scholarly journals An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases

2021 ◽  
Vol 22 (17) ◽  
pp. 9592
Author(s):  
Emilia Zgorzynska ◽  
Barbara Dziedzic ◽  
Anna Walczewska
Keyword(s):  
Leucine Zipper ◽  
Target Genes ◽  
Protective Efficacy ◽  
Antioxidant Response ◽  
Activation Mechanism ◽  
Age Related ◽  
Nrf2 Activation ◽  
Metabolic Conditions ◽  
Lateral Sclerosis

Nrf2 is a basic region leucine-zipper transcription factor that plays a pivotal role in the coordinated gene expression of antioxidant and detoxifying enzymes, promoting cell survival in adverse environmental or defective metabolic conditions. After synthesis, Nrf2 is arrested in the cytoplasm by the Kelch-like ECH-associated protein 1 suppressor (Keap1) leading Nrf2 to ubiquitin-dependent degradation. One Nrf2 activation mechanism relies on disconnection from the Keap1 homodimer through the oxidation of cysteine at specific sites of Keap1. Free Nrf2 enters the nucleus, dimerizes with small musculoaponeurotic fibrosarcoma proteins (sMafs), and binds to the antioxidant response element (ARE) sequence of the target genes. Since oxidative stress, next to neuroinflammation and mitochondrial dysfunction, is one of the hallmarks of neurodegenerative pathologies, a molecular intervention into Nrf2/ARE signaling and the enhancement of the transcriptional activity of particular genes are targets for prevention or delaying the onset of age-related and inherited neurogenerative diseases. In this study, we review evidence for the Nrf2/ARE-driven pathway dysfunctions leading to various neurological pathologies, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as amyotrophic lateral sclerosis, and the beneficial role of natural and synthetic molecules that are able to interact with Nrf2 to enhance its protective efficacy.

scholarly journals Nrf2 activation by sulforaphane restores the age-related decrease of TH1 immunity: Role of dendritic cells

2008 ◽  
Vol 121 (5) ◽  
pp. 1255-1261.e7 ◽  
Author(s):  
Hyon-Jeen Kim ◽  
Berenice Barajas ◽  
Meiying Wang ◽  
Andre E. Nel
Keyword(s):  
Dendritic Cells ◽  
Age Related ◽  
Nrf2 Activation

Contribution of a Metal-Peroxide Adduct to Neurodegeneration Is Due to Its Oxidative Protease Activity

1999 ◽  
Vol 54 (12) ◽  
pp. 1107-1114 ◽  
Author(s):  
Yuzo Nishida ◽  
Satoshi Nishino
Keyword(s):  
Prion Disease ◽  
Protease Activity ◽  
Reaction Scheme ◽  
Theoretical Point ◽  
Metal Compounds ◽  
Age Related ◽  
The Moment ◽  
The Brain ◽  
Lateral Sclerosis

Many hypotheses have been developed to explain aging and age-related neurodegenerative disorders; one of the most compelling is the role of oxidative stress to induce changes in protease activity in brains of patients of Alzheimer’s disease and prion disease. At the moment however, there is no clear answer how protein degradation may be achieved in the brain. We have observed that several metal compounds can degrade proteins in the presence of hydrogen peroxide, and elucidated the reaction scheme based on the new theoretical point for the reactivity of a metal-peroxide adduct with η1-coordination mode. In this article we would like to point out the importance of a copper(II)-peroxide adduct to promote neurodegenerative diseases such as prion disease and amyotrophic lateral sclerosis through its oxidative protease function.

scholarly journals Molecular Mechanisms Underlying Hepatocellular Carcinoma Induction by Aberrant NRF2 Activation-Mediated Transcription Networks: Interaction of NRF2-KEAP1 Controls the Fate of Hepatocarcinogenesis

2020 ◽  
Vol 21 (15) ◽  
pp. 5378 ◽  
Author(s):  
Effi Haque ◽  
M. Rezaul Karim ◽  
Aamir Salam Teeli ◽  
Magdalena Śmiech ◽  
Paweł Leszczynski ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Precancerous Lesions ◽  
Redox Homeostasis ◽  
Detoxification Enzymes ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Nrf2 Activation

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

scholarly journals Metals and Neurodegeneration

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 366 ◽  
Author(s):  
Pan Chen ◽  
Mahfuzur Rahman Miah ◽  
Michael Aschner
Keyword(s):  
Metal Accumulation ◽  
Neurological Diseases ◽  
Cell Structure ◽  
Antioxidant Response ◽  
Autism Spectrum ◽  
Metal Exposure ◽  
Gulf War Syndrome ◽  
Guillain Barré ◽  
Lateral Sclerosis

Metals play important roles in the human body, maintaining cell structure and regulating gene expression, neurotransmission, and antioxidant response, to name a few. However, excessive metal accumulation in the nervous system may be toxic, inducing oxidative stress, disrupting mitochondrial function, and impairing the activity of numerous enzymes. Damage caused by metal accumulation may result in permanent injuries, including severe neurological disorders. Epidemiological and clinical studies have shown a strong correlation between aberrant metal exposure and a number of neurological diseases, including Alzheimer’s disease, amyotrophic lateral sclerosis, autism spectrum disorders, Guillain–Barré disease, Gulf War syndrome, Huntington’s disease, multiple sclerosis, Parkinson’s disease, and Wilson’s disease. Here, we briefly survey the literature relating to the role of metals in neurodegeneration.

scholarly journals Role of the Nrf2-ARE Pathway in Liver Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Sang Mi Shin ◽  
Ji Hye Yang ◽  
Sung Hwan Ki
Keyword(s):  
Liver Diseases ◽  
Target Genes ◽  
Antioxidant Response ◽  
Related Factor ◽  
Genes Expression ◽  
Wide Range ◽  
Range Of Functions ◽  
Central Organ ◽  
Essential Transcription Factor

The liver is a central organ that performs a wide range of functions such as detoxification and metabolic homeostasis. Since it is a metabolically active organ, liver is particularly susceptible to oxidative stress. It is well documented that liver diseases including hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are highly associated with antioxidant capacity. NF-E2-related factor-2 (Nrf2) is an essential transcription factor that regulates an array of detoxifying and antioxidant defense genes expression in the liver. It is activated in response to electrophiles and induces its target genes by binding to the antioxidant response element (ARE). Therefore, the roles of the Nrf2-ARE pathway in liver diseases have been extensively investigated. Studies from several animal models suggest that the Nrf2-ARE pathway collectively exhibits diverse biological functions against viral hepatitis, alcoholic and nonalcoholic liver disease, fibrosis, and cancer via target gene expression. In this review, we will discuss the role of the Nrf2-ARE pathway in liver pathophysiology and the potential application of Nrf2 as a therapeutic target to prevent and treat liver diseases.

scholarly journals Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Debora Giunti ◽  
Chiara Marini ◽  
Benedetta Parodi ◽  
Cesare Usai ◽  
Marco Milanese ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mode Of Action ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Mapk Signaling ◽  
Target Cells ◽  
Inflammatory Phenotype ◽  
Lateral Sclerosis

AbstractMesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One mode of action through which MSCs exert their immunomodulatory effects is release of extracellular vesicles that carry proteins, mRNAs, and microRNAs (miRNAs), which, once transferred, modify the function of target cells. We identified nine miRNAs significantly dysregulated in IFN-γ-primed MSCs, but present at different levels in their derived small extracellular vesicles (s-EV). We show that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression. Further analysis of the mode of action of miR-467f and miR-466q indicated that they dampen the pro-inflammatory phenotype of microglia by modulating p38 MAPK signaling pathway via inhibition of expression of their target genes, Map3k8 and Mk2. Finally, we demonstrated that in vivo administration of s-EV leads to decreased expression of neuroinflammation markers in the spinal cord of EAE-affected mice, albeit without affecting disease course. Overall, our data suggest that MSC-derived exosomes could affect neuroinflammation possibly through specific immunomodulatory miRNAs acting on microglia.

scholarly journals Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Susanne Petri ◽  
Sonja Körner ◽  
Mahmoud Kiaei
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Leucine Zipper ◽  
Antioxidant Response ◽  
Related Factor ◽  
Mitochondrial Dysfunctions ◽  
Promising Target ◽  
Basic Region ◽  
Lateral Sclerosis

Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD).

scholarly journals The Protective Effects of Isoliquiritigenin and Glycyrrhetinic Acid against Triptolide-Induced Oxidative Stress in HepG2 Cells Involve Nrf2 Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Ling-Juan Cao ◽  
Huan-De Li ◽  
Miao Yan ◽  
Zhi-Hua Li ◽  
Hui Gong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Biological Activities ◽  
Antioxidant Response ◽  
Current Data ◽  
Glycyrrhetinic Acid ◽  
Protective Effects ◽  
Nrf2 Activation ◽  
Wide Range

Triptolide (TP), an active ingredient ofTripterygium wilfordiiHook f., possesses a wide range of biological activities. Oxidative stress likely plays a role in TP-induced hepatotoxicity. Isoliquiritigenin (ISL) and glycyrrhetinic acid (GA) are potent hepatoprotection agents. The aim of the present study was to investigate whether Nrf2 pathway is associated with the protective effects of ISL and GA against TP-induced oxidative stress or not. HepG2 cells were treated with TP (50 nM) for 24 h after pretreatment with ISL and GA (5, 10, and 20 μM) for 12 h and 24 h, respectively. The results demonstrated that TP treatment significantly increased ROS levels and decreased GSH levels. Both ISL and GA pretreatment decreased ROS and meanwhile enhanced intracellular GSH content. Additionally, TP treatment obviously decreased the protein expression of Nrf2 and its target genes including HO-1 and MRP2 except NQO1. Moreover, both ISL and GA displayed activities as inducers of Nrf2 and increased the expression of HO-1, NQO1, and MRP2. Taken together the current data confirmed that ISL and GA could activate the Nrf2 antioxidant response in HepG2 cells, increasing the expression of its target genes which may be partly associated with their protective effects in TP-induced oxidative stress.

scholarly journals Xanthophylls Modulate Palmitoylation of Mammalian β-Carotene Oxygenase 2

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 413
Author(s):  
Sheetal Uppal ◽  
Sergey A. Dergunov ◽  
Weiyu Zhang ◽  
Susan Gentleman ◽  
T. Michael Redmond ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Protein Translocation ◽  
Antioxidant Response ◽  
Human Vision ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Extensive Body ◽  
Β Carotene

An extensive body of work has documented the antioxidant role of xanthophylls (lutein and zeaxanthin) in human health and specifically how they provide photoprotection in human vision. More recently, evidence is emerging for the transcriptional regulation of antioxidant response by lutein/lutein cleavage products, similar to the role of β-carotene cleavage products in the modulation of retinoic acid receptors. Supplementation with xanthophylls also provides additional benefits for the prevention of age-related macular degeneration (AMD) and attenuation of Alzheimer’s disease symptoms. Mammalian β-carotene oxygenase 2 (BCO2) asymmetrically cleaves xanthophylls as well as β-carotene in vitro. We recently demonstrated that mouse BCO2 (mBCO2) is a functionally palmitoylated enzyme and that it loses palmitoylation when cells are treated with β-carotene. The mouse enzyme is the easiest model to study mammalian BCO2 because it has only one isoform, unlike human BCO2 with several major isoforms with various properties. Here, we used the same acyl-RAC methodology and confocal microscopy to elucidate palmitoylation and localization status of mBCO2 in the presence of xanthophylls. We created large unilamellar vesicle-based nanocarriers for the successful delivery of xanthophylls into cells. We demonstrate here that, upon treatment with low micromolar concentration of lutein (0.15 µM), mBCO2 is depalmitoylated and shows partial nuclear localization (38.00 ± 0.04%), while treatment with zeaxanthin (0.45 µM) and violaxanthin (0.6 µM) induces depalmitoylation and protein translocation from mitochondria to a lesser degree (20.00 ± 0.01% and 35.00 ± 0.02%, respectively). Such a difference in the behavior of mBCO2 toward various xanthophylls and its translocation into the nucleus in the presence of various xanthophylls suggests a possible mechanism for transport of lutein/lutein cleavage products to the nucleus to affect transcriptional regulation.

scholarly journals Neuroprotective Role of the Basic Leucine Zipper Transcription Factor NFIL3 in Models of Amyotrophic Lateral Sclerosis

2013 ◽  
Vol 289 (3) ◽  
pp. 1629-1638 ◽  
Author(s):  
So-ichi Tamai ◽  
Keisuke Imaizumi ◽  
Nobuhiro Kurabayashi ◽  
Minh Dang Nguyen ◽  
Takaya Abe ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transcription Factor ◽  
Motor Neurons ◽  
Leucine Zipper ◽  
Neuronal Damage ◽  
Disease Onset ◽  
Basic Leucine Zipper ◽  
A Cell ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons. Here we show that the basic leucine zipper transcription factor NFIL3 (also called E4BP4) confers neuroprotection in models of ALS. NFIL3 is up-regulated in primary neurons challenged with neurotoxic insults and in a mouse model of ALS. Overexpression of NFIL3 attenuates excitotoxic neuronal damage and protects neurons against neurodegeneration in a cell-based ALS model. Conversely, reduction of NFIL3 exacerbates neuronal demise in adverse conditions. Transgenic neuronal expression of NFIL3 in ALS mice delays disease onset and attenuates motor axon and neuron degeneration. These results suggest that NFIL3 plays a neuroprotective role in neurons and constitutes a potential therapeutic target for neurodegeneration.

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