Diet-derived Flavonoids: Bridging Epidemiological Chemoprevention and Preclinical Anti-tumor Mechanisms in Clinical Oncology

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Authors

  • Department of Pharmacy, Sumandeep Vidyapeeth Deemed to be University, Piparia, Waghodia, Vadodara - 391760, Gujarat ,IN
  • Department of Pharmaceutical Chemistry, A. R. College of Pharmacy and G. H. Patel Institute of Pharmacy, Vallabh Vidyanagar, Anand - 388120, Gujarat ,IN

DOI:

https://doi.org/10.18311/jnr/2024/43883

Keywords:

Anticancer Activity, Epidemiological, Flavonoids, Molecular Mechanisms, Translational Research

Abstract

Flavonoids are an abundantly consumed group of dietary polyphenols present in fruits, vegetables, teas, herbs and other plant-derived foods composed of a diphenylpropane (C6-C3-C6) ring structure, allowing subclassification into flavonols, flavones, flavan-3-ols, anthocyanins and isoflavones based on substitutions on the heterocyclic C ring. Multiple case-control studies and prospective cohort analyses reveal higher intake of certain flavonoid subgroups associated with reduced risk of various epithelial cancers like lung, breast, pancreatic, oral and liver. In vitro studies across diverse human cancer cell lines and in vivo, animal models demonstrate anticancer effects of select flavonoids either directly or in synergy with chemotherapy by targeting hallmark capabilities that enable tumours including resisting cell death, sustaining proliferation, inducing angiogenesis, activating invasion and metastasis. The well-explored anticancer mechanisms range from direct antioxidant activity, quenching free radicals and bolstering endogenous defenses; to anti-inflammatory signalling via NF-κB and cytokine modulation; epigenetic alterations by chromatin remodeling; to direct regulation of cell cycle controllers (CDKs, cyclins) and apoptotic mediators (caspases, Bcl-2. Early human trials mostly indicate the safe use of certain flavonoids and subclasses at tested doses however, progression to therapeutic benefit faces challenges like suboptimal systemic availability upon metabolism, unclear metabolite activities and study design limitations regarding delivery methods, combination treatments and clinical priority. In essence, dietary flavonoids exhibit pleiotropic pharmacological strengths against cancer progression warranting expanded translational research and human trials to develop formulations/delivery systems and validate targeted clinical integration, especially alongside chemotherapy regimens.

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Published

2024-08-31

How to Cite

Panchal, N. B., & Vaghela, V. M. (2024). Diet-derived Flavonoids: Bridging Epidemiological Chemoprevention and Preclinical Anti-tumor Mechanisms in Clinical Oncology. Journal of Natural Remedies, 24(8), 1633–1651. https://doi.org/10.18311/jnr/2024/43883

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Received 2024-05-06
Accepted 2024-07-09
Published 2024-08-31

 

References

Xiao ZP, Peng ZY, Peng MJ, Yan WB, Ouyang YZ, Zhu HL. Flavonoids health benefits and their molecular mechanism. Mini Rev Med Chem. 2011; 11(2):169-77. https://doi.org/10.2174/138955711794519546 PMid:21222576

Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: An overview. Sci World J. 2013; 2013:16. https:// doi.org/10.1155/2013/162750 PMid:24470791 PMCid: PMC3891543

Panche AN, Diwan AD, Chandra SR. Flavonoids: An overview. J Nutr Sci. 2016; 5:e47. https://doi.org/10.1017/ jns.2016.41 PMid:28620474 PMCid: PMC5465813

Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther. 2002; 96(2-3):67-202. https://doi.org/10.1016/S0163-7258(02)00298-X PMid: 12453566

Mahmud AR, Ema TI, Siddiquee MFR, Shahriar A, Ahmed H, Mosfeq-Ul-Hasan M, et al. Natural flavonols: actions, mechanisms, and potential therapeutic utility for various diseases. Beni-Suef Univ J Basic Appl Sci. 2023; 12(1):1-18. https://doi.org/10.1186/s43088-023-00387-4 PMid:37216013 PMCid: PMC10183303

Singh M, Kaur M, Silakari O. Flavones: An important scaffold for medicinal chemistry. Eur J Med Chem. 2014; 84:206-39. https://doi.org/10.1016/j.ejmech.2014.07.013 PMid:25019478

Křížová L, Dadáková K, Kašparovská J, Kašparovský T. Isoflavones. Molecules. 2019; 24(6). https://doi.org/10.3390/ molecules24061076 PMid:30893792 PMCid: PMC6470817

Shen N, Wang T, Gan Q, Liu S, Wang L, Jin B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 2022; 383:132531.https:// doi.org/10.1016/j.foodchem.2022.132531 PMid:35413752

Aron PM, Kennedy JA. Flavan-3-ols: nature, occurrence and biological activity. Mol Nutr Food Res. 2008; 52(1):79-104. https://doi.org/10.1002/mnfr.200700137 PMid:18081206

Khoo HE, Azlan A, Tang ST, Lim SM. Anthocyanidins and anthocyanins: coloured pigments as food, pharmaceutical ingredients, and the potential health benefits. Food Nutr Res. 2017; 61(1). https://doi.org/10.1080/16546628.2017.13 61779 PMid:28970777 PMCid: PMC5613902

Ramesh P, Jagadeesan R, Sekaran S, Dhanasekaran A, Vimalraj S. Flavonoids: Classification, function, and molecular mechanisms involved in bone remodelling. Front Endocrinol (Lausanne). 2021; 12. https://doi.org/10.3389/ fendo.2021.779638 PMid:34887836 PMCid: PMC8649804

Dabeek WM, Marra MV. Dietary quercetin and kaempferol: Bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients. 2019; 11(10). https:// doi.org/10.3390/nu11102288 PMid:31557798 PMCid: PMC6835347

Pérez-Jiménez J, Neveu V, Vos F, Scalbert A. Identification of the 100 richest dietary sources of polyphenols: An application of the phenol-explorer database. Eur J Clin Nutr. 2010; 64(Suppl 3):S112-20. https://doi.org/10.1038/ ejcn.2010.221 PMid:21045839

Ock KC, Sang JC, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007; 137(5):1244-52. https://doi.org/10.1093/jn/137.5.1244 PMid:17449588

Seashore RH, Mccollom IN. The chemical nature of vitamin C. Science. 1932; 75:357-9. https://doi.org/10.1126/ science.75.1944.358 PMid:17750034

CFR. CFR - Code of Federal Regulations Title 21 (cited 2023 Nov 25). Available from: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.25

Pietta PG. Flavonoids as antioxidants. J Nat Prod. 2000; 63(7):1035-42. https://doi.org/10.1021/np9904509 PMid: 10924197

Williams RJ, Spencer JPE, Rice-Evans C. Flavonoids: Antioxidants or signalling molecules? Free Radic Biol Med. 2004; 36(7):838-49. https://doi.org/10.1016/j.freeradbiomed.2004.01.001 PMid:15019969

Hananya N, Koren S, Muir TW. Interrogating epigenetic mechanisms with chemically customized chromatin. Nat Rev Genet. 2023. p. 1-17. Available from: https://www.nature.com/articles/s41576-023-00664-z

Bo Y, Sun J, Wang M, Ding J, Lu Q, Yuan L. Dietary flavonoid intake and the risk of digestive tract cancers: A systematic review and meta-analysis. Sci Rep. 2016; 6:24836. https:// doi.org/10.1038/srep24836 PMid:27112267 PMCid: PMC4845003

Petrick JL, Steck SE, Bradshaw PT, Trivers KF, Abrahamson PE, Engel LS, et al. Dietary intake of flavonoids and oesophageal and gastric cancer: Incidence and survival in the United States of America (USA). Br J Cancer. 2015; 112(7):1291-300. https://doi.org/10.1038/bjc.2015.25 PMid:25668011 PMCid: PMC4385952

Zamora-Ros R, Agudo A, Luján-Barroso L, Romieu I, Ferrari P, Knaze V, et al. Dietary flavonoid and lignan intake and gastric adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr. 2012; 96(6):1398-408. https://doi.org/10.3945/ajcn.112.037358 PMid:23076618

Theodoratou E, Kyle J, Cetnarskyj R, Farrington SM, Tenesa A, Barnetson R, et al. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007; 16(4):684-93. https://doi.org/10.1158/1055-9965.EPI-060785 PMid:17416758

Chang H, Lei L, Zhou Y, Ye F, Zhao G. Dietary flavonoids and the risk of colorectal cancer: An updated meta-analysis of epidemiological studies. Nutrients. 2018; 10(7). https:// doi.org/10.3390/nu10070950 PMid:30041489 PMCid: PMC6073812

Grosso G, Micek A, Godos J, Pajak A, Sciacca S, Galvano F, et al. Dietary flavonoid and lignan intake and mortality in prospective cohort studies: Systematic review and doseresponse meta-analysis. Am J Epidemiol. 2017; 185(12):130416. https://doi.org/10.1093/aje/kww207 PMid:28472215

Russo M, Spagnuolo C, Tedesco I, Bilotto S, Russo GL. The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem Pharmacol. 2012; 83(1):6-15. https:// doi.org/10.1016/j.bcp.2011.08.010 PMid:21856292

Pietta PG, Gardana C, Mauri PL, Maffei-Facino R, Carini M. Identification of flavonoid metabolites after oral administration to rats of a Ginkgo biloba extract. J Chromatogr B Biomed Sci Appl. 1995; 673(1):75-80. https:// doi.org/10.1016/0378-4347(95)00252-E PMid: 8925077

Naeimi AF, Alizadeh M. Antioxidant properties of the flavonoid fisetin: An updated review of in vivo and in vitro studies. Trends Food Sci Technol. 2017; 70:34-44. https:// doi.org/10.1016/j.tifs.2017.10.003

Ravula AR, Teegala SB, Kalakotla S, Pasangulapati JP, Perumal V, Boyina HK. Fisetin, a potential flavonoid with multifarious targets for treating neurological disorders: An updated review. Eur J Pharmacol. 2021; 910:174492. https:// doi.org/10.1016/j.ejphar.2021.174492 PMid:34516952

Jang JH, Lee SH, Jung K, Yoo H, Park G. Inhibitory effects of myricetin on lipopolysaccharide-induced neuroinflammation. Brain Sci. 2020; 10(1):32. https://doi.org/10.3390/brainsci10010032 PMid:31935983 PMCid: PMC7016734

Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, et al. Apigenin blocks lipopolysaccharideinduced lethality in vivo and proinflammatory cytokines expression by inactivating NF-κb through the suppression of p65 phosphorylation. J Immunol. 2007; 179(10):71217. https://doi.org/10.4049/jimmunol.179.10.7121 PMid: 17982104

Ye X, Zhu M, Che X, Wang H, Liang XJ, Wu C, et al. Lipopolysaccharide induces neuroinflammation in microglia by activating the MTOR pathway and downregulating Vps34 to inhibit autophagosome formation. J Neuroinflammation. 2020; 17(1):1-17. https://doi.org/ 10.1186/s12974-019-1644-8 PMid:31926553 PMCid: PMC6954631

Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran Sulfate Sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014; 104(SUPPL.104). https:// doi.org/10.1002/0471142735.im1525s104 PMid:24510619 PMCid: PMC3980572

Park YH, Kim N, Shim YK, Choi YJ, Nam RH, Choi YJ, et al. Adequate dextran sodium sulfate-induced colitis model in mice and effective outcome measurement method. J Cancer Prev. 2015; 20(4):260. https://doi.org/10.15430/JCP.2015.20.4.260 PMid:26734588 PMCid: PMC4699753

Saeidnia S, Manayi A, Abdollahi M. From in vitro experiments to in vivo and clinical studies; pros and cons. Curr Drug Discov Technol. 2015; 12(4):218-24. https://doi.org/10.2174/1570163813666160114093140 PMid:26778084

Emadi SA, Rahbardar MG, Mehri S, Hosseinzadeh H. A review of therapeutic potentials of milk thistle (Silybum marianum L.) and its main constituent, silymarin, on cancer, and their related patents. Iran J Basic Med Sci. 2022; 25(10):1166.

Fahrenholtz CD, Swanner J, Ramirez-Perez M, Singh RN. Heterogeneous responses of ovarian cancer cells to silver nanoparticles as a single agent and in combination with cisplatin. J Nanomater. 2017; 2017. https://doi.org/10.1155/2017/5107485 PMid:30034459 PMCid: PMC6052800

Yin M, Xu X, Han H, Dai J, Sun R, Yang L, et al. Preparation of triangular silver nanoparticles and their biological effects in the treatment of ovarian cancer. J Ovarian Res. 2022; 15(1):1-14. https://doi.org/10.1186/s13048-022-01056-3 PMid:36411490 PMCid: PMC9680130

Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, et al. Tea polyphenol (-)-Epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003; 63(22):7563-70.

Shankar E, Goel A, Gupta K, Gupta S. Plant flavone apigenin: An emerging anticancer agent. Curr Pharmacol Reports. 2017; 3(6):423. https://doi.org/10.1007/s40495017-0113-2 PMid:29399439 PMCid: PMC5791748

Hnit SST, Yao M, Xie C, Bi L, Wong M, Liu T, et al. Apigenin impedes cell cycle progression at the G2 phase in prostate cancer cells. Discov Oncol. 2022; 13(1):44. https://doi.org/10.1007/s12672-022-00505-1 PMid:35670862 PMCid: PMC9174405

Deep G, Agarwal R. Antimetastatic efficacy of silibinin: molecular mechanisms and therapeutic potential against cancer. Cancer Metastasis Rev. 2010; 29(3):447-63. https:// doi.org/10.1007/s10555-010-9237-0 PMid:20714788 PMCid: PMC3928361

Agarwal C, Wadhwa R, Deep G, Biedermann D, Gažák R, Křen V, et al. Anti-cancer efficacy of silybin derivatives — a structure-activity relationship. PLoS One. 2013; 8(3). https:// doi.org/10.1371/journal.pone.0060074 PMid:23555889 PMCid: PMC3610875

Li Z, Li J, Mo B, Hu C, Liu H, Qi H, et al. Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicol Vitr. 2008; 22(7):1749-53. https://doi.org/10.1016/j.tiv.2008.08.001 PMid:18761399

Tuli HS, Tuorkey MJ, Thakral F, Sak K, Kumar M, Sharma AK, et al. Molecular mechanisms of action of genistein in cancer: Recent advances. Front Pharmacol. 2019; 10. https://doi.org/10.3389/fphar.2019.01336 PMid:31866857 PMCid: PMC6910185

Rahmani AH, Almatroudi A, Allemailem KS, Khan AA, Almatroodi SA. The potential role of fisetin, a flavonoid in cancer prevention and treatment. Molecules. 2022; 27(24). https://doi.org/10.3390/molecules27249009 PMid: 36558146 PMCid: PMC9782831

Sundarraj K, Raghunath A, Perumal E. A review on the chemotherapeutic potential of fisetin: In vitro evidence. Biomed Pharmacother. 2018; 97:928-40. https://doi.org/10.1016/j.biopha.2017.10.164 PMid:29136771

Imran M, Saeed F, Gilani SA, Shariati MA, Imran A, Afzaal M, et al. Fisetin: An anticancer perspective. Food Sci Nutr. 2021; 9(1):3. https://doi.org/10.1002/fsn3.1872 PMid:33473265 PMCid: PMC7802565

Yan X, Qi M, Li P, Zhan Y, Shao H. Apigenin in cancer therapy: Anti-cancer effects and mechanisms of action. Cell Biosci. 2017; 7(1):50. https://doi.org/10.1186/s13578-0170179-x PMid:29034071 PMCid: PMC5629766

Kang CH, Molagoda IMN, Choi YH, Park C, Moon DO, Kim GY. Apigenin promotes TRAIL-mediated apoptosis regardless of ROS generation. Food Chem Toxicol. 2018; 111:623-30. https://doi.org/10.1016/j.fct.2017.12.018 PMid:29247770

Chen M, Wang X, Zha D, Cai F, Zhang W, He Y, et al. Apigenin potentiates TRAIL therapy of non-small cell lung cancer via upregulating DR4/DR5 expression in a p53-dependent manner. Sci Reports. 2016; 6(1):1-17. https://doi.org/10.1038/srep35468 PMid:27752089 PMCid: PMC5067669

Rahmani AH, Alsahli MA, Almatroudi A, Almogbel MA, Khan AA, Anwar S, et al. The potential role of apigenin in cancer prevention and treatment. Molecules. 2022; 27(18). https://doi.org/10.3390/molecules27186051 PMid: 36144783 PMCid: PMC9505045

Koirala N, Thuan NH, Ghimire GP, Thang D Van, Sohng JK. Methylation of flavonoids: Chemical structures, bioactivities, progress and perspectives for biotechnological production. Enzyme Microb Technol. 2016; 86:103-16. https://doi.org/10.1016/j.enzmictec.2016.02.003 PMid: 26992799

Romagnolo DF, Selmin OI. Flavonoids and cancer prevention: A review of the evidence. J Nutr Gerontol Geriatr. 2012; 31(3):206-38. https://doi.org/10.1080/21551 197.2012.702534 PMid:22888839

Liskova A, Koklesova L, Samec M, Smejkal K, Samuel SM, Varghese E, et al. Flavonoids in cancer metastasis. Cancers (Basel). 2020; 12(6):1-29. https://doi.org/10.3390/ cancers12061498 PMid:32521759 PMCid: PMC7352928

Eltahir S, Ahmad A. Flavonoids on the frontline against cancer metastasis. Cancers (Basel). 2023; 15(16). https:// doi.org/10.3390/cancers15164139 PMid:37627166 PMCid: PMC10452402

Sahoo S, Mohapatra P, Sahoo SK. Flavonoids for the treatment of breast cancer, present status and future prospective. Anticancer Agents Med Chem. 2023; 23(6):658-75. https://doi.org/10.2174/18715206236662210 24114521 PMid:36284374

Park MY, Kim Y, Ha SE, Kim HH, Bhosale PB, Abusaliya A, et al. Function and application of flavonoids in breast cancer. Int J Mol Sci. 2022; 23(14). https://doi.org/10.3390/ ijms23147732 PMid:35887080 PMCid: PMC9323071

Javed Z, Khan K, Herrera-Bravo J, Naeem S, Iqbal MJ, Sadia H, et al. Genistein is a regulator of signalling pathways and microRNAs in different types of cancers. Cancer Cell Int. 2021; 21(1):1-12. https://doi.org/10.1186/s12935-02102091-8 PMid:34289845 PMCid: PMC8296701

Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG. Metalloproteinases and their inhibitors: Potential for the development of new therapeutics. Cells. 2020; 9(5). https:// doi.org/10.3390/cells9051313 PMid:32466129 PMCid: PMC7290391

Niedzwiecki A, Roomi MW, Kalinovsky T, Rath M. Anticancer efficacy of polyphenols and their combinations. Nutrients. 2016; 8(9). https://doi.org/10.3390/nu8090552 PMid:27618095 PMCid: PMC5037537

Shukla S, Gupta S. Apigenin: A promising molecule for cancer prevention. Pharm Res. 2010; 27(6):962-78. https:// doi.org/10.1007/s11095-010-0089-7 PMid:20306120 PMCid: PMC2874462

Spagnuolo C, Russo GL, Orhan IE, Habtemariam S, Daglia M, Sureda A, et al. Genistein and cancer: current status, challenges, and future directions. Adv Nutr. 2015; 6(4):40819. https://doi.org/10.3945/an.114.008052 PMid:26178025 PMCid: PMC4496735

Sharifi-Rad J, Quispe C, Imran M, Rauf A, Nadeem M, Gondal TA, et al. Genistein: An integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid Med Cell Longev. 2021; 2021. https:// doi.org/10.1155/2021/3268136 PMid:34336089 PMCid: PMC8315847

Abotaleb M, Samuel SM, Varghese E, Varghese S, Kubatka P, Liskova A, et al. Flavonoids in cancer and apoptosis. Cancers (Basel). 2019; 11(1). https://doi.org/10.3390/ cancers11010028 PMid:30597838 PMCid: PMC6357032

Zhang HW, Hu JJ, Fu RQ, Liu X, Zhang YH, Li J, et al. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signalling pathway in human breast cancer cells. Sci Rep. 2018; 8(1):11255. https:// doi.org/10.1038/s41598-018-29308-7 PMid:30050147 PMCid: PMC6062549

Seibold T, Waldenmaier M, Seufferlein T, Eiseler T. Small extracellular vesicles and metastasis-blame the messenger. Cancers. 2021; 13(17):4380. https://doi.org/10.3390/ cancers13174380 PMid:34503190 PMCid: PMC8431296

Cossarizza A, Gibellini L, Pinti M, Nasi M, Montagna JP, De Biasi S, et al. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med. 2011; 2011. https:// doi.org/10.1093/ecam/neq053 PMid:21792362 PMCid: PMC3136711

Hosseinzadeh E, Hassanzadeh A, Marofi F, Alivand MR, Solali S. Flavonoid-based cancer therapy: An updated review. Anticancer Agents Med Chem. 2020; 20(12):1398414. https://doi.org/10.2174/1871520620666200423071759 PMid:32324520

Gürler SB, Kiraz Y, Baran Y. Flavonoids in cancer therapy: current and future trends. Biodivers Biomed Our Futur. 2020; 403-40. https://doi.org/10.1016/B978-0-12-8195413.00021-9

Verdura S, Cuyàs E, Ruiz-Torres V, Micol V, Joven J, BoschBarrera J, et al. Lung cancer management with silibinin: A historical and translational perspective. Pharmaceuticals (Basel). 2021; 14(6). https://doi.org/10.3390/ph14060559 PMid:34208282 PMCid: PMC8230811

Wing Ying Cheung C, Gibbons N, Wayne Johnson D, Lawrence Nicol D. Silibinin--a promising new treatment for cancer. Anticancer Agents Med Chem. 2010; 10(3):18695. https://doi.org/10.2174/1871520611009030186 PMid: 20015009

Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011; 82(12):1807-21. https://doi.org/10.1016/j.bcp.2011.07.093 PMid:21827739 PMCid: PMC4082721

Farhan M. Green tea catechins: Nature’s way of preventing and treating cancer. Int J Mol Sci. 2022; 23(18). https:// doi.org/10.3390/ijms231810713 PMid:36142616 PMCid: PMC9501439

Németh K, Plumb GW, Berrin JG, Juge N, Jacob R, Naim HY, et al. Deglycosylation by small intestinal epithelial cell β-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans. Eur J Nutr. 2003; 42(1):29-42. https://doi.org/10.1007/s00394003-0397-3 PMid:12594539

Rodriguez-Mateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L, et al. Bioavailability, bioactivity and impact on the health of dietary flavonoids and related compounds: an update. Arch Toxicol. 2014; 88(10):1803-53. https://doi.org/10.1007/s00204-014-13307 PMid:25182418

Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med. 2013; 2013. https:// doi.org/10.1155/2013/270418 PMid:23781257 PMCid: PMC3679724

Thilakarathna SH, Vasantha Rupasinghe HP. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients. 2013; 5(9):3367. https://doi.org/10.3390/ nu5093367 PMid:23989753 PMCid: PMC3798909

Zou H, Ye H, Kamaraj R, Zhang T, Zhang J, Pavek P. A review on pharmacological activities and synergistic effect of quercetin with small molecule agents. Phytomedicine. 2021; 92:153736. https://doi.org/10.1016/j.phymed.2021.153736 PMid:34560520

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

Krautkramer KA, Fan J, Bäckhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol. 2020; 19(2):77-94. https://doi.org/10.1038/ s41579-020-0438-4 PMid:32968241

Iyer N, Corr SC. Gut microbial metabolite-mediated regulation of the intestinal barrier in the pathogenesis of inflammatory bowel disease. Nutrients. 2021; 13(12). https:// doi.org/10.3390/nu13124259 PMid:34959809 PMCid: PMC8704337

Umamaheswaran G, Krishna Kumar D, Adithan C. Distribution of genetic polymorphisms of genes encoding drug-metabolizing enzymes and drug transporters - A review with an Indian perspective. Indian Journal of Medical Research. 2014; 139:27-65.

Gummadi AC, Guddati AK. Genetic polymorphisms in pharmaceuticals and chemotherapy. World J Oncol. 2021; 12(5):149. https://doi.org/10.14740/wjon1405 PMid:34804277 PMCid: PMC8577603

Liu J, Tian M, Wang Z, Xiao F, Huang X, Shan Y. Production of hesperetin from naringenin in an engineered Escherichia coli consortium. J Biotechnol. 2022; 347:67-76. https://doi.org/10.1016/j.jbiotec.2022.02.008 PMid:35192875

Ur Rehman MF, Batool AI, Qadir R, Aslam M. Hesperidin and naringenin. A Centum Valuab Plant Bioact. 2021; 403-44. https://doi.org/10.1016/B978-0-12-822923-1.00027-3

Koroleva M, Portnaya I, Mischenko E, Abutbul-Ionita I, Kolik-Shmuel L, Danino D. Solid lipid nanoparticles and nanoemulsions with solid shell: Physical and thermal stability. J Colloid Interface Sci. 2022; 610:61-9. https://doi.org/10.1016/j.jcis.2021.12.010 PMid:34922082

Sguizzato M, Esposito E, Cortesi R. Lipid-based nanosystems as a tool to overcome skin barrier. Int J Mol Sci.2021; 22(15):8319. https://doi.org/10.3390/ijms22158319 PMid:34361084 PMCid: PMC8348303

Wang Z. Knorr quinoline synthesis. Compr Org Name React Reagents. 2010. p. 1638-41. https://doi. org/10.1002/9780470638859.conrr365 PMid:21194205

Wu B, Basu S, Meng S, Wang X, Zhang S, Hu M. Regioselective sulfation and glucuronidation of phenolics: Insights into the structural basis of conjugation. Curr Drug Metab. 2011; 12(9):900. https://doi.org/10.2174/138920011797470100 PMid:21933112 PMCid: PMC3426368

Xiao J, Muzashvili TS, Georgiev MI. Advances in the biotechnological glycosylation of valuable flavonoids. Biotechnol Adv. 2014; 32(6):1145-56. https://doi.org/10.1016/j.biotechadv.2014.04.006 PMid:24780153

Slámová K, Kapešová J, Valentová K. Sweet flavonoids: Glycosidase-catalyzed modifications. Int J Mol Sci. 2018; 19(7). https://doi.org/10.3390/ijms19072126 PMid:30037103 PMCid: PMC6073497

Soukup ST, Stoll DA, Danylec N, Schoepf A, Kulling SE, Huch M. Metabolism of daidzein and genistein by gut bacteria of the class coriobacteriia. Foods. 2021; 10(11). https://doi.org/10.3390/foods10112741 PMid:34829025 PMCid: PMC8618169

Yang G, Ge S, Singh R, Basu S, Shatzer K, Zen M, et al. Glucuronidation: Driving factors and their impact on glucuronide disposition. Drug Metab Rev. 2017; 49(2):105. https://doi.org/10.1080/03602532.2017.129368 2 PMid:28266877 PMCid: PMC7660525

Bondonno NP, Dalgaard F, Kyrø C, Murray K, Bondonno CP, Lewis JR, et al. Flavonoid intake is associated with lower mortality in the Danish diet cancer and health cohort. Nat Commun. 2019; 10(1):1-10. https://doi.org/10.1038/ s41467-019-11622-x PMid:31409784 PMCid: PMC6692395

Mazidi M, Katsiki N, Banach M. A greater flavonoid intake is associated with lower total and cause-specific mortality: A meta-analysis of cohort studies. Nutrients. 2020; 12(8): 1-14. https://doi.org/10.3390/nu12082350 PMid:32781562 PMCid: PMC7469069

Rodríguez-García C, Sánchez-Quesada C, Gaforio JJ, Gaforio JJ. Dietary flavonoids as cancer chemopreventive agents: An updated review of human studies. Antioxidants. 2019; 8(5). https://doi.org/10.3390/antiox8050137 PMid: 31109072 PMCid: PMC6562590

Arem H, Bobe G, Sampson J, Subar AF, Park Y, Risch H, et al. Flavonoid intake and risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study Cohort. Br J Cancer. 2013; 108(5):1168. https:// doi.org/10.1038/bjc.2012.584 PMid:23299536 PMCid: PMC3619057

Courtney D, Davey MG, Moloney BM, Barry MK, Sweeney K, McLaughlin RP, et al. Breast cancer recurrence: factors impacting occurrence and survival. Ir J Med Sci. 2022; 191(6):2501. https://doi.org/10.1007/s11845-022-02926-x PMid:35076871 PMCid: PMC9671998

Arfaoui L. Dietary plant polyphenols: Effects of food processing on their content and bioavailability. Molecules. 2021; 26(10). https://doi.org/10.3390/molecules26102959 PMid:34065743 PMCid: PMC8156030

Ghosh S, Hazra J, Pal K, Nelson VK, Pal M. Prostate cancer: Therapeutic prospect with herbal medicine. Curr Res Pharmacol Drug Discov. 2021; 2. https://doi.org/10.1016/j.crphar.2021.100034 PMid:34909665 PMCid: PMC8663990

Lee AH, Su D, Pasalich M, Tang L, Binns CW, Qiu L. Soy and isoflavone intake associated with reduced risk of ovarian cancer in southern Chinese women. Nutr Res. 2014; 34(4):302-7. https://doi.org/10.1016/j.nutres.2014.02.005 PMid:24774066

Pallmann P, Wan F, Mander AP, Wheeler GM, Yap C, Clive S, et al. Designing and evaluating dose-escalation studies made easy: The MoDEsT web app. Clin Trials. 2020; 17(2):147. https://doi.org/10.1177/1740774519890146 PMid:31856600 PMCid: PMC7227124

Azman M, Sabri AH, Anjani QK, Mustaffa MF, Hamid KA. Intestinal absorption study: Challenges and absorption enhancement strategies in improving oral drug delivery. Pharmaceuticals. 2022; 15(8). https://doi.org/10.3390/ ph15080975 PMid:36015123 PMCid: PMC9412385

Chen Z, Zheng S, Li L, Jiang H. Metabolism of flavonoids in human: A comprehensive review. Curr Drug Metab. 2014; 15(1):48-61. https://doi.org/10.2174/138920021501 140218125020 PMid:24588554

Torres-Saavedra PA, Winter KA. An overview of phase II clinical trial designs. Int J Radiat Oncol Biol Phys. 2022; 112(1):22. https://doi.org/10.1016/j.ijrobp.2021.07.1700 PMid:34363901 PMCid: PMC8688307

Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004; 79(5):727-47. https://doi.org/10.1093/ ajcn/79.5.727 PMid:15113710

Boots AW, Haenen GRMM, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008; 585(2-3):325-37. https://doi.org/10.1016/j.ejphar.2008.03.008 PMid:18417116

Erlund I. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr Res. 2004; 24(10):851-74. https:// doi.org/10.1016/j.nutres.2004.07.005

Wollenweber E, H. Dietz V. Occurrence and distribution of free flavonoid aglycones in plants. Phytochemistry. 1981; 20(5):869-932. https://doi.org/10.1016/0031-9422(81)83001-4

Mazzanti G, Menniti-Ippolito F, Moro PA, Cassetti F, Raschetti R, Santuccio C, et al. Hepatotoxicity from green tea: a review of the literature and two unpublished cases. Eur J Clin Pharmacol. 2009; 65(4):331-41. https://doi.org/10.1007/s00228-008-0610-7 PMid:19198822

Du GJ, Zhang Z, Wen XD, Yu C, Calway T, Yuan CS, et al. Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients. 2012; 4(11):1679. https://doi.org/10.3390/ nu4111679 PMid:23201840 PMCid: PMC3509513

Aggarwal BB, Deb L, Prasad S. Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses. Molecules. 2014; 20(1):185-205. https://doi.org/10.3390/ molecules20010185 PMid:25547723 PMCid: PMC6272158

Kay CD. The future of flavonoid research. Br J Nutr. 2010; 104(S3):S91-5. https://doi.org/10.1017/ S000711451000396X PMid:20955652

Sudhakaran M, Sardesai S, Doseff AI. Flavonoids: New frontier for immuno-regulation and breast cancer control. Antioxidants. 2019; 8(4). https://doi.org/10.3390/antiox8040103 PMid:30995775 PMCid: PMC6523469

Gupta M, Ahmad J, Ahamad J, Kundu S, Goel A, Mishra A. Flavonoids as promising anticancer therapeutics: Contemporary research, nanoantioxidant potential, and future scope. Phytother Res. 2023; 37(11):5159-92. https://doi.org/10.1002/ptr.7975 PMid:37668281

Hussain Y, Luqman S, Meena A. Research progress in flavonoids as potential anticancer drugs including synergy with other approaches. Curr Top Med Chem. 2020; 20(20):1791-809. https://doi.org/10.2174/1568026620666200502005411 PMid:32357817

Liskova A, Samec M, Koklesova L, Brockmueller A, Zhai K, Abdellatif B, et al. Flavonoids as an effective sensitizer for anti-cancer therapy: insights into multi-faceted mechanisms and applicability towards individualized patient profiles. EPMA J. 2021; 12(2):155. https://doi.org/10.1007/s13167-021-00242-5 PMid:34025826 PMCid: PMC8126506

Wen L, Li G, Huang T, Geng W, Pei H, Yang J, et al. Single-cell technologies: From research to application. Innov Cambridge. 2022; 3(6). https://doi.org/10.1016/j.xinn.2022.100342 PMid:36353677 PMCid: PMC9637996

Yuan D, Guo Y, Pu F, Yang C, Xiao X, Du H, et al. Opportunities and challenges in enhancing the bioavailability and bioactivity of dietary flavonoids: A novel delivery system perspective. Food Chem. 2024; 430:137115. https://doi.org/10.1016/j.foodchem.2023.137115 PMid:37566979

Yetisgin AA, Cetinel S, Zuvin M, Kosar A, Kutlu O. Therapeutic nanoparticles and their targeted delivery applications. Molecules. 2020; 25(9). https://doi.org/10.3390/molecules25092193 PMid:32397080 PMCid: PMC7248934

Farhan M, Rizvi A, Aatif M, Ahmad A. Current understanding of flavonoids in cancer therapy and prevention. Metabolites. 2023; 13(4). https://doi.org/10.3390/metabo13040481 PMid: 37110140 PMCid: PMC10142845

Audulv Å, Hall EOC, Kneck Å, Westergren T, Fegran L, Pedersen MK, et al. Qualitative longitudinal research in health research: a method study. BMC Med Res Methodol. 2022; 22(1):1-19. https://doi.org/10.1186/s12874-022-01732-4 PMid:36182899 PMCid: PMC9526289

Lalu MM, Montroy J, Begley CG, Bubela T, Hunniford V, Ripsman D, et al. Identifying and understanding factors that affect the translation of therapies from the laboratory to patients: A study protocol. F1000Research. 2020; 9. https://doi.org/10.12688/f1000research.23663.2 PMid:33123348 PMCid: PMC7570319

Fernandez-Moure JS. Lost in translation: The gap in scientific advancements and clinical application. Front Bioeng Biotechnol. 2016; 4(JUN):202918. https://doi.org/10.3389/fbioe.2016.00043 PMid:27376058 PMCid: PMC4891347

Wagner J, Kroetz D. Transforming translation: Impact of clinical and translational science. Clin Transl Sci. 2016; 9(1):3. https://doi.org/10.1111/cts.12380 PMid:26678255 PMCid: PMC5351317

Chen L, Cao H, Huang Q, Xiao J, Teng H. Absorption, metabolism and bioavailability of flavonoids: A review. Crit Rev Food Sci Nutr. 2022; 62(28):7730-42. https://doi.org/10.1080/10408398.2021.1917508 PMid:34078189

Verse F, Janani L, Moradi Y, Solaymani-Dodaran M, Baradaran HR, Rimaz S. Challenges in the design, conduct, analysis, and reporting in randomized clinical trial studies: A systematic review. Med J Islam Repub Iran. 2019; 33(1):37. https://doi.org/10.47176/mjiri.33.37 PMid:31456961 PMCid: PMC6708114

Butcher NJ, Mew EJ, Monsour A, Chan AW, Moher D, Offringa M. Outcome reporting recommendations for clinical trial protocols and reports: A scoping review. Trials. 2020; 21(1). https://doi.org/10.1186/s13063-020-04440-w PMid:32641085 PMCid: PMC7341657

Xiong HH, Lin SY, Chen LL, Ouyang KH, Wang WJ. The interaction between flavonoids and intestinal microbes: A review. Foods. 2023; 12(2). https://doi.org/10.3390/foods12020320 PMid:36673411 PMCid: PMC9857828

Safe S, Jayaraman A, Chapkin RS, Howard M, Mohankumar K, Shrestha R. Flavonoids: structure-function and mechanisms of action and opportunities for drug development. Toxicol Res. 2021; 37(2):147. https://doi.org/10.1007/s43188-020-00080-z PMid:33868973 PMCid: PMC8007671

Solnier J, Chang C, Pizzorno J. Consideration for flavonoidcontaining dietary supplements to tackle deficiency and optimize health. Int J Mol Sci. 2023; 24(10). https://doi.org/10.3390/ijms24108663 PMid:37240008 PMCid: PMC10218363

Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG, et al. Important flavonoids and their role as a therapeutic agent. Molecules. 2020; 25(22). https://doi.org/10.3390/molecules25225243 PMid:33187049 PMCid: PMC7697716

Redelmeier DA, Zipursky JS. A dose of reality about doseresponse relationships. J Gen Intern Med. 2023; 1-6.

Kikuchi H, Yuan B, Hu X, Okazaki M. Chemopreventive and anticancer activity of flavonoids and its possibility for clinical use by combining with conventional chemotherapeutic agents. Am J Cancer Res. 2019; 9(8):1517.

Johnson JL, Adkins D, Chauvin S. A review of the quality indicators of rigour in qualitative research. Am J Pharm Educ. 2020; 84(1):138-46. https://doi.org/10.5688/ajpe7120 PMid:32292186 PMCid: PMC7055404

Bentley C, Cressman S, van der Hoek K, Arts K, Dancey J, Peacock S. Conducting clinical trials-costs, impacts, and the value of clinical trials networks: A scoping review. Clin Trials. 2019; 16(2):183-93. https://doi.org/10.1177/1740774518820060 PMid:30628466

Rist PM, Sesso HD, Manson JAE. Innovation in the design of large-scale hybrid randomized clinical trials. Contemp Clin Trials. 2020; 99:106178. https://doi.org/10.1016/j.cct.2020.106178 PMid:33086158 PMCid: PMC7568770