Nrf2 regulates ROS production by mitochondria and NADPH oxidase

Biochimica et Biophysica Acta (BBA) - General Subjects, Год журнала: 2014, Номер 1850(4), С. 794 - 801

Опубликована: Дек. 6, 2014

Nuclear factor (erythroid-derived 2) 2 (Nrf2) is a crucial transcription mediating protection against oxidants. Nrf2 negatively regulated by cytoplasmic Kelch-like ECH associated protein 1 (Keap1) thereby providing inducible antioxidant defence. Antioxidant properties of are thought to be mainly exerted stimulating proteins, whereas its effects on ROS production within the cell uncertain.Live imaging and qPCR in brain hippocampal glio-neuronal cultures explants slice with graded expression Nrf2, i.e. Nrf2-knockout (Nrf2-KO), wild-type (WT), Keap1-knockdown (Keap1-KD).We here show that Nrf2-KO cells tissues increased compared their WT counterparts. Mitochondrial Keap1-Nrf2 pathway controlling mitochondrial bioenergetics. Surprisingly, Keap1-KD also showed higher rates when WT, although smaller magnitude. Analysis mRNA levels two NOX isoforms implicated pathology showed, NOX2 dramatically upregulated under conditions deficiency, NOX4 constitutively activated (Keap1-KD) degree which paralleled increases production.These observations suggest regulates both cytosolic through NADPH oxidase.Findings supports key role redox homeostasis cell.

Язык: Английский

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NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches

Redox Biology, Год журнала: 2018, Номер 21, С. 101059 - 101059

Опубликована: Ноя. 28, 2018

Electrophiles and reactive oxygen species (ROS) play a major role in modulating cellular defense mechanisms as well physiological functions, intracellular signaling. However, excessive ROS generation (endogenous exogenous) can create state of redox imbalance leading to tissue damage (Ma He, 2012) [1]. A growing body research data strongly suggests that imbalanced electrophile overproduction are among the prodromal factors onset progression several cerebrovascular neurodegenerative disorders such amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's disease (AD), Parkinson's (PD), aging 2012; Ramsey et al., 2017; Salminen Sandberg 2014; Sarlette 2008; Tanji 2013) [1–6]. Cells offset oxidative stress by action housekeeping antioxidative enzymes (such superoxide dismutase, catalase, glutathione peroxidase) direct indirect antioxidants (Dinkova-Kostova Talalay, 2010) [7]. The DNA sequence responsible for cytoprotective responses cells has been identified antioxidant response element (ARE), while nuclear factor erythroid 2-related (NRF2) is regulator xenobiotic-activated receptor (XAR) activating ARE-pathway, thus defined NRF2-ARE system In addition, interplay between kappa-light-chain-enhancer activated B (NF-ĸB, protein complex controls cytokine production cell survival), further investigated relation neuroinflammatory disorders. On these premises, we provide review analysis current understanding NRF2-NF-ĸB interplay, their specific CNS disorders, consequent therapeutic implication treatment diseases.

Язык: Английский

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Heavy metal associated health hazards: An interplay of oxidative stress and signal transduction

Chemosphere, Год журнала: 2020, Номер 262, С. 128350 - 128350

Опубликована: Сен. 16, 2020

Язык: Английский

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Sulforaphane treatment of autism spectrum disorder (ASD)

Proceedings of the National Academy of Sciences, Год журнала: 2014, Номер 111(43), С. 15550 - 15555

Опубликована: Окт. 13, 2014

Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, no recognized treatment targets the core features ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe received phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo 15). effects on behavior daily oral doses (50-150 µmol) for 18 wk, followed 4 wk without treatment, were quantified three widely accepted behavioral measures completed parents/caregivers physicians: Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), Clinical Global Impression Improvement (CGI-I). Initial scores ABC SRS closely matched participants assigned sulforaphane. After receiving experienced minimal change (<3.3%), whereas those showed substantial declines (improvement behavior): 34% (P < 0.001, comparing treatments) 17% 0.017). On CGI-I, significantly greater number had improvement abnormal verbal 0.015-0.007). Upon discontinuation sulforaphane, total all scales rose toward pretreatment levels. Dietary low toxicity, was selected its capacity reverse abnormalities that have been associated ASD, including oxidative stress lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function phosphorylation, increased lipid peroxidation, neuroinflammmation.

Язык: Английский

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Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

Biology Open, Год журнала: 2013, Номер 2(8), С. 761 - 770

Опубликована: Июнь 20, 2013

Summary Transcription factor Nrf2 and its repressor Keap1 regulate a network of cytoprotective genes involving more than 1% the genome, their best known targets being drug-metabolizing antioxidant genes. Here we demonstrate novel role for this pathway in directly regulating mitochondrial bioenergetics murine neurons embryonic fibroblasts. Loss leads to depolarisation, decreased ATP levels impaired respiration, whereas genetic activation increases membrane potential levels, rate respiration efficiency oxidative phosphorylation. We further show that Nrf2-deficient cells have increased production glycolysis, which is then used by F1Fo-ATPase maintenance potential. While vitro activities respiratory complexes are unaffected deletion, isolated mitochondria intact live substantially impaired. In addition, regeneration NADH after inhibition much slower Nrf2-knockout wild-type counterparts. Taken together, these results regulates cellular energy metabolism through modulating availability substrates respiration. Our findings highlight importance efficient Nrf2-mediated cytoprotection.

Язык: Английский

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Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2011, Номер 1822(5), С. 753 - 783

Опубликована: Ноя. 7, 2011

Язык: Английский

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Immune mechanisms linked to depression via oxidative stress and neuroprogression

Immunology, Год журнала: 2015, Номер 144(3), С. 365 - 373

Опубликована: Янв. 10, 2015

Emerging evidence suggests the significant role of inflammation and oxidative stress as main contributors to neuroprogression that is observed in major depressive disorder (MDD), where patients show increased inflammatory biomarkers. The process includes stage-related neurodegeneration, cell death, reduced neurogenesis, neuronal plasticity autoimmune responses. Oxidative a consequence biological imbalance between Reactive Oxygen Species (ROS) antioxidants, leading alteration biomolecules loss control intracellular redox-related signaling pathways. ROS serve crucial secondary messengers signal transduction significantly affect pathways by activating NF-κB MAPK family kinases. When present excess, inflict damage, affecting cellular constituents with formation pro-inflammatory molecules, such malondialdehyde, 4-Hydroxynonenal, neoepitopes damage-associated molecular patterns promoting immune response, ultimately death. failure cells adapt changes redox homeostasis subsequent together damage caused mediators, have been considered causes hence MDD. Both an activated immune-inflammatory system act synergistically, complicating our understanding pathogenesis depression. cascade antioxidative events orchestrated several transcription factors, Nrf2 having particular relevance This review focuses on potential mechanisms through which impaired neuroinflammation can environment contribute depression article protected copyright. All rights reserved.

Язык: Английский

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The multifaceted role of Nrf2 in mitochondrial function

Current Opinion in Toxicology, Год журнала: 2016, Номер 1, С. 80 - 91

Опубликована: Окт. 11, 2016

The transcription factor nuclear erythroid 2 p45-related (Nrf2) is the master regulator of cellular redox homeostasis. Nrf2 target genes comprise a large network antioxidant enzymes, proteins involved in xenobiotic detoxification, repair and removal damaged proteins, inhibition inflammation, as well other factors. In recent years it has emerged that part its role cytoprotective gene expression, impacts mitochondrial function. Increased activity defends against toxins. Reduced glutathione, principal small molecule mammalian cell product several downstream Nrf2, counterbalances ROS production. function suppressed mitochondria-related disorders, such Parkinson's disease Friedrich's ataxia. Studies using isolated mitochondria cultured cells have demonstrated deficiency leads to impaired fatty acid oxidation, respiration ATP Small activators support integrity by promoting mitophagy conferring resistance oxidative stress-mediated permeability transition. Excitingly, studies shown also affects stem with implications for self-renewal, cardiomyocyte regeneration, neural stem/progenitor survival.

Язык: Английский

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Reactive oxygen species, nutrition, hypoxia and diseases: Problems solved?

Redox Biology, Год журнала: 2015, Номер 6, С. 372 - 385

Опубликована: Авг. 28, 2015

Within the last twenty years view on reactive oxygen species (ROS) has changed; they are no longer only considered to be harmful but also necessary for cellular communication and homeostasis in different organisms ranging from bacteria mammals. In latter, ROS were shown modulate diverse physiological processes including regulation of growth factor signaling, hypoxic response, inflammation immune response. During 60–100 life style, at least Western world, changed enormously. This became obvious with an increase caloric intake, decreased energy expenditure as well appearance alcoholism smoking; These changes contribute generation which are, part, associated occurrence several chronic diseases like adiposity, atherosclerosis, type II diabetes, cancer. this review we discuss aspects problems role intracellular formation nutrition link their problematic therapeutical issues. • Oxidative stress is linked overnutrition, obesity or Reactive crucially involved modulation signaling cascades. NOX proteins hypoxia under nutrient regimes. powerful post-transcriptional epigenetic regulators. Treatment antioxidants requires more, larger, better monitored clinical trials.

Язык: Английский

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Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases

Natural Product Reports, Год журнала: 2013, Номер 31(1), С. 109 - 139

Опубликована: Ноя. 30, 2013

Covering: 2000 to 2013. Oxidative stress is the central component of chronic diseases. The nuclear factor erythroid 2-related 2/antioxidant response element (Nrf2/ARE) pathway vital in up-regulation cytoprotective genes and enzymes oxidative treatment with certain dietary phytochemicals. Herein, we classify bioactive compounds derived from natural products that are Nrf2/ARE activators recapitulate molecular mechanisms for inducing Nrf2 provide favorable effects experimental models Moreover, pharmacological inhibition signalling has emerged as promising strategy against multi-drug resistance thereby improving efficacy. We have also enlisted product-derived inhibitors pathway.

Язык: Английский

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