Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase

Hoffmann, Christina; Dietrich, Michael; Herrmann, Ann-Kathrin; Schacht, Teresa; Albrecht, Philipp; Methner, Axel

doi:10.1155/2017/6093903

Cited by 28 publications

(19 citation statements)

References 26 publications

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“…At a dose of 50 µM, DMF strongly induced the expression of the nrf2 gene in fibroblasts from SSc patients. Such an antioxidative effect was already observed by Hoffmann et al who demonstrated that DMF was able to restore the GSH pool even in the context of total GSH depletion ( 40 ) as observed in fibroblasts from humans or mice with SSc. Increasing GSH was associated with a decreased production of ROS and a decreased proliferation of these cells.…”

Section: Discussionsupporting

confidence: 57%

The Nrf2-Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma

et al. 2018

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Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and internal organs and vascular alterations. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of the disease. Indeed, reactive oxygen species (ROS) trigger neoepitopes leading to a breach of immune tolerance and autoimmune responses, activate fibroblasts to proliferate and to produce excess of type I collagen. ROS also alter endothelial cells leading to vascular dysfunction. Glutathione (GSH) is the most potent antioxidant system in eukaryotic cells. Numerous studies have reported a defect in GSH in SSc animal models and humans, but the origin of this defect remains unknown. The transcription factor NRF2 is a key player in the antioxidant defense, as it can induce the transcription of antioxidant and cytoprotective genes, including GSH, through its interaction with the antioxidant response elements. In this work, we investigated whether NRF2 could be implicated in the pathogenesis of SSc, and if this pathway could represent a new therapeutic target in this orphan disease with no curative medicine. Skin biopsies from 11 patients and 10 controls were harvested, and skin fibroblasts were extracted. Experimental SSc was induced both in BALB/c and in nrf2−/− mice by daily intradermal injections of hypochloric acid. In addition, diseased BALB/c mice were treated with an nrf2 agonist, dimethyl fumarate, or placebo. A drop in nrf2 and target genes mRNA levels was observed in skin fibroblasts of SSc patients compared to controls. Moreover, the nrf2 pathway is also downregulated in skins and lungs of SSc mice. In addition, we observed that nrf2−/− mice have a more severe form of SSc with increased fibrosis and inflammation compared to wild-type SSc mice. Diseased mice treated with the nrf2 agonist dimethyl fumarate (DMF) exhibited reduced fibrosis and immune activation compared to untreated mice. The ex vivo treatment of skin fibroblasts from SSc mice with DMF restores GSH intracellular content, decreases ROS production and cell proliferation. These results suggest that the nrf2 pathway is highly dysregulated in human and SSc mice with deleterious consequences on fibrosis and inflammation and that Nrf2 modulation represents a therapeutic target in SSc.

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Section: Discussionsupporting

confidence: 57%

The Nrf2-Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma

et al. 2018

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“…Concerning the effect of dietary AX supplementation on endogenous antioxidant enzymes (both in terms of activities and mRNA level of GR), the enzyme involved in the reduction of GSSG to GSH using NADPH as a reducing cofactor [60] was increased, whereas other antioxidant enzymes were not significantly affected. Similar to our results, an enhanced GR activity was reported in liver of rainbow trout after 8 weeks of AX supplementation [12].…”

Section: Control Of Antioxidant Enzymes By Episodic Hyperoxia and Diementioning

confidence: 98%

Influence of Dietary Astaxanthin on the Hepatic Oxidative Stress Response Caused by Episodic Hyperoxia in Rainbow Trout

et al. 2019

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A 13-week feeding trial was carried out with juvenile rainbow trout to test two diets: a control diet without astaxanthin (AX) supplementation (CTRL diet), and a diet supplemented with 100 mg/kg of synthetic AX (ASTA diet). During the last week of the feeding trial, fish were exposed to episodic hyperoxia challenge for 8 consecutive hours per day. Episodic hyperoxia induced physiological stress responses characterized by a significant increase in plasma cortisol and hepatic glycogen and a decrease in plasma glucose levels. The decrease of plasma glucose and the increase of hepatic glycogen content due to episodic hyperoxia were emphasized with the ASTA diet. Hyperoxia led to an increase in thiobarbituric acid-reactive substances in the muscle, diminished by dietary AX supplementation in both liver and muscle. Muscle and liver AX were increased and decreased respectively after 7-day episodic hyperoxia, leading to an increase in flesh redness. This augment of muscle AX could not be attributed to AX mobilization, since plasma AX was not affected by hyperoxia. Moreover, hyperoxia decreased most of antioxidant enzyme activities in liver, whereas dietary AX supplementation specifically increased glutathione reductase activity. A higher mRNA level of hepatic glutathione reductase, thioredoxin reductase, and glutamate-cysteine ligase in trout fed the ASTA diet suggests the role of AX in glutathione and thioredoxin recycling and in de novo glutathione synthesis. Indeed, dietary AX supplementation improved the ratio between reduced and oxidized glutathione (GSH/GSSG) in liver. In addition, the ASTA diet up-regulated glucokinase and glucose-6-phosphate dehydrogenase mRNA level in the liver, signaling that dietary AX supplementation may also stimulate the oxidative phase of the pentose phosphate pathway that produces NADPH, which provides reducing power that counteracts oxidative stress. The present results provide a broader understanding of the mechanisms by which dietary AX is involved in the reduction of oxidative status. very much linked to oxidative stress, which is the result of an imbalance between the production of reactive oxygen (ROS) and nitrogen species (RNS) by cell respiration and immune responses, and the state of the antioxidant defenses [1]. In order to protect against oxidative stress, organisms have developed antioxidant systems consisting of low-molecular-mass compounds including glutathione, ascorbic and uric acid, tocopherols, and carotenoids, and high-molecular-mass proteins including superoxide dismutases, catalases, Se-dependent glutathione peroxidases, glutathione reductase, and glucose-6-phosphate dehydrogenase [2].Carotenoids are natural pigments with immune-stimulant and antioxidant properties [3,4] and are present in the integument of many vertebrate species, generating bright-colored traits [5] Among carotenoids, astaxanthin (AX) is the most commonly used feed additive in order to achieve the characteristic red-pink coloration in crustaceans and salmonids [6,7]. The red coloration of AX is due ...

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“…Our previous study has shown that DMF exerts antioxidant effects by upregulating the protein expressions of CAT, GCLM, and endothelial nitric oxide synthase (eNOS), but not NQO1, HO-1, GCLC or GPX in the liver tissue of mice with liver reperfusion injury [11]. Moreover, in addition to activating NQO1 and HO-1, studies in MS have found that DMF increases the expression of GCLC and GPX [13], which indicates that the antioxidant pathway activated by DMF may be tissue-specific.…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Alleviates Dextran Sulfate Sodium-Induced Colitis, through the Activation of Nrf2-Mediated Antioxidant and Anti-inflammatory Pathways

Takasu

Lau

et al. 2020

Antioxidants

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Oxidative stress and chronic inflammation play critical roles in the pathogenesis of ulcerative colitis (UC) and inflammatory bowel diseases (IBD). A previous study has demonstrated that dimethyl fumarate (DMF) protects mice from dextran sulfate sodium (DSS)-induced colitis via its potential antioxidant capacity, and by inhibiting the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This study aims to clarify the nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway pharmacological activation and anti-inflammatory effect by DMF, through focusing on other crucial antioxidant enzymes and inflammatory mediator, including glutamate-cysteine ligase catalytic subunit (GCLC), glutathione peroxidase (GPX) and cyclooxygenase-2 (COX-2), in a DSS-induced colitis mouse model. The oral administration of DMF attenuated the shortening of colons and alleviated colonic inflammation. Furthermore, the expression of key antioxidant enzymes, including GCLC and GPX, in the colonic tissue were significantly increased by DMF administration. In addition, protein expression of the inflammatory mediator, COX-2, was reduced by DMF administration. Our results suggest that DMF alleviates DSS-induced colonic inflammatory damage, likely via up-regulating GCLC and GPX and down-regulating COX-2 protein expression in colonic tissue.

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Dimethyl Fumarate Induces Glutathione Recycling by Upregulation of Glutathione Reductase

Cited by 28 publications

References 26 publications

The Nrf2-Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma

The Nrf2-Antioxidant Response Element Signaling Pathway Controls Fibrosis and Autoimmunity in Scleroderma

Influence of Dietary Astaxanthin on the Hepatic Oxidative Stress Response Caused by Episodic Hyperoxia in Rainbow Trout

Dimethyl Fumarate Alleviates Dextran Sulfate Sodium-Induced Colitis, through the Activation of Nrf2-Mediated Antioxidant and Anti-inflammatory Pathways

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