Nrf2 Regulates Oxidative Stress and Its Role in Cerebral Ischemic Stroke

Antioxidants, Год журнала: 2022, Номер 11(12), С. 2377 - 2377

Опубликована: Ноя. 30, 2022

Cerebral ischemic stroke is characterized by acute ischemia in a certain part of the brain, which leads to brain cells necrosis, apoptosis, ferroptosis, pyroptosis, etc. At present, there are limited effective clinical treatments for cerebral stroke, and recovery blood circulation will lead ischemia-reperfusion injury (CIRI). involves many pathological processes such as oxidative stress, inflammation, mitochondrial dysfunction. Nuclear factor erythroid 2-related 2 (Nrf2), one most critical antioxidant transcription factors cells, can coordinate various cytoprotective inhibit stress. Targeting Nrf2 considered potential strategy prevent treat injury. During ischemia, participates signaling pathways Keap1, PI3K/AKT, MAPK, NF-κB, HO-1, then alleviates or CIRI inhibiting anti-inflammation, maintaining homeostasis, protecting blood–brain barrier, ferroptosis. In this review, we have discussed structure Nrf2, mechanisms related research on treatment through pathway recent years, expounded important role future stroke.

Язык: Английский

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Revisiting the Oxidation of Flavonoids: Loss, Conservation or Enhancement of Their Antioxidant Properties

Antioxidants, Год журнала: 2022, Номер 11(1), С. 133 - 133

Опубликована: Янв. 7, 2022

Flavonoids display a broad range of health-promoting bioactivities. Among these, their capacity to act as antioxidants has remained most prominent. The canonical reactive oxygen species (ROS)-scavenging mode the antioxidant action flavonoids relies on high susceptibility phenolic moieties undergo oxidation. As consequence, upon reaction with ROS, is severely compromised. Other phenol-compromising reactions, such those involved in biotransformation flavonoids, can also markedly affect properties. In recent years, however, increasing evidence indicated that, at least for some oxidation residues fact enhance original apparent paradoxical cases, activity arises from pro-oxidant and/or electrophilic character oxidation-derived metabolites and exerted by activating Nrf2-Keap1 pathway, which upregulates cell's endogenous capacity, and/or, preventing activation pro-inflammatory NF-κB pathway. This review focuses effects that oxidative non-oxidative modification groups may have ability resulting promote direct indirect actions. Considering case metabolite quercetin, we offer comprehensive description increasingly supports concept certain phenolics emerges mechanism amplifies An overlooked topic great phytomedicine potential thus unraveled.

Язык: Английский

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Nrf2: Redox and Metabolic Regulator of Stem Cell State and Function

Trends in Molecular Medicine, Год журнала: 2019, Номер 26(2), С. 185 - 200

Опубликована: Ноя. 3, 2019

As a cellular metabolic and stress sensor, the transcription factor Nrf2 is pivotal regulator of stem cell self-renewal, proliferation, differentiation.Nrf2 displays type-specific and/or stage-dependent impact on biology in response to various environmental cues.Nrf2 modulates PSCs through regulation pluripotency factors, metabolism, redox homeostasis, responses.Nrf2 maintain ASCs quiescence, regenerative capacity while protecting against ASC depletion aging. Nuclear erythroid 2-related 2 (Nrf2) ubiquitously expressed most eukaryotic cells functions induce broad range defenses exogenous endogenous stresses, including oxidants, xenobiotics, excessive nutrient/metabolite supply. Because production fate are often modulated by important roles have emerged survival, senescence, differentiation. In rapidly advancing field, this review summarizes signaling context state function provides rationale for as therapeutic target cell-based medicine. stress-responsive encoded NFE2L2 gene humans [1Moi P. et al.Isolation NF-E2-related (Nrf2), NF-E2-like basic leucine zipper transcriptional activator that binds tandem NF-E2/AP1 repeat beta-globin locus control region.Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9926-9930Crossref PubMed Scopus (931) Google Scholar]. Although previously considered primarily an antioxidative factor, now recognized be involved multiple stressors supply, inflammation, accumulation misfolded proteins (Box 1) [2Swamy S.M. al.Nuclear factor-erythroid-2-related aging lung fibrosis.Am. J. Pathol. 2016; 186: 1712-1723Abstract Full Text PDF (26) Scholar, 3Niture S.K. al.Regulation Nrf2-an update.Free Radic. Biol. Med. 2014; 66: 36-44Crossref (403) 4Matzinger M. al.Activation natural products—can it alleviate diabetes?.Biotechnol. Adv. 2018; 36: 1738-1767Crossref (19) cancer, diabetes, well studied 5Menegon al.The dual NRF2 cancer.Trends Mol. 22: 578-593Abstract (192) 6Moon E.J. Giaccia Dual tumor prevention progression: possible implications cancer treatment.Free 2015; 79: 292-299Crossref (69) 7David J.A. Nrf2/Keap1/ARE pathway oxidative type II diabetes mellitus.J. Diabetes Res. 2017; 2017: 4826724Crossref (25) 8Cloer E.W. al.NRF2 activation cancer: from DNA protein.Cancer 2019; 889-898Crossref (7) 9Rojo de la Vega hallmarks cancer.Cancer Cell. 34: 21-43Abstract (99) Scholar], role not clear.Box 1Nrf2 Structure FunctionNrf2 belongs cap 'n' collar family. Human possesses conserved structure seven functional Nrf2-ECH homology (Neh) domains, Neh1–7 [98Tonelli C. al.Transcriptional Nrf2.Antioxid Redox Signal. 29: 1727-1745Crossref (73) Scholar]: Neh1 interacts with small musculoaponeurotic fibrosarcoma (Maf) antioxidant element (ARE)-DNA; Neh2 Keap1; Neh3–5 required transactivation Nrf2; Neh6 regulates stability Neh7 transcription, retinoid X receptor α domain downregulates Nrf2, suggesting mechanism repression independent Neh2-Keap1.Nrf2 activity can regulated at levels, post-transcriptional regulation, post-translational modification. At level, nuclear kappa-light-chain-enhancer activated B (NF-κB) [99Rushworth S.A. high expression human acute myeloid leukemia driven NF-kappaB underlies its chemo-resistance.Blood. 2012; 120: 5188-5198Crossref (107) aryl hydrocarbon [100Miao W. NF-E2 p45-related (NRF2) receptor-xenobiotic pathway: direct cross-talk between phase I drug-metabolizing enzymes.J. Chem. 2005; 280: 20340-20348Crossref (293) Kras, Braf, Myc, Jun [101DeNicola G.M. al.Oncogene-induced promotes ROS detoxification tumorigenesis.Nature. 2011; 475: 106-109Crossref (990) Scholar] bind promoter enhance transcription. The phosphoinositide-3-kinase–protein kinase (PI3K–Akt) [102Mitsuishi Y. al.Nrf2 redirects glucose glutamine into anabolic pathways reprogramming.Cancer 66-79Abstract (562) Notch [103Wakabayashi N. al.Notch-Nrf2 axis: cytoprotection notch signaling.Mol. 653-663Crossref (55) also been reported augment appears autoregulate own ARE-like located proximal region, leading persistent protracted induction genes chemopreventative agents [104Kwak M.K. al.Enhanced chemopreventive agents: element-like sequences nrf2 promoter.Mol. 2002; 2883-2892Crossref (0) transcriptionally repressed. For example, modifications, hypermethylation or single nucleotide polymorphisms result decreased [105Li al.Curcumin derivative epigenetically reactivates mouse prostate TRAMP C1 cells.Chem. Toxicol. 31: 88-96Crossref (8) occurs mainly via miRNA. Several miRNAs, miR-27a, miR-144, miR-93 identified reduce mRNA [106Wang al.MicroRNA-93 downregulation ameliorates cerebral ischemic injury Nrf2/HO-1 defense pathway.Neurochem. 41: 2627-2635Crossref (17) 107Zhou al.miR-144 reverses chemoresistance hepatocellular carcinoma lines targeting Nrf2-dependent pathway.Am. Transl. 8: 2992-3002PubMed 108Xue W.L. al.rhTNFR:Fc increases miR-27a mediation protect myocardium sepsis injury.Biochem. Biophys. Commun. 464: 855-861Crossref addition, alternative splicing, splice variants lack Keap1 interaction resulting stabilization [109Goldstein L.D. al.Recurrent loss exon cancers.Cell Rep. 16: 2605-2617Abstract (46) subject modifications phosphorylation, acetylation, ubiquitination, sumoylation, distinct chaperon interactions may finely tune degradation, translocation, residence, export, [4Matzinger Scholar].Nrf2 serves primary numerous inducible systems more than 200 downstream cytoprotective genes, proteins, metabolism enzymes, transport proteasome subunits, chaperones, growth factors their receptors, [90Hayes J.D. Dinkova-Kostova A.T. regulatory network interface intermediary metabolism.Trends Biochem. 39: 199-218Abstract (651) 110Al-Sawaf O. health disease: current future clinical implications.Clin. (Lond). 129: 989-999Crossref (60) Extensive research has deciphered regulating detoxification, autophagy, mitochondrial bioenergetics, lipid synthesis, fatty acid oxidation, gluconeogenesis, reprogramming. Neh2-Keap1. Stem cells, pluripotent (PSCs) adult tissue (ASCs) 2), possess unique programs reduction–oxidation (redox) states sustain proliferation maintaining (see Glossary) multipotency specified differentiation [10Zhang al.Metabolic during reprogramming self-renewal.Cell 11: 589-595Abstract (232) 11Zhong X. al.Mitochondrial dynamics critical full embryonic developmental potential cells.Cell Metab. 979-992.e4Abstract (10) 12Ito K. Suda T. Metabolic requirements maintenance self-renewing cells.Nat. Rev. Cell 15: 243-256Crossref (431) ATP produced glycolysis phosphorylation (OXPHOS) self-renewal [13Shyh-Chang Ng H.H. programming cells.Genes Dev. 336-346Crossref Quiescent rely energy lower respiration rates, reduced reactive oxygen species (ROS) production, elevated enzyme PSC results shift OXPHOS, which shown revert back after 14Mathieu al.Hypoxia-inducible stage-specific pluripotency.Cell 14: 592-605Abstract (110) Most quiescent niches tend prefer oxidation levels such suppress Upon injury, proliferating increase use influence signaling, alter metabolite states, activate 13Shyh-Chang Therefore, profile used index multipotency, Consistent essential survival function, programming-related among enriched transcripts present 15Ramalho-Santos al."Stemness": profiling cells.Science. 298: 597-600Crossref (1349) 16Munoz quantitative proteomes human-induced cells.Mol. Syst. 7: 550Crossref (91) 17Konze al.Proteomic analysis cardiomyogenesis revealed altered enzymes PDLIM5 isoforms.J. Proteome 1133-1149Crossref (12) common upstream many these serve master homeostasis 18Jang al.Nrf2, proteasome, controls cells.Stem Cells. 32: 2616-2625Crossref 19Tsai J.J. haematopoietic function.Nat. 2013; 309-316Crossref (108) review, we summarize discuss recent progress understanding highlight controlling pluripotency, differentiation, (Table 1).Box 2Stem Cells Progenitor CellsIn mammals, there two types cells: ASCs. subcategorized germline ESCs iPSCs. derived inner mass preimplantation embryos. iPSCs reprogrammed somatic vitro simultaneous overexpression four core factors: Oct4, Sox2, Klf4, c-Myc. Both indefinitely maintained expanded capable differentiating derivatives all three germ layers.ASCs characterized ability self-renew differentiate generate tissue. Based locations turnover rates tissues/organs, HSCs, MSCs, EPCs, NSCs.During development, organ- tissue-specialized but repair organs, BM, solid skin, postnatal heart. progenitor support replenishment tissues, though declines age.Table 1Function CellsStem cells/progenitor cellsSpecies originNrf2 functionManipulating approachMechanismRefsESCsHuman embryoSelf-renewal ↑Re-establishment ↑Differentiation ↓Nrf2 siRNA shRNA knockdown pharmacological activationNrf2 maintains POMP18Jang ScholarNeuroectoderm knockdownNrf2 directly regions OCT4 NANOG promote repress neuroectoderm derivation20Jang al.Primary cilium-autophagy-Nrf2 (PAN) axis commits fate.Cell. 165: 410-420Abstract ScholarOsteogenic ↑Nrf2 Runx2 facilitates mineralization ESCs21Sim H.J. al.Glucose oxidase osteogenic ERK signal transduction pathways.Mol. 419: 157-163Crossref (4) ScholarNeuronal decreases level inhibit neuronal differentiation22Hu Q. al.Oxidative exit spontaneous differentiation.Oncotarget. 9: 4223-4238Crossref (6) ScholariPSCsHuman fibroblastsReprograming ↑Keap1 overexpressionNrf2 HIF-1α26Hawkins K.E. orchestrates induced reprogramming.Cell 1883-1891Abstract ScholarHuman chimpanzee skin fibroblastNeuroectoderm ↓Mesendoderm represses mesendoderm genes20Jang ScholarHSCsMouse BMSurvival knockoutNrf2 HSC enhancing prosurvival cytokine (such G-CSF) levels34Merchant A.A. redox-sensitive murine hematopoietic independently levels.Blood. 118: 6572-6579Crossref (62) ScholarProliferation ↓Expansion ↓Differentiation ↓Self-renewal ↑Quiescence ↑Migration migration partially CXCR4 transcription19Tsai ScholarQuiescence Maintenance knockout Nrf2Nrf2 drives cycle entry possibly JAK–STAT3 pathway36Murakami impairs quiescence bone marrow reconstitution 37 (e00086-17)Crossref ScholarFunction↑Survival ↑Expansion activations knockoutNrf2-mediated improves following ionizing radiation exposure; under conditions41Kim J.H. al.NRF2-mediated enhances myelosuppressive radiation.J. Clin. Invest. 124: 730-741Crossref 43Xue X.L. al.Astaxanthin attenuates total body irradiation-induced system mice inhibition apoptosis.Stem Ther. 7Crossref ScholarMSCsHuman BMApoptosis ↓Oxidative upregulates SOD HO-1 expression52Mohammadzadeh al.Nrf-2 mesenchymal reduces stress-induced apoptosis cytotoxicity.Cell Stress Chaperones. 17: 553-565Crossref umbilical cordProliferation ↑Stemness ↑Osteogenesis ↑Apoptosis might lead alterations MSC genome sequences53Yuan Z. induces stem-cell marker osteoblastic differentiation.Biochem. 491: 228-235Crossref amnionHoming ↑Differentiation↑Apoptosis overexpressionUpregulation binding expression54Zhang transfection efficacy amniotic lipopolysaccharide.J. 119: 1627-1636Crossref (9) BMSelf-renewal ↑Osteogenic Differentiation MSCs p53-SIRT1 signaling61Yoon D.S. al.Cellular localization determines P53-SIRT1 axis.Cell Death Dis. e2093Crossref ScholarRat adiposeOsteoblastic inhibits ROS-induced adipose downregulating BMP2 Runx262Tao al.Downregulation autophagy-dependent adipose-derived cells.Exp. 349: 221-229Crossref (13) ScholarNSCsRat/mouse subventricular zoneSurvival ↑Proliferation ↑Regeneration knockdownThe clear64Corenblum M.J. al.Reduced mediates decline neural middle-age period.Aging 725-736Crossref ScholarRat/mouse dentate gyrus hippocampusProliferation ↑Neuronal clear70Ray al.A defining hippocampal Transplant. 27: 589-606Crossref ScholarMouse subgranular zoneProliferation knockdownNrf2-knockout activationThe clear65Robledinos-Anton al.Transcription

Язык: Английский

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S-Nitrosylation: An Emerging Paradigm of Redox Signaling

Antioxidants, Год журнала: 2019, Номер 8(9), С. 404 - 404

Опубликована: Сен. 17, 2019

Nitric oxide (NO) is a highly reactive molecule, generated through metabolism of L-arginine by NO synthase (NOS). Abnormal levels in mammalian cells are associated with multiple human diseases, including cancer. Recent studies have uncovered that the signaling compartmentalized, owing to localization NOS and nature biochemical reactions NO, S-nitrosylation. S-nitrosylation selective covalent post-translational modification adding nitrosyl group thiol cysteine form S-nitrosothiol (SNO), which key mechanism transferring NO-mediated signals. While occurs only at select thiols, such spatial constraint partially resolved transnitrosylation, where moiety transferred between two interacting proteins successively transfer signal distant location. As present various subcellular locales, stress could trigger concerted transnitrosylation large number involved divergent cascades. an emerging paradigm redox confer protection against oxidative stress.

Язык: Английский

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A novel compound DBZ ameliorates neuroinflammation in LPS-stimulated microglia and ischemic stroke rats: Role of Akt(Ser473)/GSK3β(Ser9)-mediated Nrf2 activation

Redox Biology, Год журнала: 2020, Номер 36, С. 101644 - 101644

Опубликована: Июль 17, 2020

Microglia-mediated neuroinflammation plays a crucial role in the pathophysiological process of multiple neurological disorders such as ischemic stroke, yet lacks effective therapeutic agents. Previously, we discovered one novel synthetic compound, tanshinol borneol ester (DBZ), possesses anti-inflammatory and anti-atherosclerotic activities, whereas little is known about its effects CNS. Therefore, present study aims to explore potential mechanism DBZ on microglial function. Our studies revealed that significantly inhibited NF-κB activity, suppressed production pro-inflammatory mediators meanwhile promoted M2 expression LPS-stimulated BV2 cells mouse primary microglia cells. also exhibited antioxidant activity by enhancing Nrf2 nuclear accumulation transcriptional increasing HO-1 NQO1 expression, inhibiting LPS-induced ROS generation Importantly, anti-neuroinflammatory above were reversed knockdown. Additionally, ameliorated sickness behaviors neuroinflammatory mice induced systemic LPS administration, reduced infract volume, improved sensorimotor cognitive function rats subjected transient middle cerebral artery occlusion (tMCAO); besides, restored morphological alterations shifted M1/M2 polarization both murine models. Mechanistically, DBZ-induced enzymes accompanied increased level p-Akt(Ser473) (activation) p-GSK3β(Ser9) (inactivation), decreased Fyn vitro vivo. Pharmacologically PI3K or activating GSK3β markedly density cells, which blocked promoting effect activities. Collectively, these results indicated microglia-mediated strongly associated with stabilization via Akt(Ser473)/GSK3β(Ser9)/Fyn pathway. With properties, could be promising new drug candidate for prevention and/or treatment ischemia other disorders.

Язык: Английский

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