Dimethyl fumarate attenuates lipopolysaccharide-induced mitochondrial injury by activating Nrf2 pathway in cardiomyocytes

The mechanisms underlying poor outcome following subarachnoid haemorrhage (SAH) are complex and multifactorial. They include early brain injury, spreading depolarisation, inflammation, oxidative stress, macroscopic cerebral vasospasm, and microcirculatory disturbances. Nrf2 is a global promoter of the antioxidant and anti-inflammatory response and has potential protective effects against all of these mechanisms. It has been shown to be upregulated after SAH, and Nrf2 knockout animals have poorer functional and behavioural outcomes after SAH. There are many agents known to activate the Nrf2 pathway. Of these, the actions of sulforaphane, curcumin, astaxanthin, lycopene,tert-butylhydroquinone, dimethyl fumarate, melatonin, and erythropoietin have been studied in SAH models. This review details the different mechanisms of injury after SAH including the contribution of haemoglobin (Hb) and its breakdown products. It then summarises the evidence that the Nrf2 pathway is active and protective after SAH and finally examines the evidence supporting Nrf2 upregulation as a therapy after SAH.

Download Full-text

Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the Phase 3 DEFINE and CONFIRM studies

Multiple Sclerosis Journal ◽

10.1177/1352458517690617 ◽

2017 ◽

Vol 23 (14) ◽

pp. 1875-1883 ◽

Cited By ~ 33

Author(s):

Sreeja Gopal ◽

Alvydas Mikulskis ◽

Ralf Gold ◽

Robert J Fox ◽

Katherine T Dawson ◽

...

Keyword(s):

Multiple Sclerosis ◽

Ex Vivo ◽

Dimethyl Fumarate ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Phase 3 ◽

Potent Inducer ◽

Nrf2 Pathway ◽

Delayed Release ◽

Multiple Sclerosis Patients

Background: Delayed-release dimethyl fumarate (DMF) is an approved oral treatment for relapsing forms of multiple sclerosis (MS). Preclinical studies demonstrated that DMF activated the nuclear factor E2–related factor 2 (Nrf2) pathway. DMF and its primary metabolite monomethyl fumarate (MMF) were also shown to promote cytoprotection of cultured central nervous system (CNS) cells via the Nrf2 pathway. Objective: To investigate the activation of Nrf2 pathway following ex vivo stimulation of human peripheral blood mononuclear cells (PBMCs) with DMF or MMF, and in DMF-treated patients from two Phase 3 relapsing MS studies DEFINE and CONFIRM. Methods: Transcription of Nrf2 target genes NADPH:quinone oxidoreductase-1 (NQO1) and heme-oxygenase-1 (HO1) was measured using Taqman® assays. RNA samples were isolated from ex vivo–stimulated PBMCs and from whole blood samples of 200 patients each from placebo, twice daily (BID) and three times daily (TID) treatments. Results: DMF and MMF induced NQO1 and HO1 gene expression in ex vivo–stimulated PBMCs, DMF being the more potent inducer. Induction of NQO1 occurred at lower DMF concentrations compared to that of HO1. In DMF-treated patients, a statistically significant induction of NQO1 was observed relative to baseline and compared to placebo. No statistical significance was reached for HO1 induction. Conclusion: These data provide the first evidence of Nrf2 pathway activation from two large pivotal Phase 3 studies of DMF-treated MS patients.

Download Full-text

Dimethyl Fumarate is a Potential Therapeutic Option for Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-215074 ◽

2021 ◽

pp. 1-14

Author(s):

Xiaodi Sun ◽

Xinjun Suo ◽

Xianyou Xia ◽

Chunshui Yu ◽

Yan Dou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Antioxidant Enzymes ◽

Therapeutic Option ◽

Amyloid Β ◽

Dimethyl Fumarate ◽

Therapeutic Effects ◽

Embryonic Mouse ◽

Nrf2 Pathway ◽

Anti Inflammatory

Background: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer’s disease (AD), DMF is a potential therapeutic option for AD. Objective: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. Methods: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. Results: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition. Conclusion: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.

Download Full-text

Dimethyl fumarate and the oleanane triterpenoids, CDDO-imidazolide and CDDO-methyl ester, both activate the Nrf2 pathway but have opposite effects in the A/J model of lung carcinogenesis

Carcinogenesis ◽

10.1093/carcin/bgv061 ◽

2015 ◽

Vol 36 (7) ◽

pp. 769-781 ◽

Cited By ~ 36

Author(s):

Ciric To ◽

Carol S. Ringelberg ◽

Darlene B. Royce ◽

Charlotte R. Williams ◽

Renee Risingsong ◽

...

Keyword(s):

Methyl Ester ◽

Dimethyl Fumarate ◽

Lung Carcinogenesis ◽

Nrf2 Pathway

Download Full-text

Activation of Nrf2 Pathway by Dimethyl Fumarate Attenuates Renal Ischemia-Reperfusion Injury

Transplantation Proceedings ◽

10.1016/j.transproceed.2021.07.017 ◽

2021 ◽

Author(s):

Xu Zhen ◽

Li Jindong ◽

Zhou Yang ◽

Ruan Yashi ◽

Guo Wei ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Dimethyl Fumarate ◽

Renal Ischemia ◽

Nrf2 Pathway ◽

Renal Ischemia Reperfusion Injury

Download Full-text

Current Landscape of NRF2 Biomarkers in Clinical Trials

Antioxidants ◽

10.3390/antiox9080716 ◽

2020 ◽

Vol 9 (8) ◽

pp. 716 ◽

Cited By ~ 2

Author(s):

Yoko Yagishita ◽

Tonibelle N. Gatbonton-Schwager ◽

Melissa L. McCallum ◽

Thomas W. Kensler

Keyword(s):

Clinical Trials ◽

Target Genes ◽

Critical Role ◽

Dimethyl Fumarate ◽

Related Factor ◽

Oxidative Stress Biomarkers ◽

Cellular Redox ◽

Nrf2 Pathway ◽

Drug Candidates ◽

Carcinogen Metabolism

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) plays a critical role in the maintenance of cellular redox and metabolic homeostasis, as well as the regulation of inflammation and cellular detoxication pathways. The contribution of the NRF2 pathway to organismal homeostasis is seen in many studies using cell lines and animal models, raising intense attention towards targeting its clinical promise. Over the last three decades, an expanding number of clinical studies have examined NRF2 inducers targeting an ever-widening range of diseases. Full understanding of the pharmacokinetic and pharmacodynamic properties of drug candidates rely partly on the identification, validation, and use of biomarkers to optimize clinical applications. This review focuses on results from clinical trials with four agents known to target NRF2 signaling in preclinical studies (dimethyl fumarate, bardoxolone methyl, oltipraz, and sulforaphane), and evaluates the successes and limitations of biomarkers focused on expression of NRF2 target genes and others, inflammation and oxidative stress biomarkers, carcinogen metabolism and adduct biomarkers in unavoidably exposed populations, and targeted and untargeted metabolomics. While no biomarkers excel at defining pharmacodynamic actions in this setting, it is clear that these four lead clinical compounds do touch the NRF2 pathway in humans.

Download Full-text

Dimethyl fumarate reduces TNF and Plasmodium falciparum induced brain endothelium activation in vitro

Malaria Journal ◽

10.1186/s12936-020-03447-7 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Neida K. Mita-Mendoza ◽

Ariel Magallon-Tejada ◽

Priyanka Parmar ◽

Raquel Furtado ◽

Margaret Aldrich ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Endothelial Cell ◽

Signaling Pathway ◽

Adjunctive Therapy ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Dimethyl Fumarate ◽

Related Factor ◽

Nrf2 Pathway

Abstract Background Cerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses. Methods To accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined. Results Transcriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC. Conclusions These findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.

Download Full-text

Dimethyl Fumarate Named Allergen of the Year

Skin & Allergy News ◽

10.1016/s0037-6337(11)70097-3 ◽

2011 ◽

Vol 42 (3) ◽

pp. 11

Author(s):

DAMIAN McNAMARA

Keyword(s):

Dimethyl Fumarate

Download Full-text