Anti-inflammatory potential of dandelion polyphenols through modulation of AGE-RAGE signaling: key bioactive compounds and implications for functional foods

Abstract

Dandelion, a widely used traditional medicinal and edible plant in China, is known for its anti-inflammatory properties, primarily attributed to polyphenols. Although the underlying mechanisms have yet to be fully clarified, in this study, a network pharmacology approach was combined with molecular docking to identify key bioactive polyphenols, followed by validation of their anti-inflammatory effects using cell-based assays, transcriptomics, proteomics profiling, quantitative polymerase chain reaction (qPCR), Western blot, and computational analysis. A total of 29 protein targets were identified for dandelion-derived polyphenols, among which quercetin and caffeic acid were found to regulate 11 key proteins within the advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway, a central route linking dietary AGEs to chronic inflammation. Inflammatory cytokine assays showed that both 100% quercetin, and a combination of 50% quercetin + 50% caffeic acid exhibited the strongest inhibition of tumor necrosis factor-α (TNF-α), and interleukin-1 beta (IL-1β) expression. This effect was primarily associated with the downregulation of ICAM1, IL1B, and THBD, while caffeic acid reduced IL-1β secretion. Calculation results revealed that both compounds strongly bound to receptors for advanced glycation end products (RAGE) without competing with advanced glycation end products (AGEs), disrupting protein and receptor interactions, and impeding inflammatory signal transduction. Overall, quercetin and caffeic acid effectively regulate AGE-RAGE-mediated inflammation, with their combination showing enhanced anti-inflammatory potential, and supporting the development of dandelion-based functional foods aimed at mitigating diet-induced inflammation.

Keywords

Dandelion / Functional food / Polyphenols / Anti-inflammatory activity / Quercetin / Caffeic acid

Author contributions

The authors confirm contribution to the paper as follows: Data curation and writing − original draft: Gao L; Conceptualization and methodology: Gao L, Li G; Investigation: Li G; Validation: Liu T; Visualisation: Gao L, Li G, Liu T, Zou H, Chen Y; Writing − review and editing, supervision, project administration, and funding acquisition: Zou H, Chen Y. All authors reviewed the results and approved the final version of the manuscript.

Data availability

The data that support the findings of this study are available upon request from the corresponding author.

Acknowledgments

This work was supported by the Innovation Project of Shandong Province Agricultural Application Technology (Grant No. 2130106), and the Natural Science Foundation of Shandong Province (Grant No. ZR2021QC049).

Conflict of interest

The authors declare that they have no conflict of interest.

References

[1] González-Castejón M, Visioli F, Rodriguez-Casado A. 2012. Diverse biological activities of dandelion. Nutrition Reviews 70:534-547 doi: 10.1111/j.1753-4887.2012.00509.x

[2] Ivanov I, Petkova N, Tumbarski J, Dincheva I, Badjakov I, et al. 2018. GC-MS characterization of n-hexane soluble fraction from dandelion (Taraxacum officinale Weber ex F. H. Wigg. ) aerial parts and its antioxidant and antimicrobial properties. Zeitschrift für Naturforschung C 73: 41-47 doi: 10.1515/znc-2017-0107

[3] Davaatseren M, Hur HJ, Yang HJ, Hwang JT, Park JH, et al. 2013. Taraxacum official (dandelion) leaf extract alleviates high-fat diet-induced nonalcoholic fatty liver. Food and Chemical Toxicology 58:30-36 doi: 10.1016/j.fct.2013.04.023

[4] Guo H, Zhang W, Jiang Y, Wang H, Chen G, et al. 2019. Physicochemical, structural, and biological properties of polysaccharides from dandelion. Molecules 24:1485 doi: 10.3390/molecules24081485

[5] Lis B, Rolnik A, Jedrejek D, Soluch A, Stochmal A, et al. 2019. Dandelion (Taraxacum officinale L.) root components exhibit anti-oxidative and antiplatelet action in an in vitro study. Journal of Functional Foods 59:16-24 doi: 10.1016/j.jff.2019.05.019

[6] Tanasa Acretei MV, Negreanu-Pirjol T, Olariu L, Negreanu-Pirjol BS, Lepadatu AC, et al. 2025. Bioactive compounds from vegetal organs of Taraxacum species (dandelion) with biomedical applications: a review. International Journal of Molecular Sciences 26:450 doi: 10.3390/ijms26020450

[7] Xue Y, Zhang S, Du M, Zhu MJ. 2017. Dandelion extract suppresses reactive oxidative species and inflammasome in intestinal epithelial cells. Journal of Functional Foods 29:10-18 doi: 10.1016/j.jff.2016.11.032

[8] Zhou S, Wang Z, Hao Y, An P, Luo J, et al. 2023. Dandelion polysaccharides ameliorate high-fat-diet-induced atherosclerosis in mice through antioxidant and anti-inflammatory capabilities. Nutrients 15:4120 doi: 10.3390/nu15194120

[9] Wu Z, Zhang T, Ma X, Guo S, Zhou Q, et al. 2023. Recent advances in anti-inflammatory active components and action mechanisms of natural medicines. Inflammopharmacology 31:2901-2937 doi: 10.1007/s10787-023-01369-9

[10] Gautam R, Jachak SM. 2009. Recent developments in anti-inflammatory natural products. Medicinal Research Reviews 29:767-820 doi: 10.1002/med.20156

[11] Ambriz-Pérez DL, Leyva-López N, Gutierrez-Grijalva EP, Heredia JB. 2016. Phenolic compounds: natural alternative in inflammation treatment. A review. Cogent Food & Agriculture 2: 1131412 doi: 10.1080/23311932.2015.1131412

[12] Kim HP, Son KH, Chang HW, Kang SS. 2004. Anti-inflammatory plant flavonoids and cellular action mechanisms. Journal of Pharmacological Sciences 96:229-245 doi: 10.1254/jphs.CRJ04003X

[13] Serafini M, Peluso I, Raguzzini A. 2010. Flavonoids as anti-inflammatory agents. Proceedings of the Nutrition Socirty 69:273-278 doi: 10.1017/S002966511000162X

[14] Zhang X, Xiong H, Li H, Cheng Y. 2014. Protective effect of taraxasterol against LPS-induced endotoxic shock by modulating inflammatory responses in mice. Immunopharmacology and Immunotoxicology 36:11-16 doi: 10.3109/08923973.2013.861482

[15] Huwait EA, Saddeek SY, Al-Massabi RF, Almowallad SJ, Pushparaj PN, et al. 2021. Antiatherogenic effects of quercetin in the THP-1 macrophage model in vitro, with insights into its signaling mechanisms using in silico analysis. Frontiers in Pharmacology 12:698138 doi: 10.3389/fphar.2021.698138

[16] Yoo H, Ku SK, Baek YD, Bae JS. 2014. Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflammation Research 63:197-206 doi: 10.1007/s00011-013-0689-x

[17] Wan Y, Xu L, Liu Z, Yang M, Jiang X, et al. 2019. Utilising network pharmacology to explore the underlying mechanism of Wumei Pill in treating pancreatic neoplasms. BMC Complementary and Alternative Medicine 19:158 doi: 10.1186/s12906-019-2580-y

[18] Sun Y, Yang J. 2019. A bioinformatics investigation into the pharmacological mechanisms of the effect of Fufang Danshen on pain based on methodologies of network pharmacology. Scientific Reports 1:5913 doi: 10.1038/s41598-019-40694-4

[19] Xiong Y, Yang Y, Xiong W, Yao Y, Wu H, et al. 2019. Network pharmacology-based research on the active component and mechanism of the antihepatoma effect of Rubia cordifolia L. Journal of Cellular Biochemistry 120:12461-12472 doi: 10.1002/jcb.28513

[20] Li W, Yuan G, Pan Y, Wang C, Chen H. 2017. Network pharmacology studies on the bioactive compounds and action mechanisms of natural products for the treatment of diabetes mellitus: a review. Frontiers in Pharmacology 8:74 doi: 10.3389/fphar.2017.00074

[21] Kibble M, Saarinen N, Tang J, Wennerberg K, Mäkelä S, et al. 2015. Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Natural Product Reports 32:1249-1266 doi: 10.1039/C5NP00005J

[22] Fang S, Dong L, Liu L, Guo J, Zhao L, et al. 2021. HERB: a high-throughput experiment- and reference-guided database of traditional Chinese medicine. Nucleic Acids Research 49:D1197-D1206 doi: 10.1093/nar/gkaa1063

[23] Ru J, Li P, Wang J, Zhou W, Li B, et al. 2014. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. Journal of Cheminformatics 6:13 doi: 10.1186/1758-2946-6-13

[24] Sherman BT, Huang DW, Tan Q, Guo Y, Bour S, et al. 2007. DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics 8:426 doi: 10.1186/1471-2105-8-426

[25] Kanehisa M, Furumichi M, Sato Y, Matsuura Y, Ishiguro-Watanabe M. 2025. KEGG: biological systems database as a model of the real world. Nucleic Acids Research 53:D672-D677 doi: 10.1093/nar/gkae909

[26] Chanput W, Mes JJ, Wichers HJ. 2014. THP-1 cell line: an in vitro cell model for immune modulation approach. International Immunopharmacology 23:37-45 doi: 10.1016/j.intimp.2014.08.002

[27] Kong F, Ye B, Lin L, Cai X, Huang W, et al. 2016. Atorvastatin suppresses NLRP 3 inflammasome activation via TLR4/MyD88/NF-κB signaling in PMA-stimulated THP-1 monocytes. Biomedicine & Pharmacotherapy 82: 167-172 doi: 10.1016/j.biopha.2016.04.043

[28] Ayele Y, Kim JA, Park E, Kim YJ, Retta N, et al. 2013. A methanol extract of Adansonia digitata L. leaves inhibits pro-inflammatory iNOS possibly via the inhibition of NF-κB activation. Biomolecules & Therapeutics 21: 146-152 doi: 10.4062/biomolther.2012.098

[29] Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. 2012. Metformin inhibits advanced glycation end products (AGEs)-induced renal tubular cell injury by suppressing reactive oxygen species generation via reducing receptor for AGEs (RAGE) expression. Hormone and Metabolic Research 44:891-895 doi: 10.1055/s-0032-1321878

[30] Ge X, Gu Y, Wang W, Guo W, Wang P, et al. 2024. Corynoline alleviates hepatic ischemia-reperfusion injury by inhibiting NLRP3 inflammasome activation through enhancing Nrf2/HO-1 signaling. Inflammation Research 73:2069-2085 doi: 10.1007/s00011-024-01949-7

[31] Xiang R, Xiao X, Liu J, Guo Z, He H, et al. 2024. Protective effects of functional Nano-Selenium supplementation on spleen injury through regulation of p38 MAPK and NF-κB protein expression. International Immunopharmacology 130:111574 doi: 10.1016/j.intimp.2024.111574

[32] Kleemann R, Verschuren L, Morrison M, Zadelaar S, van Erk MJ, et al. 2011. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis 218:44-52 doi: 10.1016/j.atherosclerosis.2011.04.023

[33] Lee ES, Park SH, Kim MS, Han SY, Kim HS, et al. 2012. Caffeic acid disturbs monocyte adhesion onto cultured endothelial cells stimulated by adipokine resistin. Journal of Agricultural and Food Chemistry 60:2730-2739 doi: 10.1021/jf203774y

[34] Prasad K, Mishra M. 2018. AGE-RAGE stress, stressors, and antistressors in health and disease. International Journal of Angiology 27:1-12 doi: 10.1055/s-0037-1613678

[35] González I, Morales MA, Rojas A. 2020. Polyphenols and AGEs/RAGE axis trends and challenges. Food Research International 129:108843 doi: 10.1016/j.foodres.2019.108843

[36] Schmidt AM, Yan SD, Wautier JL, Stern D. 1999. Activation of receptor for advanced glycation end products. Circulation Research 84:489-497 doi: 10.1161/01.RES.84.5.489

[37] Simm A, Caßelmann C, Schubert A, Hofmann S, Reimann A, et al. 2004. Age associated changes of AGE-receptor expression: RAGE upregulation is associated with human heart dysfunction. Experimental Gerontology 39:407-413 doi: 10.1016/j.exger.2003.12.006

[38] Alves M, Calegari VC, Cunha DA, Saad MJA, Velloso LA, et al. 2005. Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats. Diabetologia 48:2675-2681 doi: 10.1007/s00125-005-0010-9

[39] Jang DI, Lee AH, Shin HY, Song HR, Park JH, et al. 2021. The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. International Journal of Molecular Sciences 22:2719 doi: 10.3390/ijms22052719

[40] Matarazzo L, Hernandez Santana YE, Walsh PT, Fallon PG. 2022. The IL-1 cytokine family as custodians of barrier immunity. Cytokine 154:155890 doi: 10.1016/j.cyto.2022.155890

[41] Bode JG, Ehlting C, Häussinger D. 2012. The macrophage response towards LPS and its control through the p38MAPK-STAT3 axis. Cellular Signalling 24:1185-1194 doi: 10.1016/j.cellsig.2012.01.018

[42] Chen T, Zhang X, Zhu G, Liu H, Chen J, et al. 2020. Quercetin inhibits TNF-α induced HUVECs apoptosis and inflammation via downregulating NF-kB and AP-1 signaling pathway in vitro. Medicine 99:e22241 doi: 10.1097/MD.0000000000022241

[43] Huang X, Xi Y, Pan Q, Mao Z, Zhang R, et al. 2018. Caffeic acid protects against IL-1β-induced inflammatory responses and cartilage degradation in articular chondrocytes. Biomedicine & Pharmacotherapy 107: 433-439 doi: 10.1016/j.biopha.2018.07.161

[44] Jang EA, Han HJ, Tin TD, Cho E, Lee S, et al. 2023. The effect of caffeic acid phenethyl ester (CAPE) on phagocytic activity of septic neutrophil in vitro. Biomedical Science Letters 29:211-219 doi: 10.15616/BSL.2023.29.4.211

[45] Awwad O, Coperchini F, Pignatti P, Denegri M, Massara S, et al. 2018. The AMPK-activator AICAR in thyroid cancer: effects on CXCL 8 secretion and on CXCL8-induced neoplastic cell migration. Journal of Endocrinological Investigation 41:1275-1282 doi: 10.1007/s40618-018-0862-8

[46] Maity S, Kinra M, Nampoothiri M, Arora D, Pai KSR, et al. 2022. Caffeic acid, a dietary polyphenol, as a promising candidate for combination therapy. Chemical Papers 76:1271-1283 doi: 10.1007/s11696-021-01947-7

[47] Nakanishi K, Yanase E, Jang YP. 2010. Syntheses of antioxidant flavonoid derivatives. Heterocycles 82:1151-1155 doi: 10.3987/com-10-s(e)102