Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Seminotti, Bianca; Grings, Mateus; Tucci, Paolo; Leipnitz, Guilhian; Saso, Luciano

doi:10.3389/fncel.2021.785057

Cited by 27 publications

(19 citation statements)

References 146 publications

(228 reference statements)

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“…Kelch-like ECH-associated protein (KEAP1) is one of the main regulators of Nrf2 protein stability. Under normal homeostatic conditions, Nrf2 is located in the cytosol and binds KEAP1 [2].…”

Section: The Nrf2-are Pathway As a Therapeutic Targetmentioning

confidence: 99%

“…Excess ROS formation causes critically important changes in cellular biomolecules, such as proteins, DNA, and lipids. There are numerous studies that confirm a major relationship between OS and neurodegenerative disorders [1,2] like Alzheimer's disease (AD) [3], Huntington's disease (HD) [4], Parkinson's disease (PD) [5], Multiple sclerosis (MS) [6] and Amyotrophic Lateral Sclerosis (ALS) [7].…”

Section: Introductionmentioning

confidence: 99%

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A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

et al. 2022

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Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents.

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“…Kelch-like ECH-associated protein (KEAP1) is one of the main regulators of Nrf2 protein stability. Under normal homeostatic conditions, Nrf2 is located in the cytosol and binds KEAP1 [2].…”

Section: The Nrf2-are Pathway As a Therapeutic Targetmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

et al. 2022

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“…Nrf2 regulates the adaptive response to oxidative stress [119]. The evolution of Nrf2 is correlated with increasing atmospheric oxygen [120].…”

Section: Transcription Factorsmentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase, Redox Homeostasis and Embryogenesis

Chen

Tjong

Yang

et al. 2022

IJMS

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Normal embryogenesis requires complex regulation and precision, which depends on multiple mechanistic details. Defective embryogenesis can occur by various mechanisms. Maintaining redox homeostasis is of importance during embryogenesis. NADPH, as produced from the action of glucose-6-phosphate dehydrogenase (G6PD), has an important role in redox homeostasis, serving as a cofactor for glutathione reductase in the recycling of glutathione from oxidized glutathione and for NADPH oxidases and nitric oxide synthases in the generation of reactive oxygen (ROS) and nitrogen species (RNS). Oxidative stress differentially influences cell fate and embryogenesis. While low levels of stress (eustress) by ROS and RNS promote cell growth and differentiation, supra-physiological concentrations of ROS and RNS can lead to cell demise and embryonic lethality. G6PD-deficient cells and organisms have been used as models in embryogenesis for determining the role of redox signaling in regulating cell proliferation, differentiation and migration. Embryogenesis is also modulated by anti-oxidant enzymes, transcription factors, microRNAs, growth factors and signaling pathways, which are dependent on redox regulation. Crosstalk among transcription factors, microRNAs and redox signaling is essential for embryogenesis.

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“…When bound to KEAP1, NRF2 is targeted for degradation by the proteasome. However, in the presence of electrophiles or oxidative stress the nucleophilic cysteine sulfhydryl groups on KEAP1 are modified resulting in an allosteric conformational change that diminishes the KEAP-dependent degradation of NRF2 and allows the transcription factor to accumulate in the nucleus [ 1 ] ( Figure 1 ). Nuclear translocation can also result from the phosphorylation of NRF2 at serine 40.…”

Section: Introductionmentioning

confidence: 99%

The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function

et al. 2022

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in mitochondrial function and biogenesis. Moreover, NRF2 has been shown to directly regulate the expression of anti-inflammatory mediators reducing the expression of pro-inflammatory cytokines. In recent years, attention has turned to the role NRF2 plays in the brain in different diseases such Alzheimer's disease, Parkinson’s disease, Huntington’s disease and others. This review focused on the evidence, derived in vitro, in vivo and from clinical trials, supporting a role for NRF2 activation in maintaining and improving cognitive function and how its activation can be used to elicit neuroprotection and lead to cognitive enhancement. The review also brings a critical discussion concerning the possible prophylactic and/or therapeutic use of NRF2 activators in treating cognitive impairment-related conditions.

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Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders

Cited by 27 publications

References 146 publications

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

Glucose-6-Phosphate Dehydrogenase, Redox Homeostasis and Embryogenesis

The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function

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