The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

Oxidative Medicine and Cellular Longevity, Journal Year: 2021, Volume and Issue: 2021(1)

Published: Jan. 1, 2021

Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to disruption of redox signals causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence‐related diseases aging itself. The Kelch‐like ECH‐associated protein 1‐ (Keap1‐) nuclear factor‐erythroid 2‐related factor 2 (Nrf2) system can be used monitor stress; Keap1‐Nrf2 is closely associated with controls transcription multiple antioxidant enzymes. Simultaneously, signaling also modulated by more complex regulatory network, including phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt), C, mitogen‐activated kinase. This review presents information on aging‐related mechanisms involving Keap1‐Nrf2. Furthermore, we highlight several major involved Nrf2 unbinding Keap1, cysteine modification Keap1 phosphorylation Nrf2, PI3K/Akt/glycogen synthase 3 β , sequestosome 1, Bach1 c ‐ Myc . Additionally, discuss direct interaction mammalian target rapamycin pathway. In summary, focus recent progress research aging, providing an empirical basis for development antiaging drugs.

Language: Английский

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Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Cell Death Discovery, Journal Year: 2022, Volume and Issue: 8(1)

Published: Feb. 2, 2022

Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As form of iron hydroperoxide-dependent regulated cell death, ferroptosis plays critical role sepsis-induced acute lung injury (ALI). However, the relationship between itaconate remains unclear. This study aims explore regulatory on ALI. In vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h generate experimental sepsis models. Differential gene expression analysis indicated that genes associated existed significant differences after pretreatment. 4-octyl (4-OI), cell-permeable derivative endogenous itaconate, can significantly alleviate injury, increase LPS-induced levels glutathione peroxidase 4 (GPX4) reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), ROS. vitro experiments showed both 4-OI ferrostatin-1 inhibited peroxidation THP-1 macrophage. Mechanistically, we identified GPX4-dependent through increased accumulation activation Nrf2. The silence Nrf2 abolished inhibition from cells. Additionally, protection ALI was Nrf2-knockout mice. We concluded one mechanisms contributing Itaconate is promising as therapeutic candidate against inhibiting ferroptosis.

Language: Английский

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Ferroptosis and NRF2: an emerging battlefield in the neurodegeneration of Alzheimer's disease

Essays in Biochemistry, Journal Year: 2021, Volume and Issue: 65(7), P. 925 - 940

Published: Oct. 10, 2021

Ferroptosis is an iron- and lipid peroxidation-dependent cell death modality emerging evidence indicates that ferroptosis has great explanatory potential for neuronal loss associated CNS dysfunction in a range of neurodegenerative diseases (e.g., Alzheimer's, Parkinson's Huntington's diseases, Motor neuron disease, Friedreich ataxia (FRDA)). Ferroptotic results from lethal levels phospholipid hydroperoxides are generated by iron-dependent peroxidation polyunsaturated fatty acids (PUFAs), such as arachidonic adrenic acids, which conjugated to specific phospholipids phosphatidylethanolamines (PEs)). The major cellular protector against glutathione peroxidase 4 (GPX4), membrane-associated selenoenzyme reduces deleterious their corresponding benign alcohols glutathione-dependent manner. Other complementary protective systems have also been identified act bolster defences ferroptosis. Many pharmacological modulators the pathway identified, targeting proteins involved iron homoeostasis autophagy; production detoxification peroxides, cyst(e)ine/glutathione metabolism. While growing number signalling pathways converge regulate cascade, understanding regulation suggests ferroptotic 'tone' cells can be set transcription factor, nuclear factor erythroid 2-related 2 (NRF2), transcriptionally controls many key components pathway. In this review, we provide critical overview relationship between NRF2 signalling. With focus on role Alzheimer's disease (AD), discuss how therapeutic modulation viable strategy explore treatment ferroptosis-driven neurodegeneration.

Language: Английский

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The signaling pathways and therapeutic potential of itaconate to alleviate inflammation and oxidative stress in inflammatory diseases

Redox Biology, Journal Year: 2022, Volume and Issue: 58, P. 102553 - 102553

Published: Nov. 24, 2022

Endogenous small molecules are metabolic regulators of cell function. Itaconate is a key molecule that accumulates in cells when the Krebs cycle disrupted. derived from cis-aconitate decarboxylation by decarboxylase (ACOD1) mitochondrial matrix and also known as immune-responsive gene 1 (IRG1). Studies have demonstrated itaconate plays an important role regulating signal transduction posttranslational modification through its immunoregulatory activities. bridge among metabolism, inflammation, oxidative stress, immune response. This review summarizes structural characteristics classical pathways itaconate, derivatives, compounds release itaconate. Here, mechanisms action, including transcriptional regulation ATF3/IκBζ axis type I IFN, protein KEAP1, inflammasome, JAK1/STAT6 pathway, TET2, TFEB, succinate dehydrogenase glycolytic enzyme presented. Moreover, roles diseases related to inflammation stress induced autoimmune responses, viruses, sepsis IRI discussed this review. We hope information provided will help increase understanding cellular metabolism improve clinical treatment stress.

Language: Английский

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Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(3), P. 579 - 615

Published: Jan. 24, 2024

Abstract This article provides an overview of the background knowledge ferroptosis in nervous system, as well key role nuclear factor E2-related 2 (Nrf2) regulating ferroptosis. The takes Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), and amyotrophic lateral sclerosis (ALS) starting point to explore close association between Nrf2 ferroptosis, which is clear significant importance for understanding mechanism neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links pathogenesis NDs. As progresses, damage antioxidant excessive OS, altered expression levels, especially inhibition by lipid peroxidation inhibitors adaptive enhancement signaling, demonstrate potential clinical significance detecting identifying targeted therapy neuronal loss mitochondrial dysfunction. These findings provide new insights possibilities treatment prevention

Language: Английский

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Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection

PLoS Pathogens, Journal Year: 2022, Volume and Issue: 18(1), P. e1010219 - e1010219

Published: Jan. 13, 2022

Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there need for therapeutic interventions that dampen redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate an immunomodulatory metabolite which also reprograms cell metabolism when applied exogenously. We evaluated effects endogenous itaconate exogenous application its variants dimethyl- 4-octyl-itaconate (DI, 4OI) on host to influenza A virus (IAV). Infection induced expression ACOD1, the enzyme catalyzing synthesis, monocytes macrophages, correlated with replication was abrogated by DI 4OI treatment. In IAV-infected mice, pulmonary weight loss were greater Acod1 -/- than wild-type treatment reduced mortality. The compounds reversed infection-triggered interferon modulated human cells supporting non-productive productive infection, peripheral blood mononuclear cells, lung tissue. All three itaconates ROS levels STAT1 phosphorylation, whereas AKT phosphorylation but increased itaconate. Single-cell RNA sequencing identified as main target infection exclusive source ACOD1 mRNA blood. silenced IFN-responses predominantly monocytes, lymphocytes natural killer cells. Ectopic synthesis A549 do not physiologically express , infection-driven inflammation, IAV- IFNγ-induced CXCL10 murine macrophages independent presence . differed greatly their cellular gene homeostasis released cytokines/chemokines, all markedly release pro-inflammatory chemokines (IP-10) CCL2 (MCP-1). Viral did increase under despite dramatically repressed IFN responses. fact, strongly inhibited transcription titers (4OI>Ita>DI) unaffected. Taken together, these results reveal infection.

Language: Английский

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Effects of the Edaravone, a Drug Approved for the Treatment of Amyotrophic Lateral Sclerosis, on Mitochondrial Function and Neuroprotection

Antioxidants, Journal Year: 2022, Volume and Issue: 11(2), P. 195 - 195

Published: Jan. 20, 2022

Edaravone, the first known free radical scavenger, has demonstrated cellular protective properties in animals and humans. Owing to its antioxidant activity, edaravone modulates oxidative damage various diseases, especially neurodegenerative diseases. In 2015, was approved Japan treat amyotrophic lateral sclerosis. The distinguishing pathogenic features of diseases include high reactive oxygen species levels mitochondrial dysfunction. However, correlation between mitochondria not been elucidated. This review highlights recent studies on novel therapeutic perspectives terms effect stress function.

Language: Английский

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Four-Octyl itaconate ameliorates periodontal destruction via Nrf2-dependent antioxidant system

International Journal of Oral Science, Journal Year: 2022, Volume and Issue: 14(1)

Published: May 31, 2022

Abstract Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate (4-OI) cell-permeable derivative has been recognized as promising therapeutic target for treatment inflammatory diseases. Here, we explored, first time, protective effect 4-OI on inhibiting destruction, ameliorating local inflammation, underlying mechanism in periodontitis. Here showed that ameliorates induced lipopolysaccharide microenvironment. can also significantly alleviate loss via Nrf2 activation observed samples from experimental periodontitis C57BL/6 mice. This was further confirmed silencing blocked antioxidant downregulating expression downstream enzymes. Additionally, molecular docking simulation indicated possible under activation. Also, −/− mice, did not protect against dysfunction due periodontitis, underlined importance mediated treatment. Our results attenuates oxidative stress disassociation KEAP1-Nrf2 signaling cascade. Taken together, administration offers clinical potential inhibit ameliorate more predictable

Language: Английский

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Luteolin Protects Chondrocytes from H2O2-Induced Oxidative Injury and Attenuates Osteoarthritis Progression by Activating AMPK-Nrf2 Signaling

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 20

Published: Feb. 1, 2022

Osteoarthritis (OA) is a chronic degenerative disease featured by cartilage erosion and inflammation. Luteolin, member of the flavonoid family, has been shown to exert anti-inflammatory antioxidative activities. However, potential biological effects underlying mechanism luteolin on chondrocytes OA progression remain largely elusive. In this study, effect were investigated in vitro vivo. Our data revealed that inhibited H2O2-induced cell death, apoptosis, oxidative stress, programmed necrosis, inflammatory mediator production primary murine chondrocytes. addition, could activate AMPK Nrf2 pathways, serves as positive upstream regulator Nrf2. vivo results demonstrated therapeutic DMM mouse model. Collectively, our findings showed might serve novel effective treatment for provided new research direction clinical therapies.

Language: Английский

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Itaconate: A Potent Macrophage Immunomodulator

Inflammation, Journal Year: 2023, Volume and Issue: 46(4), P. 1177 - 1191

Published: May 4, 2023

Language: Английский

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