scholarly journals Current Landscape of NRF2 Biomarkers in Clinical Trials

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 716 ◽  
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.

scholarly journals Peripheral Blood NRF2 Expression as a Biomarker in Human Health and Disease

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 28
Author(s):  
Lee E. Neilson ◽  
Joseph F. Quinn ◽  
Nora E. Gray
Keyword(s):  
Clinical Trials ◽  
Peripheral Blood ◽  
Target Genes ◽  
Mononuclear Cells ◽  
Critical Role ◽  
Related Factor ◽  
Peripheral Blood Mononuclear ◽  
Duration Of Action ◽  
Nrf2 Activation ◽  
Health And Disease

Nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor which plays a critical role in maintenance of cellular redox, has been identified as a therapeutic target in a number of human diseases. Several reports have demonstrated beneficial effects of NRF2 manipulation in animal models of disease, and one NRF2-activating drug, dimethyl fumarate, is already approved for the treatment of multiple sclerosis. However, drug discovery is slowed due to a dearth of biomarkers which can inform target engagement and magnitude and duration of action. Peripheral blood mononuclear cells (PBMCs) are an accessible, minimally-invasive source of biomarkers which can be readily assayed and objectively monitored as a surrogate endpoint of NRF2 activation in clinical trials. We undertook a review of the literature on PBMC NRF2 measurements in human studies to explore its role as a suitable biomarker in various contexts of health and disease. It is clear that NRF2 and its target genes can be readily assayed from PBMCs in multiple disease contexts and may track with disease progression. Further work needs to be undertaken to evaluate its stability but should be considered as an exploratory marker in clinical trials targeting NRF2 activation.

scholarly journals Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

2021 ◽  
Author(s):  
Huayu Li ◽  
Mengyan Li ◽  
Chao Dong ◽  
Bing Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Specific Effect ◽  
Dimethyl Fumarate ◽  
Related Factor ◽  
Pyrin Domain ◽  
Anti Inflammatory

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is established that Dimethyl fumarate (DMF) exhibits anti inflammatory effects, however, the specific effect of DMF on ALI remains largely unknown. The aim of the present study was to investigate whether, and by which mechanism, DMF alleviated lipopolysaccharide (LPS)-induced ALI. We found that intraperitoneal injection of DMF markedly reduced the pulmonary injury, decreased pulmonary edema and pulmonary permeability. Emerging studies suggested that the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis played a critical role during ALI. NLRP3 inflammasome-mediated pyroptosis is significantly activated with the cleavage of caspase-1 and GSDMD occurring in the lung of LPS-induced ALI. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nuclear factor erythroid-2-related factor 2 (Nrf2), leading to inactivation of NLRP3 inflammasome and reduction of pyroptosis in both ALI mice and LPS-induced BEAS-2B cells. Conversely, Nrf2 inhibitor reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI in mice. This study for the first time demonstrated that DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.

scholarly journals Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis

2013 ◽  
Vol 4 (11) ◽  
pp. e921-e921 ◽  
Author(s):  
S Tanigawa ◽  
C H Lee ◽  
C S Lin ◽  
C C Ku ◽  
H Hasegawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcriptional Activation ◽  
Leucine Zipper ◽  
Target Genes ◽  
Critical Role ◽  
Notch Receptor ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mobility Shift ◽  
Basic Leucine Zipper

Abstract Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.

scholarly journals Nrf2—A Molecular Target for Sepsis Patients in Critical Care

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1688
Author(s):  
Sandra Gunne ◽  
Ulrike Heinicke ◽  
Michael J. Parnham ◽  
Volker Laux ◽  
Kai Zacharowski ◽  
...  
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Inflammatory Diseases ◽  
Redox Balance ◽  
Molecular Target ◽  
Special Focus ◽  
Related Factor ◽  
Oxygen Species ◽  
Metabolizing Enzymes ◽  
Cellular Redox

The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU).

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

2017 ◽  
Vol 23 (14) ◽  
pp. 1875-1883 ◽  
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.

scholarly journals Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-26 ◽  
Author(s):  
Choongho Lee
Keyword(s):  
Oxidative Stress ◽  
Host Response ◽  
Critical Role ◽  
Viral Diseases ◽  
Ros Generation ◽  
Related Factor ◽  
Defense System ◽  
Front Line ◽  
Nrf2 Pathway ◽  
Pharmacological Manipulations

Virus-induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral diseases. In response to reactive oxygen species (ROS) generation by a virus, a host cell activates an antioxidative defense system for its own protection. Particularly, a nuclear factor erythroid 2p45-related factor 2 (Nrf2) pathway works in a front-line for cytoprotection and detoxification. Recently, a series of studies suggested that a group of clinically relevant viruses have the capacity for positive and negative regulations of the Nrf2 pathway. This virus-induced modulation of the host antioxidative response turned out to be a crucial determinant for the progression of several viral diseases. In this review, virus-specific examples of positive and negative modulations of the Nrf2 pathway will be summarized first. Then a number of successful genetic and pharmacological manipulations of the Nrf2 pathway for suppression of the viral replication and the pathogenesis-associated oxidative damage will be discussed later. Understanding of the interplay between virus-induced oxidative stress and antioxidative host response will aid in the discovery of potential antiviral supplements for better management of viral diseases.

scholarly journals Dimethyl fumarate accelerates wound healing under diabetic conditions

2018 ◽  
Vol 61 (4) ◽  
pp. 163-172 ◽  
Author(s):  
Ying Li ◽  
Fuzhe Ma ◽  
Huimin Li ◽  
Yuguo Song ◽  
Huan Zhang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Oxidative Damage ◽  
Critical Role ◽  
Dimethyl Fumarate ◽  
Related Factor ◽  
Diabetic Wound ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Diabetic Wound Healing

Impaired wound healing is a common complication among patients with diabetes mellitus (DM), resulting in high rates of disability and mortality. Recent findings highlighted the critical role of nuclear factor erythroid 2-related factor 2 (NRF2) – a master of cellular antioxidants scavenging excessive DM-induced free radicals – in accelerating diabetic wound healing. Dimethyl fumarate (DMF) is a potent NRF2 activator used for the treatment of multiple sclerosis. However, the effect of DMF on wound healing has not been determined. The present study investigated the effect of DMF on the diabetic and the non-diabetic wound healing in streptozotocin-induced diabetic mice and non-diabetic control mice. DMF activated NRF2 signaling under both conditions. Interestingly, DMF attenuated oxidative damage and inflammation and accelerated wound closure in diabetic mice. However, this effect was not observed in non-diabetic mice. Keratinocytes were treated with normal glucose (NG), high glucose (HG) or hydrogen peroxide (H2O2), in the presence or absence of DMF to assess the role of reactive oxygen species (ROS) – inducible in DM – in mediating DMF-induced protection. Both HG and H2O2 elevated ROS, oxidative damage and inflammation, the effects of which were similarly blunted by DMF. However, in spite of the activation of NRF2, DMF lost this capability under the NG condition. The findings of this study demonstrate that ROS activate the protective effect of DMF on the diabetic wound healing.

scholarly journals Nrf2 plays a critical role in the metabolic response during and after spaceflight

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Akira Uruno ◽  
Daisuke Saigusa ◽  
Takafumi Suzuki ◽  
Akane Yumoto ◽  
Tomohiro Nakamura ◽  
...  
Keyword(s):  
Stress Responses ◽  
Knockout Mice ◽  
Target Genes ◽  
Metabolic Response ◽  
Critical Role ◽  
Wild Type Mouse ◽  
Related Factor ◽  
Adaptive Responses ◽  
Wild Type ◽  
Space Stress

AbstractSpace travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

Dysregulation of the Keap1–Nrf2 pathway in cancer

2015 ◽  
Vol 43 (4) ◽  
pp. 645-649 ◽  
Author(s):  
Hanna M. Leinonen ◽  
Emilia Kansanen ◽  
Petri Pölönen ◽  
Merja Heinäniemi ◽  
Anna-Liisa Levonen
Keyword(s):  
Cancer Cells ◽  
Large Scale ◽  
Target Genes ◽  
Metabolic Reprogramming ◽  
Pivotal Role ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Cancer Types ◽  
Constitutively Active

Accumulating evidence suggests that dysregulation of the Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor E2-related factor 2 (Nrf2) pathway resulting in constitutively active Nrf2 and increased expression of cytoprotective Nrf2 target genes, has a pivotal role in cancer. Cancer cells are able to hijack the Keap1–Nrf2 system via multiple mechanisms leading to enhanced chemo- and radio-resistance and proliferation via metabolic reprogramming as well as inhibition of apoptosis. In this mini-review, we will describe the mechanisms leading to increased Nrf2 activity in cancer with a focus on the information achieved from large-scale multi-omics projects across various cancer types.

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

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.

Sign in / Sign up

Export Citation Format

Share Document