We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages

    Kamal Rullah

    *Author for correspondence: Tel.: +60 95 704 934;

    E-mail Address: kamalrullah@iium.edu.my

    Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia

    ,
    Nur Farisya Shamsudin

    Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia

    ,
    Andreas Koeberle

    Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, 6020 Innsbruck, Austria

    ,
    Chau Ling Tham

    Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

    ,
    Mohd Fadhlizil Fasihi Mohd Aluwi

    Faculty of Industrial Sciences and Technology, Universiti Malaysia Pahang Al-Sultan Abdullah, Lebuhraya Tun Razak, 26300 Gambang, Kuantan, Pahang, Malaysia

    ,
    Sze-Wei Leong

    Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia

    ,
    Ibrahim Jantan

    Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, 43600 Bangi, Malaysia

    &
    Kok Wai Lam

    Centre for Drug & Herbal Development, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia

    Published Online:https://doi.org/10.4155/fmc-2023-0174

    Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPK and PI3K/Akt or modulating LPS-related gene expression.

    Graphical abstract

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Mihlan M, Safaiyan S, Stecher M, Paterson N, Lämmermann T. Surprises from intravital imaging of the innate immune response. Ann. Rev. Cell Dev. Biol. 38(1), 467–489 (2022).
    • 2. Auffray C, Sieweke MH, Geissmann F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27(1), 669–692 (2009).
    • 3. Ardura JA, Rackov G, Izquierdo E, Alonso V, Gortazar AR, Escribese MM. Targeting macrophages: friends or foes in disease? Front. Pharmacol. 10(1255), (2019).
    • 4. Chen L, Deng H, Cui H et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget 9(6), 7204–7218 (2017).
    • 5. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat. Rev. Immunol. 11(11), 762–774 (2011). • Review describing the mechanisms that control monocyte trafficking under infectious and inflammatory conditions.
    • 6. Van Amersfoort ES, Van Berkel TJC, Kuiper J. Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock. Clin. Microbiol. Rev. 16(3), 379–414 (2003).
    • 7. Raetz CRH, Whitfield C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71(1), 635–700 (2002).
    • 8. Alvim J, Severino RP, Marques EF et al. Solution phase synthesis of a combinatorial library of chalcones and flavones as potent cathepsin V inhibitors. J. Comb. Chem. 12(5), 687–695 (2010).
    • 9. Hert J, Irwin JJ, Laggner C, Keiser MJ, Shoichet BK. Quantifying biogenic bias in screening libraries. Nat. Chem. Biol. 5(7), 479–483 (2009).
    • 10. Tapas AR, Sakarkar D, Kakde R. Flavonoids as nutraceuticals: a review. Trop. J. Pharm. Res. 7(3), 1089–1099 (2008).
    • 11. Hughes SD, Ketheesan N, Haleagrahara N. The therapeutic potential of plant flavonoids on rheumatoid arthritis. Crit. Rev. Food Sci. Nutr. 57(17), 3601–3613 (2017).
    • 12. Vezza T, Rodríguez-Nogales A, Algieri F, Utrilla MP, Rodriguez-Cabezas ME, Galvez J. Flavonoids in inflammatory bowel disease: a review. Nutrients 8(4), 211 (2016).
    • 13. Rakha A, Umar N, Rabail R et al. Anti-inflammatory and anti-allergic potential of dietary flavonoids: a review. Biomed. Pharmacother. 156, 113945 (2022).
    • 14. Filingeri V, Buonomo O, Sforza D. Use of flavonoids for the treatment of symptoms after hemorrhoidectomy with radiofrequency scalpel. Eur. Rev. Med. Pharmacol. Sci. 18(5), 612–616 (2014).
    • 15. García-Lafuente A, Guillamón E, Villares A, Rostagno MA, Martínez JA. Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease. Inflamm. Res. 58(9), 537–552 (2009).
    • 16. Maleki SJ, Crespo JF, Cabanillas B. Anti-inflammatory effects of flavonoids. Food Chem. 299, 125124 (2019).
    • 17. Rathee P, Chaudhary H, Rathee S, Rathee D, Kumar V, Kohli K. Mechanism of action of flavonoids as anti-inflammatory agents: a review. Inflamm. Allergy Drug Targets 8(3), 229–235 (2009).
    • 18. Manthey JA. Biological properties of flavonoids pertaining to inflammation. Microcirculation 7(Suppl. 1), S29–S34 (2000).
    • 19. Kim HP, Son KH, Chang HW, Kang SS. Anti-inflammatory plant flavonoids and cellular action mechanisms. J. Pharmacol. Sci. 96(3), 229–245 (2004).
    • 20. Mahapatra DK, Bharti SK, Asati V. Chalcone derivatives: anti-inflammatory potential and molecular targets perspectives. Curr. Top. Med. Chem. 17(28), 3146–3169 (2017).
    • 21. Gao W, Xiong Y, Li Q, Yang H. Inhibition of toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front. Physiol. 8, doi: 10.3389/fphys.2017.00508 (2017).
    • 22. Park BS, Lee J-O. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp. Mol. Med. 45, e66 (2013).
    • 23. Zhang Y, Liang X, Bao X, Xiao W, Chen G. Toll-like receptor 4 (TLR4) inhibitors: current research and prospective. Eur. J. Med. Chem. 235, 114291 (2022).
    • 24. Pålsson-McDermott EM, O'Neill LAJ. Signal transduction by the lipopolysaccharide receptor, toll-like receptor-4. Immunology 113(2), 153–162 (2004).
    • 25. Madalina M, Deleanu M, Manduteanu I et al. Lipopolysaccharide-induced inflammation in monocytes/macrophages is blocked by liposomal delivery of Gi-protein inhibitor. Int. J. Nanomedicine 13, 63–76 (2018).
    • 26. Meng F, Lowell CA. Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. J. Exp. Med. 185(9), 1661–1670 (1997).
    • 27. Zhang X, Wang G, Gurley EC, Zhou H. Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in macrophages. PLOS ONE 9(9), e107072 (2014).
    • 28. Rossol M, Heine H, Meusch U et al. LPS-induced cytokine production in human monocytes and macrophages. Crit. Rev. Immunol. 31(5), 379–446 (2011).
    • 29. Nunes-Alves C. Host response: new LPS receptors discovered. Nat. Rev. Microbiol. 12(10), 658–658 (2014).
    • 30. Shi J, Zhao Y, Wang Y et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514(7521), 187–192 (2014). • Review describing the mechanism underlying cytosolic lipopolysaccharide sensing and the responsible pattern recognition receptor in human monocytes.
    • 31. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 124(4), 783–801 (2006).
    • 32. Valkov E, Stamp A, Dimaio F et al. Crystal structure of toll-like receptor adaptor MAL/TIRAP reveals the molecular basis for signal transduction and disease protection. Proc. Natl Acad. Sci. USA 108(36), 14879–14884 (2011).
    • 33. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell. Signal. 13(2), 85–94 (2001).
    • 34. McNab F, Mayer-Barber K, Sher A, Wack A, O'Garra A. Type I interferons in infectious disease. Nat. Rev. Immunol. 15(2), 87–103 (2015).
    • 35. May MJ, Ghosh S. IκB kinases: kinsmen with different crafts. Science 284(5412), 271–273 (1999).
    • 36. Nakano H, Shindo M, Sakon S et al. Differential regulation of IκB kinase α and β by two upstream kinases, NF-κB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc. Natl Acad. Sci. USA 95(7), 3537–3542 (1998).
    • 37. Irie T, Muta T, Takeshige K. TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-κB in lipopolysaccharide-stimulated macrophages. FEBS Lett. 467(2–3), 160–164 (2000).
    • 38. Kopp E, Medzhitov R, Carothers J et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 13(16), 2059–2071 (1999).
    • 39. Takaesu G, Kishida S, Hiyama A et al. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by Linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol. Cell 5(4), 649–658 (2000).
    • 40. Ghosh S, Hayden MS. New regulators of NF-κB in inflammation. Nat. Rev. Immunol. 8(11), 837–848 (2008).
    • 41. Kang Y-J, Wingerd BA, Arakawa T, Smith WL. Cyclooxygenase-2 gene transcription in a macrophage model of inflammation. J. Immunol. 177(11), 8111–8122 (2006).
    • 42. Díaz-Muñoz MD, Osma-García IC, Cacheiro-Llaguno C, Fresno M, Íñiguez MA. Coordinated up-regulation of cyclooxygenase-2 and microsomal prostaglandin E synthase 1 transcription by nuclear factor kappa B and early growth response-1 in macrophages. Cell Signal. 22(10), 1427–1436 (2010).
    • 43. Griscavage JM, Wilk S, Ignarro LJ. Inhibitors of the proteasome pathway interfere with induction of nitric oxide synthase in macrophages by blocking activation of transcription factor NF-kappa B. Proc. Natl Acad. Sci. USA 93(8), 3308–3312 (1996).
    • 44. Lowenstein CJ, Alley EW, Raval P et al. Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc. Natl Acad. Sci. USA 90(20), 9730–9734 (1993).
    • 45. Stefanová I, Corcoran ML, Horak EM, Wahl LM, Bolen JB, Horak ID. Lipopolysaccharide induces activation of CD14-associated protein tyrosine kinase p53/56lyn. J. Biol. Chem. 268(28), 20725–20728 (1993).
    • 46. Seow V, Lim J, Iyer A et al. Inflammatory responses induced by lipopolysaccharide are amplified in primary human monocytes but suppressed in macrophages by complement protein C5a. J. Immunol. 191(8), 4308–4316 (2013).
    • 47. Rao KM. MAP kinase activation in macrophages. J. Leukoc. Biol. 69(1), 3–10 (2001).
    • 48. Herrera-Velit P, Knutson KL, Reiner NE. Phosphatidylinositol 3-kinase-dependent activation of protein kinase C-ζ in bacterial lipopolysaccharide-treated human monocytes. J. Biol. Chem. 272(26), 16445–16452 (1997).
    • 49. Loegering DJ, Lennartz MR. Protein kinase C and toll-like receptor signaling. Enzyme Res. 2011, 7 (2011).
    • 50. Díaz-Guerra MJ, Castrillo A, Martín-Sanz P, Boscá L. Negative regulation by phosphatidylinositol 3-kinase of inducible nitric oxide synthase expression in macrophages. J. Immunol. 162(10), 6184–6190 (1999).
    • 51. Guha M, Mackman N. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J. Biol. Chem. 277(35), 32124–32132 (2002).
    • 52. Lee JS, Nauseef WM, Moeenrezakhanlou A et al. Monocyte p110α phosphatidylinositol 3-kinase regulates phagocytosis, the phagocyte oxidase, and cytokine production. J. Leukoc. Biol. 81(6), 1548–1561 (2007).
    • 53. Luyendyk JP, Schabbauer GA, Tencati M, Holscher T, Pawlinski R, Mackman N. Genetic analysis of the role of the PI3K–Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages. J. Immunol. 180(6), 4218–4226 (2008).
    • 54. Weichhart T, Hengstschläger M, Linke M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 15(10), 599–614 (2015).
    • 55. Diaz-Meco MT, Dominguez I, Sanz L et al. Zeta PKC induces phosphorylation and inactivation of I kappa B-alpha in vitro. EMBO J. 13(12), 2842–2848 (1994).
    • 56. Martin M, Rehani K, Jope RS, Michalek SM. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6(8), 777–784 (2005).
    • 57. Cortés-Vieyra R, Bravo-Patiño A, Valdez-Alarcón JJ, Juárez MC, Finlay BB, Baizabal-Aguirre VM. Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens. J. Inflamm. (Lond.) 9(1), 1–9 (2012).
    • 58. Medunjanin S, Schleithoff L, Fiegehenn C, Weinert S, Zuschratter W, Braun-Dullaeus RC. GSK-3β controls NF-kappaB activity via IKKγ/NEMO. Sci. Rep. 6(1), 38553 (2016).
    • 59. Miyake K. Invited review: roles for accessory molecules in microbial recognition by toll-like receptors. J. Endotoxin Res. 12(4), 195–204 (2006).
    • 60. Kim HM, Park BS, Kim J-I et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist eritoran. Cell 130(5), 906–917 (2007).
    • 61. Park BS, Song DH, Kim HM, Choi B-S, Lee H, Lee J-O. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458(7242), 1191–1195 (2009).
    • 62. Park SH, Kim ND, Jung J-K, Lee C-K, Han S-B, Kim Y. Myeloid differentiation 2 as a therapeutic target of inflammatory disorders. Pharmacol. Ther. 133(3), 291–298 (2012).
    • 63. Gradišar H, Keber MM, Pristovšek P, Jerala R. MD-2 as the target of curcumin in the inhibition of response to LPS. J. Leukoc. Biol. 82(4), 968–974 (2007).
    • 64. Peluso MR, Miranda CL, Hobbs DJ, Proteau RR, Stevens JF. Xanthohumol and related prenylated flavonoids inhibit inflammatory cytokine production in LPS-Activated THP-1 monocytes: structure–activity relationships and in silico binding to myeloid differentiation protein-2 (MD-2). Planta Med. 76(14), 1536–1543 (2010).
    • 65. Roh E, Lee H-S, Kwak J-A et al. MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity. J. Infect. Dis. 203(7), 1012–1020 (2011).
    • 66. Kim SY, Koo JE, Seo YJ et al. Suppression of toll-like receptor 4 activation by caffeic acid phenethyl ester is mediated by interference of LPS binding to MD2. Br. J. Pharmacol. 168(8), 1933–1945 (2013).
    • 67. Chen G, Zhang Y, Liu X et al. Discovery of a new inhibitor of myeloid differentiation 2 from cinnamamide derivatives with anti-inflammatory activity in sepsis and acute lung injury. J. Med. Chem. doi: 10.1021/acs.jmedchem.5b01574 (.2016) (Online).
    • 68. Wang Y, Shan X, Chen G et al. MD-2 as the target of a novel small molecule, L6H 21, in the attenuation of LPS-induced inflammatory response and sepsis. Br. J. Pharmacol. 172(17), 4391–4405 (2015). • Presents a flavonoid derivative as a sepsis treatment and emphasizes MD-2 as a key target for inflammatory disorders.
    • 69. Zhang Y, Wu J, Ying S et al. Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS-induced acute lung injury. Sci. Rep. 6(1), 25130 (2016).
    • 70. Ye J, Guan M, Lu Y et al. Protective effects of hesperetin on lipopolysaccharide-induced acute lung injury by targeting MD2. Eur. J. Pharmacol. 852, 151–158 (2019).
    • 71. Yang Y, Han C, Sheng Y et al. The mechanism of aureusidin in suppressing inflammatory response in acute liver injury by regulating MD2. Front. Pharmacol. 11, 570776 (2020).
    • 72. Yue B, Ren J, Yu Z et al. Pinocembrin alleviates ulcerative colitis in mice via regulating gut microbiota, suppressing TLR4/MD2/NF-κB pathway and promoting intestinal barrier. Biosci. Rep. 40(7), BSR20200986 (2020).
    • 73. Wu P, Yan H, Qi J et al. L6H9 attenuates LPS-induced acute lung injury in rats through targeting MD2. Drug Dev. Res. 81(1), 85–92 (2020).
    • 74. Chen ZJ, Parent L, Maniatis T. Site-specific phosphorylation of IκBα by a novel ubiquitination-dependent protein kinase activity. Cell 84(6), 853–862 (1996).
    • 75. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388(6642), 548–554 (1997).
    • 76. Yamamoto Y, Gaynor RB. IκB kinases: key regulators of the NF-κB pathway. Trends Biochem. Sci. 29(2), 72–79 (2004).
    • 77. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18(1), 621–663 (2000).
    • 78. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M. IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 434(7037), 1138–1143 (2005).
    • 79. O'Connell MA, Bennett BL, Mercurio F, Manning AM, Mackman N. Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. J. Biol. Chem. 273(46), 30410–30414 (1998).
    • 80. Hu Y, Baud V, Delhase M et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284(5412), 316–320 (1999).
    • 81. Liddle J, Bamborough P, Barker MD et al. 4-Phenyl-7-azaindoles as potent, selective and bioavailable IKK2 inhibitors demonstrating good in vivo efficacy. Bioorg. Med. Chem. Lett. 22(16), 5222–5226 (2012).
    • 82. Christopher JA, Bamborough P, Alder C et al. Discovery of 6-aryl-7-alkoxyisoquinoline inhibitors of IκB kinase-β (IKK-β). J. Med. Chem. 52(9), 3098–3102 (2009).
    • 83. Crombie AL, Sum F-W, Powell DW et al. Synthesis and biological evaluation of tricyclic anilinopyrimidines as IKKβ inhibitors. Bioorg. Med. Chem. Lett. 20(12), 3821–3825 (2010).
    • 84. Park H, Shin Y, Choe H, Hong S. Computational design and discovery of nanomolar inhibitors of IκB kinase β. J. Am. Chem. Soc. 137(1), 337–348 (2015).
    • 85. Pandey MK, Sandur SK, Sung B, Sethi G, Kunnumakkara AB, Aggarwal BB. Butein, a tetrahydroxychalcone, inhibits nuclear factor (NF)-κB and NF-κB-regulated gene expression through direct inhibition of IκBα kinase β on cysteine 179 residue. J. Biol. Chem. 282(24), 17340–17350 (2007).
    • 86. Byun M-S, Choi J, Jue D-M. Cysteine-179 of IκB kinase β plays a critical role in enzyme activation by promoting phosphorylation of activation loop serines. Exp. Mol. Med. 38, 546–552 (2006).
    • 87. Harikumar KB, Kunnumakkara AB, Ahn KS et al. Modification of the cysteine residues in IκBα kinase and NF-κB (p65) by xanthohumol leads to suppression of NF-κB–regulated gene products and potentiation of apoptosis in leukemia cells. Blood 113(9), 2003–2013 (2009).
    • 88. Funakoshi-Tago M, Tanabe S, Tago K et al. Licochalcone a potently inhibits tumor necrosis factor α-induced nuclear factor-κB activation through the direct inhibition of IκB kinase complex activation. Mol. Pharmacol. 76(4), 745–753 (2009).
    • 89. Funakoshi-Tago M, Ohsawa K, Ishikawa T et al. Inhibitory effects of flavonoids extracted from Nepalese propolis on the LPS signaling pathway. Int. Immunopharmacol. 40, 550–560 (2016).
    • 90. Kim J-Y, Park SJ, Yun K-J, Cho Y-W, Park H-J, Lee K-T. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-κB in RAW 264.7 macrophages. Eur. J. Pharmacol. 584(1), 175–184 (2008).
    • 91. Kim Y-J, Kim H-C, Ko H, Amor EC, Lee JW, Yang HO. Inhibitory effects of aurentiacin from Syzygium samarangense on lipopolysaccharide-induced inflammatory response in mouse macrophages. Food Chem. Toxicol. 50(3–4), 1027–1035 (2012).
    • 92. Li C, Yang D, Cao X et al. LFG-500, a newly synthesized flavonoid, attenuates lipopolysaccharide-induced acute lung injury and inflammation in mice. Biochem. Pharmacol. 113, 57–69 (2016).
    • 93. Sun Y-W, Bao Y, Yu H et al. Anti-rheumatoid arthritis effects of flavonoids from Daphne genkwa. Int. Immunopharmacol. 83, 106384 (2020).
    • 94. Dhar R, Kimseng R, Chokchaisiri R et al. 2′, 4-Dihydroxy-3′, 4′, 6′-trimethoxychalcone from Chromolaena odorata possesses anti-inflammatory effects via inhibition of NF-κB and p38 MAPK in lipopolysaccharide-activated RAW 264.7 macrophages. Immunopharmacol. Immunotoxicol. 40(1), 43–51 (2018).
    • 95. Elsasser S, Finley D. Delivery of ubiquitinated substrates to protein-unfolding machines. Nat. Cell Biol. 7(8), 742–749 (2005).
    • 96. Skaug B, Jiang X, Chen ZJ. The role of ubiquitin in NF-κB regulatory pathways. Annu. Rev. Biochem. 78(1), 769–796 (2009).
    • 97. Musial A, Eissa NT. Inducible nitric-oxide synthase is regulated by the proteasome degradation pathway. J. Biol. Chem. 276(26), 24268–24273 (2001).
    • 98. Mbonye UR, Wada M, Rieke CJ, Tang H-Y, Dewitt DL, Smith WL. The 19-amino acid cassette of cyclooxygenase-2 mediates entry of the protein into the endoplasmic reticulum-associated degradation system. J. Biol. Chem. 281(47), 35770–35778 (2006).
    • 99. Silswal N, Reis J, Qureshi AA, Papasian C, Qureshi N. Of mice and men: proteasome's role in LPS-induced inflammation and tolerance. Shock 47(4), 445–454 (2017).
    • 100. Adams J, Kauffman M. Development of the proteasome inhibitor Velcade™ (bortezomib). Cancer Invest. 22(2), 304–311 (2004).
    • 101. McBride A, Klaus JO, Stockerl-Goldstein K. Carfilzomib: a second-generation proteasome inhibitor for the treatment of multiple myeloma. Am. J. Health Syst. Pharm. 72(5), 353–360 (2015).
    • 102. Beck F, Unverdorben P, Bohn S et al. Near-atomic resolution structural model of the yeast 26S proteasome. Proc. Natl Acad. Sci. USA 109(37), 14870–14875 (2012).
    • 103. Śledź P, Baumeister W. Structure-driven developments of 26S proteasome inhibitors. Annu. Rev. Pharmacol. Toxicol. 56(1), 191–209 (2016).
    • 104. Achanta G, Modzelewska A, Feng L, Khan SR, Huang P. A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome. Mol. Pharmacol. 70(1), 426–433 (2006).
    • 105. Shi D, Jiang P. A different facet of p53 function: regulation of immunity and inflammation during tumor development. Front. Cell Dev. Biol. 9, 762651 (2021).
    • 106. Bazzaro M, Anchoori RK, Mudiam MKR et al. α,β-Unsaturated carbonyl system of chalcone-based derivatives is responsible for broad inhibition of proteasomal activity and preferential killing of human papilloma virus (HPV) positive cervical cancer cells. J. Med. Chem. 54(2), 449–456 (2011).
    • 107. Lee Y-H, Yun J, Jung J-C, Seikwan O, Jung Y-S. Anti-tumor activity of benzylideneacetophenone derivatives via proteasomal inhibition in prostate cancer cells. Pharmazie 71(5), 274–279 (2016).
    • 108. Wang J, Wang Y, He S, Wang Z, Deng Q, Liang H. Proteasome inhibition induces macrophage apoptosis via mitochondrial dysfunction. J. Biochem. Mol. Toxicol. 35(11), e22894 (2021).
    • 109. Qureshi N, Perera P-Y, Shen J et al. The proteasome as a lipopolysaccharide-binding protein in macrophages: differential effects of proteasome inhibition on lipopolysaccharide-induced signaling events. J. Immunol. 171(3), 1515–1525 (2003).
    • 110. Ren B-Z, Ablise M, Yang X-C, Liao B-E, Yang Z. Synthesis and biological evaluation of α-methyl-chalcone for anti-cervical cancer activity. Med. Chem. Res. 26(9), 1871–1883 (2017).
    • 111. Chang T-L. Inhibitory effect of flavonoids on 26S proteasome activity. J. Agric. Food Chem. 57(20), 9706–9715 (2009).
    • 112. Pradhan D, Pradhan RK, Tripathy G, Pradhan S. Inhibition of proteasome activity by the dietary flavonoid quercetin associated with growth inhibition in cultured breast cancer cells and xenografts. J. Young Pharm. 7(3), 225 (2015).
    • 113. Ding Y, Chen X, Wang B, Yu B, Ge J, Shi X. Quercetin suppresses the chymotrypsin-like activity of proteasome via inhibition of MEK1/ERK1/2 signaling pathway in hepatocellular carcinoma HepG2 cells. Can. J. Physiol. Pharmacol. 96(5), 521–526 (2018).
    • 114. Chang T-L, Wang C-H. Combination of quercetin and tannic acid in inhibiting 26S proteasome affects S5a and 20S expression, and accumulation of ubiquitin resulted in apoptosis in cancer chemoprevention. Biol. Chem. 394(4), 561–575 (2013).
    • 115. Singh V, Sharma V, Verma V et al. Apigenin manipulates the ubiquitin–proteasome system to rescue estrogen receptor-β from degradation and induce apoptosis in prostate cancer cells. Eur. J. Nutr. 54(8), 1255–1267 (2015).
    • 116. Li S, Yang L-J, Wang P et al. Dietary apigenin potentiates the inhibitory effect of interferon-α on cancer cell viability through inhibition of 26S proteasome-mediated interferon receptor degradation. Food Nutr. Res. 60(1), 31288 (2016).
    • 117. Shim SH. 20S proteasome inhibitory activity of flavonoids isolated from Spatholobus suberectus. Phytother. Res. 25(4), 615–618 (2011).
    • 118. Piedfer M, Bouchet S, Tang R, Billard C, Dauzonne D, Bauvois B. p70S6 kinase is a target of the novel proteasome inhibitor 3, 3′-diamino-4′-methoxyflavone during apoptosis in human myeloid tumor cells. Biochim. Biophys. Acta Molecular Cell Research 1833(6), 1316–1328 (2013).
    • 119. Pevzner Y, Metcalf R, Kantor M, Sagaro D, Daniel K. Recent advances in proteasome inhibitor discovery. Expert Opin. Drug Discov. 8(5), 537–568 (2013).
    • 120. Metcalf R, Scott LM, Daniel KG, Dou QP. Proteasome inhibitor patents (2010 – present). Expert. Opin. Ther. Pat. 24(4), 369–382 (2014).
    • 121. Thalhamer T, McGrath MA, Harnett MM. MAPKs and their relevance to arthritis and inflammation. Rheumatology 47(4), 409–414 (2008).
    • 122. Champion A, Picaud A, Henry Y. Reassessing the MAP3K and MAP4K relationships. Trends Plant Sci. 9(3), 123–129 (2004).
    • 123. Moens U, Kostenko S, Sveinbjørnsson B. The role of mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) in inflammation. Genes 4(2), 101 (2013).
    • 124. Plotnikov A, Zehorai E, Procaccia S, Seger R. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim. Biophys. Acta Molecular Cell Research 1813(9), 1619–1633 (2011).
    • 125. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 12(1), 9–18 (2002).
    • 126. Hoshino R, Chatani Y, Yamori T et al. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 18(3), 813–822 (1999).
    • 127. Zheng CF, Guan KL. Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J. Biol. Chem. 268(15), 11435–11439 (1993).
    • 128. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl Acad. Sci. USA 92(17), 7686–7689 (1995).
    • 129. Redwan IN, Dyrager C, Solano C et al. Towards the development of chromone-based MEK1/2 modulators. Eur. J. Med. Chem. 85, 127–138 (2014).
    • 130. Xagorari A, Roussos C, Papapetropoulos A. Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin. Br. J. Pharmacol. 136(7), 1058–1064 (2002).
    • 131. Lee J-P, Li Y-C, Chen H-Y et al. Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils. Acta Pharmacol. Sin. 31(7), 831–838 (2010).
    • 132. Hambleton J, Weinstein SL, Lem L, Defranco AL. Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages. Proc. Natl Acad. Sci. USA 93(7), 2774–2778 (1996).
    • 133. Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK) – from inflammation to development. Curr. Opin. Cell Biol. 10(2), 205–219 (1998).
    • 134. Lee E, Jeong K-W, Shin A et al. Binding model for eriodictyol to Jun-N terminal kinase and its anti-inflammatory signaling pathway. BMB Rep. 46(12), 594–599 (2013).
    • 135. Lee E, Jeong K-W, Jnawali H, Shin A, Heo Y-S, Kim Y. Cytotoxic activity of 3,6-dihydroxyflavone in human cervical cancer cells and its therapeutic effect on c-Jun N-terminal kinase inhibition. Molecules 19(9), 13200 (2014).
    • 136. Jnawali HN, Jeon D, Park Y-G, Lee E, Heo Y-S, Kim Y. Rhamnetin is a potent inhibitor of extracellular signal-regulated kinase 1 and c-Jun N-terminal kinase 1. Bull. Korean Chem. Soc. 36(8), 2107–2110 (2015).
    • 137. Baek S, Kang NJ, Popowicz GM et al. Structural and functional analysis of the natural JNK1 inhibitor quercetagetin. J. Mol. Biol. 425(2), 411–423 (2013).
    • 138. Hierold J, Baek S, Rieger R et al. Design, synthesis, and biological evaluation of quercetagetin analogues as JNK1 inhibitors. Chemistry 21(47), 16887–16894 (2015).
    • 139. Gao Y, Liu F, Fang L, Cai R, Zong C, Qi Y. Genkwanin inhibits proinflammatory mediators mainly through the regulation of miR-101/MKP-1/MAPK pathway in LPS-activated macrophages. PLOS ONE 9(5), e96741 (2014).
    • 140. Kim K-Y, Kang H. Sakuranetin inhibits inflammatory enzyme, cytokine, and costimulatory molecule expression in macrophages through modulation of JNK, p38, and STAT1. Evid. Based Complement. Alternat. Med. 2016, (2016).
    • 141. Cho YH, Kim NH, Khan I et al. Anti-inflammatory potential of quercetin-3-O-β-D-(‘2’-galloyl)-glucopyranoside and quercetin isolated from Diospyros kaki calyx via suppression of MAP signaling molecules in LPS-induced RAW 264.7 macrophages. J. Food Sci. 81(10), C2447–C2456 (2016).
    • 142. Park J-Y, Lim M-S, Kim S-I et al. Quercetin-3-O-β-D-glucuronide suppresses lipopolysaccharide-induced JNK and ERK phosphorylation in LPS-challenged RAW264.7 cells. Biomol. Ther. (Seoul) 24(6), 610 (2016).
    • 143. Lee HN, Shin SA, Choo GS et al. Anti-inflammatory effect of quercetin and galangin in LPS-stimulated RAW264.7 macrophages and DNCB-induced atopic dermatitis animal models. Int. J. Mol. Med. 41(2), 888–898 (2018).
    • 144. Xin Y-J, Choi S, Roh K-B et al. Anti-inflammatory activity and mechanism of isookanin, isolated by bioassay-guided fractionation from Bidens pilosa L. Molecules 26(2), 255 (2021).
    • 145. Park MY, Ha SE, Kim HH et al. Scutellarein inhibits LPS-induced inflammation through NF-κB/MAPKs signaling pathway in RAW264.7 cells. Molecules 27(12), 3782 (2022).
    • 146. Hada Y, Uchida HA, Wada J. Fisetin attenuates lipopolysaccharide-induced inflammatory responses in macrophage. Biomed. Res. Int. 2021, 5570885 (2021).
    • 147. Kim S-C, Kang S-H, Jeong S-J, Kim S-H, Ko HS, Kim S-H. Inhibition of c-Jun N-terminal kinase and nuclear factor κ B pathways mediates fisetin-exerted anti-inflammatory activity in lipopolysccharide-treated RAW264.7 cells. Immunopharmacol. Immunotoxicol. 34(4), 645–650 (2012).
    • 148. Kim EJ, Lee MY, Jeon YJ. Silymarin inhibits morphological changes in LPS-stimulated macrophages by blocking NF-κB pathway. Korean J. Physiol. Pharmacol. 19(3), 211–218 (2015).
    • 149. Lee D-H, Park J-K, Choi J, Jang H, Seol J-W. Anti-inflammatory effects of natural flavonoid diosmetin in IL-4 and LPS-induced macrophage activation and atopic dermatitis model. Int. Immunopharmacol. 89, 107046 (2020).
    • 150. Xie C, Kang J, Li Z et al. The açaí flavonoid velutin is a potent anti-inflammatory agent: blockade of LPS-mediated TNF-α and IL-6 production through inhibiting NF-κB activation and MAPK pathway. J. Nutr. Biochem. 23(9), 1184–1191 (2012).
    • 151. Abarikwu SO. Kolaviron, a natural flavonoid from the seeds of Garcinia kola, reduces LPS-induced inflammation in macrophages by combined inhibition of IL-6 secretion, and inflammatory transcription factors, ERK1/2, NF-κB, p38, Akt, pc-JUN and JNK. Biochim. Biophys. Acta General Subjects 1840(7), 2373–2381 (2014).
    • 152. Chung YC, Lee A, Ryuk JA, Hwang Y-H. Isodorsmanin a prevents inflammatory response in LPS-stimulated macrophages by inhibiting the JNK and NF-κB signaling pathways. Curr. Issues Mol. Biol. 45(2), 1601–1612 (2023).
    • 153. Jin XY, Lee SH, Park PH et al. 2′-Methoxy-4′ 6′-bis (methoxymethoxy) chalcone inhibits nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Basic Clin. Pharmacol. Toxicol. 106(6), 454–460 (2010).
    • 154. Reddy MVB, Hung H-Y, Kuo P-C et al. Synthesis and biological evaluation of chalcone, dihydrochalcone, and 1, 3-diarylpropane analogs as anti-inflammatory agents. Bioorg. Med. Chem. Lett. 27(7), 1547–1550 (2017).
    • 155. Jin X, Song S, Wang J, Zhang Q, Qiu F, Zhao F. Tiliroside, the major component of Agrimonia pilosa Ledeb ethanol extract, inhibits MAPK/JNK/p38-mediated inflammation in lipopolysaccharide-activated RAW 264.7 macrophages. Exp. Ther. Med. 12(1), 499–505 (2016).
    • 156. Lee E, Jeong K-W, Shin A, Kim Y. Anti-inflammatory activity of 3, 6, 3′-trihydroxyflavone in mouse macrophages, in vitro. Bull. Korean Chem. Soc. 35(11), 3169–3174 (2014).
    • 157. Jnawali HN, Lee E, Jeong K-W, Shin A, Heo Y-S, Kim Y. Anti-inflammatory activity of rhamnetin and a model of its binding to c-Jun NH2-terminal kinase 1 and p38 MAPK. J. Nat. Prod. 77(2), 258–263 (2014).
    • 158. Han J, Lee J, Bibbs L, Ulevitch R. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265(5173), 808–811 (1994).
    • 159. Arthur JSC, Ley SC. Mitogen-activated protein kinases in innate immunity. Nat. Rev. Immunol. 13(9), 679–692 (2013).
    • 160. Guan Z, Buckman SY, Pentland AP, Templeton DJ, Morrison AR. Induction of cyclooxygenase-2 by the activated MEKK1 → SEK1/MKK4 → p38 mitogen-activated protein kinase pathway. J. Biol. Chem. 273(21), 12901–12908 (1998).
    • 161. Masuko-Hongo K, Berenbaum F, Humbert L, Salvat C, Goldring MB, Thirion S. Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways. Arthritis Rheumatol. 50(9), 2829–2838 (2004).
    • 162. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim. Biophys. Acta Molecular Cell Research 1773(8), 1358–1375 (2007).
    • 163. Feng G-J, Goodridge HS, Harnett MM et al. Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J. Immunol. 163(12), 6403–6412 (1999).
    • 164. Pietersma A, Tilly BC, Gaestel M et al. P38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level. Biochem. Biophys. Res. Commun. 230(1), 44–48 (1997).
    • 165. Tong L, Pav S, White DM et al. A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat. Struct. Mol. Biol. 4(4), 311–316 (1997).
    • 166. Borst O, Walker B, Münzer P et al. Skepinone-L, a novel potent and highly selective inhibitor of p38 MAP kinase, effectively impairs platelet activation and thrombus formation. Cell. Physiol. Biochem. 31(6), 914–924 (2013).
    • 167. Guenthoer P, Fuchs K, Reischl G et al. Evaluation of the therapeutic potential of the selective p38 MAPK inhibitor Skepinone-L and the dual p38/JNK 3 inhibitor LN 950 in experimental K/BxN serum transfer arthritis. Inflammopharmacology 27(6), 1217–1227 (2019).
    • 168. Koeberle SC, Romir J, Fischer S et al. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor. Nat. Chem. Biol. 8(2), 141–143 (2012).
    • 169. Dyrager C, Möllers LN, Kjäll LK et al. Design, synthesis, and biological evaluation of chromone-based p38 MAP kinase inhibitors. J. Med. Chem. 54(20), 7427–7431 (2011).
    • 170. Hassan AH, Yoo SY, Lee KW et al. Repurposing mosloflavone/5, 6, 7-trimethoxyflavone-resveratrol hybrids: discovery of novel p38-α MAPK inhibitors as potent interceptors of macrophage-dependent production of proinflammatory mediators. Eur. J. Med. Chem. 180, 253–267 (2019).
    • 171. Youn CK, Park SJ, Lee MY et al. Silibinin inhibits LPS-induced macrophage activation by blocking p38 MAPK in RAW 264.7 cells. Biomol. Ther. (Seoul) 21(4), 258 (2013).
    • 172. Liu X, Wang N, Fan S et al. The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway. Sci. Rep. 6(1), 1–14 (2016).
    • 173. Chen Y, Lin Y, Li Y, Li C. Total flavonoids of Hedyotis diffusa Willd inhibit inflammatory responses in LPS-activated macrophages via suppression of the NF-κB and MAPK signaling pathways. Exp. Ther. Med. 11(3), 1116–1122 (2016).
    • 174. Jia X, Zhang C, Bao J et al. Flavonoids from Rhynchosia minima root exerts anti-inflammatory activity in lipopolysaccharide-stimulated RAW 264.7 cells via MAPK/NF-κB signaling pathway. Inflammopharmacology 28(1), 289–297 (2020).
    • 175. Jiang F, Guan H, Liu D, Wu X, Fan M, Han J. Flavonoids from sea buckthorn inhibit the lipopolysaccharide-induced inflammatory response in RAW264.7 macrophages through the MAPK and NF-κB pathways. Food and Function 8(3), 1313–1322 (2017).
    • 176. Kang SR, Park KI, Park HS et al. Anti-inflammatory effect of flavonoids isolated from Korea Citrus aurantium L. on lipopolysaccharide-induced mouse macrophage RAW 264.7 cells by blocking of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling pathways. Food Chem. 129(4), 1721–1728 (2011).
    • 177. Peng Y, Hu M, Lu Q et al. Flavonoids derived from Exocarpium citri Grandis inhibit LPS-induced inflammatory response via suppressing MAPK and NF-κB signalling pathways. Food Agric. Immunol. 30(1), 564–580 (2019).
    • 178. Hong G-E, Kim J-A, Nagappan A et al. Flavonoids identified from Korean Scutellaria baicalensis Georgi inhibit inflammatory signaling by suppressing activation of NF-κB and MAPK in RAW 264.7 cells. Evid. Based Complement. Alternat. Med. 2013, doi: 10.1155/2013/912031 (2013) (Online).
    • 179. Sen SS, Sukumaran V, Giri SS, Park SC. Flavonoid fraction of guava leaf extract attenuates lipopolysaccharide-induced inflammatory response via blocking of NF-κB signalling pathway in Exocarpium citri macrophages. Fish Shellfish Immunol. 47(1), 85–92 (2015).
    • 180. Nam TG, Lim T-G, Lee BH et al. Comparison of anti-inflammatory effects of flavonoid-rich common and tartary buckwheat sprout extracts in lipopolysaccharide-stimulated RAW 264.7 and peritoneal macrophages. Oxid. Med. Cell. Longev. 2017, doi: 10.1155/2017/9658030 (2017) (Online).
    • 181. Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell 169(3), 381–405 (2017).
    • 182. Zhang X, Jiang D, Jiang W, Zhao M, Gan J. Role of TLR4-mediated PI3K/AKT/GSK-3β signaling pathway in apoptosis of rat hepatocytes. Biomed. Res. Int. 2015, 631326 (2015).
    • 183. Alexander W. Inhibiting the Akt pathway in cancer treatment: three leading candidates. PT 36(4), 225–227 (2011).
    • 184. Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C. Akt signaling pathway in macrophage activation and M1/M2 polarization. J. Immunol. 198(3), 1006–1014 (2017).
    • 185. Tang F, Wang Y, Hemmings BA, Rüegg C, Xue G. PKB/Akt-dependent regulation of inflammation in cancer. Semin. Cancer Biol. 48, 62–69 (2018).
    • 186. Acosta-Martinez M, Cabail MZ. The PI3K/Akt pathway in meta-inflammation. Int. J. Mol. Sci. 23(23), 15330 (2022).
    • 187. Luo J, Manning BD, Cantley LC. Targeting the PI3K–Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4), 257–262 (2003).
    • 188. Jing H, Zhou X, Dong X et al. Abrogation of Akt signaling by Isobavachalcone contributes to its anti-proliferative effects towards human cancer cells. Cancer Lett. 294(2), 167–177 (2010).
    • 189. Song NR, Kim JE, Park JS et al. Licochalcone A, a polyphenol present in licorice, suppresses UV-induced COX-2 expression by targeting PI3K, MEK1, and B-Raf. Int. J. Mol. Sci. 16(3), 4453–4470 (2015).
    • 190. Lee YH, Jeon S-H, Kim SH et al. A new synthetic chalcone derivative, 2-hydroxy-3′,5,5′-trimethoxychalcone (DK-139), suppresses the toll-like receptor 4-mediated inflammatory response through inhibition of the Akt/NF-κB pathway in BV2 microglial cells. Exp. Mol. Med. 44, 369–377 (2012).
    • 191. Kim MJ, Kadayat T, Um YJ, Jeong TC, Lee ES, Park PH. Inhibitory effect of 3-(4-hydroxyphenyl)-1-(thiophen-2-yl) prop-2-en-1-one, a chalcone derivative on MCP-1 expression in macrophages via inhibition of ROS and Akt signaling. Biomol. Ther. (Seoul) 23(2), 119–127 (2015).
    • 192. Lee H, Cho H, Lim D, Kang Y-H, Lee K, Park J. Mechanisms by which licochalcone E exhibits potent anti-inflammatory properties: studies with phorbol ester-treated mouse skin and lipopolysaccharide-stimulated murine macrophages. Int. J. Mol. Sci. 14(6), 10926 (2013).
    • 193. Bai D, Zhao Y, Zhu Q et al. LZ205, a newly synthesized flavonoid compound, exerts anti-inflammatory effect by inhibiting M1 macrophage polarization through regulating PI3K/AKT/mTOR signaling pathway. Exp. Cell Res. 364(1), 84–94 (2018).
    • 194. Park CM, Song Y-S. Luteolin and luteolin-7-O-glucoside inhibit lipopolysaccharide-induced inflammatory responses through modulation of NF-κB/AP-1/PI3K-Akt signaling cascades in RAW 264.7 cells. Nutr. Res. Pract. 7(6), 423–429 (2013).
    • 195. Lee H-C, Liu F-C, Tsai C-N, Chou A-H, Liao C-C, Yu H-P. Esculetin ameliorates lipopolysaccharide-induced acute lung injury in mice via modulation of the AKT/ERK/NF-κB and RORγt/IL-17 pathways. Inflammation 43(3), 962–974 (2020).
    • 196. Qi S, Xin Y, Guo Y et al. Ampelopsin reduces endotoxic inflammation via repressing ROS-mediated activation of PI3K/Akt/NF-κB signaling pathways. Int. Immunopharmacol. 12(1), 278–287 (2012).
    • 197. Sun Y, Qin H, Zhang H et al. Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells. Food Nutr. Res. 65, doi: 10.29219/fnr.v65.6355 (2021) (Online).
    • 198. Zhao M, Li C, Shen F, Wang M, Jia N, Wang C. Naringenin ameliorates LPS-induced acute lung injury through its anti-oxidative and anti-inflammatory activity and by inhibition of the PI3K/AKT pathway. Exp. Ther. Med. 14(3), 2228–2234 (2017).
    • 199. Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell. Mol. Life Sci. 78(4), 1233–1261 (2021).
    • 200. Orecchioni M, Ghosheh Y, Pramod AB, Ley K. Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS–) vs. alternatively activated macrophages. Front. Immunol. 10, (2019).
    • 201. Hirai S, Kim YI, Goto T et al. Inhibitory effect of naringenin chalcone on inflammatory changes in the interaction between adipocytes and macrophages. Life Sci. 81(16), 1272–1279 (2007).
    • 202. Wang Z, Guan Y, Yang R, Li J, Wang J, Jia A-Q. Anti-inflammatory activity of 3-cinnamoyltribuloside and its metabolomic analysis in LPS-activated RAW 264.7 cells. BMC Complement. Med. Ther. 20(1), 329 (2020).
    • 203. Cao L, Li R, Chen X, Xue Y, Liu D. Neougonin A inhibits lipopolysaccharide-induced inflammatory responses via downregulation of the NF-kB signaling pathway in RAW 264.7 macrophages. Inflammation 39(6), 1939–1948 (2016).
    • 204. Molagoda IMN, Jayasingha JACC, Choi YH, Jayasooriya RGPT, Kang C-H, Kim G-Y. Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. Sci. Rep. 11(1), 1–17 (2021).
    • 205. Mendes LF, Gaspar VM, Conde TA, Mano JF, Duarte IF. Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways. Sci. Rep. 9(1), 1–10 (2019).
    • 206. Yang H-L, Yang T-Y, Gowrisankar YV et al. Suppression of LPS-induced inflammation by chalcone flavokawain a through activation of Nrf2/ARE-mediated antioxidant genes and inhibition of ROS/NFκB signaling pathways in primary splenocytes. Oxid. Med. Cell. Longev. 2020, 3476212 (2020).
    • 207. Park P-H, Kim HS, Hur J, Jin XY, Jin YL, Sohn DH. YL-I-108, a synthetic chalcone derivative, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 murine macrophages: involvement of heme oxygenase-1 induction and blockade of activator protein-1. Arch. Pharm. Res. 32(1), 79–89 (2009).
    • 208. Zhang Y, Xu T, Wu B et al. Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury. J. Cell. Mol. Med. 21(4), 746–757 (2017).
    • 209. Bandyopadhyay S, Romero JR, Chattopadhyay N. Kaempferol and quercetin stimulate granulocyte-macrophage colony-stimulating factor secretion in human prostate cancer cells. Mol. Cell. Endocrinol. 287(1–2), 57–64 (2008).
    • 210. Kim J-A, Kim D-K, Kang O-H et al. Inhibitory effect of luteolin on TNF-α-induced IL-8 production in human colon epithelial cells. Int. Immunopharmacol. 5(1), 209–217 (2005).
    • 211. Lee S-H, Kim Y-J, Kwon S-H et al. Inhibitory effects of flavonoids on TNF-α-induced IL-8 gene expression in HEK 293 cells. BMB Rep. 42(5), 265–270 (2009).
    • 212. Wilczok T. Effect of kaempferol on the production and gene expression of monocyte chemoattractant protein-1 in J774. 2 macrophages. Pharmacol. Rep. 57(107), 107–112 (2005).
    • 213. Di Santo A, Mezzetti A, Napoleone E et al. Resveratrol and quercetin down-regulate tissue factor expression by human stimulated vascular cells. J. Thromb. Haemost. 1(5), 1089–1095 (2003).
    • 214. Orlikova B, Tasdemir D, Golais F, Dicato M, Diederich M. The aromatic ketone 4′-hydroxychalcone inhibits TNFα-induced NF-κB activation via proteasome inhibition. Biochem. Pharmacol. 82(6), 620–631 (2011).
    • 215. Lee J-H, Jung HS, Giang PM et al. Blockade of nuclear factor-κB signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera. J. Pharmacol. Exp. Ther. 316(1), 271–278 (2006).
    • 216. Furusawa J-I, Funakoshi-Tago M, Tago K et al. Licochalcone A significantly suppresses LPS signaling pathway through the inhibition of NF-κB p65 phosphorylation at serine 276. Cell. Signal. 21(5), 778–785 (2009).
    • 217. Xia Y, Lian S, Khoi PN et al. Chrysin inhibits cell invasion by inhibition of Recepteur d'origine Nantais via suppressing early growth response-1 and NF-κB transcription factor activities in gastric cancer cells. Int. J. Oncol. 46(4), 1835–1843 (2015).
    • 218. Nizamutdinova IT, Kim YM, Chung JI et al. Anthocyanins from black soybean seed coats preferentially inhibit TNF-α-mediated induction of VCAM-1 over ICAM-1 through the regulation of GATAs and IRF-1. J. Agric. Food Chem. 57(16), 7324–7330 (2009).
    • 219. Kim MJ, Kadayat T, Kim DE, Lee ES, Park PH. TI-I-174, a synthetic chalcone derivative, suppresses nitric oxide production in murine macrophages via heme oxygenase-1 induction and inhibition of AP-1. Biomol. Ther. (Seoul) 22(5), 390 (2014).
    • 220. Hošek J, Toniolo A, Neuwirth O, Bolego C. Prenylated and geranylated flavonoids increase production of reactive oxygen species in mouse macrophages but inhibit the inflammatory response. J. Nat. Prod. 76(9), 1586–1591 (2013).
    • 221. Hämäläinen M, Nieminen R, Asmawi MZ, Vuorela P, Vapaatalo H, Moilanen E. Effects of flavonoids on prostaglandin E2 production and on COX-2 and mPGES-1 expressions in activated macrophages. Planta Med. 77(13), 1504–1511 (2011).
    • 222. Rullah K, Mohd Aluwi MFF, Yamin BM et al. Inhibition of prostaglandin E2 production by synthetic minor prenylated chalcones and flavonoids: synthesis, biological activity, crystal structure, and in silico evaluation. Bioorg. Med. Chem. Lett. 24(16), 3826–3834 (2014). •• Report flavonoids significantly suppress PGE2 production in mouse macrophage cells lipopolysaccharide-induced.
    • 223. Rullah K, Mohd Aluwi MFF, Yamin BM et al. Molecular characterization, biological activity, and in silico study of 2-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-6-methoxy-4H-chromen-4-one as a novel selective COX-2 inhibitor. J. Mol. Struct. 1081, 51–61 (2015). •• Reports flavonoids as selective COX-2 inhibitors.
    • 224. Kil J-S, Son Y, Cheong Y-K et al. Okanin, a chalcone found in the genus Bidens, and 3-penten-2-one inhibit inducible nitric oxide synthase expression via heme oxygenase-1 induction in RAW264.7 macrophages activated with lipopolysaccharide. J. Clin. Biochem. Nutr. 1112130134–1112130134 (2011).
    • 225. Hatziieremia S, Gray A, Ferro V, Paul A, Plevin R. The effects of cardamonin on lipopolysaccharide-induced inflammatory protein production and MAP kinase and NFκB signalling pathways in monocytes/macrophages. Br. J. Pharmacol. 149(2), 188–198 (2006).