NLRP3 inflammasome; Nrf2; central nervous system; dimethyl fumarate; inflammation; sulforaphane; Inflammasomes; NF-E2-Related Factor 2; NLR Family, Pyrin Domain-Containing 3 Protein; Humans; Inflammation/metabolism; NF-E2-Related Factor 2/metabolism; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Central Nervous System Diseases; Inflammasomes/metabolism; GA-Binding Protein Transcription Factor; Immunology and Allergy; Immunology
Abstract :
[en] The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.
Precision for document type :
Review article
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
TASTAN, Bora ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuroinflammation Group ; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
Arioz, Burak I; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
Genc, Sermin; Genc Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey ; Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey
External co-authors :
yes
Language :
English
Title :
Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders.
Yang QQ Zhou JW. Neuroinflammation in the Central Nervous System: Symphony of Glial Cells. Glia (2019) 67:1017–35. doi: 10.1002/glia.23571
Ransohoff RM Brown MA. Innate Immunity in the Central Nervous System. J Clin Invest (2012) 122:1164–71. doi: 10.1172/JCI58644
Liston A Masters SL. Homeostasis-Altering Molecular Processes as Mechanisms of Inflammasome Activation. Nat Rev Immunol (2017) 17:208–14. doi: 10.1038/nri.2016.151
Walsh JG Muruve DA Power C. Inflammasomes in the CNS. Nat Rev Neurosci (2014) 15:84–97. doi: 10.1038/nrn3638
Hanamsagar R Torres V Kielian T. Inflammasome Activation and IL-1beta/IL-18 Processing are Influenced by Distinct Pathways in Microglia. J Neurochem (2011) 119:736–48. doi: 10.1111/j.1471-4159.2011.07481.x
He Y Hara H Nunez G. Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends Biochem Sci (2016) 41:1012–21. doi: 10.1016/j.tibs.2016.09.002
Kanneganti TD Body-Malapel M Amer A Park JH Whitfield J Franchi L et al. Critical Role for Cryopyrin/Nalp3 in Activation of Caspase-1 in Response to Viral Infection and Double-Stranded RNA. J Biol Chem (2006) 281:36560–8. doi: 10.1074/jbc.M607594200
Gross O Poeck H Bscheider M Dostert C Hannesschlager N Endres S et al. Syk Kinase Signalling Couples to the Nlrp3 Inflammasome for Anti-Fungal Host Defence. Nature (2009) 459:433–6. doi: 10.1038/nature07965
Areschoug T Gordon S. Pattern Recognition Receptors and Their Role in Innate Immunity: Focus on Microbial Protein Ligands. Contrib Microbiol (2008) 15:45–60. doi: 10.1159/000135685
Duncan JA Bergstralh DT Wang Y Willingham SB Ye Z Zimmermann AG et al. Cryopyrin/NALP3 Binds ATP/dATP, is an ATPase, and Requires ATP Binding to Mediate Inflammatory Signaling. Proc Natl Acad Sci U S A (2007) 104:8041–6. doi: 10.1073/pnas.0611496104
Olcum M Tastan B Ercan I Eltutan IB Genc S. Inhibitory Effects of Phytochemicals on NLRP3 Inflammasome Activation: A Review. Phytomedicine (2020) 75:153238. doi: 10.1016/j.phymed.2020.153238
Bauernfeind FG Horvath G Stutz A Alnemri ES Macdonald K Speert D et al. Cutting Edge: NF-kappaB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression. J Immunol (2009) 183:787–91. doi: 10.4049/jimmunol.0901363
Song N Liu ZS Xue W Bai ZF Wang QY Dai J et al. NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation. Mol Cell (2017) 68:185–97.e186. doi: 10.1016/j.molcel.2017.08.017
Mangan MSJ Olhava EJ Roush WR Seidel HM Glick GD Latz E. Targeting the NLRP3 Inflammasome in Inflammatory Diseases. Nat Rev Drug Discov (2018) 17:588–606. doi: 10.1038/nrd.2018.97
Liu X Zhang Z Ruan J Pan Y Magupalli VG Wu H et al. Inflammasome-Activated Gasdermin D Causes Pyroptosis by Forming Membrane Pores. Nature (2016) 535:153–8. doi: 10.1038/nature18629
Kayagaki N Warming S Lamkanfi M Vande Walle L Louie S Dong J et al. Non-Canonical Inflammasome Activation Targets Caspase-11. Nature (2011) 479:117–21. doi: 10.1038/nature10558
Vigano E Diamond CE Spreafico R Balachander A Sobota RM Mortellaro A. Human Caspase-4 and Caspase-5 Regulate the One-Step Non-Canonical Inflammasome Activation in Monocytes. Nat Commun (2015) 6:8761. doi: 10.1038/ncomms9761
Schauvliege R Vanrobaeys J Schotte P Beyaert R. Caspase-11 Gene Expression in Response to Lipopolysaccharide and Interferon-Gamma Requires Nuclear Factor-Kappa B and Signal Transducer and Activator of Transcription (STAT) 1. J Biol Chem (2002) 277:41624–30. doi: 10.1074/jbc.M207852200
Meunier E Dick MS Dreier RF Schurmann N Kenzelmann Broz D Warming S et al. Caspase-11 Activation Requires Lysis of Pathogen-Containing Vacuoles by IFN-Induced GTPases. Nature (2014) 509:366–70. doi: 10.1038/nature13157
Shi J Zhao Y Wang K Shi X Wang Y Huang H et al. Cleavage of GSDMD by Inflammatory Caspases Determines Pyroptotic Cell Death. Nature (2015) 526:660–5. doi: 10.1038/nature15514
Gaidt MM Ebert TS Chauhan D Schmidt T Schmid-Burgk JL Rapino F et al. Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity (2016) 44:833–46. doi: 10.1016/j.immuni.2016.01.012
Ge Q Chen X Zhao Y Mu H Zhang J. Modulatory Mechanisms of NLRP3: Potential Roles in Inflammasome Activation. Life Sci (2021) 267:118918. doi: 10.1016/j.lfs.2020.118918
Huai W Zhao R Song H Zhao J Zhang L Zhang L et al. Aryl Hydrocarbon Receptor Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting NLRP3 Transcription. Nat Commun (2014) 5:4738. doi: 10.1038/ncomms5738
Chen D Xiong XQ Zang YH Tong Y Zhou B Chen Q et al. BCL6 Attenuates Renal Inflammation via Negative Regulation of NLRP3 Transcription. Cell Death Dis (2017) 8:e3156. doi: 10.1038/cddis.2017.567
Ollivier V Parry GC Cobb RR De Prost D Mackman N. Elevated Cyclic AMP Inhibits NF-kappaB-Mediated Transcription in Human Monocytic Cells and Endothelial Cells. J Biol Chem (1996) 271:20828–35. doi: 10.1074/jbc.271.34.20828
Lv H Liu Q Wen Z Feng H Deng X Ci X. Xanthohumol Ameliorates Lipopolysaccharide (LPS)-Induced Acute Lung Injury via Induction of AMPK/GSK3beta-Nrf2 Signal Axis. Redox Biol (2017) 12:311–24. doi: 10.1016/j.redox.2017.03.001
Wang S Lin Y Yuan X Li F Guo L Wu B. REV-ERBalpha Integrates Colon Clock With Experimental Colitis Through Regulation of NF-Kappab/NLRP3 Axis. Nat Commun (2018) 9:4246. doi: 10.1038/s41467-018-06568-5
Gurung P Anand PK Malireddi RK Vande Walle L Van Opdenbosch N Dillon CP et al. FADD and Caspase-8 Mediate Priming and Activation of the Canonical and Noncanonical Nlrp3 Inflammasomes. J Immunol (2014) 192:1835–46. doi: 10.4049/jimmunol.1302839
Kang LL Zhang DM Ma CH Zhang JH Jia KK Liu JH et al. Cinnamaldehyde and Allopurinol Reduce Fructose-Induced Cardiac Inflammation and Fibrosis by Attenuating CD36-Mediated TLR4/6-IRAK4/1 Signaling to Suppress NLRP3 Inflammasome Activation. Sci Rep (2016) 6:27460. doi: 10.1038/srep27460
Su Q Li L Sun Y Yang H Ye Z Zhao J. Effects of the TLR4/Myd88/NF-kappaB Signaling Pathway on NLRP3 Inflammasome in Coronary Microembolization-Induced Myocardial Injury. Cell Physiol Biochem (2018) 47:1497–508. doi: 10.1159/000490866
Temiz-Resitoglu M Kucukkavruk SP Guden DS Cecen P Sari AN Tunctan B et al. Activation of mTOR/IkappaB-Alpha/NF-kappaB Pathway Contributes to LPS-Induced Hypotension and Inflammation in Rats. Eur J Pharmacol (2017) 802:7–19. doi: 10.1016/j.ejphar.2017.02.034
Cao G Jiang N Hu Y Zhang Y Wang G Yin M et al. Ruscogenin Attenuates Cerebral Ischemia-Induced Blood-Brain Barrier Dysfunction by Suppressing TXNIP/NLRP3 Inflammasome Activation and the MAPK Pathway. Int J Mol Sci (2016) 17(9):1418. doi: 10.3390/ijms17091418
Zhao W Ma L Cai C Gong X. Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK/NF-kappaB and A2aR Signaling in LPS-Induced THP-1 Macrophages. Int J Biol Sci (2019) 15:1571–81. doi: 10.7150/ijbs.34211
Zhou Y Lu M Du RH Qiao C Jiang CY Zhang KZ et al. MicroRNA-7 Targets Nod-Like Receptor Protein 3 Inflammasome to Modulate Neuroinflammation in the Pathogenesis of Parkinson's Disease. Mol Neurodegener (2016) 11:28. doi: 10.1186/s13024-016-0094-3
Li S Liang X Ma L Shen L Li T Zheng L et al. MiR-22 Sustains NLRP3 Expression and Attenuates H. Pylori-Induced Gastric Carcinogenesis. Oncogene (2018) 37:884–96. doi: 10.1038/onc.2017.381
Li D Yang H Ma J Luo S Chen S Gu Q. MicroRNA-30e Regulates Neuroinflammation in MPTP Model of Parkinson's Disease by Targeting Nlrp3. Hum Cell (2018) 31:106–15. doi: 10.1007/s13577-017-0187-5
Xiao L Jiang L Hu Q Li Y. MicroRNA-133b Ameliorates Allergic Inflammation and Symptom in Murine Model of Allergic Rhinitis by Targeting Nlrp3. Cell Physiol Biochem (2017) 42:901–12. doi: 10.1159/000478645
Long FQ Kou CX Li K Wu J Wang QQ. MiR-223-3p Inhibits Rtp17-Induced Inflammasome Activation and Pyroptosis by Targeting NLRP3. J Cell Mol Med (2020) 24:14405–14. doi: 10.1111/jcmm.16061
Zhang P Cao L Zhou R Yang X Wu M. The lncRNA Neat1 Promotes Activation of Inflammasomes in Macrophages. Nat Commun (2019) 10:1495. doi: 10.1038/s41467-019-09482-6
Meng J Ding T Chen Y Long T Xu Q Lian W et al. LncRNA-Meg3 Promotes Nlrp3-Mediated Microglial Inflammation by Targeting miR-7a-5p. Int Immunopharmacol (2021) 90:107141. doi: 10.1016/j.intimp.2020.107141
Zhang Q Huang XM Liao JX Dong YK Zhu JL He CC et al. LncRNA HOTAIR Promotes Neuronal Damage Through Facilitating NLRP3 Mediated-Pyroptosis Activation in Parkinson's Disease via Regulation of miR-326/ELAVL1 Axis. Cell Mol Neurobiol (2021) 41:1773–86. doi: 10.1007/s10571-020-00946-8
Du P Wang J Han Y Feng J. Blocking the LncRNA MALAT1/miR-224-5p/NLRP3 Axis Inhibits the Hippocampal Inflammatory Response in T2DM With OSA. Front Cell Neurosci (2020) 14:97. doi: 10.3389/fncel.2020.00097
Luo D Dai W Feng X Ding C Shao Q Xiao R et al. Suppression of lncRNA NLRP3 Inhibits NLRP3-Triggered Inflammatory Responses in Early Acute Lung Injury. Cell Death Dis (2021) 12:898. doi: 10.1038/s41419-021-04180-y
Ma M Pei Y Wang X Feng J Zhang Y Gao MQ. LncRNA XIST Mediates Bovine Mammary Epithelial Cell Inflammatory Response via NF-Kappab/NLRP3 Inflammasome Pathway. Cell Prolif (2019) 52:e12525. doi: 10.1111/cpr.12525
Xu Y Fang H Xu Q Xu C Yang L Huang C. LncRNA GAS5 Inhibits NLRP3 Inflammasome Activation-Mediated Pyroptosis in Diabetic Cardiomyopathy by Targeting miR-34b-3p/AHR. Cell Cycle (2020) 19:3054–65. doi: 10.1080/15384101.2020.1831245
Chen Z He M Chen J Li C Zhang Q. Long non-Coding RNA SNHG7 Inhibits NLRP3-Dependent Pyroptosis by Targeting the miR-34a/SIRT1 Axis in Liver Cancer. Oncol Lett (2020) 20:893–901. doi: 10.3892/ol.2020.11635
Py BF Kim MS Vakifahmetoglu-Norberg H Yuan J. Deubiquitination of NLRP3 by BRCC3 Critically Regulates Inflammasome Activity. Mol Cell (2013) 49:331–8. doi: 10.1016/j.molcel.2012.11.009
Kawashima A Karasawa T Tago K Kimura H Kamata R Usui-Kawanishi F et al. ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages. J Immunol (2017) 199:3614–22. doi: 10.4049/jimmunol.1700184
Wan P Zhang Q Liu W Jia Y Ai S Wang T et al. Cullin1 Binds and Promotes NLRP3 Ubiquitination to Repress Systematic Inflammasome Activation. FASEB J (2019) 33:5793–807. doi: 10.1096/fj.201801681R
Han S Lear TB Jerome JA Rajbhandari S Snavely CA Gulick DL et al. Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase. J Biol Chem (2015) 290:18124–33. doi: 10.1074/jbc.M115.645549
Song H Liu B Huai W Yu Z Wang W Zhao J et al. The E3 Ubiquitin Ligase TRIM31 Attenuates NLRP3 Inflammasome Activation by Promoting Proteasomal Degradation of NLRP3. Nat Commun (2016) 7:13727. doi: 10.1038/ncomms13727
Spalinger MR Kasper S Gottier C Lang S Atrott K Vavricka SR et al. NLRP3 Tyrosine Phosphorylation is Controlled by Protein Tyrosine Phosphatase PTPN22. J Clin Invest (2016) 126:1783–800. doi: 10.1172/JCI83669
Stutz A Kolbe CC Stahl R Horvath GL Franklin BS Van Ray O et al. NLRP3 Inflammasome Assembly is Regulated by Phosphorylation of the Pyrin Domain. J Exp Med (2017) 214:1725–36. doi: 10.1084/jem.20160933
Shao L Liu Y Wang W Li A Wan P Liu W et al. SUMO1 SUMOylates and SENP3 Desumoylates NLRP3 to Orchestrate the Inflammasome Activation. FASEB J (2020) 34:1497–515. doi: 10.1096/fj.201901653R
Heneka MT Kummer MP Stutz A Delekate A Schwartz S Vieira-Saecker A et al. NLRP3 is Activated in Alzheimer's Disease and Contributes to Pathology in APP/PS1 Mice. Nature (2013) 493:674–8. doi: 10.1038/nature11729
Codolo G Plotegher N Pozzobon T Brucale M Tessari I Bubacco L et al. Triggering of Inflammasome by Aggregated Alpha-Synuclein, an Inflammatory Response in Synucleinopathies. PloS One (2013) 8:e55375. doi: 10.1371/journal.pone.0055375
Meissner F Molawi K Zychlinsky A. Mutant Superoxide Dismutase 1-Induced IL-1beta Accelerates ALS Pathogenesis. Proc Natl Acad Sci U S A (2010) 107:13046–50. doi: 10.1073/pnas.1002396107
Gris D Ye Z Iocca HA Wen H Craven RR Gris P et al. NLRP3 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis by Mediating Th1 and Th17 Responses. J Immunol (2010) 185:974–81. doi: 10.4049/jimmunol.0904145
Bhattacharya A Jones DNC. Emerging Role of the P2X7-NLRP3-IL1beta Pathway in Mood Disorders. Psychoneuroendocrinology (2018) 98:95–100. doi: 10.1016/j.psyneuen.2018.08.015
Mortezaee K Khanlarkhani N Beyer C Zendedel A. Inflammasome: Its Role in Traumatic Brain and Spinal Cord Injury. J Cell Physiol (2018) 233:5160–9. doi: 10.1002/jcp.26287
Stancu IC Cremers N Vanrusselt H Couturier J Vanoosthuyse A Kessels S et al. Aggregated Tau Activates NLRP3-ASC Inflammasome Exacerbating Exogenously Seeded and non-Exogenously Seeded Tau Pathology In Vivo. Acta Neuropathol (2019) 137:599–617. doi: 10.1007/s00401-018-01957-y
Friker LL Scheiblich H Hochheiser IV Brinkschulte R Riedel D Latz E et al. Beta-Amyloid Clustering Around ASC Fibrils Boosts Its Toxicity in Microglia. Cell Rep (2020) 30:3743–54.e3746. doi: 10.1016/j.celrep.2020.02.025
Li L Ismael S Nasoohi S Sakata K Liao FF Mcdonald MP et al. Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain. J Alzheimers Dis (2019) 68:255–65. doi: 10.3233/JAD-180814
Sarkar S Malovic E Harishchandra DS Ghaisas S Panicker N Charli A et al. Mitochondrial Impairment in Microglia Amplifies NLRP3 Inflammasome Proinflammatory Signaling in Cell Culture and Animal Models of Parkinson's Disease. NPJ Parkinsons Dis (2017) 3:30. doi: 10.1038/s41531-017-0032-2
Mouton-Liger F Rosazza T Sepulveda-Diaz J Ieang A Hassoun SM Claire E et al. Parkin Deficiency Modulates NLRP3 Inflammasome Activation by Attenuating an A20-Dependent Negative Feedback Loop. Glia (2018) 66:1736–51. doi: 10.1002/glia.23337
Panicker N Sarkar S Harischandra DS Neal M Kam TI Jin H et al. Fyn Kinase Regulates Misfolded Alpha-Synuclein Uptake and NLRP3 Inflammasome Activation in Microglia. J Exp Med (2019) 216:1411–30. doi: 10.1084/jem.20182191
Wang W Nguyen LT Burlak C Chegini F Guo F Chataway T et al. Caspase-1 Causes Truncation and Aggregation of the Parkinson's Disease-Associated Protein Alpha-Synuclein. Proc Natl Acad Sci U S A (2016) 113:9587–92. doi: 10.1073/pnas.1610099113
Zahid A Li B Kombe AJK Jin T Tao J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Front Immunol (2019) 10:2538. doi: 10.3389/fimmu.2019.02538
Yang Y Wang H Kouadir M Song H Shi F. Recent Advances in the Mechanisms of NLRP3 Inflammasome Activation and its Inhibitors. Cell Death Dis (2019) 10:128. doi: 10.1038/s41419-019-1413-8
El-Sharkawy LY Brough D Freeman S. Inhibiting the NLRP3 Inflammasome. Molecules (2020) 25(23):5533. doi: 10.3390/molecules25235533
Jaramillo MC Zhang DD. The Emerging Role of the Nrf2-Keap1 Signaling Pathway in Cancer. Genes Dev (2013) 27:2179–91. doi: 10.1101/gad.225680.113
Motohashi H Yamamoto M. Nrf2-Keap1 Defines a Physiologically Important Stress Response Mechanism. Trends Mol Med (2004) 10:549–57. doi: 10.1016/j.molmed.2004.09.003
Moi P Chan K Asunis I Cao A Kan YW. Isolation of NF-E2-Related Factor 2 (Nrf2), a NF-E2-Like Basic Leucine Zipper Transcriptional Activator That Binds to the Tandem NF-E2/AP1 Repeat of the Beta-Globin Locus Control Region. Proc Natl Acad Sci U S A (1994) 91:9926–30. doi: 10.1073/pnas.91.21.9926
Mcmahon M Thomas N Itoh K Yamamoto M Hayes JD. Redox-Regulated Turnover of Nrf2 is Determined by at Least Two Separate Protein Domains, the Redox-Sensitive Neh2 Degron and the Redox-Insensitive Neh6 Degron. J Biol Chem (2004) 279:31556–67. doi: 10.1074/jbc.M403061200
Nioi P Nguyen T Sherratt PJ Pickett CB. The Carboxy-Terminal Neh3 Domain of Nrf2 is Required for Transcriptional Activation. Mol Cell Biol (2005) 25:10895–906. doi: 10.1128/MCB.25.24.10895-10906.2005
Chowdhry S Zhang Y Mcmahon M Sutherland C Cuadrado A Hayes JD. Nrf2 is Controlled by Two Distinct Beta-TrCP Recognition Motifs in its Neh6 Domain, One of Which can be Modulated by GSK-3 Activity. Oncogene (2013) 32:3765–81. doi: 10.1038/onc.2012.388
Wang H Liu K Geng M Gao P Wu X Hai Y et al. RXRalpha Inhibits the NRF2-ARE Signaling Pathway Through a Direct Interaction With the Neh7 Domain of NRF2. Cancer Res (2013) 73:3097–108. doi: 10.1158/0008-5472.CAN-12-3386
Song MY Lee DY Chun KS Kim EH. The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism. Int J Mol Sci (2021) 22(9):4376. doi: 10.3390/ijms22094376
Ahmed SM Luo L Namani A Wang XJ Tang X. Nrf2 Signaling Pathway: Pivotal Roles in Inflammation. Biochim Biophys Acta Mol Basis Dis (2017) 1863:585–97. doi: 10.1016/j.bbadis.2016.11.005
Miao W Hu L Scrivens PJ Batist G. Transcriptional Regulation of NF-E2 P45-Related Factor (NRF2) Expression by the Aryl Hydrocarbon Receptor-Xenobiotic Response Element Signaling Pathway: Direct Cross-Talk Between Phase I and II Drug-Metabolizing Enzymes. J Biol Chem (2005) 280:20340–8. doi: 10.1074/jbc.M412081200
Rushworth SA Zaitseva L Murray MY Shah NM Bowles KM Macewan DJ. The High Nrf2 Expression in Human Acute Myeloid Leukemia is Driven by NF-kappaB and Underlies its Chemo-Resistance. Blood (2012) 120:5188–98. doi: 10.1182/blood-2012-04-422121
Valadi H Ekstrom K Bossios A Sjostrand M Lee JJ Lotvall JO. Exosome-Mediated Transfer of mRNAs and microRNAs is a Novel Mechanism of Genetic Exchange Between Cells. Nat Cell Biol (2007) 9:654–9. doi: 10.1038/ncb1596
Fabrizio FP Sparaneo A Trombetta D Muscarella LA. Epigenetic Versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs. Oxid Med Cell Longev (2018) 2018:2492063. doi: 10.1155/2018/2492063
Sangokoya C Telen MJ Chi JT. microRNA miR-144 Modulates Oxidative Stress Tolerance and Associates With Anemia Severity in Sickle Cell Disease. Blood (2010) 116:4338–48. doi: 10.1182/blood-2009-04-214817
Tonelli C Chio IIC Tuveson DA. Transcriptional Regulation by Nrf2. Antioxid Redox Signal (2018) 29:1727–45. doi: 10.1089/ars.2017.7342
Jayasuriya R Ramkumar KM. Role of Long non-Coding RNAs on the Regulation of Nrf2 in Chronic Diseases. Life Sci (2021) 270:119025. doi: 10.1016/j.lfs.2021.119025
Goldstein LD Lee J Gnad F Klijn C Schaub A Reeder J et al. Recurrent Loss of NFE2L2 Exon 2 Is a Mechanism for Nrf2 Pathway Activation in Human Cancers. Cell Rep (2016) 16:2605–17. doi: 10.1016/j.celrep.2016.08.010
Cano Sanchez M Lancel S Boulanger E Neviere R. Targeting Oxidative Stress and Mitochondrial Dysfunction in the Treatment of Impaired Wound Healing: A Systematic Review. Antioxidants (Basel) (2018) 7(8):98. doi: 10.3390/antiox7080098
Zhou R Tardivel A Thorens B Choi I Tschopp J. Thioredoxin-Interacting Protein Links Oxidative Stress to Inflammasome Activation. Nat Immunol (2010) 11:136–40. doi: 10.1038/ni.1831
Thimmulappa RK Lee H Rangasamy T Reddy SP Yamamoto M Kensler TW et al. Nrf2 is a Critical Regulator of the Innate Immune Response and Survival During Experimental Sepsis. J Clin Invest (2006) 116:984–95. doi: 10.1172/JCI25790
Pan H Wang H Wang X Zhu L Mao L. The Absence of Nrf2 Enhances NF-kappaB-Dependent Inflammation Following Scratch Injury in Mouse Primary Cultured Astrocytes. Mediators Inflamm (2012) 2012:217580. doi: 10.1155/2012/217580
Frakes AE Ferraiuolo L Haidet-Phillips AM Schmelzer L Braun L Miranda CJ et al. Microglia Induce Motor Neuron Death via the Classical NF-kappaB Pathway in Amyotrophic Lateral Sclerosis. Neuron (2014) 81:1009–23. doi: 10.1016/j.neuron.2014.01.013
Soares MP Seldon MP Gregoire IP Vassilevskaia T Berberat PO Yu J et al. Heme Oxygenase-1 Modulates the Expression of Adhesion Molecules Associated With Endothelial Cell Activation. J Immunol (2004) 172:3553–63. doi: 10.4049/jimmunol.172.6.3553
Liu X Zhang X Ding Y Zhou W Tao L Lu P et al. Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming. Antioxid Redox Signal (2017) 26:28–43. doi: 10.1089/ars.2015.6615
Kobayashi EH Suzuki T Funayama R Nagashima T Hayashi M Sekine H et al. Nrf2 Suppresses Macrophage Inflammatory Response by Blocking Proinflammatory Cytokine Transcription. Nat Commun (2016) 7:11624. doi: 10.1038/ncomms11624
Lee D-F Kuo H-P Liu M Chou C-K Xia W Du Y et al. KEAP1 E3 Ligase-Mediated Downregulation of NF-κB Signaling by Targeting IKKβ. Mol Cell (2009) 36:131–40. doi: 10.1016/j.molcel.2009.07.025
Ricote M Li AC Willson TM Kelly CJ Glass CK. The Peroxisome Proliferator-Activated Receptor-γ is a Negative Regulator of Macrophage Activation. Nature (1998) 391:79–82. doi: 10.1038/34178
Sánchez-Gómez FJ Cernuda-Morollón E Stamatakis K Pérez-Sala D. Protein Thiol Modification by 15-Deoxy-Δ12,14-Prostaglandin J2Addition in Mesangial Cells: Role in the Inhibition of Pro-Inflammatory Genes. Mol Pharmacol (2004) 66:1349–58. doi: 10.1124/mol.104.002824
Hosoya T Maruyama A Kang M-I Kawatani Y Shibata T Uchida K et al. Differential Responses of the Nrf2-Keap1 System to Laminar and Oscillatory Shear Stresses in Endothelial Cells. J Biol Chem (2005) 280:27244–50. doi: 10.1074/jbc.M502551200
Hwang Y-J Lee E-W Song J Kim H-R Jun Y-C Hwang K-A. MafK Positively Regulates NF-κB Activity by Enhancing CBP-Mediated P65 Acetylation. Sci Rep (2013) 3:3242. doi: 10.1038/srep03242
Freigang S Ampenberger F Spohn G Heer S Shamshiev AT Kisielow J et al. Nrf2 is Essential for Cholesterol Crystal-Induced Inflammasome Activation and Exacerbation of Atherosclerosis. Eur J Immunol (2011) 41:2040–51. doi: 10.1002/eji.201041316
Zhao C Gillette DD Li X Zhang Z Wen H. Nuclear Factor E2-Related Factor-2 (Nrf2) is Required for NLRP3 and AIM2 Inflammasome Activation. J Biol Chem (2014) 289:17020–9. doi: 10.1074/jbc.M114.563114
Cleasby A Yon J Day PJ Richardson C Tickle IJ Williams PA et al. Structure of the BTB Domain of Keap1 and its Interaction With the Triterpenoid Antagonist CDDO. PloS One (2014) 9:e98896. doi: 10.1371/journal.pone.0098896
Linker RA Lee DH Ryan S Van Dam AM Conrad R Bista P et al. Fumaric Acid Esters Exert Neuroprotective Effects in Neuroinflammation via Activation of the Nrf2 Antioxidant Pathway. Brain (2011) 134:678–92. doi: 10.1093/brain/awq386
Tastan B Arioz BI Tufekci KU Tarakcioglu E Gonul CP Genc K et al. Dimethyl Fumarate Alleviates NLRP3 Inflammasome Activation in Microglia and Sickness Behavior in LPS-Challenged Mice. Front Immunol (2021) 12:737065. doi: 10.3389/fimmu.2021.737065
Cho H Hartsock MJ Xu Z He M Duh EJ. Monomethyl Fumarate Promotes Nrf2-Dependent Neuroprotection in Retinal Ischemia-Reperfusion. J Neuroinflamm (2015) 12:239. doi: 10.1186/s12974-015-0452-z
Merrell MD Jackson JP Augustine LM Fisher CD Slitt AL Maher JM et al. The Nrf2 Activator Oltipraz Also Activates the Constitutive Androstane Receptor. Drug Metab Dispos (2008) 36:1716–21. doi: 10.1124/dmd.108.020867
Okada K Shoda J Taguchi K Maher JM Ishizaki K Inoue Y et al. Ursodeoxycholic Acid Stimulates Nrf2-Mediated Hepatocellular Transport, Detoxification, and Antioxidative Stress Systems in Mice. Am J Physiol Gastrointest Liver Physiol (2008) 295:G735–747. doi: 10.1152/ajpgi.90321.2008
Lin X Bai D Wei Z Zhang Y Huang Y Deng H et al. Curcumin Attenuates Oxidative Stress in RAW264.7 Cells by Increasing the Activity of Antioxidant Enzymes and Activating the Nrf2-Keap1 Pathway. PloS One (2019) 14:e0216711. doi: 10.1371/journal.pone.0216711
Kim EN Lim JH Kim MY Ban TH Jang IA Yoon HE et al. Resveratrol, an Nrf2 Activator, Ameliorates Aging-Related Progressive Renal Injury. Aging (Albany NY) (2018) 10:83–99. doi: 10.18632/aging.101361
Jin Y Huang ZL Li L Yang Y Wang CH Wang ZT et al. Quercetin Attenuates Toosendanin-Induced Hepatotoxicity Through Inducing the Nrf2/GCL/GSH Antioxidant Signaling Pathway. Acta Pharmacol Sin (2019) 40:75–85. doi: 10.1038/s41401-018-0024-8
Bai Y Wang X Zhao S Ma C Cui J Zheng Y. Sulforaphane Protects Against Cardiovascular Disease via Nrf2 Activation. Oxid Med Cell Longev (2015) 2015:407580. doi: 10.1155/2015/407580
Arioz BI Tastan B Tarakcioglu E Tufekci KU Olcum M Ersoy N et al. Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway. Front Immunol (2019) 10:1511. doi: 10.3389/fimmu.2019.01511
Jnoff E Albrecht C Barker JJ Barker O Beaumont E Bromidge S et al. Binding Mode and Structure-Activity Relationships Around Direct Inhibitors of the Nrf2-Keap1 Complex. ChemMedChem (2014) 9:699–705. doi: 10.1002/cmdc.201300525
Marcotte D Zeng W Hus JC Mckenzie A Hession C Jin P et al. Small Molecules Inhibit the Interaction of Nrf2 and the Keap1 Kelch Domain Through a non-Covalent Mechanism. Bioorg Med Chem (2013) 21:4011–9. doi: 10.1016/j.bmc.2013.04.019
Jiang ZY Lu MC Xu LL Yang TT Xi MY Xu XL et al. Discovery of Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis. J Med Chem (2014) 57:2736–45. doi: 10.1021/jm5000529
Armagan G Sevgili E Gurkan FT Kose FA Bilgic T Dagci T et al. Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3beta in MPP(+)-Induced Cell Damage. Molecules (2019) 24(7):1377. doi: 10.3390/molecules24071377
Yagishita N Aratani S Leach C Amano T Yamano Y Nakatani K et al. RING-Finger Type E3 Ubiquitin Ligase Inhibitors as Novel Candidates for the Treatment of Rheumatoid Arthritis. Int J Mol Med (2012) 30:1281–6. doi: 10.3892/ijmm.2012.1129
Ki SH Cho IJ Choi DW Kim SG. Glucocorticoid Receptor (GR)-Associated SMRT Binding to C/EBPbeta TAD and Nrf2 Neh4/5: Role of SMRT Recruited to GR in GSTA2 Gene Repression. Mol Cell Biol (2005) 25:4150–65. doi: 10.1128/MCB.25.10.4150-4165.2005
Choi EJ Jung BJ Lee SH Yoo HS Shin EA Ko HJ et al. A Clinical Drug Library Screen Identifies Clobetasol Propionate as an NRF2 Inhibitor With Potential Therapeutic Efficacy in KEAP1 Mutant Lung Cancer. Oncogene (2017) 36:5285–95. doi: 10.1038/onc.2017.153
Wang XJ Hayes JD Henderson CJ Wolf CR. Identification of Retinoic Acid as an Inhibitor of Transcription Factor Nrf2 Through Activation of Retinoic Acid Receptor Alpha. Proc Natl Acad Sci U S A (2007) 104:19589–94. doi: 10.1073/pnas.0709483104
Kankia IH Khalil HS Langdon SP Moult PR Bown JL Deeni YY. NRF2 Regulates HER1 Signaling Pathway to Modulate the Sensitivity of Ovarian Cancer Cells to Lapatinib and Erlotinib. Oxid Med Cell Longev (2017) 2017:1864578. doi: 10.1155/2017/1864578
Tang X Wang H Fan L Wu X Xin A Ren H et al. Luteolin Inhibits Nrf2 Leading to Negative Regulation of the Nrf2/ARE Pathway and Sensitization of Human Lung Carcinoma A549 Cells to Therapeutic Drugs. Free Radic Biol Med (2011) 50:1599–609. doi: 10.1016/j.freeradbiomed.2011.03.008
Zhong Y Zhang F Sun Z Zhou W Li ZY You QD et al. Drug Resistance Associates With Activation of Nrf2 in MCF-7/DOX Cells, and Wogonin Reverses it by Down-Regulating Nrf2-Mediated Cellular Defense Response. Mol Carcinog (2013) 52:824–34. doi: 10.1002/mc.21921
Tarumoto T Nagai T Ohmine K Miyoshi T Nakamura M Kondo T et al. Ascorbic Acid Restores Sensitivity to Imatinib via Suppression of Nrf2-Dependent Gene Expression in the Imatinib-Resistant Cell Line. Exp Hematol (2004) 32:375–81. doi: 10.1016/j.exphem.2004.01.007
Limonciel A Jennings P. A Review of the Evidence That Ochratoxin A is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity. Toxins (Basel) (2014) 6:371–9. doi: 10.3390/toxins6010371
Chen F Wang H Zhu J Zhao R Xue P Zhang Q et al. Camptothecin Suppresses NRF2-ARE Activity and Sensitises Hepatocellular Carcinoma Cells to Anticancer Drugs. Br J Cancer (2017) 117:1495–506. doi: 10.1038/bjc.2017.317
Tsuchida K Tsujita T Hayashi M Ojima A Keleku-Lukwete N Katsuoka F et al. Halofuginone Enhances the Chemo-Sensitivity of Cancer Cells by Suppressing NRF2 Accumulation. Free Radic Biol Med (2017) 103:236–47. doi: 10.1016/j.freeradbiomed.2016.12.041
Arlt A Sebens S Krebs S Geismann C Grossmann M Kruse ML et al. Inhibition of the Nrf2 Transcription Factor by the Alkaloid Trigonelline Renders Pancreatic Cancer Cells More Susceptible to Apoptosis Through Decreased Proteasomal Gene Expression and Proteasome Activity. Oncogene (2013) 32:4825–35. doi: 10.1038/onc.2012.493
Tufekci KU Ercan I Isci KB Olcum M Tastan B Gonul CP et al. Sulforaphane Inhibits NLRP3 Inflammasome Activation in Microglia Through Nrf2-Mediated miRNA Alteration. Immunol Lett (2021) 233:20–30. doi: 10.1016/j.imlet.2021.03.004
Zhu X Liu J Huang S Zhu W Wang Y Chen O et al. Neuroprotective Effects of Isoliquiritigenin Against Cognitive Impairment via Suppression of Synaptic Dysfunction, Neuronal Injury, and Neuroinflammation in Rats With Kainic Acid-Induced Seizures. Int Immunopharmacol (2019) 72:358–66. doi: 10.1016/j.intimp.2019.04.028
Zeng J Chen Y Ding R Feng L Fu Z Yang S et al. Isoliquiritigenin Alleviates Early Brain Injury After Experimental Intracerebral Hemorrhage via Suppressing ROS- and/or NF-kappaB-Mediated NLRP3 Inflammasome Activation by Promoting Nrf2 Antioxidant Pathway. J Neuroinflamm (2017) 14:119. doi: 10.1186/s12974-017-0895-5
Zhu W Cao FS Feng J Chen HW Wan JR Lu Q et al. NLRP3 Inflammasome Activation Contributes to Long-Term Behavioral Alterations in Mice Injected With Lipopolysaccharide. Neuroscience (2017) 343:77–84. doi: 10.1016/j.neuroscience.2016.11.037
Wang CY Xu Y Wang X Guo C Wang T Wang ZY. Dl-3-N-Butylphthalide Inhibits NLRP3 Inflammasome and Mitigates Alzheimer's-Like Pathology via Nrf2-TXNIP-TrX Axis. Antioxid Redox Signal (2019) 30:1411–31. doi: 10.1089/ars.2017.7440
Zhang C Zhao M Wang B Su Z Guo B Qin L et al. The Nrf2-NLRP3-Caspase-1 Axis Mediates the Neuroprotective Effects of Celastrol in Parkinson's Disease. Redox Biol (2021) 47:102134. doi: 10.1016/j.redox.2021.102134
Zhang ZH Liu JQ Hu CD Zhao XT Qin FY Zhuang Z et al. Luteolin Confers Cerebroprotection After Subarachnoid Hemorrhage by Suppression of NLPR3 Inflammasome Activation Through Nrf2-Dependent Pathway. Oxid Med Cell Longev (2021) 2021:5838101. doi: 10.1155/2021/5838101
Fu J Sun H Zhang Y Xu W Wang C Fang Y et al. Neuroprotective Effects of Luteolin Against Spinal Cord Ischemia-Reperfusion Injury by Attenuation of Oxidative Stress, Inflammation, and Apoptosis. J Med Food (2018) 21:13–20. doi: 10.1089/jmf.2017.4021
Xiao L Dai Z Tang W Liu C Tang B. Astragaloside IV Alleviates Cerebral Ischemia-Reperfusion Injury Through NLRP3 Inflammasome-Mediated Pyroptosis Inhibition via Activating Nrf2. Oxid Med Cell Longev (2021) 2021:9925561. doi: 10.1155/2021/9925561
Yang C Mo Y Xu E Wen H Wei R Li S et al. Astragaloside IV Ameliorates Motor Deficits and Dopaminergic Neuron Degeneration via Inhibiting Neuroinflammation and Oxidative Stress in a Parkinson's Disease Mouse Model. Int Immunopharmacol (2019) 75:105651. doi: 10.1016/j.intimp.2019.05.036
Xu Y Gao X Wang L Yang M Xie R. Bakuchiol Ameliorates Cerebral Ischemia-Reperfusion Injury by Modulating NLRP3 Inflammasome and Nrf2 Signaling. Respir Physiol Neurobiol (2021) 292:103707. doi: 10.1016/j.resp.2021.103707
Tao W Hu Y Chen Z Dai Y Hu Y Qi M. Magnolol Attenuates Depressive-Like Behaviors by Polarizing Microglia Towards the M2 Phenotype Through the Regulation of Nrf2/HO-1/NLRP3 Signaling Pathway. Phytomedicine (2021) 91:153692. doi: 10.1016/j.phymed.2021.153692
Yu Y Wu DM Li J Deng SH Liu T Zhang T et al. Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 Inflammasome Activity and Activating NRF2 Signaling. Front Immunol (2020) 11:593368. doi: 10.3389/fimmu.2020.593368
Arruri VK Gundu C Kalvala AK Sherkhane B Khatri DK Singh SB. Carvacrol Abates NLRP3 Inflammasome Activation by Augmenting Keap1/Nrf-2/P62 Directed Autophagy and Mitochondrial Quality Control in Neuropathic Pain. Nutr Neurosci (2021), 1–16. doi: 10.1080/1028415X.2021.1892985
Gao W Wang W Liu G Zhang J Yang J Deng Z. Allicin Attenuated Chronic Social Defeat Stress Induced Depressive-Like Behaviors Through Suppression of NLRP3 Inflammasome. Metab Brain Dis (2019) 34:319–29. doi: 10.1007/s11011-018-0342-z
Jiang W Li M He F Bian Z He Q Wang X et al. Neuroprotective Effect of Asiatic Acid Against Spinal Cord Injury in Rats. Life Sci (2016) 157:45–51. doi: 10.1016/j.lfs.2016.05.004
Bian H Wang G Huang J Liang L Zheng Y Wei Y et al. Dihydrolipoic Acid Protects Against Lipopolysaccharide-Induced Behavioral Deficits and Neuroinflammation via Regulation of Nrf2/HO-1/NLRP3 Signaling in Rat. J Neuroinflamm (2020) 17:166. doi: 10.1186/s12974-020-01836-y
Shaheen MJ Bekdash AM Itani HA Borjac JM. Saffron Extract Attenuates Neuroinflammation in rmTBI Mouse Model by Suppressing NLRP3 Inflammasome Activation via SIRT1. PloS One (2021) 16:e0257211. doi: 10.1371/journal.pone.0257211
De Paula Martins R Ghisoni K Lim CK Aguiar AS Jr.Guillemin GJ Latini A. Neopterin Preconditioning Prevents Inflammasome Activation in Mammalian Astrocytes. Free Radic Biol Med (2018) 115:371–82. doi: 10.1016/j.freeradbiomed.2017.11.022
Dinesh P Rasool M. Berberine, an Isoquinoline Alkaloid Suppresses TXNIP Mediated NLRP3 Inflammasome Activation in MSU Crystal Stimulated RAW 264.7 Macrophages Through the Upregulation of Nrf2 Transcription Factor and Alleviates MSU Crystal Induced Inflammation in Rats. Int Immunopharmacol (2017) 44:26–37. doi: 10.1016/j.intimp.2016.12.031
Li Q Wu J Huang L Zhao B Li Q. Ephedrine Ameliorates Cerebral Ischemia Injury via Inhibiting NOD-Like Receptor Pyrin Domain 3 Inflammasome Activation Through the Akt/GSK3beta/NRF2 Pathway. Hum Exp Toxicol (2021) 40:S540–52. doi: 10.1177/09603271211052981
Yang X Ji J Liu C Zhou M Li H Ye S et al. HJ22, a Novel Derivative of Piperine, Attenuates Ibotenic Acid-Induced Cognitive Impairment, Oxidativestress, Apoptosis and Inflammation via Inhibiting the Protein-Protein Interaction of Keap1-Nrf2. Int Immunopharmacol (2020) 83:106383. doi: 10.1016/j.intimp.2020.106383
Yang X Zhi J Leng H Chen Y Gao H Ma J et al. The Piperine Derivative HJ105 Inhibits Abeta1-42-Induced Neuroinflammation and Oxidative Damage via the Keap1-Nrf2-TXNIP Axis. Phytomedicine (2021) 87:153571. doi: 10.1016/j.phymed.2021.153571
Wang H Lv J Jiang N Huang H Wang Q Liu X. Ginsenoside Re Protects Against Chronic Restraint Stress-Induced Cognitive Deficits Through Regulation of NLRP3 and Nrf2 Pathways in Mice. Phytother Res (2021) 35:2523–5. doi: 10.1002/ptr.6947
Zhang Z Yang H Yang J Xie J Xu J Liu C et al. Pseudoginsenoside-F11 Attenuates Cognitive Impairment by Ameliorating Oxidative Stress and Neuroinflammation in Dgalactose-Treated Mice. Int Immunopharmacol (2019) 67:78–86. doi: 10.1016/j.intimp.2018.11.026
Arioz BI Tarakcioglu E Olcum M Genc S. The Role of Melatonin on NLRP3 Inflammasome Activation in Diseases. Antioxidants (Basel) (2021) 10(7):1020. doi: 10.3390/antiox10071020
Madhu LN Kodali M Attaluri S Shuai B Melissari L Rao X et al. Melatonin Improves Brain Function in a Model of Chronic Gulf War Illness With Modulation of Oxidative Stress, NLRP3 Inflammasomes, and BDNF-ERK-CREB Pathway in the Hippocampus. Redox Biol (2021) 43:101973. doi: 10.1016/j.redox.2021.101973
Liu H Wu X Luo J Zhao L Li X Guo H et al. Adiponectin Peptide Alleviates Oxidative Stress and NLRP3 Inflammasome Activation After Cerebral Ischemia-Reperfusion Injury by Regulating AMPK/GSK-3beta. Exp Neurol (2020) 329:113302. doi: 10.1016/j.expneurol.2020.113302
Cheng Y Chen B Xie W Chen Z Yang G Cai Y et al. Ghrelin Attenuates Secondary Brain Injury Following Intracerebral Hemorrhage by Inhibiting NLRP3 Inflammasome Activation and Promoting Nrf2/ARE Signaling Pathway in Mice. Int Immunopharmacol (2020) 79:106180. doi: 10.1016/j.intimp.2019.106180
Luo X Zeng H Fang C Zhang BH. N-Acetylserotonin Derivative Exerts a Neuroprotective Effect by Inhibiting the NLRP3 Inflammasome and Activating the PI3K/Akt/Nrf2 Pathway in the Model of Hypoxic-Ischemic Brain Damage. Neurochem Res (2021) 46:337–48. doi: 10.1007/s11064-020-03169-x
Hou Y Wang Y He Q Li L Xie H Zhao Y et al. Nrf2 Inhibits NLRP3 Inflammasome Activation Through Regulating Trx1/TXNIP Complex in Cerebral Ischemia Reperfusion Injury. Behav Brain Res (2018) 336:32–9. doi: 10.1016/j.bbr.2017.06.027
Xu X Zhang L Ye X Hao Q Zhang T Cui G et al. Nrf2/ARE Pathway Inhibits ROS-Induced NLRP3 Inflammasome Activation in BV2 Cells After Cerebral Ischemia Reperfusion. Inflammation Res (2018) 67:57–65. doi: 10.1007/s00011-017-1095-6
Yu J Wang WN Matei N Li X Pang JW Mo J et al. Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway After MCAO in Rats. Oxid Med Cell Longev (2020) 2020:4717258. doi: 10.1155/2020/4717258
Li W Ali T He K Liu Z Shah FA Ren Q et al. Ibrutinib Alleviates LPS-Induced Neuroinflammation and Synaptic Defects in a Mouse Model of Depression. Brain Behav Immun (2021) 92:10–24. doi: 10.1016/j.bbi.2020.11.008
Shan W Liao X Tang Y Liu J. Dexmedetomidine Alleviates Inflammation in Neuropathic Pain by Suppressing NLRP3 via Nrf2 Activation. Exp Ther Med (2021) 22:1046. doi: 10.3892/etm.2021.10479
Wang N Nie H Zhang Y Han H Wang S Liu W et al. Dexmedetomidine Exerts Cerebral Protective Effects Against Cerebral Ischemic Injury by Promoting the Polarization of M2 Microglia via the Nrf2/HO-1/NLRP3 Pathway. Inflamm Res (2022) 71:93–106. doi: 10.1007/s00011-021-01515-5
Fahmy EK El-Sherbiny M Said E Elkattawy HA Qushawy M Elsherbiny N. Tranilast Ameliorated Subchronic Silver Nanoparticles-Induced Cerebral Toxicity in Rats: Effect on TLR4/NLRP3 and Nrf-2. Neurotoxicology (2021) 82:167–76. doi: 10.1016/j.neuro.2020.12.008
Derangula K Javalgekar M Kumar Arruri V Gundu C Kumar Kalvala A Kumar A. Probucol Attenuates NF-Kappab/NLRP3 Signalling and Augments Nrf-2 Mediated Antioxidant Defence in Nerve Injury Induced Neuropathic Pain. Int Immunopharmacol (2022) 102:108397. doi: 10.1016/j.intimp.2021.108397
Bayazid AB Jang YA Kim YM Kim JG Lim BO. Neuroprotective Effects of Sodium Butyrate Through Suppressing Neuroinflammation and Modulating Antioxidant Enzymes. Neurochem Res (2021) 46:2348–58. doi: 10.1007/s11064-021-03369-z
Zhang C Wang H Liang W Yang Y Cong C Wang Y et al. Diphenyl Diselenide Protects Motor Neurons Through Inhibition of Microglia-Mediated Inflammatory Injury in Amyotrophic Lateral Sclerosis. Pharmacol Res (2021) 165:105457. doi: 10.1016/j.phrs.2021.105457
Xu LL Wu YF Yan F Li CC Dai Z You QD et al. 5-(3,4-Difluorophenyl)-3-(6-Methylpyridin-3-Yl)-1,2,4-Oxadiazole (DDO-7263), a Novel Nrf2 Activator Targeting Brain Tissue, Protects Against MPTP-Induced Subacute Parkinson's Disease in Mice by Inhibiting the NLRP3 Inflammasome and Protects PC12 Cells Against Oxidative Stress. Free Radic Biol Med (2019) 134:288–303. doi: 10.1016/j.freeradbiomed.2019.01.003
Wang Q Li WX Dai SX Guo YC Han FF Zheng JJ et al. Meta-Analysis of Parkinson's Disease and Alzheimer's Disease Revealed Commonly Impaired Pathways and Dysregulation of NRF2-Dependent Genes. J Alzheimers Dis (2017) 56:1525–39. doi: 10.3233/JAD-161032
Paupe V Dassa EP Goncalves S Auchere F Lonn M Holmgren A et al. Impaired Nuclear Nrf2 Translocation Undermines the Oxidative Stress Response in Friedreich Ataxia. PloS One (2009) 4:e4253. doi: 10.1371/journal.pone.0004253
Prasad KN Bondy SC. Inhibition of Early Biochemical Defects in Prodromal Huntington's Disease by Simultaneous Activation of Nrf2 and Elevation of Multiple Micronutrients. Curr Aging Sci (2016) 9:61–70. doi: 10.2174/1874609809666151124231127
Dinkova-Kostova AT Kostov RV Kazantsev AG. The Role of Nrf2 Signaling in Counteracting Neurodegenerative Diseases. FEBS J (2018) 285:3576–90. doi: 10.1111/febs.14379
Fao L Mota SI Rego AC. Shaping the Nrf2-ARE-Related Pathways in Alzheimer's and Parkinson's Diseases. Ageing Res Rev (2019) 54:100942. doi: 10.1016/j.arr.2019.100942
Saha S Buttari B Profumo E Tucci P Saso L. A Perspective on Nrf2 Signaling Pathway for Neuroinflammation: A Potential Therapeutic Target in Alzheimer's and Parkinson's Diseases. Front Cell Neurosci (2021) 15:787258. doi: 10.3389/fncel.2021.787258
Ahuja M Ammal Kaidery N Yang L Calingasan N Smirnova N Gaisin A et al. Distinct Nrf2 Signaling Mechanisms of Fumaric Acid Esters and Their Role in Neuroprotection Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Experimental Parkinson's-Like Disease. J Neurosci (2016) 36:6332–51. doi: 10.1523/JNEUROSCI.0426-16.2016
Robledinos-Anton N Fernandez-Gines R Manda G Cuadrado A. Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development. Oxid Med Cell Longev (2019) 2019:9372182. doi: 10.1155/2019/9372182
Pallesen JS Tran KT Bach A. Non-Covalent Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1-Nrf2) Inhibitors and Their Potential for Targeting Central Nervous System Diseases. J Med Chem (2018) 61:8088–103. doi: 10.1021/acs.jmedchem.8b00358
Dhakshinamoorthy S Jain AK Bloom DA Jaiswal AK. Bach1 Competes With Nrf2 Leading to Negative Regulation of the Antioxidant Response Element (ARE)-Mediated NAD(P)H:quinone Oxidoreductase 1 Gene Expression and Induction in Response to Antioxidants. J Biol Chem (2005) 280:16891–900. doi: 10.1074/jbc.M500166200
Jain A Lamark T Sjottem E Larsen KB Awuh JA Overvatn A et al. P62/SQSTM1 is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-Driven Gene Transcription. J Biol Chem (2010) 285:22576–91. doi: 10.1074/jbc.M110.118976
Shao BZ Cao Q Liu C. Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases. Front Mol Neurosci (2018) 11:320. doi: 10.3389/fnmol.2018.00320
Lozanovski VJ Polychronidis G Gross W Gharabaghi N Mehrabi A Hackert T et al. Broccoli Sprout Supplementation in Patients With Advanced Pancreatic Cancer is Difficult Despite Positive Effects-Results From the POUDER Pilot Study. Invest New Drugs (2020) 38:776–84. doi: 10.1007/s10637-019-00826-z
Rabbani N Xue M Weickert MO Thornalley PJ. Reversal of Insulin Resistance in Overweight and Obese Subjects by Trans-Resveratrol and Hesperetin Combination-Link to Dysglycemia, Blood Pressure, Dyslipidemia, and Low-Grade Inflammation. Nutrients (2021) 13(7):2374. doi: 10.3390/nu13072374
Lastra D Fernandez-Gines R Manda G Cuadrado A. Perspectives on the Clinical Development of NRF2-Targeting Drugs. Handb Exp Pharmacol (2021) 264:93–141. doi: 10.1007/164_2020_381
Rosito M Testi C Parisi G Cortese B Baiocco P Di Angelantonio S. Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment. Antioxidants (Basel) (2020) 9(8):700. doi: 10.3390/antiox9080700
Schimrigk S Brune N Hellwig K Lukas C Bellenberg B Rieks M et al. Oral Fumaric Acid Esters for the Treatment of Active Multiple Sclerosis: An Open-Label, Baseline-Controlled Pilot Study. Eur J Neurol (2006) 13:604–10. doi: 10.1111/j.1468-1331.2006.01292.x
Gold R Kappos L Arnold DL Bar-Or A Giovannoni G Selmaj K et al. Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis. N Engl J Med (2012) 367:1098–107. doi: 10.1056/NEJMoa1114287
Gold R Arnold DL Bar-Or A Fox RJ Kappos L Mokliatchouk O et al. Long-Term Safety and Efficacy of Dimethyl Fumarate for Up to 13 Years in Patients With Relapsing-Remitting Multiple Sclerosis: Final ENDORSE Study Results. Mult Scler (2021), 13524585211037909. doi: 10.1177/13524585211037909
Ruggieri S Tortorella C Gasperini C. Pharmacology and Clinical Efficacy of Dimethyl Fumarate (BG-12) for Treatment of Relapsing-Remitting Multiple Sclerosis. Ther Clin Risk Manag (2014) 10:229–39. doi: 10.2147/TCRM.S53285
Paik J. Diroximel Fumarate in Relapsing Forms of Multiple Sclerosis: A Profile of Its Use. CNS Drugs (2021) 35:691–700. doi: 10.1007/s40263-021-00830-z
Lynch DR Chin MP Delatycki MB Subramony SH Corti M Hoyle JC et al. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol (2021) 89:212–25. doi: 10.1002/ana.25934
Lovestone S Boada M Dubois B Hull M Rinne JO Huppertz HJ et al. A Phase II Trial of Tideglusib in Alzheimer's Disease. J Alzheimers Dis (2015) 45:75–88. doi: 10.3233/JAD-141959
Martinez-Gonzalez L Gonzalo-Consuegra C Gomez-Almeria M Porras G De Lago E Martin-Requero A et al. Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3beta as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis. Int J Mol Sci (2021) 22(16):8975. doi: 10.3390/ijms22168975
Grossman SA Ye X Peereboom D Rosenfeld MR Mikkelsen T Supko JG et al. Phase I Study of Terameprocol in Patients With Recurrent High-Grade Glioma. Neuro Oncol (2012) 14:511–7. doi: 10.1093/neuonc/nor230
Kiser C Gonul CP Olcum M Genc S. Inhibitory Effects of Sulforaphane on NLRP3 Inflammasome Activation. Mol Immunol (2021) 140:175–85. doi: 10.1016/j.molimm.2021.10.014
Zolnourian AH Franklin S Galea I Bulters DO. Study Protocol for SFX-01 After Subarachnoid Haemorrhage (SAS): A Multicentre Randomised Double-Blinded, Placebo Controlled Trial. BMJ Open (2020) 10:e028514. doi: 10.1136/bmjopen-2018-028514
Hellwig K Rog D Mcguigan C Houtchens MK Bruen DR Mokliatchouk O et al. Interim Analysis of Pregnancy Outcomes After Exposure to Dimethyl Fumarate in a Prospective International Registry. Neurol Neuroimmunol Neuroinflamm (2022) 9. doi: 10.1212/NXI.0000000000001114
Chaves C Ganguly R Ceresia C Camac A. Lymphocyte Subtypes in Relapsing-Remitting Multiple Sclerosis Patients Treated With Dimethyl Fumarate. Mult Scler J Exp Transl Clin (2017) 3:2055217317702933. doi: 10.1177/2055217317702933
Satoh T Lipton S. Recent Advances in Understanding NRF2 as a Druggable Target: Development of Pro-Electrophilic and non-Covalent NRF2 Activators to Overcome Systemic Side Effects of Electrophilic Drugs Like Dimethyl Fumarate. F1000Res (2017) 6:2138. doi: 10.12688/f1000research.12111.1
