Dual targeting of Keap1 and Gsk-3 by hexaraphane in the regulation of transcription factor Nrf2.

6-(Methylsulfinyl)hexyl isothiocyanate, here referred to as hexaraphane, is a bioactive compound found in wasabi, which exhibits cytoprotective, anti-inflammatory, and chemopreventive properties. The beneficial effects of hexaraphane are largely mediated through derepression of transcription factor Nrf2, which is typically repressed via proteasomal degradation mediated by its two-site interaction with the ubiquitin E3 ligase adapter Keap1. Like other isothiocyanates, hexaraphane increases Nrf2 activity by perturbing the Nrf2-Keap1 interaction and stalling Keap1-directed ubiquitination.

CD5L is a target of transcription factor Nrf2.

CD5 antigen-like (CD5L), also known as apoptosis inhibitor expressed by macrophages (AIM), is a secreted protein produced by macrophages, which has both cell-autonomous and non-autonomous functions: it has been implicated in multiple biological processes, including inflammation, infection, and fibrosis. The transcriptional regulation of CD5L is complex, and a comparison of the proteomes of bone marrow-derived macrophages from mice with graded expression of transcription factor NF-E2 p45-related factor 2 (Nrf2) indicated that Nrf2 controls expression of the CD5L gene. Using genetic and pharmacological means to increase or decrease Nrf2 activity, we found a correlation between the abundance of Nrf2 and CD5L expression in both murine macrophages and primary human monocyte-derived macrophages.

Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects.

Regulating Nrf2 activity: ubiquitin ligases and signaling molecules in redox homeostasis.

Transcription factor NF-E2 p45-related factor 2 (Nrf2) orchestrates defenses against oxidants and thiol-reactive electrophiles. It is controlled at the protein stability level by several E3 ubiquitin ligases (CRL3, CRL4, SCF, and Hrd1). CRL3 is of the greatest importance because it constitutively targets Nrf2 for proteasomal degradation under homeostatic conditions but is prevented from doing so by oxidative stressors.

Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells.

Accumulation of reactive oxygen species (i.e., oxidative stress) is a leading cause of beta cell dysfunction and apoptosis in diabetes.

An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter β-TrCP delivers anti-inflammatory responses in mouse liver.

It is widely accepted that activating the transcription factor NRF2 will blast the physiological anti-inflammatory mechanisms, which will help combat pathologic inflammation. Much effort is being put in inhibiting the main NRF2 repressor, KEAP1, with either electrophilic small molecules or disrupters of the KEAP1/NRF2 interaction. However, targeting β-TrCP, the non-canonical repressor of NRF2, has not been considered yet.

Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2.

Non-alcoholic steatohepatitis (NASH) represents a global health concern. It is characterised by fatty liver, hepatocyte cell death and inflammation, which are associated with lipotoxicity, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, iron overload and oxidative stress. NF-E2 p45-related factor 2 (Nrf2) is a transcription factor that combats oxidative stress.

Necrotic Granulomatous Inflammation after Use of Small Intestine Submucosa Matrix for Recurrent Compression Neuropathy.

Various techniques exist for treating recurrent carpal and ulnar tunnel syndrome, but AxoGuard nerve wrap has shown promising results for treatment of compression neuropathies when used in conjunction with neurolysis and tenosynovectomy. Prior results demonstrate no safety concerns, and there have not been any reported cases of infection, persistent inflammation, or recurrent perineural fibrosis. A 41-year-old, right-hand-dominant woman experienced repeated bouts of carpal and ulnar tunnel syndromes, which were treated with a small intestine submucosa matrix wrap around the median and ulnar nerves in the wrist.

Hand Injuries of Coal Miners in Southern West Virginia: A Pilot Study on Health-Care Resources in Southern West Virginia.

Introduction: Distance and other factors may play a significant role in both the implementation of care and the number of secondary health outcomes. The distance from an injury site can play a substantial impact on the mortality of different injuries and access to health-related services. Within this study, we sought to understand the effect of the site to treating center distance and access to relevant health-care services on effect and secondary injuries of coal mining-related injuries.

NRF2 and the Ambiguous Consequences of Its Activation during Initiation and the Subsequent Stages of Tumourigenesis.

NF-E2 p45-related factor 2 (NRF2, encoded in the human by ) mediates short-term adaptation to thiol-reactive stressors. In normal cells, activation of NRF2 by a thiol-reactive stressor helps prevent, for a limited period of time, the initiation of cancer by chemical carcinogens through induction of genes encoding drug-metabolising enzymes. However, in many tumour types, NRF2 is permanently upregulated.

Oxidative Stress in Cancer.

Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP).

Farming Related Trauma Injuries in Southern West Virginia With a Focus on Risks, Injury Trends, and Associated Co-morbidities.

Background The implementation of safety policies in farming-related injuries in West Virginia has been lacking. Farming-related injuries have resulted in massive injuries that have resulted in life long injuries and death. Therefore, this study aims to review 12 years of our level 1 trauma data and describe the incidence rate and patterns of priority-related farming injuries in West Virginia, as well as the specific co-morbidities and related injuries that might be more susceptible to damage.

Induction of the Antioxidant Response by the Transcription Factor NRF2 Increases Bioactivation of the Mutagenic Air Pollutant 3-Nitrobenzanthrone in Human Lung Cells.

3-Nitrobenzanthrone (3-NBA) is a suspected human carcinogen present in diesel exhaust. It requires metabolic activation via nitroreduction in order to form DNA adducts and promote mutagenesis. We have determined that human aldo-keto reductases (AKR1C1-1C3) and NAD(P)H:quinone oxidoreductase 1 (NQO1) contribute equally to the nitroreduction of 3-NBA in lung epithelial cell lines and collectively represent 50% of the nitroreductase activity.

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases.

The transcription factor NF-E2 p45-related factor 2 (NRF2; encoded by NFE2L2) and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP1), are critical in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Thus, NRF2 activation provides cytoprotection against numerous pathologies including chronic diseases of the lung and liver; autoimmune, neurodegenerative and metabolic disorders; and cancer initiation. One NRF2 activator has received clinical approval and several electrophilic modifiers of the cysteine-based sensor KEAP1 and inhibitors of its interaction with NRF2 are now in clinical development.

Zinc-binding triggers a conformational-switch in the cullin-3 substrate adaptor protein KEAP1 that controls transcription factor NRF2.

Kelch-like ECH-associated protein 1 (Keap1) is a cullin-3 (Cul3)-RING ubiquitin ligase (CRL) adaptor/scaffold protein that enables cells to adapt to environmental stressors because modification of certain of its Cys residues initiates de-repression of the NF-E2 p45-related factor-2 (Nrf2) transcription factor. Thus, in normal unstressed cells, the cytoprotective Nrf2 is continuously ubiquitylated by CRL, thereby ensuring that Nrf2 is efficiently degraded by the proteasome and expression of Nrf2 target genes restricted. By contrast, this process is attenuated in stressed cells, allowing Nrf2 protein to accumulate in the nucleus and induce genes that promote cell survival.

Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2).

Background & Aims: Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis.

Methods: and C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control.

Oncogene-Stimulated Congestion at the KEAP1 Stress Signaling Hub Allows Bypass of NRF2 and Induction of NRF2-Target Genes that Promote Tumor Survival.

In this issue of Cancer Cell, Ge et al. show that overexpression of the oncoprotein iASPP in cancer cells provokes NRF2-mediated induction of cytoprotective genes, because it logjams the ubiquitin ligase substrate adaptor function of KEAP1 by virtue of the fact that it possesses a novel DLT-containing KEAP1-interaction motif.

A partnership with the proteasome; the destructive nature of GSK3.

Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems.

Epigenetic Control of NRF2-Directed Cellular Antioxidant Status in Dictating Life-Death Decisions.

In this issue of Molecular Cell, Chen et al. (2017) demonstrate that the tumor suppressor protein ARF sensitizes cancer cells to programmed death through a surprising mechanism: ARF physically interacts with and antagonizes activation by acetylation of the master redox regulator NRF2, providing an unusual mode of posttranslational NRF2 regulation.

Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice.

We recently generated glutathione S-transferase (GST) A3 knockout (KO) mice as a novel model to study the risk factors for liver cancer. GSTA3 KO mice are sensitive to the acute cytotoxic and genotoxic effects of aflatoxin B1 (AFB1), confirming the crucial role of GSTA3 in resistance to AFB1. We now report histopathological changes, tumor formation, biochemical changes and gender response following AFB1 treatment as well as the contribution of oxidative stress.

Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer.

This corrects the article DOI: 10.1038/bjc.2016.