Therapeutic potential of flavonoids in gastrointestinal cancer: Focus on signaling pathways and improvement strategies (Review)

Ding,Ye; Yu,Yong

doi:10.3892/mmr.2025.13474

Therapeutic potential of flavonoids in gastrointestinal cancer: Focus on signaling pathways and improvement strategies (Review)

Authors:
- Ye Ding
- Yong Yu
View Affiliations

Affiliations: Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: February 24, 2025 https://doi.org/10.3892/mmr.2025.13474
Article Number: 109
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Flavonoids are a group of polyphenolic compounds distributed in vegetables, fruits and other plants, which have considerable antioxidant, anti‑tumor and anti‑inflammatory activities. Several types of gastrointestinal (GI) cancer are the most common malignant tumors in the world. A large number of studies have shown that flavonoids have inhibitory effects on cancer, and they are recognized as a class of potential anti‑tumor drugs. Therefore, the present review investigated the molecular mechanisms of flavonoids in the treatment of different types of GI cancer and summarized the drug delivery systems commonly used to improve their bioavailability. First, the classification of flavonoids and the therapeutic effects of various flavonoids on human diseases were briefly introduced. Then, to clarify the mechanism of action of flavonoids on different types of GI cancer in the human body, the metabolic process of flavonoids in the human body and the associated signaling pathways causing five common types of GI cancer were discussed, as well as the corresponding therapeutic targets of flavonoids. Finally, in clinical settings, flavonoids have poor water solubility, low permeability and inferior stability, which lead to low absorption efficiency in vivo. Therefore, the three most widely used drug delivery systems were summarized. Suggestions for improving the bioavailability of flavonoids and the focus of the next stage of research were also put forward.

View Figures

View References

1	Guo M, Jin J, Zhao D, Rong Z, Cao LQ, Li AH, Sun XY, Jia LY, Wang YD, Huang L, et al: Research advances on Anti-cancer natural products. Front Oncol. 12:8661542022. View Article : Google Scholar : PubMed/NCBI
2	Nandi SK, Chatterjee N, Roychowdhury T, Pradhan A, Moiz S, Manna K, Sarkar DK, Dhar P, Dutta A, Mukhopadhyay S and Bhattacharya R: Kaempferol with Verapamil impeded panoramic chemoevasion pathways in breast cancer through ROS overproduction and disruption of lysosomal biogenesis. Phytomedicine. 113:1546892023. View Article : Google Scholar : PubMed/NCBI
3	Deng Y, Li S, Wang M, Chen X, Tian L, Wang L, Yang W, Chen L, He F and Yin W: Flavonoid-rich extracts from okra flowers exert antitumor activity in colorectal cancer through induction of mitochondrial dysfunction-associated apoptosis, senescence and autophagy. Food Funct. 11:10448–10466. 2020. View Article : Google Scholar : PubMed/NCBI
4	Siqueira EDS, Concato VM, Tomiotto-Pellissier F, Silva TF, Bortoleti BTDS, Gonçalves MD, Costa IN, Junior WAV, Pavanelli WR, Panis C, et al: Trans-chalcone induces death by autophagy mediated by p53 up-regulation and beta-catenin down-regulation on human hepatocellular carcinoma HuH7.5 cell line. Phytomedicine. 80:1533732021. View Article : Google Scholar : PubMed/NCBI
5	Singla RK, Dubey AK, Garg A, Sharma RK, Fiorino M, Ameen SM, Haddad MA and Al-Hiary M: Natural polyphenols: Chemical classification, definition of classes, subcategories, and structures. J AOAC Int. 102:1397–1400. 2019. View Article : Google Scholar : PubMed/NCBI
6	Khoddami A, Wilkes MA and Roberts TH: Techniques for analysis of plant phenolic compounds. Molecules. 18:2328–2375. 2013. View Article : Google Scholar : PubMed/NCBI
7	Chen S, Wang X, Cheng Y, Gao H and Chen X: A review of classification, biosynthesis, biological activities and potential applications of flavonoids. Molecules. 28:49822023. View Article : Google Scholar : PubMed/NCBI
8	Shah FLA, Ramzi AB, Baharum SN, Noor NM, Goh HH, Leow TC, Oslan SN and Sabri S: Recent advancement of engineering microbial hosts for the biotechnological production of flavonoids. Mol Biol Rep. 46:6647–6659. 2019. View Article : Google Scholar : PubMed/NCBI
9	Shen N, Wang T, Gan Q, Liu S, Wang L and Jin B: Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 383:1325312022. View Article : Google Scholar : PubMed/NCBI
10	Stalikas CD: Extraction, separation, and detection methods for phenolic acids and flavonoids. J Sep Sci. 30:3268–3295. 2007. View Article : Google Scholar : PubMed/NCBI
11	Romagnolo DF and Selmin OI: Flavonoids and cancer prevention: A review of the evidence. J Nutr Gerontol Geriatr. 31:206–238. 2012. View Article : Google Scholar : PubMed/NCBI
12	Slika H, Mansour H, Wehbe N, Nasser SA, Iratni R, Nasrallah G, Shaito A, Ghaddar T, Kobeissy F and Eid AH: Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms. Biomed Pharmacother. 146:1124422022. View Article : Google Scholar : PubMed/NCBI
13	Jardim SR, de Souza LMP and de Souza HSP: The rise of gastrointestinal cancers as a global phenomenon: Unhealthy behavior or progress? Int J Environ Res Public Health. 20:36402023. View Article : Google Scholar : PubMed/NCBI
14	Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R and Srivastava V: Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. Int Rev Cell Mol Biol. 385:41–99. 2024. View Article : Google Scholar : PubMed/NCBI
15	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
16	Griffin-Sobel JP: Gastrointestinal cancers: Screening and early detection. Semin Oncol Nurs. 33:165–171. 2017. View Article : Google Scholar : PubMed/NCBI
17	Veitch AM, Uedo N, Yao K and East JE: Optimizing early upper gastrointestinal cancer detection at endoscopy. Nat Rev Gastroenterol Hepatol. 12:660–667. 2015. View Article : Google Scholar : PubMed/NCBI
18	Al-Ishaq RK, Overy AJ and Busselberg D: Phytochemicals and gastrointestinal cancer: Cellular mechanisms and effects to change cancer progression. Biomolecules. 10:1052020. View Article : Google Scholar : PubMed/NCBI
19	Ross JA and Kasum CM: Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutr. 22:19–34. 2002. View Article : Google Scholar : PubMed/NCBI
20	Malvicini M, Aquino JB and Mazzolini G: Combined therapy for gastrointestinal carcinomas: Exploiting synergies between gene therapy and classical chemo-radiotherapy. Curr Gene Ther. 15:151–160. 2015. View Article : Google Scholar : PubMed/NCBI
21	Middleton G and Cunningham D: Current options in the management of gastrointestinal cancer. Ann Oncol. 6:17–26. 1995. View Article : Google Scholar : PubMed/NCBI
22	Uzunoglu FG, Reeh M, Kutup A and Izbicki JR: Surgery of esophageal cancer. Langenbecks Arch Surg. 398:189–193. 2013. View Article : Google Scholar : PubMed/NCBI
23	Joshi SS and Badgwell BD: Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 71:264–279. 2021. View Article : Google Scholar : PubMed/NCBI
24	Clancy TE: Surgery for pancreatic cancer. Hematol Oncol Clin North Am. 29:701–716. 2015. View Article : Google Scholar : PubMed/NCBI
25	Orcutt ST and Anaya DA: Liver resection and surgical strategies for management of primary liver cancer. Cancer Control. 25:10732748177446212018. View Article : Google Scholar : PubMed/NCBI
26	Shinji S, Yamada T, Matsuda A, Sonoda H, Ohta R, Iwai T, Takeda K, Yonaga K, Masuda Y and Yoshida H: Recent advances in the treatment of colorectal cancer: A review. J Nippon Med Sch. 89:246–254. 2022. View Article : Google Scholar : PubMed/NCBI
27	Choi HS and Hwang JH: Endoscopic resection of early luminal cancer. Gastrointest Endosc Clin N Am. 34:51–78. 2024. View Article : Google Scholar : PubMed/NCBI
28	Wang AY and Yachimski PS: Endoscopic management of pancreatobiliary neoplasms. Gastroenterology. 154:1947–1963. 2018. View Article : Google Scholar : PubMed/NCBI
29	Sun V and Fong Y: Minimally invasive cancer surgery: Indications and outcomes. Semin Oncol Nurs. 33:23–36. 2017. View Article : Google Scholar : PubMed/NCBI
30	Guzman EA, Pigazzi A, Lee B, Soriano PA, Nelson RA, Benjamin Paz I, Trisal V, Kim J and Ellenhorn JD: Totally laparoscopic gastric resection with extended lymphadenectomy for gastric adenocarcinoma. Ann Surg Oncol. 16:2218–2223. 2009. View Article : Google Scholar : PubMed/NCBI
31	Huscher CG, Mingoli A, Sgarzini G, Binda B, Di Paola M and Ponzano C: Totally laparoscopic total and subtotal gastrectomy with extended lymph node dissection for early and advanced gastric cancer: Early and long-term results of a 100-patient series. Am J Surg. 194:839–844. 2007. View Article : Google Scholar : PubMed/NCBI
32	Fleshman J, Sargent DJ, Green E, Anvari M, Stryker SJ, Beart RW Jr, Hellinger M, Flanagan R Jr, Peters W and Nelson H; Clinical Outcomes of Surgical Therapy Study Group, : Laparoscopic colectomy for cancer is not inferior to open surgery based on 5-year data from the COST Study Group trial. Ann Surg. 246:655–664. 2007. View Article : Google Scholar : PubMed/NCBI
33	Galan C, Hernandez MP, Martinez MC, Sanchez A, Bollo J and Targarona EM: Surgical treatment of retrorectal tumors: A plea for a laparoscopic approach. Surg Endosc. 37:9080–9088. 2023. View Article : Google Scholar : PubMed/NCBI
34	Henckens SPG, Schuring N, Elliott JA, Johar A, Markar SR, Gantxegi A, Lagergren P, Hanna GB, Pera M, Reynolds JV, et al: Recurrence and survival after minimally invasive and open esophagectomy for esophageal cancer: A post hoc analysis of the ensure study. Ann Surg. 280:267–273. 2024. View Article : Google Scholar : PubMed/NCBI
35	van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, et al: Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 366:2074–2084. 2012. View Article : Google Scholar : PubMed/NCBI
36	Ilson DH and Al-Batran SE: Preoperative chemoradiotherapy or perioperative chemotherapy for patients with gastro-oesophageal junction adenocarcinoma. Lancet Oncol. 24:593–595. 2023. View Article : Google Scholar : PubMed/NCBI
37	Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, et al: Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): A randomised, phase 2/3 trial. Lancet. 393:1948–1957. 2019. View Article : Google Scholar : PubMed/NCBI
38	Rahman S, Thomas B, Maynard N, Park MH, Wahedally M, Trudgill N, Crosby T, Cromwell DA and Underwood TJ: Impact of postoperative chemotherapy on survival for oesophagogastric adenocarcinoma after preoperative chemotherapy and surgery. Br J Surg. 109:227–236. 2022. View Article : Google Scholar : PubMed/NCBI
39	Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, et al: Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): A randomised, open-label, phase 3 trial. Lancet Oncol. 22:29–42. 2021. View Article : Google Scholar : PubMed/NCBI
40	Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, et al: Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 355:11–20. 2006. View Article : Google Scholar : PubMed/NCBI
41	Nagahama H, Okada S, Okusaka T, Ishii H, Ikeda M, Nakasuka H and Yoshimori M: Predictive factors for tumor response to systemic chemotherapy in patients with hepatocellular carcinoma. Jpn J Clin Oncol. 27:321–324. 1997. View Article : Google Scholar : PubMed/NCBI
42	Zhou L, Wang H and Li Y: Stimuli-responsive nanomedicines for overcoming cancer multidrug resistance. Theranostics. 8:1059–1074. 2018. View Article : Google Scholar : PubMed/NCBI
43	Weiss J, Moghanaki D, Plastaras JP and Haller DG: Improved patient and regimen selection in locally advanced rectal cancer: Who, how, and what next? Clin Colorectal Cancer. 8:194–199. 2009. View Article : Google Scholar : PubMed/NCBI
44	Braendengen M, Tveit KM, Berglund A, Birkemeyer E, Frykholm G, Påhlman L, Wiig JN, Byström P, Bujko K and Glimelius B: Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer. J Clin Oncol. 26:3687–3694. 2008. View Article : Google Scholar : PubMed/NCBI
45	Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 351:1731–1740. 2004. View Article : Google Scholar : PubMed/NCBI
46	Ritter AR and Miller ED: Intraoperative radiation therapy for gastrointestinal malignancies. Surg Oncol Clin N Am. 32:537–552. 2023. View Article : Google Scholar : PubMed/NCBI
47	Schaue D and McBride WH: Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol. 12:527–540. 2015. View Article : Google Scholar : PubMed/NCBI
48	Grau C, Durante M, Georg D, Langendijk JA and Weber DC: Particle therapy in Europe. Mol Oncol. 14:1492–1499. 2020. View Article : Google Scholar : PubMed/NCBI
49	Qi WX, Fu S, Zhang Q and Guo XM: Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: A systematic review and meta-analysis. Radiother Oncol. 114:289–295. 2015. View Article : Google Scholar : PubMed/NCBI
50	Larghi A, Rimbas M, Rizzatti G, Carbone C, Gasbarrini A, Costamagna G, Alfieri S and Tortora G: Endoscopic ultrasound-guided therapies for pancreatic solid tumors: An overview. Semin Oncol. 48:95–105. 2021. View Article : Google Scholar : PubMed/NCBI
51	Wang KX, Jin ZD, Du YQ, Zhan XB, Zou DW, Liu Y, Wang D, Chen J, Xu C and Li ZS: EUS-guided celiac ganglion irradiation with iodine-125 seeds for pain control in pancreatic carcinoma: A prospective pilot study. Gastrointest Endosc. 76:945–952. 2012. View Article : Google Scholar : PubMed/NCBI
52	Cha JH, Chan LC, Song MS and Hung MC: New approaches on cancer immunotherapy. Cold Spring Harb Perspect Med. 10:a0368632020. View Article : Google Scholar : PubMed/NCBI
53	Xie N, Shen G, Gao W, Huang Z, Huang C and Fu L: Neoantigens: Promising targets for cancer therapy. Signal Transduct Target Ther. 8:92023. View Article : Google Scholar : PubMed/NCBI
54	Sun J, Zheng Y, Mamun M, Li X, Chen X and Gao Y: Research progress of PD-1/PD-L1 immunotherapy in gastrointestinal tumors. Biomed Pharmacother. 129:1105042020. View Article : Google Scholar : PubMed/NCBI
55	Luo H, Lu J, Bai Y, Mao T, Wang J, Fan Q, Zhang Y, Zhao K, Chen Z, Gao S, et al: Effect of camrelizumab vs placebo added to chemotherapy on survival and progression-Free survival in patients with advanced or metastatic esophageal squamous cell carcinoma: The ESCORT-1st randomized clinical trial. JAMA. 326:916–925. 2021. View Article : Google Scholar : PubMed/NCBI
56	Galluzzi L, Humeau J, Buque A, Zitvogel L and Kroemer G: Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol. 17:725–741. 2020. View Article : Google Scholar : PubMed/NCBI
57	Kelly RJ, Zaidi AH, Smith MA, Omstead AN, Kosovec JE, Matsui D, Martin SA, DiCarlo C, Werts ED, Silverman JF, et al: The dynamic and transient immune microenvironment in locally advanced esophageal adenocarcinoma post chemoradiation. Ann Surg. 268:992–999. 2018. View Article : Google Scholar : PubMed/NCBI
58	Mamdani H, Schneider B, Perkins SM, Burney HN, Kasi PM, Abushahin LI, Birdas T, Kesler K, Watkins TM, Badve SS, et al: A Phase II trial of adjuvant durvalumab following trimodality therapy for locally advanced esophageal and gastroesophageal junction adenocarcinoma: A big ten cancer research consortium study. Front Oncol. 11:7366202021. View Article : Google Scholar : PubMed/NCBI
59	Chami P, Diab Y, Khalil DN, Azhari H, Jarnagin WR, Abou-Alfa GK, Harding JJ, Hajj J, Ma J, El Homsi M, et al: Radiation and immune checkpoint inhibitors: Combination therapy for treatment of hepatocellular carcinoma. Int J Mol Sci. 24:167732023. View Article : Google Scholar : PubMed/NCBI
60	Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 376:687–697. 2010. View Article : Google Scholar : PubMed/NCBI
61	Cunningham D, Stenning SP, Smyth EC, Okines AF, Allum WH, Rowley S, Stevenson L, Grabsch HI, Alderson D, Crosby T, et al: Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): Primary analysis results of a multicentre, open-label, randomised phase 2–3 trial. Lancet Oncol. 18:357–370. 2017. View Article : Google Scholar : PubMed/NCBI
62	Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, et al: Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): A double-blind, randomised phase 3 trial. Lancet Oncol. 15:1224–1235. 2014. View Article : Google Scholar : PubMed/NCBI
63	Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, et al: Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20:282–296. 2019. View Article : Google Scholar : PubMed/NCBI
64	Shen L: Current status and challenges of gastrointestinal cancer treatment in China. Int J Cancer. 153:1875–1876. 2023. View Article : Google Scholar : PubMed/NCBI
65	Serafini M, Peluso I and Raguzzini A: Flavonoids as anti-inflammatory agents. Proc Nutr Soc. 69:273–278. 2010. View Article : Google Scholar : PubMed/NCBI
66	Kopustinskiene DM, Jakstas V, Savickas A and Bernatoniene J: Flavonoids as Anticancer Agents. Nutrients. 12:4572020. View Article : Google Scholar : PubMed/NCBI
67	Vissenaekens H, Criel H, Grootaert C, Raes K, Smagghe G and Van Camp J: Flavonoids and cellular stress: A complex interplay affecting human health. Crit Rev Food Sci Nutr. 62:8535–8566. 2022. View Article : Google Scholar : PubMed/NCBI
68	Rossi M, Garavello W, Talamini R, La Vecchia C, Franceschi S, Lagiou P, Zambon P, Dal Maso L, Bosetti C and Negri E: Flavonoids and risk of squamous cell esophageal cancer. Int J Cancer. 120:1560–1564. 2007. View Article : Google Scholar : PubMed/NCBI
69	Cai J, Tan X, Hu Q, Pan H, Zhao M, Guo C, Zeng J, Ma X and Zhao Y: Flavonoids and gastric cancer therapy: From signaling pathway to therapeutic significance. Drug Des Devel Ther. 18:3233–3253. 2024. View Article : Google Scholar : PubMed/NCBI
70	Niu C, Zhang J and Okolo PI III: Harnessing plant flavonoids to fight pancreatic cancer. Curr Nutr Rep. 13:566–581. 2024. View Article : Google Scholar : PubMed/NCBI
71	Stagos D, Amoutzias GD, Matakos A, Spyrou A, Tsatsakis AM and Kouretas D: Chemoprevention of liver cancer by plant polyphenols. Food Chem Toxicol. 50:2155–2170. 2012. View Article : Google Scholar : PubMed/NCBI
72	Ansari B, Aschner M, Hussain Y, Efferth T and Khan H: Suppression of colorectal carcinogenesis by naringin. Phytomedicine. 96:1538972022. View Article : Google Scholar : PubMed/NCBI
73	Shao L, Zhu L, Su R, Yang C, Gao X, Xu Y, Wang H, Guo C and Li H: Baicalin enhances the chemotherapy sensitivity of oxaliplatin-resistant gastric cancer cells by activating p53-mediated ferroptosis. Sci Rep. 14:107452024. View Article : Google Scholar : PubMed/NCBI
74	Hu Y, Li R, Jin J, Wang Y and Ma R: Quercetin improves pancreatic cancer chemo-sensitivity by regulating oxidative-inflammatory networks. J Food Biochem. 46:e144532022. View Article : Google Scholar : PubMed/NCBI
75	Tiwari P and Mishra KP: Flavonoids sensitize tumor cells to radiation: Molecular mechanisms and relevance to cancer radiotherapy. Int J Radiat Biol. 96:360–369. 2020. View Article : Google Scholar : PubMed/NCBI
76	Yahyapour R, Shabeeb D, Cheki M, Musa AE, Farhood B, Rezaeyan A, Amini P, Fallah H and Najafi M: Radiation protection and mitigation by natural antioxidants and flavonoids: Implications to radiotherapy and radiation disasters. Curr Mol Pharmacol. 11:285–304. 2018. View Article : Google Scholar : PubMed/NCBI
77	Zhuang WB, Li YH, Shu XC, Pu YT, Wang XJ, Wang T and Wang Z: The classification, molecular structure and biological biosynthesis of flavonoids, and their roles in biotic and abiotic stresses. Molecules. 28:35992023. View Article : Google Scholar : PubMed/NCBI
78	Kisiriko M, Anastasiadi M, Terry LA, Yasri A, Beale MH and Ward JL: Phenolics from medicinal and aromatic plants: Characterisation and potential as biostimulants and bioprotectants. Molecules. 26:63432021. View Article : Google Scholar : PubMed/NCBI
79	Hussein RA and El-Anssary A: Plants secondary metabolites: The key drivers of the pharmacological actions of medicinal plants. Herbal Medicine. 2019. View Article : Google Scholar
80	Ferraz CR, Carvalho TT, Manchope MF, Artero NA, Rasquel-Oliveira FS, Fattori V, Casagrande R and Verri WA Jr: Therapeutic potential of flavonoids in pain and inflammation: Mechanisms of action, Pre-clinical and clinical data, and pharmaceutical development. Molecules. 25:7622020. View Article : Google Scholar : PubMed/NCBI
81	Aherne SA and O'Brien NM: Dietary flavonols: Chemistry, food content, and metabolism. Nutrition. 18:75–81. 2002. View Article : Google Scholar : PubMed/NCBI
82	Scalbert A, Johnson IT and Saltmarsh M: Polyphenols: Antioxidants and beyond. Am J Clin Nutr. 81:215–217. 2005. View Article : Google Scholar
83	Pearson DA, Holt RR, Rein D, Paglieroni T, Schmitz HH and Keen CL: Flavanols and platelet reactivity. Clin Dev Immunol. 12:1–9. 2005.PubMed/NCBI
84	Karim M, McCormick K and Kappagoda CT: Effects of cocoa extracts on endothelium-dependent relaxation. J Nutr. 130 (Suppl 8):2105S–2108S. 2000. View Article : Google Scholar : PubMed/NCBI
85	Aviram M and Fuhrman B: Wine flavonoids protect against LDL oxidation and atherosclerosis. Ann N Y Acad Sci. 957:146–161. 2002. View Article : Google Scholar : PubMed/NCBI
86	Chang X, Zhang T, Meng Q, Shiyuan Wang Yan P, Wang X, Luo D, Zhou X and Ji R: Quercetin improves cardiomyocyte vulnerability to hypoxia by regulating SIRT1/TMBIM6-related mitophagy and endoplasmic reticulum stress. Oxid Med Cell Longev. 2021:55299132021. View Article : Google Scholar : PubMed/NCBI
87	Chang X, Zhang T, Wang J, Liu Y, Yan P, Meng Q, Yin Y and Wang S: SIRT5-Related desuccinylation modification contributes to Quercetin-induced protection against heart failure and High-glucose-prompted cardiomyocytes injured through regulation of mitochondrial quality surveillance. Oxid Med Cell Longev. 2021:58768412021. View Article : Google Scholar : PubMed/NCBI
88	Zhang Q, Zhao X and Qiu H: Flavones and flavonols: Phytochemistry and biochemistry. Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes. Ramawat KG and Mérillon JM: Springer; Berlin Heidelberg, Berlin: pp. 1821–1847. 2013, View Article : Google Scholar
89	Hostetler GL, Ralston RA and Schwartz SJ: Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv Nutr. 8:423–435. 2017. View Article : Google Scholar : PubMed/NCBI
90	Martens S and Mithofer A: Flavones and flavone synthases. Phytochemistry. 66:2399–2407. 2005. View Article : Google Scholar : PubMed/NCBI
91	Salehi B, Venditti A, Sharifi-Rad M, Kręgiel D, Sharifi-Rad J, Durazzo A, Lucarini M, Santini A, Souto EB, Novellino E, et al: The therapeutic potential of apigenin. Int J Mol Sci. 20:13052019. View Article : Google Scholar : PubMed/NCBI
92	Imran M, Aslam Gondal T, Atif M, Shahbaz M, Batool Qaisarani T, Hanif Mughal M, Salehi B, Martorell M and Sharifi-Rad J: Apigenin as an anticancer agent. Phytother Res. 34:1812–1828. 2020. View Article : Google Scholar : PubMed/NCBI
93	Nabavi SF, Khan H, D'Onofrio G, Šamec D, Shirooie S, Dehpour AR, Argüelles S, Habtemariam S and Sobarzo-Sanchez E: Apigenin as neuroprotective agent: Of mice and men. Pharmacol Res. 128:359–365. 2018. View Article : Google Scholar : PubMed/NCBI
94	Rahmani AH, Alsahli MA, Almatroudi A, Almogbel MA, Khan AA, Anwar S and Almatroodi SA: The potential role of apigenin in cancer prevention and treatment. Molecules. 27:60512022. View Article : Google Scholar : PubMed/NCBI
95	Gaur K and Siddique YH: Effect of apigenin on neurodegenerative diseases. CNS Neurol Disord Drug Targets. 23:468–475. 2024. View Article : Google Scholar : PubMed/NCBI
96	Ku YS, Ng MS, Cheng SS, Lo AW, Xiao Z, Shin TS, Chung G and Lam HM: Understanding the composition, biosynthesis, accumulation and transport of flavonoids in crops for the promotion of crops as healthy sources of flavonoids for human consumption. Nutrients. 12:17172020. View Article : Google Scholar : PubMed/NCBI
97	Krizova L, Dadakova K, Kasparovska J and Kasparovsky T: Isoflavones. Molecules. 24:10762019. View Article : Google Scholar : PubMed/NCBI
98	Ahmad MZ, Li P, Wang J, Rehman NU and Zhao J: Isoflavone malonyltransferases GmIMaT1 and GmIMaT3 differently modify isoflavone glucosides in soybean (Glycine max) under various stresses. Front Plant Sci. 8:7352017. View Article : Google Scholar : PubMed/NCBI
99	Lethaby A, Brown J, Marjoribanks J, Kronenberg F, Roberts H and Eden J: Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database Syst Rev. CD0013952007.doi: 10.1002/14651858.CD001395.pub3. PubMed/NCBI
100	Ziegler RG: Phytoestrogens and breast cancer. Am J Clin Nutr. 79:183–184. 2004. View Article : Google Scholar : PubMed/NCBI
101	Horn-Ross PL, John EM, Canchola AJ, Stewart SL and Lee MM: Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst. 95:1158–1164. 2003. View Article : Google Scholar : PubMed/NCBI
102	Pan F, Liu Y, Liu J and Wang E: Stability of blueberry anthocyanin, anthocyanidin and pyranoanthocyanidin pigments and their inhibitory effects and mechanisms in human cervical cancer HeLa cells. RSC Adv. 9:10842–10853. 2019. View Article : Google Scholar : PubMed/NCBI
103	Zamora-Ros R, Knaze V, Lujan-Barroso L, Slimani N, Romieu I, Touillaud M, Kaaks R, Teucher B, Mattiello A, Grioni S, et al: Estimation of the intake of anthocyanidins and their food sources in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Nutr. 106:1090–1099. 2011. View Article : Google Scholar : PubMed/NCBI
104	Smeriglio A, Monteleone D and Trombetta D: Health effects of Vaccinium myrtillus L.: Evaluation of efficacy and technological strategies for preservation of active ingredients. Mini Rev Med Chem. 14:567–584. 2014. View Article : Google Scholar : PubMed/NCBI
105	Wallace TC and Giusti MM: Anthocyanins. Adv Nutr. 6:620–622. 2015. View Article : Google Scholar : PubMed/NCBI
106	Kalt W, Cassidy A, Howard LR, Krikorian R, Stull AJ, Tremblay F and Zamora-Ros R: Recent research on the health benefits of blueberries and their anthocyanins. Adv Nutr. 11:224–236. 2020. View Article : Google Scholar : PubMed/NCBI
107	Li D, Wang P, Luo Y, Zhao M and Chen F: Health benefits of anthocyanins and molecular mechanisms: Update from recent decade. Crit Rev Food Sci Nutr. 57:1729–1741. 2017. View Article : Google Scholar : PubMed/NCBI
108	Matsumoto H, Nakamura Y, Iida H, Ito K and Ohguro H: Comparative assessment of distribution of blackcurrant anthocyanins in rabbit and rat ocular tissues. Exp Eye Res. 83:348–356. 2006. View Article : Google Scholar : PubMed/NCBI
109	Pojer E, Mattivi F, Johnson D and Stockley CS: The case for anthocyanin consumption to promote human health: A review. Compr Rev Food Sci Food Saf. 12:483–508. 2013. View Article : Google Scholar : PubMed/NCBI
110	Ohguro H, Ohguro I, Katai M and Tanaka S: Two-year randomized, placebo-controlled study of black currant anthocyanins on visual field in glaucoma. Ophthalmologica. 228:26–35. 2012. View Article : Google Scholar : PubMed/NCBI
111	de Arruda Nascimento E, de Lima Coutinho L, da Silva CJ, de Lima V and Dos Santos Aguiar J: In vitro anticancer properties of anthocyanins: A systematic review. Biochim Biophys Acta Rev Cancer. 1877:1887482022. View Article : Google Scholar : PubMed/NCBI
112	Bars-Cortina D, Sakhawat A, Pinol-Felis C and Motilva MJ: Chemopreventive effects of anthocyanins on colorectal and breast cancer: A review. Semin Cancer Biol. 81:241–258. 2022. View Article : Google Scholar : PubMed/NCBI
113	Çetinkaya S, Taban Akça K and Süntar I: Chapter 3-Flavonoids and anticancer activity: Structure-activity relationship. Studies in Natural Products Chemistry. Attaur R: Elsevier; pp. 81–115. 2022, View Article : Google Scholar
114	Barreca D, Gattuso G, Bellocco E, Calderaro A, Trombetta D, Smeriglio A, Laganà G, Daglia M, Meneghini S and Nabavi SM: Flavanones: Citrus phytochemical with health-promoting properties. Biofactors. 43:495–506. 2017. View Article : Google Scholar : PubMed/NCBI
115	Chanet A, Milenkovic D, Manach C, Mazur A and Morand C: Citrus flavanones: What is their role in cardiovascular protection? J Agric Food Chem. 60:8809–8822. 2012. View Article : Google Scholar : PubMed/NCBI
116	Yamada T, Hayasaka S, Shibata Y, Ojima T, Saegusa T, Gotoh T, Ishikawa S, Nakamura Y and Kayaba K; Jichi Medical School Cohort Study Group, : Frequency of citrus fruit intake is associated with the incidence of cardiovascular disease: The Jichi Medical School cohort study. J Epidemiol. 21:169–175. 2011. View Article : Google Scholar : PubMed/NCBI
117	Jung UJ, Kim HJ, Lee JS, Lee MK, Kim HO, Park EJ, Kim HK, Jeong TS and Choi MS: Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin Nutr. 22:561–568. 2003. View Article : Google Scholar : PubMed/NCBI
118	Motallebi M, Bhia M, Rajani HF, Bhia I, Tabarraei H, Mohammadkhani N, Pereira-Silva M, Kasaii MS, Nouri-Majd S, Mueller AL, et al: Naringenin: A potential flavonoid phytochemical for cancer therapy. Life Sci. 305:1207522022. View Article : Google Scholar : PubMed/NCBI
119	Ferreira de Oliveira JMP, Santos C and Fernandes E: Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models. Phytomedicine. 73:1528872020. View Article : Google Scholar : PubMed/NCBI
120	Chandrika BB, Steephan M, Kumar TRS, Sabu A and Haridas M: Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibitors. Life Sci. 160:47–56. 2016. View Article : Google Scholar : PubMed/NCBI
121	Pico J, Xu K, Guo M, Mohamedshah Z, Ferruzzi MG and Martinez MM: Manufacturing the ultimate green banana flour: Impact of drying and extrusion on phenolic profile and starch bioaccessibility. Food Chem. 297:1249902019. View Article : Google Scholar : PubMed/NCBI
122	Zhang T, Wei X, Miao Z, Hassan H, Song Y and Fan M: Screening for antioxidant and antibacterial activities of phenolics from Golden Delicious apple pomace. Chem Cent J. 10:472016. View Article : Google Scholar : PubMed/NCBI
123	Gardener SL, Rainey-Smith SR, Weinborn M, Bondonno CP and Martins RN: Intake of products containing anthocyanins, flavanols, and flavanones, and cognitive function: A narrative review. Front Aging Neurosci. 13:6403812021. View Article : Google Scholar : PubMed/NCBI
124	Sorond FA, Lipsitz LA, Hollenberg NK and Fisher ND: Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr Dis Treat. 4:433–440. 2008.PubMed/NCBI
125	Lamport DJ, Pal D, Moutsiana C, Field DT, Williams CM, Spencer JP and Butler LT: The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: A placebo controlled, crossover, acute trial. Psychopharmacology (Berl). 232:3227–3234. 2015. View Article : Google Scholar : PubMed/NCBI
126	Desideri G, Kwik-Uribe C, Grassi D, Necozione S, Ghiadoni L, Mastroiacovo D, Raffaele A, Ferri L, Bocale R, Lechiara MC, et al: Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: The Cocoa, Cognition, and Aging (CoCoA) study. Hypertension. 60:794–801. 2012. View Article : Google Scholar : PubMed/NCBI
127	Mastroiacovo D, Kwik-Uribe C, Grassi D, Necozione S, Raffaele A, Pistacchio L, Righetti R, Bocale R, Lechiara MC, Marini C, et al: Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: The Cocoa, Cognition, and Aging (CoCoA) Study-a randomized controlled trial. Am J Clin Nutr. 101:538–548. 2015. View Article : Google Scholar : PubMed/NCBI
128	Scholey A and Owen L: Effects of chocolate on cognitive function and mood: A systematic review. Nutr Rev. 71:665–681. 2013. View Article : Google Scholar : PubMed/NCBI
129	Sasaki T, Unno K, Tahara S, Shimada A, Chiba Y, Hoshino M and Kaneko T: Age-related increase of superoxide generation in the brains of mammals and birds. Aging Cell. 7:459–469. 2008. View Article : Google Scholar : PubMed/NCBI
130	Halliwell B: Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment. Drugs Aging. 18:685–716. 2001. View Article : Google Scholar : PubMed/NCBI
131	Bernatoniene J and Kopustinskiene DM: The role of catechins in cellular responses to oxidative stress. Molecules. 23:9652018. View Article : Google Scholar : PubMed/NCBI
132	Zhuang C, Zhang W, Sheng C, Zhang W, Xing C and Miao Z: Chalcone: A Privileged Structure in Medicinal Chemistry. Chem Rev. 117:7762–7810. 2017. View Article : Google Scholar : PubMed/NCBI
133	Kuete V and Sandjo LP: Isobavachalcone: An overview. Chin J Integr Med. 18:543–547. View Article : Google Scholar : PubMed/NCBI
134	Sahu NK, Balbhadra SS, Choudhary J and Kohli DV: Exploring pharmacological significance of chalcone scaffold: A review. Curr Med Chem. 19:209–225. 2012. View Article : Google Scholar : PubMed/NCBI
135	Batovska DI and Todorova IT: Trends in utilization of the pharmacological potential of chalcones. Curr Clin Pharmacol. 5:1–29. 2021. View Article : Google Scholar : PubMed/NCBI
136	Colgate EC, Miranda CL, Stevens JF, Bray TM and Ho E: Xanthohumol, a prenylflavonoid derived from hops induces apoptosis and inhibits NF-kappaB activation in prostate epithelial cells. Cancer Lett. 246:201–209. 2007. View Article : Google Scholar : PubMed/NCBI
137	Foresti R, Hoque M, Monti D, Green CJ and Motterlini R: Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells. J Pharmacol Exp Ther. 312:686–693. 2005. View Article : Google Scholar : PubMed/NCBI
138	Williamson G, Kay CD and Crozier A: The bioavailability, transport, and bioactivity of dietary flavonoids: A review from a historical perspective. Compr Rev Food Sci Food Saf. 17:1054–1112. 2018. View Article : Google Scholar : PubMed/NCBI
139	Yang CS, Lee MJ and Chen L: Human salivary tea catechin levels and catechin esterase activities: Implication in human cancer prevention studies. Cancer Epidemiol Biomarkers Prev. 8:83–89. 1999.PubMed/NCBI
140	Spencer JPE, Schroeter H, Rechner AR and Rice-Evans C: Bioavailability of flavan-3-ols and procyanidins: Gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal. 3:1023–1039. 2001. View Article : Google Scholar : PubMed/NCBI
141	Spencer JP, Chaudry F, Pannala AS, Srai SK, Debnam E and Rice-Evans C: Decomposition of cocoa procyanidins in the gastric milieu. Biochem Biophys Res Commun. 272:236–241. 2000. View Article : Google Scholar : PubMed/NCBI
142	Pforte H, Naser T, Jacobasch G and Buhr HJ: Absorption and modification of rutin in the human stomach. Special Publication Royal Society Chemistry. 255:84–87. 2000.
143	Hollman PCH: Absorption, bioavailability, and metabolism of flavonoids. Pharmaceutical Biol. 42:74–83. 2009. View Article : Google Scholar
144	Steed AL, Christophi GP, Kaiko GE, Sun L, Goodwin VM, Jain U, Esaulova E, Artyomov MN, Morales DJ, Holtzman MJ, et al: The microbial metabolite desaminotyrosine protects from influenza through type I interferon. Science. 357:498–502. 2017. View Article : Google Scholar : PubMed/NCBI
145	Chen L, Cao H, Huang Q, Xiao J and Teng H: Absorption, metabolism and bioavailability of flavonoids: A review. Crit Rev Food Sci Nutr. 62:7730–7742. 2022. View Article : Google Scholar : PubMed/NCBI
146	Cassidy A and Minihane AM: The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr. 105:10–22. 2017. View Article : Google Scholar : PubMed/NCBI
147	Rechner AR, Kuhnle G, Bremner P, Hubbard GP, Moore KP and Rice-Evans CA: The metabolic fate of dietary polyphenols in humans. Free Radic Biol Med. 33:220–235. 2002. View Article : Google Scholar : PubMed/NCBI
148	Olthof MR, Hollman PCH, Buijsman MNCP, Amelsvoort JM and Katan MB: Chlorogenic acid, quercetin-3-rutinoside, and black tea phenols are extensively metabolized in humans. J Nutr. 133:1806–1814. 2003. View Article : Google Scholar : PubMed/NCBI
149	Setchell KD, Faughnan MS, Avades T, Zimmer-Nechemias L, Brown NM, Wolfe BE, Brashear WT, Desai P, Oldfield MF, Botting NP and Cassidy A: Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr. 77:411–419. 2003. View Article : Google Scholar : PubMed/NCBI
150	Yang H, Wang F, Hallemeier CL, Lerut T and Fu J: Oesophageal cancer. Lancet. 404:1991–2005. 2024. View Article : Google Scholar : PubMed/NCBI
151	Guo X, Tang Y and Zhu W: Distinct esophageal adenocarcinoma molecular subtype has subtype-specific gene expression and mutation patterns. BMC Genomics. 19:7692018. View Article : Google Scholar : PubMed/NCBI
152	Brown LM, Hoover RN, Greenberg RS, Schoenberg JB, Schwartz AG, Swanson GM, Liff JM, Silverman DT, Hayes RB and Pottern LM: Are racial differences in squamous cell esophageal cancer explained by alcohol and tobacco use? J Natl Cancer Inst. 86:1340–1345. 1994. View Article : Google Scholar : PubMed/NCBI
153	Napier KJ, Scheerer M and Misra S: Esophageal cancer: A Review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 6:112–120. 2014. View Article : Google Scholar : PubMed/NCBI
154	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
155	Shapiro J, van Lanschot JJB, Hulshof MCCM, van Hagen P, van Berge Henegouwen MI, Wijnhoven BPL, van Laarhoven HWM, Nieuwenhuijzen GAP, Hospers GAP, Bonenkamp JJ, et al: Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): Long-term results of a randomised controlled trial. Lancet Oncol. 16:1090–1098. 2015. View Article : Google Scholar : PubMed/NCBI
156	Liu Y, Li CL, Xu QQ, Cheng D, Liu KD and Sun ZQ: Quercetin inhibits invasion and angiogenesis of esophageal cancer cells. Pathol Res Pract. 222:1534552021. View Article : Google Scholar : PubMed/NCBI
157	Zhang Z, Yang L, Hou J, Tian S and Liu Y: Molecular mechanisms underlying the anticancer activities of licorice flavonoids. J Ethnopharmacol. 267:1136352021. View Article : Google Scholar : PubMed/NCBI
158	Liu J, Deng L, Wang L, Qian D, He C, Ren Q, Zhang Q and Chen Y: Licochalcone A induces G2/M phase arrest and apoptosis via regulating p53 pathways in esophageal cancer: In-vitro and in-vivo study. Eur J Pharmacol. 958:1760802023. View Article : Google Scholar : PubMed/NCBI
159	Jia XB, Zhang Q, Xu L, Yao WJ and Wei L: Effect of Malus asiatica nakai leaf flavonoids on the prevention of esophageal cancer in C57BL/6J mice by regulating the IL-17 signaling pathway. Onco Targets Ther. 13:6987–6996. 2020. View Article : Google Scholar : PubMed/NCBI
160	Cui L, Liu X, Tian Y, Xie C, Li Q, Cui H and Sun C: Flavonoids, flavonoid subclasses, and esophageal cancer risk: A Meta-analysis of epidemiologic studies. Nutrients. 8:3502016. View Article : Google Scholar : PubMed/NCBI
161	Bobe G, Peterson JJ, Gridley G, Hyer M, Dwyer JT and Brown LM: Flavonoid consumption and esophageal cancer among black and white men in the United States. Int J Cancer. 125:1147–1154. 2009. View Article : Google Scholar : PubMed/NCBI
162	Franklin J and Jankowski J: Recent advances in understanding and preventing oesophageal cancer. F1000Res. 9:F1000Faculty Rev 276. 2020. View Article : Google Scholar : PubMed/NCBI
163	Chang PY, Mirsalis J, Riccio ES, Bakke JP, Lee PS, Shimon J, Phillips S, Fairchild D, Hara Y and Crowell JA: Genotoxicity and toxicity of the potential cancer-preventive agent polyphenon E. Environ Mol Mutagen. 41:43–54. 2003. View Article : Google Scholar : PubMed/NCBI
164	Joe AK, Schnoll-Sussman F, Bresalier RS, Abrams JA, Hibshoosh H, Cheung K, Friedman RA, Yang CS, Milne GL, Liu DD, et al: Phase Ib randomized, Double-blinded, placebo-controlled, dose escalation study of polyphenon E in Patients with Barrett's Esophagus. Cancer Prev Res (Phila). 8:1131–1137. 2015. View Article : Google Scholar : PubMed/NCBI
165	Petrick JL, Steck SE, Bradshaw PT, Chow WH, Engel LS, He K, Risch HA, Vaughan TL and Gammon MD: Dietary flavonoid intake and Barrett's esophagus in western Washington State. Ann Epidemiol. 25:730–735.e2. 2015. View Article : Google Scholar : PubMed/NCBI
166	Tang L, Lee AH, Xu F, Zhang T, Lei J and Binns CW: Soya and isoflavone intakes associated with reduced risk of oesophageal cancer in north-west China. Public Health Nutr. 18:130–134. 2015. View Article : Google Scholar : PubMed/NCBI
167	Kwak AW, Lee MJ, Lee MH, Yoon G, Cho SS, Chae JI and Shim JH: The 3-deoxysappanchalcone induces ROS-mediated apoptosis and cell cycle arrest via JNK/p38 MAPKs signaling pathway in human esophageal cancer cells. Phytomedicine. 86:1535642021. View Article : Google Scholar : PubMed/NCBI
168	Yang Z, Liu H, Song Y, Gao N, Gao P, Hui Y, Li Y and Fan T: Luteolin enhances drug chemosensitivity by downregulating the FAK/PI3K/AKT pathway in paclitaxel-resistant esophageal squamous cell carcinoma. Int J Mol Med. 54:772024. View Article : Google Scholar : PubMed/NCBI
169	Connor CA, Adriaens M, Pierini R, Johnson IT and Belshaw NJ: Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun. Nutr Cancer. 66:335–341. 2014. View Article : Google Scholar : PubMed/NCBI
170	Kumar A, Singh UK, Kini SG, Garg V, Agrawal S, Tomar PK, Pathak P, Chaudhary A, Gupta P and Malik A: JNK pathway signaling: A novel and smarter therapeutic target for various biological diseases. Future Med Chem. 7:2065–2086. 2015. View Article : Google Scholar : PubMed/NCBI
171	Sabapathy K: Role of the JNK pathway in human diseases. Prog Mol Biol Transl Sci. 106:145–169. 2012. View Article : Google Scholar : PubMed/NCBI
172	Wu Q, Wu W, Fu B, Shi L, Wang X and Kuca K: JNK signaling in cancer cell survival. Med Res Rev. 39:2082–2104. 2019. View Article : Google Scholar : PubMed/NCBI
173	Gancz D, Donin N and Fishelson Z: Involvement of the c-jun N-terminal kinases JNK1 and JNK2 in complement-mediated cell death. Mol Immunol. 47:310–317. 2009. View Article : Google Scholar : PubMed/NCBI
174	Hess P, Pihan G, Sawyers CL, Flavell RA and Davis RJ: Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat Genet. 32:201–205. 2002. View Article : Google Scholar : PubMed/NCBI
175	Weston CR and Davis RJ: The JNK signal transduction pathway. Curr Opin Cell Biol. 19:142–149. 2007. View Article : Google Scholar : PubMed/NCBI
176	Rasul A, Zhao BJ, Liu J, Liu B, Sun JX, Li J and Li XM: Molecular mechanisms of casticin action: An update on its antitumor functions. Asian Pac J Cancer Prev. 15:9049–9058. 2014. View Article : Google Scholar : PubMed/NCBI
177	Qiao Z, Cheng Y, Liu S, Ma Z, Li S and Zhang W: Casticin inhibits esophageal cancer cell proliferation and promotes apoptosis by regulating mitochondrial apoptotic and JNK signaling pathways. Naunyn Schmiedebergs Arch Pharmacol. 392:177–187. 2019. View Article : Google Scholar : PubMed/NCBI
178	Maik-Rachline G, Hacohen-Lev-Ran A and Seger R: Nuclear ERK: Mechanism of translocation, substrates, and role in cancer. Int J Mol Sci. 20:11942019. View Article : Google Scholar : PubMed/NCBI
179	Moon H and Ro SW: MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (Basel). 13:30262021. View Article : Google Scholar : PubMed/NCBI
180	Wang X, Zhu Y, Zhu L, Chen X, Xu Y, Zhao Y, Shao Y, Li F, Jiang Y, Lu J, et al: Eupatilin inhibits the proliferation of human esophageal cancer TE1 cells by targeting the Akt-GSK3β and MAPK/ERK signaling cascades. Oncol Rep. 39:2942–2950. 2018.PubMed/NCBI
181	Yu L, Wei J and Liu P: Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin Cancer Biol. 85:69–94. 2022. View Article : Google Scholar : PubMed/NCBI
182	Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, Eng H, Nair MG, Makvandi P, Geoerger B, et al: PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 22:1382023. View Article : Google Scholar : PubMed/NCBI
183	Zhou X, Bao W, Zhu X, Wang D, Zeng P, Xia G, Xing M, Zhan Y, Yan J, Yuan M and Zhao Q: Molecular characteristics and multivariate survival analysis of 43 patients with locally advanced or metastatic esophageal squamous cell carcinoma. J Thorac Dis. 16:1843–1853. 2024. View Article : Google Scholar : PubMed/NCBI
184	Noorolyai S, Shajari N, Baghbani E, Sadreddini S and Baradaran B: The relation between PI3K/AKT signalling pathway and cancer. Gene. 698:120–128. 2019. View Article : Google Scholar : PubMed/NCBI
185	Zhao J, Li L, Wang Z, Li L, He M, Han S, Dong Y, Liu X, Zhao W, Ke Y and Wang C: Luteolin attenuates cancer cell stemness in PTX-resistant oesophageal cancer cells through mediating SOX2 protein stability. Pharmacol Res. 174:1059392021. View Article : Google Scholar : PubMed/NCBI
186	Wang Y, Chen X, Li J and Xia C: Quercetin antagonizes esophagus cancer by modulating miR-1-3p/TAGLN2 pathway-dependent growth and metastasis. Nutr Cancer. 74:1872–1881. 2022. View Article : Google Scholar : PubMed/NCBI
187	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
188	Palli D, Bianchi S, Cipriani F, Duca P, Amorosi A, Avellini C, Russo A, Saragoni A, Todde P, Valdes E, et al: Reproducibility of histologic classification of gastric cancer. Br J Cancer. 63:765–768. 1991. View Article : Google Scholar : PubMed/NCBI
189	Cheung TK, Xia HH and Wong BC: Helicobacter pylori eradication for gastric cancer prevention. J Gastroenterol. 42 (Suppl 17):S10–S15. 2007. View Article : Google Scholar
190	Correa P: Gastric cancer: Overview. Gastroenterol Clin North Am. 42:211–217. 2013. View Article : Google Scholar : PubMed/NCBI
191	Smyth EC, Nilsson M, Grabsch HI, van Grieken NC and Lordick F: Gastric cancer. Lancet. 396:635–648. 2020. View Article : Google Scholar : PubMed/NCBI
192	Ren LQ, Li Q and Zhang Y: Luteolin suppresses the proliferation of gastric cancer cells and acts in synergy with oxaliplatin. Biomed Res Int. 2020:93965122020. View Article : Google Scholar : PubMed/NCBI
193	Zarebczan B, Pinchot SN, Kunnimalaiyaan M and Chen H: Hesperetin, a potential therapy for carcinoid cancer. Am J Surg. 201:329–333. 2011. View Article : Google Scholar : PubMed/NCBI
194	Wang SW, Sheng H, Zheng F and Zhang F: Hesperetin promotes DOT1L degradation and reduces histone H3K79 methylation to inhibit gastric cancer metastasis. Phytomedicine. 84:1534992021. View Article : Google Scholar : PubMed/NCBI
195	Wang Q, Lu W, Yin T and Lu L: Calycosin suppresses TGF-β-induced epithelial-to-mesenchymal transition and migration by upregulating BATF2 to target PAI-1 via the Wnt and PI3K/Akt signaling pathways in colorectal cancer cells. J Exp Clin Cancer Res. 38:2402019. View Article : Google Scholar : PubMed/NCBI
196	Guo T, Liu ZL, Zhao Q, Zhao ZM and Liu CH: A combination of astragaloside I, levistilide A and calycosin exerts anti-liver fibrosis effects in vitro and in vivo. Acta Pharmacol Sin. 39:1483–1492. 2018. View Article : Google Scholar : PubMed/NCBI
197	Li D, Zhao L, Li Y, Kang X and Zhang S: Gastro-protective effects of calycosin against precancerous lesions of gastric carcinoma in rats. Drug Des Devel Ther. 14:2207–2219. 2020. View Article : Google Scholar : PubMed/NCBI
198	Woo HD, Lee J, Choi IJ, Kim CG, Lee JY, Kwon O and Kim J: Dietary flavonoids and gastric cancer risk in a Korean population. Nutrients. 6:4961–4973. 2014. View Article : Google Scholar : PubMed/NCBI
199	Petrick JL, Steck SE, Bradshaw PT, Trivers KF, Abrahamson PE, Engel LS, He K, Chow WH, Mayne ST, Risch HA, et al: Dietary intake of flavonoids and oesophageal and gastric cancer: Incidence and survival in the United States of America (USA). Br J Cancer. 112:1291–1300. 2015. View Article : Google Scholar : PubMed/NCBI
200	Zamora-Ros R, Agudo A, Lujan-Barroso L, Romieu I, Ferrari P, Knaze V, Bueno-de-Mesquita HB, Leenders M, Travis RC, Navarro C, 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. 96:1398–1408. 2012. View Article : Google Scholar : PubMed/NCBI
201	Natale A, Fiori F, Parpinel M, Pelucchi C, Negri E, La Vecchia C and Rossi M: Dietary isoflavones intake and gastric cancer. Nutrients. 16:27712024. View Article : Google Scholar : PubMed/NCBI
202	Ivyna de Araujo Rego R, Guedes Silvestre GF, Ferreira de Melo D, Albino SL, Pimentel MM, Silva Costa Cruz SB, Silva Wurzba SD, Rodrigues WF, Goulart de Lima Damasceno BP and Cançado Castellano LR: Flavonoids-rich plant extracts against Helicobacter pylori infection as prevention to gastric cancer. Front Pharmacol. 13:9511252022. View Article : Google Scholar : PubMed/NCBI
203	Ustun O, Ozcelik B, Akyon Y, Abbasoglu U and Yesilada E: Flavonoids with anti-Helicobacter pylori activity from Cistus laurifolius leaves. J Ethnopharmacol. 108:457–461. 2006. View Article : Google Scholar : PubMed/NCBI
204	Gonzalez A, Casado J and Lanas A: Fighting the antibiotic crisis: Flavonoids as promising antibacterial drugs against Helicobacter pylori infection. Front Cell Infect Microbiol. 11:7097492021. View Article : Google Scholar : PubMed/NCBI
205	Porta C, Paglino C and Mosca A: Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 4:642014. View Article : Google Scholar : PubMed/NCBI
206	Fattahi S, Amjadi-Moheb F, Tabaripour R, Ashrafi GH and Akhavan-Niaki H: PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci. 262:1185132020. View Article : Google Scholar : PubMed/NCBI
207	Morgos DT, Stefani C, Miricescu D, Greabu M, Stanciu S, Nica S, Stanescu-Spinu II, Balan DG, Balcangiu-Stroescu AE, Coculescu EC, et al: Targeting PI3K/AKT/mTOR and MAPK signaling pathways in gastric cancer. Int J Mol Sci. 25:18482024. View Article : Google Scholar : PubMed/NCBI
208	Li Y, Lu X, Tian P, Wang K and Shi J: Procyanidin B2 induces apoptosis and autophagy in gastric cancer cells by inhibiting Akt/mTOR signaling pathway. BMC Complement Med Ther. 21:762021. View Article : Google Scholar : PubMed/NCBI
209	Zhang G, Li Z, Dong J, Zhou W, Zhang Z, Que Z, Zhu X, Xu Y, Cao N and Zhao A: Acacetin inhibits invasion, migration and TGF-β1-induced EMT of gastric cancer cells through the PI3K/Akt/Snail pathway. BMC Complement Med Ther. 22:102022. View Article : Google Scholar : PubMed/NCBI
210	Zhang XR, Wang SY, Sun W and Wei C: Isoliquiritigenin inhibits proliferation and metastasis of MKN28 gastric cancer cells by suppressing the PI3K/AKT/mTOR signaling pathway. Mol Med Rep. 18:3429–3436. 2018.PubMed/NCBI
211	Sabharwal SS and Schumacker PT: Mitochondrial ROS in cancer: Initiators, amplifiers or an Achilles' heel? Nat Rev Cancer. 14:709–721. 2014. View Article : Google Scholar : PubMed/NCBI
212	Li L, Tan J, Miao Y, Lei P and Zhang Q: ROS and Autophagy: Interactions and Molecular Regulatory Mechanisms. Cell Mol Neurobiol. 35:615–621. 2015. View Article : Google Scholar : PubMed/NCBI
213	Filomeni G, De Zio D and Cecconi F: Oxidative stress and autophagy: The clash between damage and metabolic needs. Cell Death Differ. 22:377–388. 2015. View Article : Google Scholar : PubMed/NCBI
214	Qin W, Li C, Zheng W, Guo Q, Zhang Y, Kang M, Zhang B, Yang B, Li B, Yang H and Wu Y: Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells. Oncotarget. 6:39839–39854. 2015. View Article : Google Scholar : PubMed/NCBI
215	Liu J, Li SM, Tang YJ, Cao JL, Hou WS, Wang AQ, Wang C and Jin CH: Jaceosidin induces apoptosis and inhibits migration in AGS gastric cancer cells by regulating ROS-mediated signaling pathways. Redox Rep. 29:23133662024. View Article : Google Scholar : PubMed/NCBI
216	McGuigan A, Kelly P, Turkington RC, Jones C, Coleman HG and McCain RS: Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 24:4846–4861. 2018. View Article : Google Scholar : PubMed/NCBI
217	Stoffel EM, Brand RE and Goggins M: Pancreatic cancer: Changing epidemiology and new approaches to risk assessment, early detection, and prevention. Gastroenterology. 164:752–765. 2023. View Article : Google Scholar : PubMed/NCBI
218	Goral V: Pancreatic cancer: Pathogenesis and diagnosis. Asian Pac J Cancer Prev. 16:5619–5624. 2015. View Article : Google Scholar : PubMed/NCBI
219	Cameron JL, Riall TS, Coleman J and Belcher KA: One thousand consecutive pancreaticoduodenectomies. Ann Surg. 244:10–15. 2006. View Article : Google Scholar : PubMed/NCBI
220	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar : PubMed/NCBI
221	Ge Y, Zhang Y, Chen Y, Li Q, Chen J, Dong Y and Shi W: Silibinin causes apoptosis and cell cycle arrest in some human pancreatic cancer cells. Int J Mol Sci. 12:4861–4871. 2011. View Article : Google Scholar : PubMed/NCBI
222	Shukla SK, Dasgupta A, Mehla K, Gunda V, Vernucci E, Souchek J, Goode G, King R, Mishra A, Rai I, et al: Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth. Oncotarget. 6:41146–41161. 2015. View Article : Google Scholar : PubMed/NCBI
223	Nambiar D, Prajapati V, Agarwal R and Singh RP: In vitro and in vivo anticancer efficacy of silibinin against human pancreatic cancer BxPC-3 and PANC-1 cells. Cancer Lett. 334:109–117. 2013. View Article : Google Scholar : PubMed/NCBI
224	Phillips PA, Sangwan V, Borja-Cacho D, Dudeja V, Vickers SM and Saluja AK: Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Cancer Lett. 308:181–188. 2011. View Article : Google Scholar : PubMed/NCBI
225	Zhang L, Angst E, Park JL, Moro A, Dawson DW, Reber HA, Eibl G, Hines OJ, Go VL and Lu QY: Quercetin aglycone is bioavailable in murine pancreas and pancreatic xenografts. J Agric Food Chem. 58:7252–7257. 2010. View Article : Google Scholar : PubMed/NCBI
226	Rossi M, Lugo A, Lagiou P, Zucchetto A, Polesel J, Serraino D, Negri E, Trichopoulos D and La Vecchia C: Proanthocyanidins and other flavonoids in relation to pancreatic cancer: A case-control study in Italy. Ann Oncol. 23:1488–1493. 2012. View Article : Google Scholar : PubMed/NCBI
227	Vuong QV, Hirun S, Phillips PA, Chuen TL, Bowyer MC, Goldsmith CD and Scarlett CJ: Fruit-derived phenolic compounds and pancreatic cancer: Perspectives from Australian native fruits. J Ethnopharmacol. 152:227–242. 2014. View Article : Google Scholar : PubMed/NCBI
228	Nothlings U, Murphy SP, Wilkens LR, Henderson BE and Kolonel LN: Flavonols and pancreatic cancer risk: The multiethnic cohort study. Am J Epidemiol. 166:924–931. 2007. View Article : Google Scholar : PubMed/NCBI
229	Bobe G, Weinstein SJ, Albanes D, Hirvonen T, Ashby J, Taylor PR, Virtamo J and Stolzenberg-Solomon RZ: Flavonoid intake and risk of pancreatic cancer in male smokers (Finland). Cancer Epidemiol Biomarkers Prev. 17:553–562. 2008. View Article : Google Scholar : PubMed/NCBI
230	Shih TY, Papageorge AG, Stokes PE, Weeks MO and Scolnick EM: Guanine nucleotide-binding and autophosphorylating activities associated with the p21srcprotein of Harvey murine sarcoma virus. Nature. 287:686–691. 1980. View Article : Google Scholar : PubMed/NCBI
231	Ellis CA and Clark G: The importance of being K-Ras. Cell Signal. 12:425–434. 2000. View Article : Google Scholar : PubMed/NCBI
232	Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, et al: Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 491:399–405. 2012. View Article : Google Scholar : PubMed/NCBI
233	Siddique HR, Liao DJ, Mishra SK, Schuster T, Wang L, Matter B, Campbell PM, Villalta P, Nanda S, Deng Y and Saleem M: Epicatechin-rich cocoa polyphenol inhibits Kras-activated pancreatic ductal carcinoma cell growth in vitro and in a mouse model. Int J Cance. 131:1720–1731. 2012. View Article : Google Scholar : PubMed/NCBI
234	Simeone DM: Pancreatic cancer stem cells: Implications for the treatment of pancreatic cancer. Clin Cancer Res. 14:5646–5648. 2008. View Article : Google Scholar : PubMed/NCBI
235	Appari M, Babu KR, Kaczorowski A, Gross W and Herr I: Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition. Int J Oncol. 45:1391–1400. 2014. View Article : Google Scholar : PubMed/NCBI
236	Stanciu S, Ionita-Radu F, Stefani C, Miricescu D, Stanescu-Spinu II, Greabu M, Ripszky Totan A and Jinga M: Targeting PI3K/AKT/mTOR signaling pathway in pancreatic cancer: From molecular to clinical aspects. Int J Mol Sci. 23:101322022. View Article : Google Scholar : PubMed/NCBI
237	Prasad R, Vaid M and Katiyar SK: Grape proanthocyanidin inhibit pancreatic cancer cell growth in vitro and in vivo through induction of apoptosis and by targeting the PI3K/Akt pathway. PLoS One. 7:e430642012. View Article : Google Scholar : PubMed/NCBI
238	Enomoto A, Ping J and Takahashi M: Girdin, a novel actin-binding protein, and its family of proteins possess versatile functions in the Akt and Wnt signaling pathways. Ann N Y Acad Sci. 1086:169–184. 2006. View Article : Google Scholar : PubMed/NCBI
239	Hayashi Y, Matsuo Y, Denda Y, Nonoyama K, Murase H, Ueda G, Aoyama Y, Kato T, Omi K, Imafuji H, et al: Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines. Oncol Rep. 50:1692023. View Article : Google Scholar : PubMed/NCBI
240	Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Kulig A and Malecka-Panas E: Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci. 54:683–689. 2009. View Article : Google Scholar : PubMed/NCBI
241	Okada S, Okusaka T, Ishi H, Kyogoku A, Yoshimori M, Kajimura N, Yamaguchi K and Kakizoe T: Elevated serum Interleukin-6 levels in patients with pancreatic cancer. Jpn J Clin Oncol. 28:12–15. 1998. View Article : Google Scholar : PubMed/NCBI
242	Huang B, Lang X and Li X: The role of IL-6/JAK2/STAT3 signaling pathway in cancers. Front Oncol. 12:10231772022. View Article : Google Scholar : PubMed/NCBI
243	Bi YL, Min M, Shen W and Liu Y: Genistein induced anticancer effects on pancreatic cancer cell lines involves mitochondrial apoptosis, G0/G1 cell cycle arrest and regulation of STAT3 signalling pathway. Phytomedicine. 39:10–16. 2018. View Article : Google Scholar : PubMed/NCBI
244	McGlynn KA, Petrick JL and Groopman JD: Liver Cancer: Progress and Priorities. Cancer Epidemiol Biomarkers Prev. 33:1261–1272. 2024. View Article : Google Scholar : PubMed/NCBI
245	Calderaro J, Ziol M, Paradis V and Zucman-Rossi J: Molecular and histological correlations in liver cancer. J Hepatol. 71:616–630. 2019. View Article : Google Scholar : PubMed/NCBI
246	Llovet JM, Schwartz M and Mazzaferro V: Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 25:181–200. 2005. View Article : Google Scholar : PubMed/NCBI
247	Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W and Wang C: Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 20:203–222. 2023. View Article : Google Scholar : PubMed/NCBI
248	Mo'men YS, Hussein RM and Kandeil MA: Involvement of PI3K/Akt pathway in the protective effect of hesperidin against a chemically induced liver cancer in rats. J Biochem Mol Toxicol. 33:e223052019. View Article : Google Scholar : PubMed/NCBI
249	Vasquez-Garzon VR, Macias-Perez JR, Jimenez-Garcia MN, Villegas V, Fattel-Fazenta S and Villa-Trevino S: The chemopreventive capacity of quercetin to induce programmed cell death in hepatocarcinogenesis. Toxicol Pathol. 41:857–865. 2013. View Article : Google Scholar : PubMed/NCBI
250	Carrasco-Torres G, Monroy-Ramirez HC, Martinez-Guerra AA, Baltiérrez-Hoyos R, Romero-Tlalolini MLÁ, Villa-Treviño S, Sánchez-Chino X and Vásquez-Garzón VR: Quercetin reverses rat liver preneoplastic lesions induced by chemical carcinogenesis. Oxid Med Cell Longev. 2017:46749182017. View Article : Google Scholar : PubMed/NCBI
251	Chen CH, Huang TS, Wong CH, Hong CL, Tsai YH, Liang CC, Lu FJ and Chang WH: Synergistic anti-cancer effect of baicalein and silymarin on human hepatoma HepG2 Cells. Food Chem Toxicol. 47:638–644. 2009. View Article : Google Scholar : PubMed/NCBI
252	Lagiou P, Rossi M, Lagiou A, Tzonou A, La Vecchia C and Trichopoulos D: Flavonoid intake and liver cancer: A case-control study in Greece. Cancer Causes Control. 19:813–818. 2008. View Article : Google Scholar : PubMed/NCBI
253	Zhang W, Wang J, Gao J, Li HL, Han LH, Lan Q, Rothman N, Zheng W, Shu XO and Xiang YB: Prediagnostic level of dietary and urinary isoflavonoids in relation to risk of liver cancer in shanghai, China. Cancer Epidemiol Biomarkers Prev. 28:1712–1719. 2019. View Article : Google Scholar : PubMed/NCBI
254	Pilger A, Germadnik D, R1edel K, Meger-Kossien R, Scherer G and Rodiger HW: Longitudinal study of urinary 8-hydroxy-2′-deoxyguanosine excretion in healthy adults. Free Radic Res. 35:273–280. 2001. View Article : Google Scholar : PubMed/NCBI
255	Luo H, Tang L, Tang M, Billam M, Huang T, Yu J, Wei Z, Liang Y, Wang K, Zhang ZQ, et al: Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: Modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine. Carcinogenesis. 27:262–268. 2006. View Article : Google Scholar : PubMed/NCBI
256	Zamora-Ros R, Fedirko V, Trichopoulou A, González CA, Bamia C, Trepo E, Nöthlings U, Duarte-Salles T, Serafini M, Bredsdorff L, et al: Dietary flavonoid, lignan and antioxidant capacity and risk of hepatocellular carcinoma in the European prospective investigation into cancer and nutrition study. Int J Cancer. 133:2429–2443. 2013. View Article : Google Scholar : PubMed/NCBI
257	Mao Y and Jiang P: The crisscross between p53 and metabolism in cancer. Acta Biochim Biophys Sin (Shanghai). 55:914–922. 2023. View Article : Google Scholar : PubMed/NCBI
258	Haupt Y, Maya R, Kazaz A and Oren M: Mdm2 promotes the rapid degradation of p53. Nature. 387:296–299. 1997. View Article : Google Scholar : PubMed/NCBI
259	Honda R, Tanaka H and Yasuda H: Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420:25–27. 1997. View Article : Google Scholar : PubMed/NCBI
260	Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M, van Ham RC, van der Houven van Oordt W, Hateboer G, van der Eb AJ and Jochemsen AG: MDMX: Anovelp53-bindingproteinwithsome functional properties of MDM2. EMBO J. 15:5349–5357. 1996. View Article : Google Scholar : PubMed/NCBI
261	Zhang B, Yin X and Sui S: Resveratrol inhibited the progression of human hepatocellular carcinoma by inducing autophagy via regulating p53 and the phosphoinositide 3-kinase/protein kinase B pathway. Oncol Rep. 40:2758–2765. 2018.PubMed/NCBI
262	Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P and Moll UM: p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 11:577–590. 2003. View Article : Google Scholar : PubMed/NCBI
263	Mass P, Hoffmann K, Gambichler T, Altmeyer P and Mannherz HG: Premature keratinocyte death and expression of marker proteins of apoptosis in human skin after UVB exposure. Arch Dermatol Res. 295:71–79. 2003. View Article : Google Scholar : PubMed/NCBI
264	Liebermann DA, Hoffman B and Steinman RA: Molecular controls of growth arrest and apoptosis: P53-dependent and independent pathways. Oncogene. 11:199–210. 1995.PubMed/NCBI
265	Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B and Reed JC: Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 9:1799–1805. 1994.PubMed/NCBI
266	Sadot E, Geiger B, Oren M and Ben-Ze'ev A: Down-regulation of beta-catenin by activated p53. Mol Cell Biol. 21:6768–6781. 2001. View Article : Google Scholar : PubMed/NCBI
267	Ramakrishnan G, Lo Muzio L, Elinos-Baez CM, Jagan S, Augustine TA, Kamaraj S, Anandakumar P and Devaki T: Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells. Cell Prolif. 42:229–240. 2009. View Article : Google Scholar : PubMed/NCBI
268	Vilaseca J, Guardia J, Bacardi R and Monné J: Doxorubicin for liver cancer. Lancet. 1:13671978. View Article : Google Scholar : PubMed/NCBI
269	King PD and Perry MC: Hepatotoxicity of chemotherapy. Oncologist. 6:162–176. 2001. View Article : Google Scholar : PubMed/NCBI
270	Silber JH and Barber G: Doxorubicin-induced cardiotoxicity. N Engl J Med. 333:1359–1360. 1995. View Article : Google Scholar : PubMed/NCBI
271	Liang G, Tang A, Lin X, Li L, Zhang S, Huang Z, Tang H and Li QQ: Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer. Int J Oncol. 37:111–123. 2010.PubMed/NCBI
272	Huang HY, Niu JL, Zhao LM and Lu YH: Reversal effect of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU. Phytomedicine. 18:1086–1092. 2011. View Article : Google Scholar : PubMed/NCBI
273	Wang G, Zhang J, Liu L, Sharma S and Dong Q: Quercetin potentiates doxorubicin mediated antitumor effects against liver cancer through p53/Bcl-xl. PLoS One. 7:e517642012. View Article : Google Scholar : PubMed/NCBI
274	Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017. View Article : Google Scholar : PubMed/NCBI
275	Ciardiello F, Ciardiello D, Martini G, Napolitano S, Tabernero J and Cervantes A: Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin. 72:372–401. 2022. View Article : Google Scholar : PubMed/NCBI
276	Pretzsch E, Bosch F, Neumann J, Ganschow P, Bazhin A, Guba M, Werner J and Angele M: Mechanisms of metastasis in colorectal cancer and metastatic organotropism: Hematogenous versus peritoneal spread. J Oncol. 2019:74071902019. View Article : Google Scholar : PubMed/NCBI
277	Ma B, Gao P, Wang H, Xu Q, Song Y, Huang X, Sun J, Zhao J, Luo J, Sun Y and Wang Z: What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients. Int J Cancer. 141:1052–1065. 2017. View Article : Google Scholar : PubMed/NCBI
278	Dekker E, Tanis PJ, Vleugels JLA, Kasi PM and Wallace MB: Colorectal cancer. Lancet. 394:1467–1480. 2019. View Article : Google Scholar : PubMed/NCBI
279	Sequetto PL, Oliveira TT, Maldonado IR, Augusto LE, Mello VJ, Pizziolo VR, Almeida MR, Silva ME and Novaes RD: Naringin accelerates the regression of pre-neoplastic lesions and the colorectal structural reorganization in a murine model of chemical carcinogenesis. Food Chem Toxicol. 64:200–209. 2014. View Article : Google Scholar : PubMed/NCBI
280	Daneshvar S, Zamanian MY, Ivraghi MS, Golmohammadi M, Modanloo M, Kamiab Z, Pourhosseini SME, Heidari M and Bazmandegan G: A comprehensive view on the apigenin impact on colorectal cancer: Focusing on cellular and molecular mechanisms. Food Sci Nutr. 11:6789–6801. 2023. View Article : Google Scholar : PubMed/NCBI
281	Zhong Y, Krisanapun C, Lee SH, Nualsanit T, Sams C, Peungvicha P and Baek SJ: Molecular targets of apigenin in colorectal cancer cells: involvement of p21, NAG-1 and p53. Eur J Cancer. 46:3365–3374. 2010. View Article : Google Scholar : PubMed/NCBI
282	Wu M, Wu Y, Deng B, Li J, Cao H, Qu Y, Qian X and Zhong G: Isoliquiritigenin decreases the incidence of colitis-associated colorectal cancer by modulating the intestinal microbiota. Oncotarget. 7:85318–85331. 2016. View Article : Google Scholar : PubMed/NCBI
283	Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P, Franceschi S, Dal Maso L, Montella M, Giacosa A and La Vecchia C: Flavonoids and colorectal cancer in Italy. Cancer Epidemiol Biomarkers Prev. 15:1555–1558. 2006. View Article : Google Scholar : PubMed/NCBI
284	Shin A, Lee J, Lee J, Park MS, Park JW, Park SC, Oh JH and Kim J: Isoflavone and soyfood intake and colorectal cancer risk: A Case-control study in Korea. PLoS One. 10:e01432282015. View Article : Google Scholar : PubMed/NCBI
285	James MI, Iwuji C, Irving G, Karmokar A, Higgins JA, Griffin-Teal N, Thomas A, Greaves P, Cai H, Patel SR, et al: Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy. Cancer Lett. 364:135–141. 2015. View Article : Google Scholar : PubMed/NCBI
286	Panahi Y, Saberi-Karimian M, Valizadeh O, Behnam B, Saadat A, Jamialahmadi T, Majeed M and Sahebkar A: Effects of curcuminoids on systemic inflammation and quality of life in patients with colorectal cancer undergoing chemotherapy: A randomized controlled trial. Adv Exp Med Biol. 1328:1–9. 2021. View Article : Google Scholar : PubMed/NCBI
287	Hoensch H, Groh B, Edler L and Kirch W: Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence. World J Gastroenterol. 14:2187–2193. 2008. View Article : Google Scholar : PubMed/NCBI
288	Bobe G, Sansbury LB, Albert PS, Cross AJ, Kahle L, Ashby J, Slattery ML, Caan B, Paskett E, Iber F, et al: Dietary flavonoids and colorectal adenoma recurrence in the Polyp Prevention Trial. Cancer Epidemiol Biomarkers Prev. 17:1344–1353. 2008. View Article : Google Scholar : PubMed/NCBI
289	Shi S, Wang K, Zhong R, Cassidy A, Rimm EB, Nimptsch K, Wu K, Chan AT, Giovannucci EL, Ogino S, et al: Flavonoid intake and survival after diagnosis of colorectal cancer: A prospective study in 2 US cohorts. Am J Clin Nutr. 117:1121–1129. 2023. View Article : Google Scholar : PubMed/NCBI
290	Zwollo P, Rao S, Wallin JJ, Gackstetter ER and Koshland ME: The transcription factor NF-kappaB/p50 interacts with the blk gene during B cell activation. J Biol Chem. 273:18647–18655. 1998. View Article : Google Scholar : PubMed/NCBI
291	Zhang Q, Lenardo MJ and Baltimore D: 30 years of NF-κB: A blossoming of relevance to human pathobiology. Cell. 168:37–57. 2017. View Article : Google Scholar : PubMed/NCBI
292	Taniguchi K and Karin M: NF-κB, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol. 18:309–324. 2018. View Article : Google Scholar : PubMed/NCBI
293	Phelps CB, Sengchanthalangsy LL, Huxford T and Ghosh G: Mechanism of I kappa B alpha binding to NF-kappa B dimers. J Biol Chem. 275:29840–29846. 2000. View Article : Google Scholar : PubMed/NCBI
294	Danese S and Mantovani A: Inflammatory bowel disease and intestinal cancer: A paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene. 29:3313–3323. 2010. View Article : Google Scholar : PubMed/NCBI
295	Aggarwal BB, Shishodia S, Sandur SK, Pandey MK and Sethi G: Inflammation and cancer: How hot is the link? Biochem Pharmacol. 72:1605–1621. 2006. View Article : Google Scholar : PubMed/NCBI
296	Schmitt M and Greten FR: The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol. 21:653–667. 2021. View Article : Google Scholar : PubMed/NCBI
297	Farraye FA, Odze RD, Eaden J, Itzkowitz SH, McCabe RP, Dassopoulos T, Lewis JD, Ullman TA, James T III, McLeod R, et al: AGA medical position statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology. 138:738–745. 2010. View Article : Google Scholar : PubMed/NCBI
298	Jess T, Rungoe C and Peyrin-Biroulet L: Risk of colorectal cancer in patients with ulcerative colitis: A meta-analysis of population-based cohort studies. Clin Gastroenterol Hepatol. 10:639–645. 2012. View Article : Google Scholar : PubMed/NCBI
299	Karin M: NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 1:a0001412009. View Article : Google Scholar : PubMed/NCBI
300	Eckmann L, Nebelsiek T, Fingerle AA, Dann SM, Mages J, Lang R, Robine S, Kagnoff MF, Schmid RM, Karin M, et al: Opposing functions of IKKbeta during acute and chronic intestinal inflammation. Proc Natl Acad Sci USA. 105:15058–15063. 2008. View Article : Google Scholar : PubMed/NCBI
301	Song L, Zhu S, Liu C, Zhang Q and Liang X: Baicalin triggers apoptosis, inhibits migration, and enhances anti-tumor immunity in colorectal cancer via TLR4/NF-kappaB signaling pathway. J Food Biochem. 46:e137032022. View Article : Google Scholar : PubMed/NCBI
302	Raina K, Agarwal C and Agarwal R: Effect of silibinin in human colorectal cancer cells: Targeting the activation of NF-κB signaling. Mol Carcinog. 52:195–206. 2013. View Article : Google Scholar : PubMed/NCBI
303	Markowitz SD and Bertagnolli MM: Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med. 361:2449–2460. 2009. View Article : Google Scholar : PubMed/NCBI
304	MacDonald BT, Tamai K and He X: Wnt/beta-catenin signaling: Components, mechanisms, and diseases. Dev Cell. 17:9–26. 2009. View Article : Google Scholar : PubMed/NCBI
305	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
306	Zhao H, Ming T, Tang S, Ren S, Yang H, Liu M, Tao Q and Xu H: Wnt signaling in colorectal cancer: Pathogenic role and therapeutic target. Mol Cancer. 21:1442022. View Article : Google Scholar : PubMed/NCBI
307	Zhang X, Yao J, Shi H, Gao B, Zhou H, Zhang Y, Zhao D, Gao S, Wang C and Zhang L: Hsa_circ_0026628 promotes the development of colorectal cancer by targeting SP1 to activate the Wnt/β-catenin pathway. Cell Death Dis. 12:8022021. View Article : Google Scholar : PubMed/NCBI
308	Lepore Signorile M, Grossi V, Di Franco S, Forte G, Disciglio V, Fasano C, Sanese P, De Marco K, Susca FC, Mangiapane LR, et al: Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids. Cell Death Dis. 12:3162021. View Article : Google Scholar : PubMed/NCBI
309	Chen Y, Yang Z, He X, Zhu W, Wang Y, Li J, Han Z, Wen J, Liu W, Yang Y and Zhang K: Proanthocyanidins inhibited colorectal cancer stem cell characteristics through Wnt/β-catenin signaling. Environ Toxicol. 38:2894–2903. 2023. View Article : Google Scholar : PubMed/NCBI
310	Chen Y, Wang XQ, Zhang Q, Zhu JY, Li Y, Xie CF, Li XT, Wu JS, Geng SS, Zhong CY and Han HY: (−)-Epigallocatechin-3-gallate inhibits colorectal cancer stem cells by suppressing Wnt/β-Catenin pathway. Nutrients. 9:5722017. View Article : Google Scholar : PubMed/NCBI
311	Zeng S, Chen L, Sun Q, Zhao H, Yang H, Ren S, Liu M, Meng X and Xu H: Scutellarin ameliorates colitis-associated colorectal cancer by suppressing Wnt/β-catenin signaling cascade. Eur J Pharmacol. 906:1742532021. View Article : Google Scholar : PubMed/NCBI
312	Xu M, Wang S, Song YU, Yao J, Huang K and Zhu X: Apigenin suppresses colorectal cancer cell proliferation, migration and invasion via inhibition of the Wnt/β-catenin signaling pathway. Oncol Lett. 11:3075–3080. 2016. View Article : Google Scholar : PubMed/NCBI
313	Guo RX, Fu X, Chen J, Zhou L and Chen G: Preparation and characterization of microemulsions of myricetin for improving its antiproliferative and antioxidative activities and oral bioavailability. J Agric Food Chem. 64:6286–6294. 2016. View Article : Google Scholar : PubMed/NCBI
314	Hu Y, Liu F, Pang J, McClements DJ, Zhou Z, Li B and Li Y: Biopolymer additives enhance tangeretin bioavailability in Emulsion-based delivery systems: An in vitro and in vivo study. J Agric Food Chem. 69:730–740. 2021. View Article : Google Scholar : PubMed/NCBI
315	Li N, Wu X, Yin Q, Dong Z, Zheng L, Qian Y, Sun Y, Chen Z and Zhai K: Extraction, identification, and antioxidant activity of flavonoids from hylotelephium spectabile (Boreau) H. Ohba. Foods. 13:26522024. View Article : Google Scholar : PubMed/NCBI
316	Yusoff IM, Mat Taher Z, Rahmat Z and Chua LS: A review of ultrasound-assisted extraction for plant bioactive compounds: Phenolics, flavonoids, thymols, saponins and proteins. Food Res Int. 157:1112682022. View Article : Google Scholar : PubMed/NCBI
317	Wang J, Xie B and Sun Z: Quality parameters and bioactive compound bioaccessibility changes in probiotics fermented mango juice using ultraviolet-assisted ultrasonic pre-treatment during cold storage. Lwt. 137:1104382021. View Article : Google Scholar
318	Lin X, Wu L, Wang X, Yao L and Wang L: Ultrasonic-assisted extraction for flavonoid compounds content and antioxidant activities of India Moringa oleifera L. leaves: Simultaneous optimization, HPLC characterization and comparison with other methods. J App Res Med Aromatic Plants. 20:1002842021.
319	Li R, Xia Z, Li B, Tian Y, Zhang G, Li M and Dong J: Advances in supercritical carbon dioxide extraction of bioactive substances from different parts of Ginkgo biloba L. Molecules. 26:40112021. View Article : Google Scholar : PubMed/NCBI
320	He JZ, Shao P, Liu JH and Ru QM: Supercritical carbon dioxide extraction of flavonoids from pomelo (Citrus grandis (L.) Osbeck) peel and their antioxidant activity. Int J Mol Sci. 13:13065–13078. 2012. View Article : Google Scholar : PubMed/NCBI
321	Wang H, Cui Y, Fu Q, Deng B, Li G, Yang J, Wu T and Xie Y: A phospholipid complex to improve the oral bioavailability of flavonoids. Drug Dev Ind Pharm. 41:1693–1703. 2015. View Article : Google Scholar : PubMed/NCBI
322	Selvaraj S, Krishnaswamy S, Devashya V, Sethuraman S and Krishnan UM: Flavonoid-metal ion complexes: A novel class of therapeutic agents. Med Res Rev. 34:677–702. 2014. View Article : Google Scholar : PubMed/NCBI
323	Kovacic P, Popp WJ, Ames JR and Ryan MD: Anti-cancer action of metal complexes: Electron transfer and oxidative stress? Anticancer Drug Des. 3:205–216. 1988.PubMed/NCBI
324	Durgo K, Halec I, Sola I and Franekic J: Cytotoxic and genotoxic effects of the quercetin/lanthanum complex on human cervical carcinoma cells in vitro. Arh Hig Rada Toksikol. 62:221–227. 2011. View Article : Google Scholar : PubMed/NCBI
325	Valentova K, Havlik J, Kosina P, Papoušková B, Jaimes JD, Káňová K, Petrásková L, Ulrichová J and Křen V: Biotransformation of silymarin flavonolignans by human fecal microbiota. Metabolites. 10:292020. View Article : Google Scholar : PubMed/NCBI
326	Dominguez-Fernandez M, Ludwig IA, De Pena MP and Cid C: Bioaccessibility of Tudela artichoke (Cynara scolymus cv. Blanca de Tudela) (poly)phenols: The effects of heat treatment, simulated gastrointestinal digestion and human colonic microbiota. Food Funct. 12:1996–2011. 2021. View Article : Google Scholar : PubMed/NCBI
327	Jin MJ, Kim U, Kim IS, Kim Y, Kim DH, Han SB, Kim DH, Kwon OS and Yoo HH: Effects of gut microflora on pharmacokinetics of hesperidin: A study on non-antibiotic and pseudo-germ-free rats. J Toxicol Environ Health A. 73:1441–1450. 2010. View Article : Google Scholar : PubMed/NCBI
328	Kim DH, Jung EA, Sohng IS, Han JA, Kim TH and Han MJ: Intestinal bacterial metabolism of flavonoids and its relation to some biological activities. Arch Pharm Res. 21:17–23. 1998. View Article : Google Scholar : PubMed/NCBI
329	Solnier J, Chang C and Pizzorno J: Consideration for Flavonoid-containing dietary supplements to tackle deficiency and optimize health. Int J Mol Sci. 24:86632023. View Article : Google Scholar : PubMed/NCBI
330	Zhao J, Yang J and Xie Y: Improvement strategies for the oral bioavailability of poorly water-soluble flavonoids: An overview. Int J Pharm. 570:1186422019. View Article : Google Scholar : PubMed/NCBI
331	Chuang SY, Lin YK, Lin CF, Wang PW, Chen EL and Fang JY: Elucidating the skin delivery of aglycone and glycoside flavonoids: How the structures affect cutaneous absorption. Nutrients. 9:13042017. View Article : Google Scholar : PubMed/NCBI
332	Aungst BJ: Absorption enhancers: Applications and advances. AAPS J. 14:10–18. 2012. View Article : Google Scholar : PubMed/NCBI
333	Alama T, Katayama H, Hirai S, Ono S, Kajiyama A, Kusamori K, Katsumi H, Sakane T and Yamamoto A: Enhanced oral delivery of alendronate by sucrose fatty acids esters in rats and their absorption-enhancing mechanisms. Int J Pharm. 515:476–489. 2016. View Article : Google Scholar : PubMed/NCBI
334	Ghadiri M, Canney F, Pacciana C, Colombo G, Young PM and Traini D: The use of fatty acids as absorption enhancer for pulmonary drug delivery. Int J Pharm. 541:93–100. 2018. View Article : Google Scholar : PubMed/NCBI
335	Morales JO, Peters JI and Williams RO: Surfactants: Their critical role in enhancing drug delivery to the lungs. Ther Deliv. 2:623–641. 2011. View Article : Google Scholar : PubMed/NCBI
336	Li L, Yi T and Lam CW: Inhibition of human efflux transporter ABCC2 (MRP2) by self-emulsifying drug delivery system: Influences of concentration and combination of excipients. J Pharm Pharm Sci. 17:447–460. 2014. View Article : Google Scholar : PubMed/NCBI
337	Xiao L, Yi T, Chen M, Lam CW and Zhou H: A new mechanism for increasing the oral bioavailability of scutellarin with Cremophor EL: Activation of MRP3 with concurrent inhibition of MRP2 and BCRP. Eur J Pharm Sci. 93:456–467. 2016. View Article : Google Scholar : PubMed/NCBI
338	Xie Y, Luo H, Duan J, Hong C, Ma P, Li G, Zhang T, Wu T and Ji G: Phytic acid enhances the oral absorption of isorhamnetin, quercetin, and kaempferol in total flavones of Hippophae rhamnoides L. Fitoterapia. 93:216–225. 2014. View Article : Google Scholar : PubMed/NCBI
339	Tenorio-Barajas AY, Olvera ML, Romero-Paredes G, Altuzar V, Garrido-Guerrero E and Mendoza-Barrera C: Chitosan, Chitosan/IgG-Loaded, and N-trimethyl chitosan chloride nanoparticles as potential adjuvant and carrier-delivery systems. Molecules. 28:41072023. View Article : Google Scholar : PubMed/NCBI
340	Kim ES, Kim DY, Lee JS and Lee HG: Mucoadhesive Chitosan-gum arabic nanoparticles enhance the absorption and antioxidant activity of quercetin in the intestinal cellular environment. J Agric Food Chem. 67:8609–8616. 2019. View Article : Google Scholar : PubMed/NCBI
341	Pakhomov AG, Bowman AM, Ibey BL, Andre FM, Pakhomova ON and Schoenbach KH: Lipid nanopores can form a stable, ion channel-like conduction pathway in cell membrane. Biochem Biophys Res Commun. 385:181–186. 2009. View Article : Google Scholar : PubMed/NCBI
342	Liao D, Liu X, Dai W, Tang T, Ou G, Zhang K, Han M, Kang R, Yang S and Xiang D: N-trimethyl chitosan (TMC)-modified microemulsions for improved oral bioavailability of puerarin: Preparation and evaluation. Drug Deliv. 22:516–521. 2015. View Article : Google Scholar : PubMed/NCBI
343	Zhang XP, Zhang J, Song QL and Chen HQ: Mechanism of acute pancreatitis complicated with injury of intestinal mucosa barrier. J Zhejiang Univ Sci B. 8:888–895. 2007. View Article : Google Scholar : PubMed/NCBI
344	Chebil L, Humeau C, Falcimaigne A, Engasser JM and Ghoul M: Enzymatic acylation of flavonoids. Process Biochemistry. 41:2237–2251. 2006. View Article : Google Scholar
345	Chen Y, Liu J, Geng S, Liu Y, Ma H, Zheng J, Liu B and Liang G: Lipase-catalyzed synthesis mechanism of tri-acetylated phloridzin and its antiproliferative activity against HepG2 cancer cells. Food Chem. 277:186–194. 2019. View Article : Google Scholar : PubMed/NCBI
346	Crauste C, Rosell M, Durand T and Vercauteren J: Omega-3 polyunsaturated lipophenols, how and why? Biochimie. 120:62–74. 2016. View Article : Google Scholar : PubMed/NCBI
347	Li XF, Yuan T, Xu H, Xin X, Zhao G, Wu H and Xiao X: Whole-cell catalytic synthesis of puerarin monoesters and analysis of their antioxidant activities. J Agric Food Chem. 67:299–307. 2019. View Article : Google Scholar : PubMed/NCBI
348	Kumar V, Jahan F, Mahajan RV and Saxena RK: Efficient regioselective acylation of quercetin using Rhizopus oryzae lipase and its potential as antioxidant. Bioresour Technol. 218:1246–1248. 2016. View Article : Google Scholar : PubMed/NCBI
349	Matsumura K, Kaihatsu K, Mori S, Cho HH, Kato N and Hyon SH: Enhanced antitumor activities of (−)-epigallocatechin-3-O-gallate fatty acid monoester derivatives in vitro and in vivo. Biochem Biophys Res Commun. 377:1118–1122. 2008. View Article : Google Scholar : PubMed/NCBI
350	Yao Y, Xia M, Wang H, Li G, Shen H, Ji G, Meng Q and Xie Y: Preparation and evaluation of chitosan-based nanogels/gels for oral delivery of myricetin. Eur J Pharm Sci. 91:144–153. 2016. View Article : Google Scholar : PubMed/NCBI
351	Xiao J, Muzashvili TS and Georgiev MI: Advances in the biotechnological glycosylation of valuable flavonoids. Biotechnol Adv. 32:1145–1156. 2014. View Article : Google Scholar : PubMed/NCBI
352	Roriz CL, Barros L, Carvalho AM, Santos-Buelga C and Ferreira ICFR: Pterospartum tridentatum, Gomphrena globosa and Cymbopogon citratus: A phytochemical study focused on antioxidant compounds. Food Res Int. 62:684–693. 2014. View Article : Google Scholar
353	Xiao J: Dietary flavonoid aglycones and their glycosides: Which show better biological significance? Crit Rev Food Sci Nutr. 57:1874–1905. 2017.PubMed/NCBI
354	Zou L, Zhang Z, Chen X, Chen H, Zhang Y, Li J and Liu Y: Total synthesis of viscumneoside III of Viscum coloratum. Tetrahedron. 74:2376–2382. 2018. View Article : Google Scholar
355	Yao CH, Tsai CH and Lee JC: Total synthesis of the naturally occurring glycosylflavone aciculatin. J Nat Prod. 79:1719–1723. 2016. View Article : Google Scholar : PubMed/NCBI
356	Yang J, Lee J and Kim Y: Effect of deglycosylated rutin by acid hydrolysis on obesity and hyperlipidemia in High-Fat Diet-induced obese mice. Nutrients. 12:15392020. View Article : Google Scholar : PubMed/NCBI
357	Yuan S, Yang Y and Kong JQ: Biosynthesis of 7,8-dihydroxyflavone glycosides via OcUGT1-catalyzed glycosylation and transglycosylation. J Asian Nat Prod Res. 20:662–674. 2018. View Article : Google Scholar : PubMed/NCBI
358	Slamova K, Kapesova J and Valentova K: ‘Sweet Flavonoids’: Glycosidase-Catalyzed Modifications. Int J Mol Sci. 19:21262018. View Article : Google Scholar : PubMed/NCBI
359	Mrudulakumari Vasudevan U and Lee EY: Flavonoids, terpenoids, and polyketide antibiotics: Role of glycosylation and biocatalytic tactics in engineering glycosylation. Biotechnol Adv. 41:1075502020. View Article : Google Scholar : PubMed/NCBI
360	Sordon S, Poplonski J, Tronina T and Huszcza E: Regioselective O-glycosylation of flavonoids by fungi Beauveria bassiana, Absidia coerulea and Absidia glauca. Bioorg Chem. 93:1027502019. View Article : Google Scholar : PubMed/NCBI
361	Lyu Y, Liu S, Gao S and Zhou J: Identification and characterization of three flavonoid 3-O-glycosyltransferases from Epimedium koreanum Nakai. Biochem Engineering J. 163:1077592020. View Article : Google Scholar
362	Xia T and Eiteman MA: Quercetin glucoside production by engineered escherichia coli. Appl Biochem Biotechnol. 182:1358–1370. 2017. View Article : Google Scholar : PubMed/NCBI
363	Mamadalieva NZ, Herrmann F, El-Readi MZ, Tahrani A, Hamoud R, Egamberdieva DR, Azimova SS and Wink M: Flavonoids in Scutellaria immaculata and S. ramosissima (Lamiaceae) and their biological activity. J Pharm Pharmacol. 63:1346–1357. 2011. View Article : Google Scholar : PubMed/NCBI
364	Wen L, Jiang Y, Yang J, Zhao Y, Tian M and Yang B: Structure, bioactivity, and synthesis of methylated flavonoids. Ann N Y Acad Sci. 1398:120–129. 2017. View Article : Google Scholar : PubMed/NCBI
365	Shafek RE, Shafik NH and Michael HN: antibacterial and antioxidant activities of two new kaempferol glycosides isolated from solenostemma argel stem extract. Asian J Plant Sci. 11:143–147. 2012. View Article : Google Scholar
366	Choi JS, Islam MN, Ali MY, Kim YM, Park HJ, Sohn HS and Jung HA: The effects of C-glycosylation of luteolin on its antioxidant, anti-Alzheimer's disease, anti-diabetic, and anti-inflammatory activities. Arch Pharm Res. 37:1354–1363. 2014. View Article : Google Scholar : PubMed/NCBI
367	Bernini R, Crisante F and Ginnasi MC: A convenient and safe O-methylation of flavonoids with dimethyl carbonate (DMC). Molecules. 16:1418–1425. 2011. View Article : Google Scholar : PubMed/NCBI
368	Kim BG, Shin KH, Lee Y, Hur HG, Lim Y and Ahn JH: Multiple regiospecific methylations of a flavonoid by plant O-methyltransferases expressed in E. coli. Biotechnol Lett. 27:1861–1864. 2005. View Article : Google Scholar : PubMed/NCBI
369	Paasela T, Lim KJ, Pietiainen M and Teeri TH: The O-methyltransferase PMT2 mediates methylation of pinosylvin in Scots pine. New Phytol. 214:1537–1550. 2017. View Article : Google Scholar : PubMed/NCBI
370	Kirita M, Honma D, Tanaka Y, Usui S, Shoji T, Sami M, Yokota T, Tagashira M, Muranaka A, Uchiyama M, et al: Cloning of a novel O-methyltransferase from Camellia sinensis and synthesis of o-methylated EGCG and evaluation of their bioactivity. J Agric Food Chem. 58:7196–7201. 2010. View Article : Google Scholar : PubMed/NCBI
371	Mohammed HA, Almahmoud SA, El-Ghaly EM, Khan FA, Emwas AH, Jaremko M, Almulhim F, Khan RA and Ragab EA: Comparative anticancer potentials of taxifolin and quercetin methylated derivatives against HCT-116 cell lines: Effects of O-methylation on taxifolin and quercetin as preliminary natural leads. ACS Omega. 7:46629–46639. 2022. View Article : Google Scholar : PubMed/NCBI
372	Koirala N, Pandey RP, Thuan NH, Ghimire GP, Jung HJ, Oh TJ and Sohng JK: Metabolic engineering of Escherichia coli for the production of isoflavonoid-4′-O-methoxides and their biological activities. Biotechnol Appl Biochem. 66:484–493. 2019. View Article : Google Scholar : PubMed/NCBI
373	Cao H, Chen X, Jassbi AR and Xiao J: Microbial biotransformation of bioactive flavonoids. Biotechnol Adv. 33:214–223. 2015. View Article : Google Scholar : PubMed/NCBI
374	Abourashed EA, Mikell JR and Khan IA: Bioconversion of silybin to phase I and II microbial metabolites with retained antioxidant activity. Bioorg Med Chem. 20:2784–2788. 2012. View Article : Google Scholar : PubMed/NCBI
375	Kostrzewa-Susłow E, Dmochowska-Gładysz J and Janeczko T: Microbial transformation of selected flavanones as a method of increasing the antioxidant properties. Z Naturforsch C J Biosci. 65:55–60. 2010. View Article : Google Scholar : PubMed/NCBI
376	Ullrich R and Hofrichter M: Enzymatic hydroxylation of aromatic compounds. Cell Mol Life Sci. 64:271–293. 2007. View Article : Google Scholar : PubMed/NCBI
377	Zhang Z, He Y, Huang Y, Ding L, Chen L, Liu Y, Nie Y and Zhang X: Development and optimization of an in vitro multienzyme synthetic system for production of kaempferol from naringenin. J Agric Food Chem. 66:8272–8279. 2018. View Article : Google Scholar : PubMed/NCBI
378	Krych J and Gebicka L: Catalase is inhibited by flavonoids. Int J Biol Macromol. 58:148–153. 2013. View Article : Google Scholar : PubMed/NCBI
379	Wang TY, Li Q and Bi KS: Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian J Pharm Sci. 13:12–23. 2018.PubMed/NCBI
380	Ribeiro D, Freitas M, Tome SM, Silva AM, Porto G, Cabrita EJ, Marques MM and Fernandes E: Inhibition of LOX by flavonoids: A structure-activity relationship study. Eur J Med Chem. 72:137–145. 2014. View Article : Google Scholar : PubMed/NCBI
381	Bernini R, Pasqualetti M, Provenzano G and Tempesta S: Ecofriendly synthesis of halogenated flavonoids and evaluation of their antifungal activity. N J Chemistry. 39:2980–2987. 2015. View Article : Google Scholar
382	Zaini MF, Arshad S, Thanigaimani K, Khalib NC, Zainuri DA, Abdullah M and Razak IA: New halogenated chalcones: Synthesis, crystal structure, spectroscopic and theoretical analyses for third-order nonlinear optical properties. J Mol Structure. 1195:606–619. 2019. View Article : Google Scholar
383	Yaipakdeea P and Robertsonb LW: Enzymatic halogenation of flavanones and flavones. Phytochemistry. 57:341–347. 2001. View Article : Google Scholar
384	Xiang WS, Zhang J, Wang JD, Jiang L, Jiang B, Xiang ZD and Wang XJ: Isolation and identification of chlorinated genistein from Actinoplanes sp. HBDN08 with antioxidant and antitumor activities. J Agric Food Chem. 58:1933–1938. 2010. View Article : Google Scholar : PubMed/NCBI
385	Zhang S, Li T, Zhang Y, Xu H, Li Y, Zi X, Yu H, Li J, Jin CY and Liu HM: A new brominated chalcone derivative suppresses the growth of gastric cancer cells in vitro and in vivo involving ROS mediated up-regulation of DR5 and 4 expression and apoptosis. Toxicol Appl Pharmacol. 309:77–86. 2016. View Article : Google Scholar : PubMed/NCBI
386	Dias TA, Duarte CL, Lima CF, Proenca MF and Pereira-Wilson C: Superior anticancer activity of halogenated chalcones and flavonols over the natural flavonol quercetin. Eur J Med Chem. 65:500–510. 2013. View Article : Google Scholar : PubMed/NCBI
387	Zhang H, Zhang M, Yu L, Zhao Y, He N and Yang X: Antitumor activities of quercetin and quercetin-5′,8-disulfonate in human colon and breast cancer cell lines. Food Chem Toxicol. 50:1589–1599. 2012. View Article : Google Scholar : PubMed/NCBI
388	Paul P, Suwan J, Liu J, Dordick JS and Linhardt RJ: Recent advances in sulfotransferase enzyme activity assays. Anal Bioanal Chem. 403:1491–1500. 2012. View Article : Google Scholar : PubMed/NCBI
389	van der Horst MA, Hartog AF, El Morabet R, Marais A, Kircz M and Wever R: Enzymatic sulfation of phenolic hydroxy groups of various plant metabolites by an arylsulfotransferase. Eur J Organic Chemistry. 2015:534–541. 2014. View Article : Google Scholar
390	Brodsky K, Petrankova B, Petraskova L, Pelantová H, Křen V, Valentová K and Bojarová P: New bacterial aryl sulfotransferases: Effective tools for sulfation of polyphenols. J Agric Food Chem. 72:22208–22216. 2024. View Article : Google Scholar : PubMed/NCBI
391	Correia-da-Silva M, Sousa E, Duarte B, Marques F, Carvalho F, Cunha-Ribeiro LM and Pinto MM: Flavonoids with an oligopolysulfated moiety: A new class of anticoagulant agents. J Med Chem. 54:95–106. 2011. View Article : Google Scholar : PubMed/NCBI
392	Khan J, Alexander A, Ajazuddin Saraf S and Saraf S: Recent advances and future prospects of phyto-phospholipid complexation technique for improving pharmacokinetic profile of plant actives. J Control Release. 168:50–60. 2013. View Article : Google Scholar : PubMed/NCBI
393	Pinho E, Grootveld M, Soares G and Henriques M: Cyclodextrins as encapsulation agents for plant bioactive compounds. Carbohydr Polym. 101:121–135. 2014. View Article : Google Scholar : PubMed/NCBI
394	Teodoro GR, Gontijo AVL, Borges AC, Tanaka MH, Lima GMG, Salvador MJ and Koga-Ito CY: Gallic acid/hydroxypropyl-β-cyclodextrin complex: Improving solubility for application on in vitro/ in vivo Candida albicans biofilms. PLoS One. 12:e01811992017. View Article : Google Scholar : PubMed/NCBI
395	Kadari A, Gudem S, Kulhari H, Bhandi MM, Borkar RM, Kolapalli VR and Sistla R: Enhanced oral bioavailability and anticancer efficacy of fisetin by encapsulating as inclusion complex with HPβCD in polymeric nanoparticles. Drug Deliv. 24:224–232. 2017. View Article : Google Scholar : PubMed/NCBI
396	Song S, Gao K, Niu R, Wang J, Zhang J, Gao C, Yang B and Liao X: Inclusion complexes between chrysin and amino-appended β-cyclodextrins (ACDs): Binding behavior, water solubility, in vitro antioxidant activity and cytotoxicity. Mater Sci Eng C Mater Biol Appl. 106:1101612020. View Article : Google Scholar : PubMed/NCBI
397	Kidd P and Head K: A review of the bioavailability and clinical efficacy of milk thistle phytosome: A silybin-phosphatidylcholine complex (Siliphos). Altern Med Rev. 10:193–203. 2005.PubMed/NCBI
398	Samir A, Elgamal BM, Gabr H and Sabaawy HE: Nanotechnology applications in hematological malignancies (Review). Oncol Rep. 34:1097–1105. 2015. View Article : Google Scholar : PubMed/NCBI
399	Senthilkumar M, Mishra P and Jain NK: Long circulating PEGylated poly(D,L-lactide-co-glycolide) nanoparticulate delivery of Docetaxel to solid tumors. J Drug Target. 16:424–435. 2008. View Article : Google Scholar : PubMed/NCBI
400	Prencipe G, Tabakman SM, Welsher K, Liu Z, Goodwin AP, Zhang L, Henry J and Dai H: PEG branched polymer for functionalization of nanomaterials with ultralong blood circulation. J Am Chem Soc. 131:4783–4787. 2009. View Article : Google Scholar : PubMed/NCBI
401	Zhang J, Huang Y, Liu D, Gao Y and Qian S: Preparation of apigenin nanocrystals using supercritical antisolvent process for dissolution and bioavailability enhancement. Eur J Pharm Sci. 48:740–747. 2013. View Article : Google Scholar : PubMed/NCBI
402	Rabinow BE: Nanosuspensions in drug delivery. Nat Rev Drug Discov. 3:785–796. 2004. View Article : Google Scholar : PubMed/NCBI
403	Radhakrishnan R, Kulhari H, Pooja D, Gudem S, Bhargava S, Shukla R and Sistla R: Encapsulation of biophenolic phytochemical EGCG within lipid nanoparticles enhances its stability and cytotoxicity against cancer. Chem Phys Lipids. 198:51–60. 2016. View Article : Google Scholar : PubMed/NCBI
404	Vazhappilly CG, Amararathna M, Cyril AC, Linger R, Matar R, Merheb M, Ramadan WS, Radhakrishnan R and Rupasinghe HPV: Current methodologies to refine bioavailability, delivery, and therapeutic efficacy of plant flavonoids in cancer treatment. J Nutr Biochem. 94:1086232021. View Article : Google Scholar : PubMed/NCBI
405	Lipkin M: Gastrointestinal cancer: Pathogenesis, risk factors and the development of intermediate biomarkers for chemoprevention studies. J Cell Biochem. Suppl 16G:1–13. 1992. View Article : Google Scholar
406	Hussain Y, Luqman S and Meena A: Research progress in flavonoids as potential anticancer drug including synergy with other approaches. Curr Top Med Chem. 20:1791–1809. 2020. View Article : Google Scholar : PubMed/NCBI
407	Jaeger A, Wlti M and Neftel K: Side effects of flavonoids in medical practice. Prog Clin Biol Res. 280:3791988.PubMed/NCBI
408	Al-Shuhaib MBS and Al-Shuhaib JMB: Assessing therapeutic value and side effects of key botanical compounds for optimized medical treatments. Chem Biodivers. 22:e2024017542025. View Article : Google Scholar : PubMed/NCBI
409	Liu R, Yu X, Chen X, Zhong H, Liang C, Xu X, Xu W, Cheng Y, Wang W, Yu L, et al: Individual factors define the overall effects of dietary genistein exposure on breast cancer patients. Nutr Res. 67:1–16. 2019. View Article : Google Scholar : PubMed/NCBI
410	Orsolic N and Jazvinscak Jembrek M: Potential strategies for overcoming drug resistance pathways using propolis and its polyphenolic/Flavonoid compounds in combination with chemotherapy and radiotherapy. Nutrients. 16:37412024. View Article : Google Scholar : PubMed/NCBI
411	Liu Y, Hao Y, Chen J, Chen M, Tian J, Lv X, Zhang Y, Ma X, Zhou Y and Feng L: An injectable puerarin depot can potentiate chimeric antigen receptor natural killer cell immunotherapy against targeted solid tumors by reversing tumor immunosuppression. Small. 20:e23075212024. View Article : Google Scholar : PubMed/NCBI
412	Park K: Translation from mouse to human: Time to think in new boxes. J Control Release. 189:1872014. View Article : Google Scholar : PubMed/NCBI