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An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.

ABSTRACT: Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer's disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Interestingly, Nrf2 is proved to contribute to the regulation of the heme oxygenase-1 (HO-1) axis, which is a potent anti-inflammatory target. Recent studies showed a connection between the Nrf2/antioxidant response element (ARE) system and the expression of inflammatory mediators, NF-?B pathway and macrophage metabolism. This suggests a new strategy for designing chemical agents as modulators of Nrf2 dependent pathways to target the immune response. Therefore, the present review will examine the relationship between Nrf2 signaling and the inflammation as well as possible approaches for the therapeutic modulation of this pathway.

SUBMITTER: Saha S

PROVIDER: S-EPMC7700122 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.

Saha Sarmistha S Buttari Brigitta B Panieri Emiliano E Profumo Elisabetta E Saso Luciano L

Molecules (Basel, Switzerland) 20201123 22

Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer's disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-lik ...[more]

PMID: 33238435

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Project description:Depression is one of the most common mood disorders with a high rate of relapse. Accumulating evidence suggests that the transcription factor Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system plays a key role in inflammation which is involved in depression. Preclinical studies demonstrated that the protein expressions of Keap1 and Nrf2 in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of hippocampus in mice with depression-like phenotype were lower than control mice. In the learned helplessness paradigm, the protein levels of Keap1 and Nrf2 in the PFC and DG of hippocampus from rats with depression-like phenotype were also lower than control and resilient rats. Furthermore, rodents with depression-like phenotype have higher levels of pro-inflammatory cytokines. Interestingly, Nrf2 knock-out (KO) mice exhibit depression-like phenotype, and higher serum levels of pro-inflammatory cytokines compared with wild-type mice. Furthermore, Nrf2 KO mice have lower expression of brain-derived neurotrophic factor (BDNF) in the PFC, and CA3 and DG of hippocampus compared to wild-type mice. 7,8-Dihydroxyflavone, a TrkB agonist, showed antidepressant effects in Nrf2 KO mice, by stimulating BDNF-TrkB in the PFC, CA3, and DG. Pretreatment with sulforaphane, a naturally occurring Nrf2 activator, prevented depression-like phenotype in mice after inflammation, or chronic social defeat stress. Interestingly, dietary intake of 0.1% glucoraphanin (a precursor of sulforaphane) containing food during juvenile and adolescent stages of mice could prevent depression-like phenotype in adulthood after chronic social defeat stress. Moreover, the protein expressions of Keap1 and Nrf2 in the parietal cortex from major depressive disorder and bipolar disorder were lower than controls. These findings suggest that Keap1-Nrf2 system plays a key role in the stress resilience which is involved in the pathophysiology of mood disorders. It is, therefore, possible that dietary intake of cruciferous vegetables including glucoraphanin (or SFN) may prevent or minimize relapse from remission, induced by stress and/or inflammation in depressed patients. In the review, the author would like to discuss the role of Keap1-Nrf2 system in mood disorders.

Project description:PurposeThe purpose of this study was to investigate the therapeutic effect of perillaldehyde (PAE) on Aspergillus fumigatus (A. fumigatus) keratitis.MethodsHuman corneal epithelial cells (HCECs) were pretreated with PAE and stimulated with A. fumigatus mycelium. C57BL/6 mice were infected with A. fumigatus and treated with or without PAE 1 day after infection. Clinical scores, PCR, ELISA, and Western blotting were used to detect the expression of pro-inflammatory mediators, dendritic cell-associated c-type lectin-1 (Dectin-1), nuclear factor (erythroid-derived 2) like 2 (Nrf2), and heme oxygenase (HO-1). Nrf2 expression in HCECs pretreated with PAE was observed by immunofluorescence. NIMP-R14 protein expression and localization in mouse corneas were observed by immunofluorescence staining after treatment with PAE. Corneal colony counting, time-kill tests, and mycelial transformation inhibition tests were used to evaluate the antifungal effect of PAE.ResultsC57BL/6 mice treated with PAE at 1 day after infection had a lower clinical score and decreased IL-1β, TNF-α, IL-6, Dectin-1, and MPO levels. PAE treatment significantly reduced neutrophil recruitments to the corneal stroma. Compared with the DMSO-treated group, PAE treatment significantly decreased mRNA and protein levels of pro-inflammatory cytokines and Dectin-1 in HCECs. PAE pretreatment before A. fumigatus stimulation obviously elevated the mRNA and protein levels of components of the Nrf2/HO-1 axis. HCECs pretreated with PAE before infection showed a weakened ability to inhibit inflammation in the presence of brusatol (BT; an Nrf2 inhibitor) or ZnPP (an HO-1 inhibitor). PAE treatment significantly reduced the fungal load of C57BL/6 mouse corneas and inhibited fungal growth in vitro.ConclusionsThese data proved that PAE may ameliorate A. fumigatus keratitis by activating the Nrf2/HO-1 signaling pathway and inhibiting the Dectin-1 mediated inflammatory response and neutrophil recruitment. Furthermore, PAE exerts direct fungicidal activity on A. fumigatus.

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An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.

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An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.

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