Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.

Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE).

NRF2 activation by 6-MSITC increases the generation of neuroprotective, soluble α amyloid precursor protein by inducing the metalloprotease gene ADAM17.

Better knowledge of the molecular actors governing sequential amyloid precursor protein (APP) proteolysis is crucial to endorse novel therapies aimed to delay Alzheimer's disease (AD) progression. ADAM17 (A Disintegrin and Metalloproteinase 17) is a type-I transmembrane protease involved in the non-amyloidogenic processing of APP that contributes to the maintenance of synaptic functions. In this work, we analyzed the 5'-flanking region and first intron of ADAM17 gene employing an in silico analysis.

Evaluating the Usability and Safety of Virtual Reality Application Combined with the SWalker for Functional Gait Rehabilitation.

This research evaluates from a usability point of view the combination of a developed fully immersive virtual reality (VR) solution with the SWalker robotic device. It aims to contribute to research in the exploration of immersive experiences overground with a functional gait recovery device. We evaluated the system in a pilot study with 20 healthy participants aged 85.

Specific targeting of the NRF2/β-TrCP axis promotes beneficial effects in NASH.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease that compromises liver function, for which there is not a specifically approved medicine. Recent research has identified transcription factor NRF2 as a potential therapeutic target. However, current NRF2 activators, designed to inhibit its repressor KEAP1, exhibit unwanted side effects.

Effects of a Virtual Reality Cycling Platform on Lower Limb Rehabilitation in Patients With Ataxia and Hemiparesis: Pilot Randomized Controlled Trial.

Background: New interventions based on motor learning principles and neural plasticity have been tested among patients with ataxia and hemiparesis. Therapies of pedaling exercises have also shown their potential to induce improvements in muscle activity, strength, and balance. Virtual reality (VR) has been demonstrated as an effective tool for improving the adherence to physical therapy, but it is still undetermined if it promotes greater improvements than conventional therapy.

Augmented Reality Feedback for Exoskeleton-Assisted Walking. A Feasibility Study.

Powered lower limb exoskeletons have been used in recent decades to support and improve conventional gait rehabilitation programs. In this context, visual feedback is considered a valuable tool to facilitate patient learning and engagement. Treadmill-based lower limb robotic exoskeletons are commonly incorporated with traditional screens or virtual reality (VR) devices.

PedaleoVR: Usability study of a virtual reality application for cycling exercise in patients with lower limb disorders and elderly people.

Achieving adherence to physical exercise training is essential in elders and adults with neurological disorders. Immersive technologies are seeing wide adoption among new neurorehabilitation therapies, as they provide a highly effective motivational and stimulating component. The aim of this study is to verify whether the developed virtual reality system for pedaling exercise is accepted and could be safety, useful and motivating for these populations.

Dipeptide Repeat Pathology in -ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance.

The hexanucleotide expansion of the gene is found in 40% of familial amyotrophic lateral sclerosis (ALS) patients. This genetic alteration has been connected with impaired management of reactive oxygen species. In this study, we conducted targeted transcriptional profiling in leukocytes from patients and control subjects by examining the mRNA levels of 84 redox-related genes.

A novel virtual reality application for autonomous assessment of cervical range of motion: development and reliability study.

Background: Neck pain, one of the most common musculoskeletal diseases, affects 222 million people worldwide. The cervical range of motion (CROM) is a tool used to assess the neck's state across three movement axes: flexo-extension, rotation, and lateral flexion. People with neck pain often have a reduced CROM, and they feel pain at the end-range and/or accompany neck movements with compensatory trunk movements.

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.

Sleep-mediated regulation of reward circuits: implications in substance use disorders.

Our modern society suffers from both pervasive sleep loss and substance abuse-what may be the indications for sleep on substance use disorders (SUDs), and could sleep contribute to the individual variations in SUDs? Decades of research in sleep as well as in motivated behaviors have laid the foundation for us to begin to answer these questions. This review is intended to critically summarize the circuit, cellular, and molecular mechanisms by which sleep influences reward function, and to reveal critical challenges for future studies. The review also suggests that improving sleep quality may serve as complementary therapeutics for treating SUDs, and that formulating sleep metrics may be useful for predicting individual susceptibility to SUDs and other reward-associated psychiatric diseases.

On the Clinical Pharmacology of Reactive Oxygen Species.

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No.

Can Activation of NRF2 Be a Strategy against COVID-19?

Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated proinflammatory cytokines release (cytokine storm) and loss of T lymphocytes (leukopenia) characterize the most aggressive presentation. We propose that a multifaceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2) can be deployed against the virus.

Nordihydroguaiaretic Acid: From Herbal Medicine to Clinical Development for Cancer and Chronic Diseases.

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from , the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. NDGA presents two catechol rings that confer a very potent antioxidant activity by scavenging oxygen free radicals and this may explain part of its therapeutic action. Additional effects include inhibition of lipoxygenases (LOXs) and activation of signaling pathways that impinge on the transcription factor Nuclear Factor Erythroid 2-related Factor (NRF2).

Transcription factor NRF2 uses the Hippo pathway effector TAZ to induce tumorigenesis in glioblastomas.

Transcription factor NRF2 orchestrates a cellular defense against oxidative stress and, so far, has been involved in tumor progression by providing a metabolic adaptation to tumorigenic demands and resistance to chemotherapeutics. In this study, we discover that NRF2 also propels tumorigenesis in gliomas and glioblastomas by inducing the expression of the transcriptional co-activator TAZ, a protein of the Hippo signaling pathway that promotes tumor growth. The expression of the genes encoding NRF2 (NFE2L2) and TAZ (WWTR1) showed a positive correlation in 721 gliomas from The Cancer Genome Atlas database.

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.

A role for APP in Wnt signalling links synapse loss with β-amyloid production.

In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability.

Deficiency in the transcription factor NRF2 worsens inflammatory parameters in a mouse model with combined tauopathy and amyloidopathy.

Chronic neuroinflammation is a hallmark of the onset and progression of brain proteinopathies such as Alzheimer disease (AD) and it is suspected to participate in the neurodegenerative process. Transcription factor NRF2, a master regulator of redox homeostasis, controls acute inflammation but its relevance in low-grade chronic inflammation of AD is inconclusive due to lack of good mouse models. We have addressed this question in a transgenic mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO).

Transcription factor NFE2L2/NRF2 modulates chaperone-mediated autophagy through the regulation of LAMP2A.

Unlabelled: Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach.

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome).