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image of Therapeutic Applications of Natural Flavonoids Against Alzheimer’s Disease-like Pathology: Special Focus on PI3K/Akt and Nrf2 Signaling Pathways

Abstract

The PI3K/AKT and Nrf2 signaling systems are essential for neurogenesis, synaptic plasticity, and cellular survival, and their dysregulation has been linked to the progression of Alzheimer’s disease (AD). Due to its complex pathophysiology, currently approved therapeutic agents only provide symptomatic relief and are often associated with serious side effects. Researchers have increasingly focused on natural bioactive compounds as potential therapies, with flavonoids emerging as promising candidates due to their diverse neuroprotective properties. These polyphenolic compounds exhibit notable anti-inflammatory, anti-apoptotic, and antioxidant effects, making them attractive therapeutic agents against AD. A key mechanism by which flavonoids exert neuroprotection is through modulation of the PI3K/AKT and Nrf2 signaling pathways. By enhancing neuronal resilience, reducing oxidative stress, inhibiting apoptosis, and regulating autophagy, flavonoids can mitigate neurodegenerative processes associated with AD. Additionally, they attenuate Aβ accumulation and tau hyperphosphorylation, both of which contribute to neuronal dysfunction, PI3K/AKT activation and Nrf2 pathway regulation. In preclinical AD models, numerous flavonoids-including epicatechin, kaempferol, quercetin, and luteolin-have demonstrated neuroprotective effects through regulation of the PI3K/AKT and Nrf2 pathways. Despite these encouraging findings, further research is needed to determine optimal dosages, strategies for enhancing bioavailability, and the long-term effects of flavonoid-based therapies in AD. Future studies should focus on translating preclinical evidence into clinical trials, which could improve patient outcomes and quality of life. A deeper understanding of the molecular mechanisms underlying flavonoid activity, particularly their interaction with PI3K/AKT and Nrf2 pathways, may pave the way for novel neuroprotective therapies.

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2025-12-30
2026-01-26

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References

  1. Agnello L. Ciaccio M. Neurodegenerative Diseases: From Molecular Basis to Therapy. Int. J. Mol. Sci. 2022 23 21 12854 10.3390/ijms232112854 36361643
    [Google Scholar]
  2. Cyr B. Curiel Cid R. Loewenstein D. The inflammasome adaptor protein ASC in plasma as a biomarker of early cognitive changes. Int. J. Mol. Sci. 2024 25 14 7758 10.3390/ijms25147758 39063000
    [Google Scholar]
  3. Angelopoulou E. Papageorgiou S.G. Telemedicine in Alzheimer’s disease and other dementias: Where we are? J. Alzheimers Dis. 2025 103 1 3 18 10.1177/13872877241298295 39639574
    [Google Scholar]
  4. Simão D.O. Vieira V.S. Tosatti J.A.G. Gomes K.B. Lipids, gut microbiota, and the complex relationship with Alzheimer’s disease: A narrative review. Nutrients 2023 15 21 4661 10.3390/nu15214661 37960314
    [Google Scholar]
  5. Temple S. Advancing cell therapy for neurodegenerative diseases. Cell Stem Cell 2023 30 5 512 529 10.1016/j.stem.2023.03.017 37084729
    [Google Scholar]
  6. Yang C.Z. Wang S.H. Zhang R.H. Neuroprotective effect of astragalin via activating PI3K/Akt-mTOR-mediated autophagy on APP/PS1 mice. Cell Death Discov. 2023 9 1 15 10.1038/s41420‑023‑01324‑1 36681681
    [Google Scholar]
  7. Amoah V. Atawuchugi P. Jibira Y. Lantana camara leaf extract ameliorates memory deficit and the neuroinflammation associated with scopolamine-induced Alzheimer’s-like cognitive impairment in zebrafish and mice. Pharm. Biol. 2023 61 1 825 838 10.1080/13880209.2023.2209130 37212299
    [Google Scholar]
  8. Sengoku R. Aging and Alzheimer’s disease pathology. Neuropathology 2020 40 1 22 29 10.1111/neup.12626 31863504
    [Google Scholar]
  9. Kamal H. Tan G.C. Ibrahim S.F. Alcohol use disorder, neurodegeneration, Alzheimer’s and Parkinson’s disease: Interplay between oxidative stress, neuroimmune response and excitotoxicity. Front. Cell. Neurosci. 2020 14 1 282 10.3389/fncel.2020.00282 33061892
    [Google Scholar]
  10. Ashleigh T. Swerdlow R.H. Beal M.F. The role of mitochondrial dysfunction in Alzheimer’s disease pathogenesis. Alzheimers Dement. 2023 19 1 333 342 10.1002/alz.12683 35522844
    [Google Scholar]
  11. Wang Y. Lin Y. Wang L. TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice. Aging 2020 12 20 20862 20879 10.18632/aging.104104 33065553
    [Google Scholar]
  12. Yu T.W. Lane H.Y. Lin C.H. Novel therapeutic approaches for alzheimer’s disease: An updated review. Int. J. Mol. Sci. 2021 22 15 8208 10.3390/ijms22158208 34360973
    [Google Scholar]
  13. Zuin M. Cherubini A. Volpato S. Ferrucci L. Zuliani G. Acetyl-cholinesterase-inhibitors slow cognitive decline and decrease overall mortality in older patients with dementia. Sci. Rep. 2022 12 1 12214 10.1038/s41598‑022‑16476‑w 35842477
    [Google Scholar]
  14. Medrano-Jiménez E. Meza-Sosa K.F. Urbán-Aragón J.A. Secundino I. Pedraza-Alva G. Pérez-Martínez L. Microglial activation in Alzheimer’s disease: The role of flavonoids and microRNAs. J. Leukoc. Biol. 2022 112 1 47 77 10.1002/JLB.3MR1021‑531R 35293018
    [Google Scholar]
  15. Ullah A. Munir S. Badshah S.L. Important flavonoids and their role as a therapeutic agent. Molecules 2020 25 22 5243 10.3390/molecules25225243 33187049
    [Google Scholar]
  16. Calderaro A. Patanè G.T. Tellone E. The neuroprotective potentiality of flavonoids on Alzheimer’s disease. Int. J. Mol. Sci. 2022 23 23 14835 10.3390/ijms232314835 36499159
    [Google Scholar]
  17. Kales HC Gitlin LN Lyketsos CG Assessment and management of behavioral and psychological symptoms of dementia. BMJ 2015 350(mar02 7): h369. 10.1136/bmj.h369 25731881
    [Google Scholar]
  18. García-Morales V. González-Acedo A. Melguizo-Rodríguez L. Current understanding of the physiopathology, diagnosis and therapeutic approach to Alzheimer’s disease. Biomedicines 2021 9 12 1910 10.3390/biomedicines9121910 34944723
    [Google Scholar]
  19. Roy M. Nath A.K. Pal I. Dey S.G. Second sphere interactions in amyloidogenic diseases. Chem. Rev. 2022 122 14 12132 12206 10.1021/acs.chemrev.1c00941 35471949
    [Google Scholar]
  20. Breijyeh Z. Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules 2020 25 24 5789 10.3390/molecules25245789 33302541
    [Google Scholar]
  21. Llorente-Folch I. Rueda C.B. Pardo B. Szabadkai G. Duchen M.R. Satrustegui J. The regulation of neuronal mitochondrial metabolism by calcium. J. Physiol. 2015 593 16 3447 3462 10.1113/JP270254 25809592
    [Google Scholar]
  22. Chen G.F. Xu T.H. Yan Y. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017 38 1205 1235 10.1038/aps.2017.28
    [Google Scholar]
  23. Azargoonjahromi A. The duality of amyloid-β: Its role in normal and Alzheimer’s disease states. Mol. Brain 2024 17 1 44 10.1186/s13041‑024‑01118‑1 39020435
    [Google Scholar]
  24. Thal D.R. Walter J. Saido T.C. Fändrich M. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol. 2015 129 2 167 182 10.1007/s00401‑014‑1375‑y 25534025
    [Google Scholar]
  25. Moussa-Pacha N.M. Abdin S.M. Omar H.A. Alniss H. Al-Tel T.H. BACE1 inhibitors: Current status and future directions in treating Alzheimer’s disease. Med. Res. Rev. 2020 40 1 339 384 10.1002/med.21622 31347728
    [Google Scholar]
  26. Abeysinghe A.A.D.T. Deshapriya R.D.U.S. Udawatte C. Alzheimer’s disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci. 2020 256 117996 10.1016/j.lfs.2020.117996 32585249
    [Google Scholar]
  27. Sharma V.K. Singh T.G. CREB: A multifaceted target for alzheimer’s disease. Curr. Alzheimer Res. 2021 17 14 1280 1293 10.2174/1567205018666210218152253 33602089
    [Google Scholar]
  28. Tönnies E. Trushina E. Oxidative stress, synaptic dysfunction, and alzheimer’s disease. J. Alzheimers Dis. 2017 57 4 1105 1121 10.3233/JAD‑161088 28059794
    [Google Scholar]
  29. Tang Z. Peng Y. Jiang Y. Gastrodin ameliorates synaptic impairment, mitochondrial dysfunction and oxidative stress in N2a/APP cells. Biochem. Biophys. Res. Commun. 2024 719 150127 10.1016/j.bbrc.2024.150127 38761634
    [Google Scholar]
  30. Kumar S. Saxena J. Srivastava V.K. The interplay of oxidative stress and ROS scavenging: Antioxidants as a therapeutic potential in sepsis. Vaccines 2022 10 10 1575 10.3390/vaccines10101575 36298439
    [Google Scholar]
  31. Nandi A. Yan L.J. Jana C.K. Das N. Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases. Oxid. Med. Cell. Longev. 2019 2019 1 19 10.1155/2019/9613090 31827713
    [Google Scholar]
  32. Mihailović M. Dinić S. Arambašić Jovanović J. Uskoković A. Grdović N. Vidaković M. The influence of plant extracts and phytoconstituents on antioxidant enzymes activity and gene expression in the prevention and treatment of impaired glucose homeostasis and diabetes complications. Antioxidants 2021 10 3 480 10.3390/antiox10030480 33803588
    [Google Scholar]
  33. Wojsiat J. Zoltowska K.M. Laskowska-Kaszub K. Wojda U. Oxidant/antioxidant imbalance in Alzheimer’s disease: Therapeutic and diagnostic prospects. Oxid. Med. Cell. Longev. 2018 2018 1 6435861 10.1155/2018/6435861
    [Google Scholar]
  34. Bhatt S. Puli L. Patil C.R. Role of reactive oxygen species in the progression of Alzheimer’s disease. Drug Discov. Today 2021 26 3 794 803 10.1016/j.drudis.2020.12.004 33306995
    [Google Scholar]
  35. Atlante A. Valenti D. Mitochondrial complex I and β-amyloid peptide interplay in alzheimer’s disease: A critical review of new and old little regarded findings. Int. J. Mol. Sci. 2023 24 21 15951 10.3390/ijms242115951 37958934
    [Google Scholar]
  36. Baracaldo-Santamaría D. Avendaño-Lopez S.S. Ariza-Salamanca D.F. Role of calcium modulation in the pathophysiology and treatment of alzheimer’s disease. Int. J. Mol. Sci. 2023 24 10 9067 10.3390/ijms24109067 37240413
    [Google Scholar]
  37. Naik R.A. Mir M.N. Malik I.A. The potential mechanism and the role of antioxidants in mitigating oxidative stress in alzheimer’s disease. Front. Biosci. 2025 30 2 25551 10.31083/FBL25551 40018917
    [Google Scholar]
  38. Kowalska M. Piekut T. Prendecki M. Sodel A. Kozubski W. Dorszewska J. Mitochondrial and nuclear DNA oxidative damage in physiological and pathological aging. DNA Cell Biol. 2020 39 8 1410 1420 10.1089/dna.2019.5347 32315547
    [Google Scholar]
  39. Peng Y. Gao P. Shi L. Chen L. Liu J. Long J. Central and peripheral metabolic defects contribute to the pathogenesis of Alzheimer’s disease: Targeting mitochondria for diagnosis and prevention. Antioxid. Redox Signal. 2020 32 16 1188 1236 10.1089/ars.2019.7763 32050773
    [Google Scholar]
  40. Wang W. Zhao F. Ma X. Perry G. Zhu X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. Mol. Neurodegener. 2020 15 1 30 10.1186/s13024‑020‑00376‑6 32471464
    [Google Scholar]
  41. Garbincius J.F. Elrod J.W. Mitochondrial calcium exchange in physiology and disease. Physiol. Rev. 2022 102 2 893 992 10.1152/physrev.00041.2020 34698550
    [Google Scholar]
  42. Alevriadou B.R. Patel A. Noble M. Molecular nature and physiological role of the mitochondrial calcium uniporter channel. Am. J. Physiol. Cell Physiol. 2021 320 4 C465 C482 10.1152/ajpcell.00502.2020 33296287
    [Google Scholar]
  43. Rosencrans W.M. Rajendran M. Bezrukov S.M. Rostovtseva T.K. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease. Cell Calcium 2021 94 102356 10.1016/j.ceca.2021.102356 33529977
    [Google Scholar]
  44. Eisner D. Neher E. Taschenberger H. Smith G. Physiology of intracellular calcium buffering. Physiol. Rev. 2023 103 4 2767 2845 10.1152/physrev.00042.2022 37326298
    [Google Scholar]
  45. Endlicher R. Drahota Z. Štefková K. Červinková Z. Kučera O. The mitochondrial permeability transition pore - Current knowledge of its structure, function, and regulation, and optimized methods for evaluating its functional state. Cells 2023 12 9 1273 10.3390/cells12091273 37174672
    [Google Scholar]
  46. Ryan K.C. Ashkavand Z. Norman K.R. The role of mitochondrial calcium homeostasis in Alzheimer’s and related diseases. Int. J. Mol. Sci. 2020 21 23 9153 10.3390/ijms21239153 33271784
    [Google Scholar]
  47. Mroczko B. Groblewska M. Litman-Zawadzka A. The Role of protein misfolding and tau oligomers (TauOs) in Alzheimer′s disease (AD). Int. J. Mol. Sci. 2019 20 19 4661 10.3390/ijms20194661 31547024
    [Google Scholar]
  48. Buchholz S. Zempel H. The six brain‐specific TAU isoforms and their role in Alzheimer’s disease and related neurodegenerative dementia syndromes. Alzheimers Dement. 2024 20 5 3606 3628 10.1002/alz.13784 38556838
    [Google Scholar]
  49. Drummond E. Pires G. MacMurray C. Phosphorylated tau interactome in the human Alzheimer’s disease brain. Brain 2020 143 9 2803 2817 10.1093/brain/awaa223 32812023
    [Google Scholar]
  50. Kaur D. Sharma V. Deshmukh R. Activation of microglia and astrocytes: A roadway to neuroinflammation and Alzheimer’s disease. Inflammopharmacology 2019 27 4 663 677 10.1007/s10787‑019‑00580‑x 30874945
    [Google Scholar]
  51. Codrici E. Popescu I.D. Tanase C. Enciu A.M. Friends with benefits: Chemokines, glioblastoma-associated microglia/macrophages, and tumor microenvironment. Int. J. Mol. Sci. 2022 23 5 2509 10.3390/ijms23052509 35269652
    [Google Scholar]
  52. Biswas K. Microglia mediated neuroinflammation in neurodegenerative diseases: A review on the cell signaling pathways involved in microglial activation. J. Neuroimmunol. 2023 383 11 578180 10.1016/j.jneuroim.2023.578180 37672840
    [Google Scholar]
  53. Rabøl Andersen L. Hindsberger B. Bastrup Israelsen S. Pedersen L. Bela Szecsi P. Benfield T. Higher levels of IL-1ra, IL-6, IL-8, MCP-1, MIP-3α, MIP-3β, and fractalkine are associated with 90-day mortality in 132 non-immunomodulated hospitalized patients with COVID-19. PLoS One 2024 19 7 e0306854 10.1371/journal.pone.0306854
    [Google Scholar]
  54. Singh S. Singh T.G. Role of nuclear factor kappa B (NF-κB) signalling in neurodegenerative diseases: An mechanistic approach. Curr. Neuropharmacol. 2020 18 10 918 935 10.2174/1570159X18666200207120949 32031074
    [Google Scholar]
  55. Bitra VR Moshapa F Adiukwu PC Rapaka D Nrf2-mediated signaling as a therapeutic target in Alzheimer’s disease. Open Neurol J 2024 e1874205X319474. 10.2174/011874205X319474240611070113
    [Google Scholar]
  56. Pan J. Yao Q. Wang Y. The role of PI3K signaling pathway in Alzheimer’s disease. Front. Aging Neurosci. 2024 16 1459025 10.3389/fnagi.2024.1459025 39399315
    [Google Scholar]
  57. Marín-Aguilar F. Pavillard L. Giampieri F. Bullón P. Cordero M. Adenosine monophosphate (AMP)-activated protein kinase: A new target for nutraceutical compounds. Int. J. Mol. Sci. 2017 18 2 288 10.3390/ijms18020288 28146060
    [Google Scholar]
  58. Hur J.Y. γ-secretase in alzheimer’s disease. Exp. Mol. Med. 2022 54 4 433 446 10.1038/s12276‑022‑00754‑8 35396575
    [Google Scholar]
  59. Habashi M. Vutla S. Tripathi K. Early diagnosis and treatment of Alzheimer’s disease by targeting toxic soluble Aβ oligomers. Proc. Natl. Acad. Sci. USA 2022 119 49 e2210766119 10.1073/pnas.2210766119 36442093
    [Google Scholar]
  60. Hamilton K. Harvey J. The neuronal actions of leptin and the implications for treating alzheimer’s disease. Pharmaceuticals 2021 14 1 52 10.3390/ph14010052 33440796
    [Google Scholar]
  61. Mohamed Asik R. Suganthy N. Aarifa M.A. Alzheimer’s disease: A molecular view of β-amyloid induced morbific events. Biomedicines 2021 9 9 1126 10.3390/biomedicines9091126 34572312
    [Google Scholar]
  62. Wegmann S. Biernat J. Mandelkow E. A current view on Tau protein phosphorylation in Alzheimer’s disease. Curr. Opin. Neurobiol. 2021 69 131 138 10.1016/j.conb.2021.03.003 33892381
    [Google Scholar]
  63. Chen M. Huang N. Liu J. Huang J. Shi J. Jin F. AMPK: A bridge between diabetes mellitus and Alzheimer’s disease. Behav. Brain Res. 2021 400 113043 10.1016/j.bbr.2020.113043 33307136
    [Google Scholar]
  64. Msweli S. Pakala S.B. Syed K. NF-κB transcription factors: Their distribution, family expansion, structural conservation, and evolution in animals. Int. J. Mol. Sci. 2024 25 18 9793 10.3390/ijms25189793 39337282
    [Google Scholar]
  65. Sun E. Motolani A. Campos L. Lu T. The pivotal role of NF-kB in the pathogenesis and therapeutics of alzheimer’s disease. Int. J. Mol. Sci. 2022 23 16 8972 10.3390/ijms23168972 36012242
    [Google Scholar]
  66. Giridharan S. Srinivasan M. Mechanisms of NF-κB p65 and strategies for therapeutic manipulation. J. Inflamm. Res. 2018 11 407 419 10.2147/JIR.S140188 30464573
    [Google Scholar]
  67. Deka K. Li Y. Transcriptional regulation during aberrant activation of NF-κB signalling in cancer. Cells 2023 12 5 788 10.3390/cells12050788 36899924
    [Google Scholar]
  68. Chiarini A. Armato U. Hu P. Dal Prà I. Danger-sensing/patten recognition receptors and neuroinflammation in alzheimer’s disease. Int. J. Mol. Sci. 2020 21 23 9036 10.3390/ijms21239036 33261147
    [Google Scholar]
  69. Thawkar B.S. Kaur G. Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease. J. Neuroimmunol. 2019 326 62 74 10.1016/j.jneuroim.2018.11.010 30502599
    [Google Scholar]
  70. Ries M. Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front. Aging Neurosci. 2016 8 160 10.3389/fnagi.2016.00160 27458370
    [Google Scholar]
  71. Uddin M.S. Al Mamun A. Rahman M.A. Emerging proof of protein misfolding and interactions in multifactorial Alzheimer’s disease. Curr. Top. Med. Chem. 2020 20 26 2380 2390 10.2174/1568026620666200601161703 32479244
    [Google Scholar]
  72. Calsolaro V. Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement. 2016 12 6 719 732 10.1016/j.jalz.2016.02.010 27179961
    [Google Scholar]
  73. Srinivasan M. Lahiri D.K. Significance of NF-κB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis. Expert Opin. Ther. Targets 2015 19 4 471 487 10.1517/14728222.2014.989834 25652642
    [Google Scholar]
  74. Sivamaruthi B.S. Raghani N. Chorawala M. NF-κB pathway and its inhibitors: A promising frontier in the management of alzheimer’s disease. Biomedicines 2023 11 9 2587 10.3390/biomedicines11092587 37761028
    [Google Scholar]
  75. Jha N.K. Jha S.K. Kar R. Nand P. Swati K. Goswami V.K. Nuclear factor‐kappa β as a therapeutic target for Alzheimer’s disease. J. Neurochem. 2019 150 2 113 137 10.1111/jnc.14687 30802950
    [Google Scholar]
  76. Holland T.M. Agarwal P. Wang Y. Dietary flavonols and risk of Alzheimer dementia. Neurology 2020 94 16 e1749 e1756 10.1212/WNL.0000000000008981 31996451
    [Google Scholar]
  77. He S. Li Q. Huang Q. Cheng J. Targeting protein kinase C for cancer therapy. Cancers 2022 14 5 1104 10.3390/cancers14051104 35267413
    [Google Scholar]
  78. Corsini E. Buoso E. Galbiati V. Racchi M. Role of protein kinase C in immune cell activation and its implication chemical-induced immunotoxicity. Adv. Exp. Med. Biol. 2021 1275 151 163 10.1007/978‑3‑030‑49844‑3_6 33539015
    [Google Scholar]
  79. Tyagi K. Roy A. Evaluating the current status of protein kinase C (PKC)-protein kinase D (PKD) signalling axis as a novel therapeutic target in ovarian cancer. Biochim. Biophys. Acta Rev. Cancer 2021 1875 1 188496 10.1016/j.bbcan.2020.188496 33383102
    [Google Scholar]
  80. Jubaidi F.F. Zainalabidin S. Taib I.S. The role of PKC-MAPK signalling pathways in the development of hyperglycemia-induced cardiovascular complications. Int. J. Mol. Sci. 2022 23 15 8582 10.3390/ijms23158582 35955714
    [Google Scholar]
  81. Grados M. Salehi M. Lotfi A. Dua S. Xie I. A selective review of inhibitors of protein kinase C gamma: A neuroplasticity-related common pathway for psychiatric illness. Front. Drug Deliv. 2024 4 3 1364037 10.3389/fddev.2024.1364037 40836982
    [Google Scholar]
  82. Cassidy L. Fernandez F. Johnson J.B. Naiker M. Owoola A.G. Broszczak D.A. Oxidative stress in alzheimer’s disease: A review on emergent natural polyphenolic therapeutics. Complement. Ther. Med. 2020 49 102294 10.1016/j.ctim.2019.102294 32147039
    [Google Scholar]
  83. Singh N. Nandy S.K. Jyoti A. Protein Kinase C (PKC) in neurological health: Implications for alzheimer’s disease and chronic alcohol consumption. Brain Sci. 2024 14 6 554 10.3390/brainsci14060554 38928554
    [Google Scholar]
  84. Ramakrishna K. Nalla L.V. Naresh D. WNT-β catenin signaling as a potential therapeutic target for neurodegenerative diseases: Current status and future perspective. Diseases 2023 11 3 89 10.3390/diseases11030089 37489441
    [Google Scholar]
  85. Perluigi M. Di Domenico F. Butterfield D.A. Oxidative damage in neurodegeneration: Roles in the pathogenesis and progression of Alzheimer disease. Physiol. Rev. 2024 104 1 103 197 10.1152/physrev.00030.2022 37843394
    [Google Scholar]
  86. Lu W. Tang S. Li A. The role of PKC/PKR in aging, Alzheimer’s disease, and perioperative neurocognitive disorders. Front. Aging Neurosci. 2022 14 4 973068 10.3389/fnagi.2022.973068 36172481
    [Google Scholar]
  87. Chen Y. Yu Y. Tau and neuroinflammation in Alzheimer’s disease: Interplay mechanisms and clinical translation. J. Neuroinflammation 2023 20 1 165 10.1186/s12974‑023‑02853‑3 37452321
    [Google Scholar]
  88. Martínez-Hernández M.I. Acosta-Saavedra L.C. Hernández-Kelly L.C. Loaeza-Loaeza J. Ortega A. Microglial activation in metal neurotoxicity: Impact in neurodegenerative diseases. BioMed Res. Int. 2023 2023 1 7389508 10.1155/2023/7389508 36760476
    [Google Scholar]
  89. Morgan D. Berggren K.L. Spiess C.D. Mitogen‐activated protein kinase‐activated protein kinase‐2 (MK2) and its role in cell survival, inflammatory signaling, and migration in promoting cancer. Mol. Carcinog. 2022 61 2 173 199 10.1002/mc.23348 34559922
    [Google Scholar]
  90. Ganguly P. Macleod T. Wong C. Harland M. McGonagle D. Revisiting p38 Mitogen-Activated Protein Kinases (MAPK) in inflammatory arthritis: A narrative of the emergence of MAPK-activated protein Kinase Inhibitors (MK2i). Pharmaceuticals (Basel) 2023 16 9 1286 10.3390/ph16091286 37765094
    [Google Scholar]
  91. Germann U.A. Alam J.J. P38α MAPK signaling - A robust therapeutic target for Rab5-mediated neurodegenerative disease. Int. J. Mol. Sci. 2020 21 15 5485 10.3390/ijms21155485 32751991
    [Google Scholar]
  92. Hosseini A. Sheibani M. Valipour M. Exploring the therapeutic potential of BBB‐penetrating phytochemicals with p38 MAPK modulatory activity in addressing oxidative stress‐induced neurodegenerative disorders, with a focus on alzheimer’s disease. Phytother. Res. 2024 38 12 5598 5625 10.1002/ptr.8329 39300812
    [Google Scholar]
  93. Kanungo J. DNA-PK and P38 MAPK: A kinase collusion in alzheimer’s disease? Brain Disord. Ther. 2017 6 2 232 10.4172/2168‑975X.1000232 28706768
    [Google Scholar]
  94. D’Mello S.R. When good kinases go rogue: GSK3, p38 MAPK and CDKs as therapeutic targets for alzheimer’s and huntington’s disease. Int. J. Mol. Sci. 2021 22 11 5911 10.3390/ijms22115911 34072862
    [Google Scholar]
  95. Hugon J. Paquet C. The PKR/P38/RIPK1 signaling pathway as a therapeutic target in alzheimer’s disease. Int. J. Mol. Sci. 2021 22 6 3136 10.3390/ijms22063136 33808629
    [Google Scholar]
  96. Falcicchia C. Tozzi F. Arancio O. Watterson D.M. Origlia N. Involvement of p38 MAPK in synaptic function and dysfunction. Int. J. Mol. Sci. 2020 21 16 5624 10.3390/ijms21165624 32781522
    [Google Scholar]
  97. Kheiri G. Dolatshahi M. Rahmani F. Rezaei N. Role of p38/MAPKs in Alzheimer’s disease: Implications for amyloid beta toxicity targeted therapy. Rev. Neurosci. 2018 30 1 9 30 10.1515/revneuro‑2018‑0008 29804103
    [Google Scholar]
  98. Margiotta A. All good things must end: Termination of receptor tyrosine kinase signal. Int. J. Mol. Sci. 2021 22 12 6342 10.3390/ijms22126342 34198477
    [Google Scholar]
  99. Cuesta C. Arévalo-Alameda C. Castellano E. The importance of being PI3K in the RAS signaling network. Genes (Basel) 2021 12 7 1094 10.3390/genes12071094 34356110
    [Google Scholar]
  100. Long H.Z. Cheng Y. Zhou Z.W. Luo H.Y. Wen D.D. Gao L.C. PI3K/AKT signal pathway: A target of natural products in the prevention and treatment of alzheimer’s disease and parkinson’s disease. Front. Pharmacol. 2021 12 648636 10.3389/fphar.2021.648636 33935751
    [Google Scholar]
  101. Uko N.E. Güner O.F. Matesic D.F. Bowen J.P. Akt pathway inhibitors. Curr. Top. Med. Chem. 2020 20 10 883 900 10.2174/1568026620666200224101808 32091335
    [Google Scholar]
  102. Wei Y. Zhou J. Yu H. Jin X. AKT phosphorylation sites of Ser473 and Thr308 regulate AKT degradation. Biosci. Biotechnol. Biochem. 2019 83 3 429 435 10.1080/09168451.2018.1549974 30488766
    [Google Scholar]
  103. Ballesteros-Álvarez J. Andersen J.K. mTORC2: The other mTOR in autophagy regulation. Aging Cell 2021 20 8 e13431 10.1111/acel.13431 34250734
    [Google Scholar]
  104. Jhaveri K. Modi S. Ganetespib: Research and clinical development. OncoTargets Ther. 2015 8 1849 1858 26244021
    [Google Scholar]
  105. Sharma V.K. Singh T.G. Singh S. Garg N. Dhiman S. Apoptotic pathways and alzheimer’s disease: Probing therapeutic potential. Neurochem. Res. 2021 46 12 3103 3122 10.1007/s11064‑021‑03418‑7 34386919
    [Google Scholar]
  106. Kumari S. Dhapola R. Reddy D.H. Apoptosis in Alzheimer’s disease: Insight into the signaling pathways and therapeutic avenues. Apoptosis 2023 28 7-8 943 957 10.1007/s10495‑023‑01848‑y 37186274
    [Google Scholar]
  107. Matsuda S. Nakagawa Y. Tsuji A. Kitagishi Y. Nakanishi A. Murai T. Implications of PI3K/AKT/PTEN signaling on superoxide dismutases expression and in the pathogenesis of alzheimer’s disease. Diseases 2018 6 2 28 10.3390/diseases6020028 29677102
    [Google Scholar]
  108. Mani R. sha Sulthana A, Muthusamy G, Elangovan N. Progress in the development of naturally derived active metabolites‐based drugs: Potential therapeutics for Alzheimer’s disease. Biotechnol. Appl. Biochem. 2022 69 6 2713 2732 10.1002/bab.2317 35067971
    [Google Scholar]
  109. Suzen S. Tucci P. Profumo E. Buttari B. Saso L. A pivotal role of nrf2 in neurodegenerative disorders: A new way for therapeutic strategies. Pharmaceuticals 2022 15 6 692 10.3390/ph15060692 35745610
    [Google Scholar]
  110. Kopacz A. Kloska D. Forman H.J. Jozkowicz A. Grochot-Przeczek A. Beyond repression of Nrf2: An update on Keap1. Free Radic. Biol. Med. 2020 157 63 74 10.1016/j.freeradbiomed.2020.03.023 32234331
    [Google Scholar]
  111. Xiao J.L. Liu H.Y. Sun C.C. Tang C.F. Regulation of Keap1-Nrf2 signaling in health and diseases. Mol. Biol. Rep. 2024 51 1 809 10.1007/s11033‑024‑09771‑4 39001962
    [Google Scholar]
  112. He F. Ru X. Wen T. NRF2, a transcription factor for stress response and beyond. Int. J. Mol. Sci. 2020 21 13 4777 10.3390/ijms21134777 32640524
    [Google Scholar]
  113. Zgorzynska E. Dziedzic B. Walczewska A. An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases. Int. J. Mol. Sci. 2021 22 17 9592 10.3390/ijms22179592 34502501
    [Google Scholar]
  114. Buendia I. Michalska P. Navarro E. Gameiro I. Egea J. León R. Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol. Ther. 2016 157 84 104 10.1016/j.pharmthera.2015.11.003 26617217
    [Google Scholar]
  115. Shomali A. Das S. Arif N. Diverse physiological roles of flavonoids in plant environmental stress responses and tolerance. Plants 2022 11 22 3158 10.3390/plants11223158 36432887
    [Google Scholar]
  116. Liu W. Feng Y. Yu S. The flavonoid biosynthesis network in plants. Int. J. Mol. Sci. 2021 22 23 12824 10.3390/ijms222312824 34884627
    [Google Scholar]
  117. Dai M. Kang X. Wang Y. Functional characterization of Flavanone 3-Hydroxylase (F3H) and its role in anthocyanin and flavonoid biosynthesis in mulberry. Molecules 2022 27 10 3341 10.3390/molecules27103341 35630816
    [Google Scholar]
  118. Hill E. Goodwill A.M. Gorelik A. Szoeke C. Diet and biomarkers of Alzheimer’s disease: A systematic review and meta-analysis. Neurobiol. Aging 2019 76 45 52 10.1016/j.neurobiolaging.2018.12.008 30682676
    [Google Scholar]
  119. Mahalakshmi B. Maurya N. Lee S.D. Bharath Kumar V. Possible neuroprotective mechanisms of physical exercise in neurodegeneration. Int. J. Mol. Sci. 2020 21 16 5895 10.3390/ijms21165895 32824367
    [Google Scholar]
  120. Chen S. Wang X. Cheng Y. Gao H. Chen X. A review of classification, biosynthesis, biological activities and potential applications of flavonoids. Molecules 2023 28 13 4982 10.3390/molecules28134982 37446644
    [Google Scholar]
  121. Mohamed Yusof N.I.S. Abdullah Z.L. Othman N. Mohd Fauzi F. Structure–activity relationship analysis of flavonoids and its inhibitory activity against BACE1 enzyme toward a better therapy for alzheimer’s disease. Front Chem. 2022 10 1 874615 10.3389/fchem.2022.874615 35832462
    [Google Scholar]
  122. Shen N. Wang T. Gan Q. Liu S. Wang L. Jin B. Plant flavonoids: Classification, distribution, biosynthesis, and antioxidant activity. Food Chem. 2022 383 132531 10.1016/j.foodchem.2022.132531 35413752
    [Google Scholar]
  123. Singh S. Ahuja A. Sharma H. Maheshwari P. An overview of dietary flavonoids as a nutraceutical nanoformulation approach to life-threatening diseases. Curr. Pharm. Biotechnol. 2023 24 14 1740 1773 10.2174/1389201024666230314101654 36918792
    [Google Scholar]
  124. Ravula A.R. Teegala S.B. Kalakotla S. Pasangulapati J.P. Perumal V. Boyina H.K. Fisetin, potential flavonoid with multifarious targets for treating neurological disorders: An updated review. Eur. J. Pharmacol. 2021 910 174492 10.1016/j.ejphar.2021.174492 34516952
    [Google Scholar]
  125. Kopalli S.R. Behl T. Kyada A. Synaptic plasticity and neuroprotection: The molecular impact of flavonoids on neurodegenerative disease progression. Neuroscience 2025 569 161 183 10.1016/j.neuroscience.2025.02.007 39922366
    [Google Scholar]
  126. Houldsworth A. Role of oxidative stress in neurodegenerative disorders: A review of reactive oxygen species and prevention by antioxidants. Brain Commun. 2023 6 1 fcad356 10.1093/braincomms/fcad356 38214013
    [Google Scholar]
  127. Wang K. Wen Y. Fu X. Wei S. Liu S. Chen M. mtDNA regulates cGAS-STING signaling pathway in adenomyosis. Free Radic. Biol. Med. 2024 216 80 88 10.1016/j.freeradbiomed.2024.03.012 38494142
    [Google Scholar]
  128. Kruszka J. Martyński J. Szewczyk-Golec K. Woźniak A. Nuszkiewicz J. The role of selected flavonoids in modulating neuroinflammation in alzheimer’s disease: Mechanisms and therapeutic potential. Brain Sci. 2025 15 5 485 10.3390/brainsci15050485 40426656
    [Google Scholar]
  129. Subedi L. Lee S.E. Madiha S. Phytochemicals against TNFα-Mediated Neuroinflammatory Diseases. Int. J. Mol. Sci. 2020 21 3 764 10.3390/ijms21030764 31991572
    [Google Scholar]
  130. Numakawa T. Odaka H. Brain-derived neurotrophic factor signaling in the pathophysiology of alzheimer’s disease: Beneficial effects of flavonoids for neuroprotection. Int. J. Mol. Sci. 2021 22 11 5719 10.3390/ijms22115719 34071978
    [Google Scholar]
  131. Huang Q. Wu W. Wen Y. Lu S. Zhao C. Potential therapeutic natural compounds for the treatment of Alzheimer’s disease. Phytomedicine 2024 132 155822 10.1016/j.phymed.2024.155822 38909512
    [Google Scholar]
  132. Ahmad H.A. Wahab F. Ullah M. Khan M.I. Exploring the therapeutic power of flavonoids on chronic disease: Unraveling the mechanisms of action especially by following MAPKs/NF‐KB signaling pathways. In: Role of Flavonoids in Chronic Metabolic Diseases: From Bench to Clinic. Wiley 2024 1 49 10.1002/9781394238071.ch1
    [Google Scholar]
  133. Bellavite P. Neuroprotective potentials of flavonoids: Experimental studies and mechanisms of action. Antioxidants 2023 12 2 280 10.3390/antiox12020280 36829840
    [Google Scholar]
  134. Uddin M.S. Kabir M.T. Niaz K. Molecular insight into the therapeutic promise of flavonoids against alzheimer’s disease. Molecules 2020 25 6 1267 10.3390/molecules25061267 32168835
    [Google Scholar]
  135. Zughaibi T.A. Suhail M. Tarique M. Tabrez S. Targeting PI3K/Akt/mTOR pathway by different flavonoids: A cancer chemopreventive approach. Int. J. Mol. Sci. 2021 22 22 12455 10.3390/ijms222212455 34830339
    [Google Scholar]
  136. Roy T. Boateng S.T. Uddin M.B. The PI3K-Akt-mTOR and associated signaling pathways as molecular drivers of immune-mediated inflammatory skin diseases: Update on therapeutic strategy using natural and synthetic compounds. Cells 2023 12 12 1671 10.3390/cells12121671 37371141
    [Google Scholar]
  137. Goya-Jorge E. Jorge Rodríguez M.E. Veitía M.S.I. Giner R.M. Plant occurring flavonoids as modulators of the aryl hydrocarbon receptor. Molecules 2021 26 8 2315 10.3390/molecules26082315 33923487
    [Google Scholar]
  138. Hole K.L. Williams R.J. Flavonoids as an intervention for alzheimer’s disease: Progress and hurdles towards defining a mechanism of action. Brain Plast. 2020 6 2 167 192 10.3233/BPL‑200098 33782649
    [Google Scholar]
  139. Ferrer I. Andrés-Benito P. Ausín K. Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer’s disease. Brain Pathol. 2021 31 6 e12996 10.1111/bpa.12996 34218486
    [Google Scholar]
  140. Almatroodi S.A. Alsahli M.A. Almatroudi A. Potential therapeutic targets of quercetin, a plant flavonol, and its role in the therapy of various types of cancer through the modulation of various cell signaling pathways. Molecules 2021 26 5 1315 10.3390/molecules26051315 33804548
    [Google Scholar]
  141. Rossi G. Woods F.M. Leisner C.P. Quantification of total phenolic, anthocyanin, and flavonoid content in a diverse panel of blueberry cultivars and ecotypes. HortScience 2022 57 8 901 909 10.21273/HORTSCI16647‑22
    [Google Scholar]
  142. Azargoonjahromi A. Abutalebian F. Hoseinpour F. The role of resveratrol in neurogenesis: A systematic review. Nutr. Rev. 2025 83 2 e257 e272 10.1093/nutrit/nuae025 38511504
    [Google Scholar]
  143. Park J.I. MAPK-ERK pathway. Int. J. Mol. Sci. 2023 24 11 9666 10.3390/ijms24119666 37298618
    [Google Scholar]
  144. Proença C. Freitas M. Ribeiro D. Rufino A.T. Fernandes E. Ferreira de Oliveira J.M.P. The role of flavonoids in the regulation of epithelial‐mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis. Med. Res. Rev. 2023 43 6 1878 1945 10.1002/med.21966 37147865
    [Google Scholar]
  145. Grabska-Kobyłecka I. Szpakowski P. Król A. Polyphenols and their impact on the prevention of neurodegenerative diseases and development. Nutrients 2023 15 15 3454 10.3390/nu15153454 37571391
    [Google Scholar]
  146. Zhang Q. Liu M. Nong H. Total flavonoids of hawthorn leaves protect spinal motor neurons via promotion of autophagy after spinal cord injury. Front. Pharmacol. 2022 13 5 925568 10.3389/fphar.2022.925568 36071834
    [Google Scholar]
  147. Zhang H.W. Hu J.J. Fu R.Q. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells. Sci. Rep. 2018 8 1 11255 10.1038/s41598‑018‑29308‑7 30050147
    [Google Scholar]
  148. Yu J.S.L. Cui W. Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016 143 17 3050 3060 10.1242/dev.137075 27578176
    [Google Scholar]
  149. Chen L. Ou S. Zhou L. Tang H. Xu J. Guo K. Formononetin attenuates Aβ25-35-induced cytotoxicity in HT22 cells via PI3K/Akt signaling and non-amyloidogenic cleavage of APP. Neurosci. Lett. 2017 639 36 42 10.1016/j.neulet.2016.12.064 28034780
    [Google Scholar]
  150. Uddin M.S. Kabir M.T. Emerging signal regulating potential of genistein against alzheimer’s disease: A promising molecule of interest. Front. Cell Dev. Biol. 2019 7 197 10.3389/fcell.2019.00197 31620438
    [Google Scholar]
  151. Demuro S. Di Martino R.M.C. Ortega J.A. Cavalli A. GSK-3β, FYN, and DYRK1A: Master regulators in neurodegenerative pathways. Int. J. Mol. Sci. 2021 22 16 9098 10.3390/ijms22169098 34445804
    [Google Scholar]
  152. Guo J. Yang G. He Y. Involvement of α7nAChR in the protective effects of genistein against β-amyloid-induced oxidative stress in neurons via a PI3K/Akt/Nrf2 pathway-related mechanism. Cell. Mol. Neurobiol. 2021 41 2 377 393 10.1007/s10571‑020‑01009‑8 33215356
    [Google Scholar]
  153. Yi S. Chen S. Xiang J. Genistein exerts a cell-protective effect via Nrf2/HO-1//PI3K signaling in Ab25-35-induced Alzheimer’s disease models in vitro. Folia Histochem. Cytobiol. 2021 59 1 49 56 10.5603/FHC.a2021.0006 33605427
    [Google Scholar]
  154. Shirvanian K. Vali R. Farkhondeh T. Abderam A. Aschner M. Samarghandian S. Genistein effects on various human disorders mediated via Nrf2 signaling. Curr. Mol. Med. 2024 24 1 40 50 10.2174/1566524023666221128162753 36443970
    [Google Scholar]
  155. Baek H. Sanjay, Park M, Lee HJ. Cyanidin-3-O-glucoside protects the brain and improves cognitive function in APPswe/PS1ΔE9 transgenic mice model. J. Neuroinflammation 2023 20 1 268 10.1186/s12974‑023‑02950‑3 37978414
    [Google Scholar]
  156. Al-Ghamdi N.A.M. Virk P. Hendi A. Awad M. Elobeid M. Antioxidant potential of bulk and nanoparticles of naringenin against cadmium-induced oxidative stress in Nile tilapia, Oreochromis niloticus. Green Process Synth 2021 10 1 392 402 10.1515/gps‑2021‑0037
    [Google Scholar]
  157. Zhang N. Hu Z. Zhang Z. Protective role of naringenin against Aβ25-35-caused damage via ER and PI3K/Akt-mediated pathways. Cell. Mol. Neurobiol. 2018 38 2 549 557 10.1007/s10571‑017‑0519‑8 28699113
    [Google Scholar]
  158. He P. Yan S. Zheng J. Eriodictyol attenuates LPS-induced neuroinflammation, amyloidogenesis, and cognitive impairments via the inhibition of NF-κB in male C57BL/6J mice and BV2 microglial cells. J. Agric. Food Chem. 2018 66 39 10205 10214 10.1021/acs.jafc.8b03731 30208700
    [Google Scholar]
  159. Zubčić K. Radovanović V. Vlainić J. PI3K/Akt and ERK1/2 signalling are involved in quercetin-mediated neuroprotection against copper-induced injury. Oxid. Med. Cell. Longev. 2020 2020 1 14 10.1155/2020/9834742 32733640
    [Google Scholar]
  160. Cui Z. Zhao X. Amevor F.K. Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism. Front. Immunol. 2022 13 943321 10.3389/fimmu.2022.943321 35935939
    [Google Scholar]
  161. Zhang T. Wei W. Chang S. Liu N. Li H. Integrated network pharmacology and comprehensive bioinformatics identifying the mechanisms and molecular targets of yizhiqingxin formula for treatment of comorbidity with alzheimer’s disease and depression. Front. Pharmacol. 2022 13 853375 10.3389/fphar.2022.853375 35548356
    [Google Scholar]
  162. Jiang W. Luo T. Li S. Quercetin protects against okadaic acid-induced injury via MAPK and PI3K/Akt/GSK3β signaling pathways in HT22 hippocampal neurons. In: PLOS One. 2016 11 4 e0152371 10.1371/journal.pone.0152371
    [Google Scholar]
  163. Li Y.R. Li G.H. Zhou M.X. Discovery of natural flavonoids as activators of Nrf2-mediated defense system: Structure-activity relationship and inhibition of intracellular oxidative insults. Bioorg. Med. Chem. 2018 26 18 5140 5150 10.1016/j.bmc.2018.09.010 30227999
    [Google Scholar]
  164. Li B. Du P. Du Y. Luteolin alleviates inflammation and modulates gut microbiota in ulcerative colitis rats. Life Sci. 2021 269 119008 10.1016/j.lfs.2020.119008 33434535
    [Google Scholar]
  165. Wruck C.J. Claussen M. Fuhrmann G. Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. J. Neural Transm. Suppl. 2007 72 57 67 17982879
    [Google Scholar]
  166. Malar D.S. Suryanarayanan V. Prasanth M.I. Singh S.K. Balamurugan K. Devi K.P. Vitexin inhibits Aβ25-35 induced toxicity in Neuro-2a cells by augmenting Nrf-2/HO-1 dependent antioxidant pathway and regulating lipid homeostasis by the activation of LXR-α. Toxicol. In Vitro 2018 50 160 171 10.1016/j.tiv.2018.03.003 29545167
    [Google Scholar]
  167. Fei H.X. Zhang Y.B. Liu T. Zhang X.J. Wu S.L. Neuroprotective effect of formononetin in ameliorating learning and memory impairment in mouse model of Alzheimer’s disease. Biosci. Biotechnol. Biochem. 2018 82 1 57 64 10.1080/09168451.2017.1399788 29191087
    [Google Scholar]
  168. Fan M. Li Z. Hu M. Formononetin attenuates Aβ25-35-induced adhesion molecules in HBMECs via Nrf2 activation. Brain Res. Bull. 2022 183 162 171 10.1016/j.brainresbull.2022.03.009 35304289
    [Google Scholar]
  169. Li J. Wang T. Liu P. Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD. Food Funct. 2021 12 9 3898 3918 10.1039/D0FO02736G 33977953
    [Google Scholar]
  170. Li L. Li W.J. Zheng X.R. Eriodictyol ameliorates cognitive dysfunction in APP/PS1 mice by inhibiting ferroptosis via vitamin D receptor-mediated Nrf2 activation. Mol. Med. 2022 28 1 11 10.1186/s10020‑022‑00442‑3 35093024
    [Google Scholar]
  171. Yu X. Li Y. Mu X. Effect of quercetin on PC12 alzheimer’s disease cell model induced by A β25-35 and its mechanism based on Sirtuin1/Nrf2/HO‐1 pathway. BioMed Res. Int. 2020 2020 1 8210578 10.1155/2020/8210578 32420373
    [Google Scholar]
  172. Feng Y. Yu X. Han J. Quercetin regulates the polarization of microglia through the NRF2/HO1 pathway and mitigates alzheimer’s disease. Actas Esp. Psiquiatr. 2024 52 6 786 799 10.62641/aep.v52i6.1713 39665609
    [Google Scholar]
  173. Inthachat W. Chantong B. Pitchakarn P. Enhancing therapeutic efficacy of donepezil, an alzheimer’s disease drug, by Diplazium esculentum (Retz.) Sw. and its phytochemicals. Pharmaceuticals 2024 17 3 341 10.3390/ph17030341 38543127
    [Google Scholar]
  174. Pattanashetti L. Taranalli A. Parvatrao V. Malabade R. Kumar D. Evaluation of neuroprotective effect of quercetin with donepezil in scopolamine-induced amnesia in rats. Indian J. Pharmacol. 2017 49 1 60 64 10.4103/0253‑7613.201016 28458424
    [Google Scholar]
  175. Cornelli U. Treatment of Alzheimer’s disease with a cholinesterase inhibitor combined with antioxidants. Neurodegener. Dis. 2010 7 1-3 193 202 10.1159/000295663 20224285
    [Google Scholar]
  176. Pham D.C. Shibu M.A. Mahalakshmi B. Velmurugan B.K. Effects of phytochemicals on cellular signaling: Reviewing their recent usage approaches. Crit. Rev. Food Sci. Nutr. 2020 60 20 3522 3546 10.1080/10408398.2019.1699014 31822111
    [Google Scholar]
  177. Liu S. Jin X. Ge Y. Advances in brain-targeted delivery strategies and natural product-mediated enhancement of blood–brain barrier permeability. J. Nanobiotechnology 2025 23 1 382 10.1186/s12951‑025‑03415‑w 40420216
    [Google Scholar]
  178. Daraban B.S. Popa A.S. Stan M.S. Latest perspectives on alzheimer’s disease treatment: The role of blood-brain barrier and antioxidant-based drug delivery systems. Molecules 2024 29 17 4056 10.3390/molecules29174056 39274904
    [Google Scholar]
  179. Chen L. Cao H. Huang Q. Xiao J. Teng H. Absorption, metabolism and bioavailability of flavonoids: A review. Crit. Rev. Food Sci. Nutr. 2022 62 28 7730 7742 10.1080/10408398.2021.1917508 34078189
    [Google Scholar]
  180. Bajracharya R. Caruso A.C. Vella L.J. Nisbet R.M. Current and emerging strategies for enhancing antibody delivery to the brain. Pharmaceutics 2021 13 12 2014 10.3390/pharmaceutics13122014 34959296
    [Google Scholar]
  181. Knorz A.L. Quante A. Alzheimer’s disease: Efficacy of mono- and combination therapy. a systematic review. J. Geriatr. Psychiatry Neurol. 2022 35 4 475 486 10.1177/08919887211044746 34476990
    [Google Scholar]
  182. Hostetler G.L. Ralston R.A. Schwartz S.J. Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr. 2017 8 3 423 435 10.3945/an.116.012948 28507008
    [Google Scholar]
  183. Křížová L. Dadáková K. Kašparovská J. Kašparovský T. Isoflavones. Molecules 2019 24 6 1076 10.3390/molecules24061076 30893792
    [Google Scholar]
  184. Chanet A. Milenkovic D. Manach C. Mazur A. Morand C. Citrus flavanones: What is their role in cardiovascular protection? J. Agric. Food Chem. 2012 60 36 8809 8822 10.1021/jf300669s 22574825
    [Google Scholar]
  185. Luo Y. Jian Y. Liu Y. Jiang S. Muhammad D. Wang W. Flavanols from nature: A phytochemistry and biological activity review. Molecules 2022 27 3 719 10.3390/molecules27030719 35163984
    [Google Scholar]
  186. Sinopoli A. Calogero G. Bartolotta A. Computational aspects of anthocyanidins and anthocyanins: A review. Food Chem. 2019 297 124898 10.1016/j.foodchem.2019.05.172 31253334
    [Google Scholar]
  187. Liu B. Cui D. Liu J. Shi J.S. Transcriptome analysis of the aged SAMP8 mouse model of Alzheimer’s disease reveals novel molecular targets of formononetin protection. Front. Pharmacol. 2024 15 1440515 10.3389/fphar.2024.1440515 39234102
    [Google Scholar]
  188. Jing X. Shi H. Zhu X. Eriodictyol attenuates β-amyloid 25–35 peptide-induced oxidative cell death in primary cultured neurons by activation of Nrf2. Neurochem. Res. 2015 40 7 1463 1471 10.1007/s11064‑015‑1616‑z 25994859
    [Google Scholar]
  189. Zhang X. Wu M. Lu F. Luo N. He Z.P. Yang H. Involvement of α7 nAChR signaling cascade in epigallocatechin gallate suppression of β-amyloid-induced apoptotic cortical neuronal insults. Mol. Neurobiol. 2014 49 1 66 77 10.1007/s12035‑013‑8491‑x 23807728
    [Google Scholar]
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Therapeutic Applications of Natural Flavonoids Against Alzheimer’s Disease-like Pathology: Special Focus on PI3K/Akt and Nrf2 Signaling Pathways
Bentham Science Publishers ; https://doi.org/10.2174/0115672026423088251205120807
/content/journals/cnr/10.2174/0115672026423088251205120807
/content/journals/cnr/10.2174/0115672026423088251205120807
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  • Article Type:     Review Article
Keywords: neuroinflammation ; Alzheimer’s disease ; amyloid beta (Aβ) ; flavonoid ; Nrf2 pathway ; PI3K/AKT pathway

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