Can nitroxides evoke the Keap1–Nrf2–ARE pathway in skin?

Greenwald, Maya Ben Yehuda; Anzi, Shira; Sasson, Shmuel Ben; Bianco‐Peled, Havazelet; Kohen, Ron

doi:10.1016/j.freeradbiomed.2014.08.021

Cited by 29 publications

(10 citation statements)

References 87 publications

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“…Upon oxidation of redox sensitive cysteines of Keap1, Nrf2 transcription factor is activated, which results in upregulation of endogenous antioxidative defenses [67,68] . Nitroxides were shown to activate that pathway also [69–71] . It may be mechanism of actions of flavonoids also [70,71] (see also Scheme XX ).…”

Section: Scheme Imentioning

confidence: 99%

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

2015

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Most of the SOD mimics thus far developed belong to the classes of Mn-(MnPs) and Fe porphyrins(FePs), Mn(III) salens, Mn(II) cyclic polyamines and metal salts. Due to their remarkable stability we have predominantly explored Mn porphyrins, aiming initially at mimicking kinetics and thermodynamics of the catalysis of O2•− dismutation by SOD enzymes. Several MnPs are of potency similar to SOD enzymes. The in vivo bioavailability and toxicity of MnPs have been addressed also. Numerous in vitro and in vivo studies indicate their impressive therapeutic efficacy. Increasing insight into complex cellular redox biology has been accompanied by increasing awareness of complex redox chemistry of MnPs. During O2•− dismutation process, the most powerful Mn porphyrin-based SOD mimics reduce and oxidize O2•− with close to identical rate constants. MnPs reduce and oxidize other reactive species also (none of them specific to MnPs), acting as reductants (antioxidant) and pro-oxidants. Distinction must be made between the type of reactions of MnPs and the favorable therapeutic effects we observe; the latter may be of either anti- or pro-oxidative nature. H2O2/MnP mediated oxidation of protein thiols and its impact on cellular transcription seems to dominate redox biology of MnPs. It has been thus far demonstrated that the ability of MnPs to catalyze O2•− dismutation parallels all other reactivities (such as ONOO− reduction) and in turn their therapeutic efficacies. Assuming that all diseases have in common the perturbation of cellular redox environment, developing SOD mimics still seems to be the appropriate strategy for the design of potent redox-active therapeutics.

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Section: Scheme Imentioning

confidence: 99%

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

2015

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“…Important anti-inflammatory mechanisms are mediated by Nrf2 [ 6 ]. Nrf2 activation is associated with its dissociation from the Keap1-Cul3 complex that sequesters Nrf2 translocation to the nucleus and its binding to antioxidative response elements [ 7 ]. We examined the effect of porphyra-334 on the subcellular localization of Nrf2 ( Figure 3 A).…”

Section: Resultsmentioning

confidence: 99%

“…In skin, Nrf2 activation can be triggered by UV radiation or phytochemicals in keratinocytes, fibroblasts and melanocytes in vitro [ 7 , 8 , 9 ]. Nrf2 activation was frequently associated with the protective effects against UVA irradiation [ 7 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Nrf2 and NF-κB Signaling Pathways Contribute to Porphyra-334-Mediated Inhibition of UVA-Induced Inflammation in Skin Fibroblasts

2015

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In this study, we examined the protective effects of porphyra-334 against UVA-irradiated cellular damage and elucidated the underlying mechanisms. Porphyra-334 prevented UVA-induced cell death and exhibited scavenging activities against intracellular oxidative stress induced by UVA irradiation in skin fibroblasts. We found that porphyra-334 significantly reduced the secretion and expression of IL-6 and TNF-α, reduced nuclear expression of Nuclear factor-κB (NF-κB), and sustained NF-E2-related factor 2 (Nrf2) activation. Further mechanism research revealed that porphyra-334 promoted the Nrf2 signaling pathway in UVA-irradiated skin fibroblasts. Our results show that the antioxidant effect of porphyra-334 is due to the direct scavenging of oxidative stress and its inhibitory effects on NF-κB-dependent inflammatory genes, such as IL-6 and TNF-κ. Therefore, we hypothesize that boosting the Nrf2- NF-κB-dependent response to counteract environmental stress is a promising strategy for the prevention of UVA-related damage.

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“…Some examples of Nrf2 activators include sulforaphane, curcumin, epigallocatechin-3-gallate, resveratrol, garlic, oganosulfur compounds, lycopene, carnosol [223][224][225], nitroxides [226] and dimethyl fumarate [227].…”

Section: Nrf2-activating Agentsmentioning

confidence: 99%

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

et al. 2016

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Abstract:The skin, being the largest organ of the body, functions as a barrier between our body and the environment. It is consistently exposed to various exogenous and endogenous stressors (e.g., air pollutants, ionizing and non-ionizing irradiation, toxins, mitochondrial metabolism, enzyme activity, inflammatory process, etc.) producing reactive oxygen species (ROS) and physical damage (e.g., wounds, sunburns) also resulting in reactive oxygen species production. Although skin is equipped with an array of defense mechanisms to counteract reactive oxygen species, augmented exposure and continued reactive oxygen species might result in excessive oxidative stress leading to many skin disorders including inflammatory diseases, pigmenting disorders and some types of cutaneous malignancy. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance and of defensive enzymes such as the phase II enzymes. Induction of the Keap1-Nrf2 pathway may have a beneficial effect in the treatment of a large number of skin disorders by stimulating an endogenous defense mechanism. However, prolonged and enhanced activation of this pathway is detrimental and, thus, limits the therapeutic potential of Keap1-Nrf2 modulators. Here, we review the consequences of oxidative stress to the skin, and the defense mechanisms that skin is equipped with. We describe the challenges of maintaining skin redox balance and its impact on skin status and function. Finally, we suggest a novel strategy for maintenance of skin redox homeostasis by modulating the Keap1-Nrf2 pathway using nanotechnology-based delivery systems.

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Can nitroxides evoke the Keap1–Nrf2–ARE pathway in skin?

Cited by 29 publications

References 87 publications

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

An educational overview of the chemistry, biochemistry and therapeutic aspects of Mn porphyrins – From superoxide dismutation to H2O2-driven pathways

Nrf2 and NF-κB Signaling Pathways Contribute to Porphyra-334-Mediated Inhibition of UVA-Induced Inflammation in Skin Fibroblasts

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

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