmadi A, Chabra A. Naringin and naringenin as anticancer agents and adjuvants in cancer combination therapy: Efficacy and molecular mechanisms of action, a comprehensive narrative review. Pharm Res. 2021; 171: 105264. https://doi.org/10.1016/j.phrs.2020.105264.
• [118] Richard AJ, Amini-Vaughan Z, Ribnicky DM, Stephens JM. Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes. Evid Based Complement Alternat Med. 2013; 2013: 54950. https://doi.org/10.1155/2013/549750.
• [119] Cho KW, Kim YO, Andrade JE, Burgess JR, Kim Y-C. Dietary naringenin increases hepatic peroxisome proliferators–activated receptor α protein expression and decreases plasma triglyceride and adiposity in rats. Eur J Nutr. 2011; 50: 81-88. https://doi.org/10.1007/s00394-010-0117-8.
• [120] Sutandar VH. Potential of naringin in reducing aorta lesion atherosclerosis in hypercholesterolemia: A systematic review. OAIJMR. 2022; 2(1): 136-140. https://doi.org/10.37275/oaijmr.v2i1.150.
• [121] Nyane NA, Tlaila TB, Malefane TG, Ndwandwe DE, Owira PMO. Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights. Eur J Pharm. 2017; 803: 103-111. https://doi.org/10.1016/j.ejphar.2017.03.042.
• [122] Constantin RP, Bracht A, Yamamoto NS, Ishii-Iwamoto EL, Constantin JJF. Molecular mechanisms of citrus flavanones on hepatic gluconeogenesis. Eur J Pharm. 2014; 92: 148-162. https://doi.org/10.1016/j.ejphar.2017.03.042.
• [123] Den Hartogh DJ, Tsiani E. Antidiabetic properties of naringenin: A citrus fruit polyphenol. Biomolecules. 2019; 9(3): 99. https://doi.org/10.3390/biom9030099.
• [124] Ahmed S, Khan H, Aschner M, Hasan MM, Hassan STS. Therapeutic potential of naringin in neurological disorders. Food Chem Toxicol. 2019; 132: 110646. https://doi.org/10.1016/j.fct.2019.110646.
• [125] Jiao HY, Su WW, Li PB, Liao Y, Zhou Q, Zhu N, He LL. Therapeutic effects of naringin in a guinea pig model of ovalbumin-induced cough-variant asthma. Pulm Pharmacol Ther. 2015; 33: 59-65. https://doi.org/10.1016/j.pupt.2015.07.002.
• [126] López-Lázaro M. Distribution and biological activities of the flavonoid luteolin. Mini Rev Med Chem. 2009; 9(1): 31- 59. http://dx.doi.org/10.2174/138955709787001712.
• [127] Sarawek S, Derendorf H, Butterweck V. Pharmacokinetics of luteolin and metabolites in rats. Nat Prod Commun. 2008; 3(12): 2029-2036. https://doi.org/10.1177/1934578X0800301218.
• [128] Kim J-S, Kwon C-S, Son KH. Inhibition of alpha-glucosidase and amylase by luteolin, a flavonoid. Biosci Biotechnol Biochem. 2000; 64(11): 2458-2461. https://doi.org/10.1271/bbb.64.2458.
• [129] Sangeetha R. Luteolin in the management of type 2 diabetes mellitus. Curr Res Nutr Food Sci. 2019; 7(2): 393-398. http://dx.doi.org/10.12944/CRNFSJ.7.2.09.
• [130] Kou JJ, Shi JZ, He YY, Hao JJ, Zhang HY, Luo DM, Song JK, Yan Y, Xie XM, Du GH, Pang XB. Luteolin alleviates cognitive impairment in Alzheimer’s disease mouse model via inhibiting endoplasmic reticulum stress-dependent neuroinflammation. Acta Pharmacol Sin. 2022; 43(4): 840-849. https://doi.org/10.1038/s41401-021-00702-8.
• [131] Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Woźniak K, Nabavi SM. Luteolin as an antiinflammatory and neuroprotective agent: A brief review. Brain Res Bull. 2015; 119: 1-11. https://doi.org/10.1016/j.brainresbull.2015.09.002.
• [132] Sá C, Oliveira AR, Machado C, Azevedo M, Pereira-Wilson C. Effects on liver lipid metabolism of the naturally occurring dietary flavone luteolin-7-glucoside. Evid Based Complement Alternat Med. 2015; 2015: 647832. https://doi.org/10.1155/2015/647832.
• [133] Ding X, Zheng L, Yang B, Wang X, Ying Y. Luteolin attenuates atherosclerosis via modulating signal transducer and activator of transcription 3-mediated inflammatory response. Drug Des Devel Ther. 2019; 13: 3899-3911. https://doi.org/10.2147/DDDT.S207185.
• [134] Xue J, Ye J, Xia Z, Cheng BJC, Biology M. Effect of luteolin on apoptosis, MAPK and JNK signaling pathways in guinea pig chondrocyte with osteoarthritis. Cell Mol Biol. 2019; 65(6): 91-95. https://doi.org/10.14715/cmb/2019.65.6.15.
• [135] Mbaveng AT, Zhao Q, Kuete V. Harmful and protective effects of phenolic compounds from African medicinal plants. Toxicological survey of African medicinal plants: Elsevier. 2014, pp. 577-609. https://doi.org/10.1016/B978-0-12-800018-2.00020-0.
• [136] Goh YX, Jalil J, Lam KW, Husain K, Premakumar CM. Genistein: a review on its anti-inflammatory properties. Frontiers. 2022; 13: 820969. https://doi.org/10.3389/fphar.2022.820969.
• [137] Fukutake M, Takahashi M, Ishida K, Kawamura H, Sugimura T, Wakabayashi K. Quantification of genistein and genistin in soybeans and soybean products. Food Chem Toxicol. 1996; 34(5): 457-461. https://doi.org/10.1016/0278-6915(96)87355-8.
• [138] Barnes S, Peterson TG, Coward L. Rationale for the use of genistein‐containing soy matrices in chemoprevention trials for breast and prostate cancer. J Cell Biochem Suppl. 1995; 59(22): 181-187. https://doi.org/10.1002/jcb.240590823.
• [139] Yang Z, Zhu W, Gao S, Xu H, Wu B, Kulkarni K, Singh R, Tang L, Hu M. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC–MS/MS method: Application to an oral bioavailability study of genistein in mice. J Pharm Biomed Anal. 2010; 53(1): 81-89. https://doi.org/10.1016/j.jpba.2010.03.011.
• [140] Penza M, Montani C, Romani A, Vignolini P, Pampaloni B, Tanini A, Brandi ML, Alonso-Magdalena P, Nadal A, Ottobrini L, Parolini O, Bignotti E, Calza S, Maggi A, Grigolato PG, Di Lorenzo D. Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner. Endocrinology. 2006; 147(12): 5740-5751. https://doi.org/10.1210/en.2006-0365.
• [141] Anthony MS, Clarkson TB, Hughes CL Jr, Morgan TM, Burke GL. Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys. J Nutr. 1996; 126(1): 43-50. https://doi.org/10.1093/jn/126.1.43.
• [142] Yellayi S, Zakroczymski MA, Selvaraj V, Valli VE, V Ghanta, Helferich WG, Cooke PS. The phytoestrogen genistein suppresses cell-mediated immunity in mice. J Endocrinol. 2003; 176(2): 267-274. https://doi.org/10.1677/joe.0.1760267.
• [143]Morán J, Garrido P, Alonso A, Cabello E, González C. 17β-Estradiol and genistein acute treatments improve some cerebral cortex homeostasis aspects deteriorated by aging in female rats. Exp Gerontol. 2013; 48(4): 414-421. https://doi.org/10.1016/j.exger.2013.02.010.
• [144] Tian H-S, Zhou G-Q, Zhu Z-Y. Evaluation of cardioprotective effects of genistein against diabetes-induced cardiac dysfunction in rats. Trop J Pharm Res. 2015; 14(11): 2015-2022. https://doi.org/10.4314/tjpr.v14i11.10.
• [145] Song X, Tan L, Wang M, Ren C, Guo C, Yang B, Ren Y, Cao Z, Li Y, Pei J. Myricetin: A review of the most recent research. Biomed Pharmacother. 2021; 134: 111017. https://doi.org/10.1016/j.biopha.2020.111017.
• [146] Hou W, Hu S, Su Z, Wang Q, Meng G, Guo T, Zhang J, Gao P. Myricetin attenuates LPS-induced inflammation in RAW 264.7 macrophages and mouse models. Future Med Chem. 2018; 10(19): 2253-2264. https://doi.org/10.4155/fmc-2018-0172.
• [147] Jiang M, Zhu M, Wang L, Yu S. Anti-tumor effects and associated molecular mechanisms of myricetin. Biomed Pharmacother. 2019; 120: 109506. https://doi.org/10.1016/j.biopha.2019.109506.
• [148] Jiang S, Tang X, Chen M, He J, Su S, Liu L, He M, Xue W. Design, synthesis and antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas axonopodis pv. Citri and Ralstonia solanacearum of novel myricetin derivatives containing sulfonamide moiety. Pest Manag Sci. 2020; 76(3): 853-860. https://doi.org/10.1002/ps.5587.
• [149] Ortega JT, Suárez AI, Serrano ML, Baptista J, Pujol FH, Rangel HR. The role of the glycosyl moiety of myricetin derivatives in anti-HIV-1 activity in vitro. AIDS Res Ther. 2017; 14(1): 57. https://doi.org/10.1186/s12981-017-0183-6.
• [150] Hu T, Yuan X, Wei G, Luo H, Lee HJ, Jin W. Myricetin-induced brown adipose tissue activation prevents obesity and insulin resistance in db/db mice. Eur J Nutr. 2018; 57: 391-403. https://doi.org/10.1007/s00394-017-1433-z.
• [151] Wang L, Wu H, Yang F, Dong W. The protective effects of myricetin against cardiovascular disease. J Nutr Sci Vitaminol (Tokyo). 2019; 65(6): 470-476. https://doi.org/10.3177/jnsv.65.470.
• [152] Guo C, Xue G, Pan B, Zhao M, Chen S, Gao J, Chen T, Qiu L. Myricetin ameliorates ethanol‐induced lipid accumulation in liver cells by reducing fatty acid biosynthesis. Mol Nutr Food Res. 2019; 63(14): e1801393. https://doi.org/10.1002/mnfr.201801393.
• [153] Kandasamy N, Ashokkumar N. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats. Toxicol Appl Pharmacol. 2014; 279(2): 173-185. https://doi.org/10.1016/j.taap.2014.05.014.
• [154] Silva LN, Da Hora GCA, Soares TA, Bojer MS, Ingmer H, Macedo AJ, Trentin DS. Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors. Sci Rep. 2017; 7(1): 2823. https://doi.org/10.1038/s41598-017-02712-1.
• [155] Li G, Lu G, Qi Z, Li H, Wang L, Wang Y, Liu B, Niu X, Deng X, Wang J. Morin attenuates Streptococcus suis pathogenicity in mice by neutralizing suilysin activity. Front Microbiol. 2017; 8: 460. https://doi.org/10.3389/fmicb.2017.00460.
• [156] Li G, Wang G, Si X, Zhang X, Liu W, Li L, Wang J. Inhibition of suilysin activity and inflammation by myricetin attenuates Streptococcus suis virulence. Life Sci. 2019; 223: 62-68. https://doi.org/10.1016/j.lfs.2019.03.024.
• [157] Ghassemi‐Rad J, Maleki M, Knickle AF, Hoskin D. Myricetin‐induced oxidative stress suppresses murine T lymphocyte activation. Cell Biol Int. 2018; 42(8): 1069-1075. https://doi.org/10.1002/cbin.10977.
• [158] Abudayyeh OO, Gootenberg JS, Franklin B, Koob J, Kellner MJ, Ladha A, Joung J, Kirchgatterer P, Cox DBT, Zhang F. A cytosine deaminase for programmable single-base RNA editing. Science. 2019; 365(6451): 382-386. http://dx.doi.org/10.1126/science.aax7063.
• [159] Wang B, Hao D, Zhang Z, Gao W, Pan H, Xiao Y, He B, Kong L. Inhibition effects of a natural inhibitor on RANKL downstream cellular signalling cascades cross‐talking. J Cell Mol Med. 2018; 22(9): 4236-4242. https://doi.org/10.1111/jcmm.13703. [160] Yunusoglu O, Bukhari A, Turel C, Demirkol M, Berköz M, Akkan A. Investigation of the pharmacological potential of myricetin on alcohol addiction in mice. J Res Pharm. 2022; 26(4): 722-733. http://doi.org/10.29228/jrp.170.
• [161] King RE, Bomser JA, Min D. Bioactivity of resveratrol. Compr Rev Food Sci Food Saf. 2006; 5(3): 65-70. https://doi.org/10.1111/j.1541-4337.2006.00001.x.
• [162] Walle T. Bioavailability of resveratrol. Ann N Y Acad Sci. 2011; 1215: 9-15. http://dx.doi.org/10.1111/j.1749- 6632.2010.05842.x.
• [163] Banerjee S, Bueso-Ramos C, Aggarwal B. Suppression of 7, 12-dimethylbenz (a) anthracene-induced mammary carcinogenesis in rats by resveratrol: Role of nuclear factor-κB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 2002; 62(17): 4945-4954. https://doi.org/10.1016/j.cdp.2005.01.005.
• [164] Wolter F, Clausnitzer A, Akoglu B, Stein J. Piceatannol, a natural analog of resveratrol, inhibits progression through the S phase of the cell cycle in colorectal cancer cell lines. J Nutr. 2002; 132(2): 298-302. http://dx.doi.org/10.1093/jn/132.2.298.
• [165] Hung L-M, Chen J-K, Huang S-S, Lee R-S, Su M. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res. 2000; 47(3): 549-555. http://dx.doi.org/10.1016/S0008-6363(00)00102-4.
• [166] Manna SK, Mukhopadhyay A, Aggarwal B. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 2000; 164(12): 6509-6519. http://dx.doi.org/10.4049/jimmunol.164.12.6509.
• [167] Theodotou M, Fokianos K, Mouzouridou A, Konstantinou C, Aristotelous A, Prodromou D, Chrysikou A. The effect of resveratrol on hypertension: A clinical trial. Exp Ther Med. 2017; 13(1): 295-301. http://dx.doi.org/10.3892/etm.2016.3958.
• [168] Orallo F, Álvarez E, Camiña M, Leiro JM, Gómez E, Fernández P. The possible implication of trans-resveratrol in the cardioprotective effects of long-term moderate wine consumption. Mol Pharmacol. 2002; 61(2): 294-302. http://dx.doi.org/10.1124/mol.61.2.294.
• [169] Li H, Xia N, Hasselwander S, Daiber A. Resveratrol and vascular function. Int J Mol Sci. 2019; 20(9): 2155. http://dx.doi.org/10.3390/ijms20092155.
• [170] Martín AR, Villegas I, La Casa C, de la Lastra CA. Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats. Biochem Pharmacol. 2004; 67(7): 1399- 1410. https://doi.org/10.1016/j.bcp.2003.12.024.
• [171] Hu HC, Lei YH, Zhang WH, Luo XQ. Antioxidant and anti-inflammatory properties of resveratrol in diabetic nephropathy: a systematic review and meta-analysis of animal studies. Front Pharmacol. 2022; 13: 841818. https://doi.org/10.3389%2Ffphar.2022.841818.
• [172] Wang Z, Huang Y, Zou J, Cao K, Xu Y, Wu JM. Effects of red wine and wine polyphenol resveratrol on platelet aggregation in vivo and in vitro. Int J Mol Med. 2002; 9(1): 77-79. http://dx.doi.org/10.3892/ijmm.9.1.77.
• [173] Kaneider NC, Mosheimer B, Reinisch N, Patsch JR, Wiedermann CJ. Inhibition of thrombin-induced signaling by resveratrol and quercetin: effects on adenosine nucleotide metabolism in endothelial cells and platelet–neutrophil interactions. Thromb Res. 2004; 114(3): 185-194. https://doi.org/10.1016/j.thromres.2004.06.020.
• [174] Li Y, Yu L, Zhao L, Zeng F, Liu QS. Resveratrol modulates cocaine-induced inhibitory synaptic plasticity in VTA dopamine neurons by inhibiting phosphodiesterases (PDEs). Sci Rep. 2017; 7(1): 15657. http://dx.doi.org/10.1038/s41598-017-16034-9.
• [175] Yunusoğlu O. Resveratrol impairs acquisition, reinstatement and precipitates extinction of alcohol-induced place preference in mice. Neurol Res. 2021; 43(12): 985-994. http://dx.doi.org/10.1080/01616412.2021.1948749.
• [176] Miller DK, Oelrichs CE, Sage AS, Sun GY, Simonyi A. Repeated resveratrol treatment attenuates methamphetamine-induced hyperactivity and [3H] dopamine overflow in rodents. Neurosci Lett. 2013; 554: 53-58. http://dx.doi.org/10.1016/j.neulet.2013.08.051.
• [177] Menegas S, Ferreira CL, Cararo JH, Gava FF, Dal-Pont GC, Gomes ML, Agostini JF, Schuck PF, Scaini G, Andersen ML, Quevedo J, Valvassori SS. Resveratrol protects the brain against oxidative damage in a dopaminergic animal model of mania. Metab Brain Dis. 2019; 34(3): 941-950. https://doi.org/10.1007/s11011-019-00408-1.
• [178] Shih JH, Ma KH, Chen CF, Cheng CY, Pao LH, Weng SJ, Huang YS, Shiue CY, Yeh MK, Li IH. Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[18F]- ADAM/small-animal PET study. Eur Neuropsychopharmacol. 2016; 26(1): 92-104. http://dx.doi.org/10.1016/j.euroneuro.2015.11.001.
• [179] An X, Zhu A, Luo H, Ke H, Chen H, Zhao Y. Rational design of multi-stimuli-responsive nanoparticles for precise cancer therapy. ACS Nano. 2016; 10(6): 5947-5958. http://dx.doi.org/10.1021/acsnano.6b01296.
• [180] Soler‐Rivas C, Espín JC, Wichers HJ. Oleuropein and related compounds. J Sci Food Agric. 2000; 80(7): 1013-1023. http://dx.doi.org/10.1002/(SICI)1097-0010(20000515)80:7%3C1013::AID-JSFA571%3E3.0.CO;2-C.
• [181] Nediani C, Ruzzolini J, Romani A, Calorini L. Oleuropein, a bioactive compound from Olea europaea L., as a potential preventive and therapeutic agent in non-communicable diseases. Antioxidants (Basel). 2019; 8(12): 578. http://dx.doi.org/10.3390/antiox8120578.
• [182] Visioli F, De La Lastra CA, Andres-Lacueva C, Aviram M, Calhau C, Cassano A, D'Archivio M, Faria A, Favé G, Fogliano V, Llorach R, Vitaglione P, Zoratti M, Edeas M. Polyphenols and human health: a prospectus. Crit Rev Food Sci Nutr. 2011; 51(6): 524-546. http://dx.doi.org/10.1080/10408391003698677.
• [183] Elamin MH, Daghestani MH, Omer SA, Elobeid MA, Virk P, Al-Olayan EM, Hassan ZK, Mohammed OB, Aboussekhra A. Olive oil oleuropein has anti-breast cancer properties with higher efficiency on ER-negative cells. Food Chem Toxicol. 2013; 53: 310-316. https://doi.org/10.1016/j.fct.2012.12.009.
• [184] Psaltopoulou T, Kosti RI, Haidopoulos D, Dimopoulos M, Panagiotakos DB. Olive oil intake is inversely related to cancer prevalence: A systematic review and a meta-analysis of 13800 patients and 23340 controls in 19 observational studies. Lipids Health Dis. 2011; 10: 127. http://dx.doi.org/10.1186/1476-511X-10-127.
• [185] Da Porto A, Brosolo G, Casarsa V, Bulfone L, Scandolin L, Catena C, Sechi LA. The pivotal role of oleuropein in the anti-diabetic action of the Mediterranean diet: A concise review. Pharmaceutics. 2021; 14(1): 40. http://dx.doi.org/10.3390/pharmaceutics14010040.
• [186] Zheng S, Huang K, Tong T. Efficacy and mechanisms of oleuropein in mitigating diabetes and diabetes complications. J Agric Food Chem. 2021; 69(22): 6145-6155. http://dx.doi.org/10.1021/acs.jafc.1c01404.
• [187] Visioli F, Bellomo G, Galli C. Free radical-scavenging properties of olive oil polyphenols. Biochem Biophys Res Commun. 1998; 247(1): 60-64. https://doi.org/10.1006/bbrc.1998.8735.
• [188] Miles EA, Zoubouli P, Calder P. Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures. Nutrition. 2005; 21(3): 389-394. http://dx.doi.org/10.1016/j.nut.2004.06.031.
• [189] Sarbishegi M, Mehraein F, Soleimani M. Antioxidant role of oleuropein on midbrain and dopaminergic neurons of substantia nigra in aged rats. Iran Biomed J. 2014; 18(1): 16-22. http://dx.doi.org/10.6091/ibj.1274.2013.
• [190] Carito V, Venditti A, Bianco A, Ceccanti M, Serrilli AM, Chaldakov G, Tarani L, De Nicolò S, Fiore M. Effects of olive leaf polyphenols on male mouse brain NGF, BDNF and their receptors TrkA, TrkB and p75. Nat Prod Res. 2014; 28(22): 1970-1984. https://doi.org/10.1080/14786419.2014.918977