Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis

Michaličková, Danica; Hrnčíř, Tomáš; Canová, Nikolina Kutinová; Slanař, Ondřej

doi:10.1016/j.ejphar.2020.172973

Cited by 71 publications

(58 citation statements)

References 203 publications

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“…The anti-inflammatory action of EGCG/GTE also derives by their ability to activate Nrf2 nuclear translocation and HO-1 activity leading to protective effects, in particular, on neuronal cells [ 74 ], in arthritis [ 75 ], and in atherosclerosis [ 76 ].…”

Section: Egcg Molecular Mechanisms That Could Counteract Covid-19 mentioning

confidence: 99%

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Menegazzi

Campagnari

Bertoldi

et al. 2020

IJMS

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Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19.

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Section: Egcg Molecular Mechanisms That Could Counteract Covid-19 mentioning

confidence: 99%

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Menegazzi

Campagnari

Bertoldi

et al. 2020

IJMS

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“…Recently, 4-OI was found to mitigate H 2 O 2 -induced ROS production, lipid oxidation, and cell death in SH-SY5Y cells via KEAP1-NRF2 signaling [ 45 ]. Another study showed that itaconate attenuated cerebral ischemia/reperfusion injury by activating the NRF2 pathway and inhibiting SDH activity [ 46 ]. Moreover, liver ischemia-reperfusion damage was mitigated by 4-OI treatment.…”

Section: Itaconate Activates the Inflammation Response And Oxidatimentioning

confidence: 99%

“…Itaconate showed marked anti-inflammatory and antioxidative properties in many animal models via the regulation of many signaling pathways, including Nrf2 and ATF3, which indicated a feature similar to other Nrf2 activators. The Nrf2 pathway is pivotal in the regulation of oxidative stress and inflammation [ 46 ]. Certain agonists of Nrf2 have already been established to be effective in the treatment of some inflammatory diseases.…”

Section: Future Therapeutic Role Of Itaconatementioning

confidence: 99%

Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress

Zhang

Wang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Metabolic products can lead to crucial biological function alterations. Itaconate is probably the best example of how a metabolic process can be diverted to generate an immunomodulator effect in macrophages. Through inflammatory stimuli, such as lipopolysaccharide, the immune response gene 1 is activated and promotes the production of itaconate from the tricarboxylic acid cycle by decarboxylating cis-aconitate. Itaconate has been reported to have multiple immunoregulatory and antioxidative effects. In addition, reports have described its antibacterial and protumor effects. The involved mechanism in these effects includes the activation of nuclear factor E2-related factor 2 by alkylation of Kelch-like ECH-associated protein 1, inhibition of aerobic glycolysis by targeting glyceraldehyde-3-phosphate dehydrogenase and fructose-bisphosphate aldolase A, inhibition of succinate dehydrogenase, and blockade of IκBζ translation. All of these discoveries elucidated the transformation of the pro- into anti-inflammatory status in macrophages, which is crucial in innate immunity and set the ground for the emerging therapeutic implications of itaconate. In this review, we point out that itaconate is a novel and pivotal metabolic determinant of the immunoregulatory response in macrophages and highlight studies that have improved our understanding of the connection between the immune response and metabolism. In addition, we shed light on the therapeutic potential of itaconate and its derivatives to treat inflammatory diseases.

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“…Among the endogenous cell processes capable of promoting mitochondrial functions and the endogenous defense mechanisms there are those triggered by the peroxisome proliferator-activated receptor gamma (PPAR-γ) and by the transcription factor nuclear factor-erythroid 2 (NF-E2)-related factor (NRF2) [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Besides the very well-known role of NRF2 in the orchestration of the cell response to stress, recent evidence is accumulating on its capability to control the efficiency of the mitochondrial compartment [ 19 , 22 , 23 ]. Worthy of note, PPAR-γ and NRF2 share antioxidant and mitochondria protective functions, and both of them have been identified as targets of pharmacological approaches in therapies aimed at curing type 2 diabetes and relapsing-remitting multiple sclerosis, respectively [ 11 ]. To point out specificities and similarities in the effects of the two pathways and, as a future perspective, to consider these transcription factors as targets in a combined therapy aimed at treating myelin diseases, we analyzed two drugs currently used in clinical practice: pioglitazone, a PPAR-γ agonist belonging to the family of thiazolidinediones, and the NRF2 inducer dimethyl fumarate.…”

Section: Introductionmentioning

confidence: 99%

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation

Nuccio

Bernardo

Troiano

et al. 2020

IJMS

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An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation.

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Targeting Keap1/Nrf2/ARE signaling pathway in multiple sclerosis

Cited by 71 publications

References 203 publications

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Protective Effect of Epigallocatechin-3-Gallate (EGCG) in Diseases with Uncontrolled Immune Activation: Could Such a Scenario Be Helpful to Counteract COVID-19?

Itaconate: A Metabolite Regulates Inflammation Response and Oxidative Stress

NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation

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