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

Objective: 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. Materials and Methods: We evaluated the system in a pilot study with 20 healthy participants aged 85.1 (SD: 6.29). Participants used the SWalker-VR platform while testing one VR application focused on walking and the other on balance practice. Afterward, the participants answered three usability questionnaires. Results: The platform was validated in terms of safety using the Simulator Sickness Questionnaire, obtaining less than 20 points for all subscales: nausea (4.29 ± 14.47), oculomotor (0.38 ± 14.18), and disorientation (1.39 ± 14.52). For usability evaluation, the System Usability Scale provided an overall score of 70.63 ± 11.64, and the Post-Study System Usability Questionnaire (PSSUQ) rated 1.61 ± 0.54. The usability scores reported by both questionnaires were moderate and good, respectively. These results were similar in overall scores for both groups: participants with low cognitive level and participants with high cognitive level. Finally, the possible causes for the "no answered" responses on the PSSUQ were discussed. Conclusion: It is concluded that the SWalker-VR platform is reported to have adequate usability and high security by older adults. The potential interest of studying the effects of the long-term use of this platform by older adults with gait impairment is expressed. Clinical Trials reference: NCT06025981.

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. Objective: Our objective was to compare the effect on lower limb range of motion (ROM) when using VR technology for cycling exercise versus not using VR technology. Methods: A randomized controlled trial with 20 patients with ataxia and hemiparesis was carried out. The participants were divided into 2 groups: the experimental group (n=10, 50%) performed pedaling exercises using the VR system and the control group (n=10, 50%) performed pedaling exercises without using VR. Measurements of the active and passive ROM of the hip and knee joint were taken before and after a cycling intervention, which consisted of 3 sessions of the same duration but with progressively increasing speeds (4, 5, and 6 km/h). Repeated measures ANOVAs were conducted to compare the preintervention (Ti) and postintervention (Te) assessments within each group. Additionally, the improvement effect of using the VR system was analyzed by comparing the variation coefficient (Δ = 1 - [Te / Ti]) between the preintervention and postintervention assessments for each group. Group comparisons were made using independent 1-tailed t tests. Results: Significant improvements were shown in active left hip flexion (P=.03) over time, but there was no group-time interaction effect (P=.67). Passive left hip flexion (P=.93) did not show significant improvements, and similar results were observed for active and passive right hip flexion (P=.39 and P=.83, respectively). Neither assessments of knee flexion (active left: P=.06; passive left: P=.76; active right: P=.34; passive right: P=.06) nor knee extension showed significant changes (active left: P=.66; passive left: P=.92; active right: P=.12; passive right: P=.38). However, passive right knee extension (P=.04) showed a significant improvement over time. Overall, although active and passive ROM of the knee and hip joints showed a general improvement, no statistically significant differences were found between the groups. Conclusions: In this study, participants who underwent the cycling intervention using the VR system showed similar improvement in lower limb ROM to the participants who underwent conventional training. Ultimately, the VR system can be used to engage participants in physical activity.

Specific targeting of the NRF2/ß-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. Alternatively, we previously introduced PHAR, a protein-protein interaction inhibitor of NRF2/ß-TrCP, which induces a mild NRF2 activation and selectively activates NRF2 in the liver, close to normal physiological levels. Herein, we assessed the effect of PHAR in protection against NASH and its progression to fibrosis. We conducted experiments to demonstrate that PHAR effectively activated NRF2 in hepatocytes, Kupffer cells, and stellate cells. Then, we used the STAM mouse model of NASH, based on partial damage of endocrine pancreas and insulin secretion impairment, followed by a high fat diet. Non-invasive analysis using MRI revealed that PHAR protects against liver fat accumulation. Moreover, PHAR attenuated key markers of NASH progression, including liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. Notably, transcriptomic data indicate that PHAR led to upregulation of 3 anti-fibrotic genes (Plg, Serpina1a, and Bmp7) and downregulation of 6 pro-fibrotic (including Acta2 and Col3a1), 11 extracellular matrix remodeling, and 8 inflammatory genes. Overall, our study suggests that the mild activation of NRF2 via the protein-protein interaction inhibitor PHAR holds promise as a strategy for addressing NASH and its progression to liver fibrosis.

Systematic Review and Meta-analysis of the Relationship Between Exposure to Parental Substance Use and Attention-Deficit/Hyperactivity Disorder in Children.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by persistent patterns of inattention, hyperactivity, and impulsiveness. Among US children and adolescents aged 3-17 years, 9.4% have a diagnosis of ADHD. Previous research suggests possible links between parental substance use and ADHD among children. We conducted a systematic review and meta-analysis of 86 longitudinal or retrospective studies of prenatal or postnatal alcohol, tobacco, or other parental substance use and substance use disorders and childhood ADHD and its related behavioral dimensions of inattention and hyperactivity-impulsivity. Meta-analyses were grouped by drug class and pre- and postnatal periods with combined sample sizes ranging from 789 to 135,732. Prenatal exposure to alcohol or tobacco and parent substance use disorders were consistently and significantly associated with ADHD among children. Other parental drug use exposures resulted in inconsistent or non-significant findings. Prevention and treatment of parental substance use may have potential for impacts on childhood ADHD.

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. However, these modalities are incompatible with over-ground robotic exoskeletons, in which users should pay attention to multiple elements of the open environment and more complex tasks. Recent advances in augmented reality (AR) technology have unlocked a new way of displaying 3D graphics in untethered wearable devices like Microsoft's Hololens 2 without occluding the rest of the user's field of view. These advances can be crucial in certain situations and position AR as an excellent candidate to improve visual feedback when using robotic exoskeletons. In this work, we present the development of an AR-based audio-visual feedback system that tracks the trunk rotation from an Inertial Measurement Unit (IMU) to aid in walking tasks assisted by a lower limb robotic exoskeleton. A preliminary study was done integrating the H3 robotic exoskeleton with Hololens 2. We observed that displaying posture information is feasible and could help mitigate the unnatural posture often imposed by a robotic exoskeleton.

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. A feasibility study was conducted with patients with neuromotor disorders and elderly people from Lescer Clinic and the residential group Albertia, respectively. All the participants performed a pedaling exercise session with virtual reality platform. Then, the Intrinsic Motivation Inventory, the System Usability Scale (SUS), Credibility and Expectancy Questionnaire, were assessed in the group of 20 adults (mean age = 61.1; standard deviation = 12.617, 15 males and 5 females) with lower limb disorders. While the Simulator Sickness Questionnaire, Presence Questionnaire, Game user Experience Satisfaction Scale and SUS were assessed in the group of 18 elders (mean age = 85.16; standard deviation = 5.93, 5 males and 13 females). In light of the outcomes, PedaleoVR is considered to be a credible, usable and motivational tool towards adults with neuromotor disorders to perform cycling exercise, and therefore its usage could contribute to adherence to lower limb training activities. Moreover, PedaleoVR does not generate negative effects related to cybersickness while the sensation of presence and the degree of satisfaction generated have been positively evaluated by the geriatric population. This trial has been registered at ClinicalTrials.gov under the identifier: NCT05162040, Dec 2021.

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.

Dipeptide Repeat Pathology in C9orf72-ALS Is Associated with Redox, Mitochondrial and NRF2 Pathway Imbalance.

The hexanucleotide expansion of the C9orf72 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 C9orf72 patients and control subjects by examining the mRNA levels of 84 redox-related genes. The expression of ten redox genes was altered in samples from C9orf72 ALS patients compared to healthy controls. Considering that Nuclear factor erythroid 2-Related Factor 2 (NRF2) modulates the expression of a wide range of redox genes, we further investigated its status on an in vitro model of dipeptide repeat (DPR) toxicity. This model mimics the gain of function, toxic mechanisms attributed to C9orf72 pathology. We found that exposure to DPRs increased superoxide levels and reduced mitochondrial potential as well as cell survival. Importantly, cells overexpressing DPRs exhibited reduced protein levels of NRF2 and its target genes upon inhibition of the proteasome or its canonical repressor, the E3 ligase adapter KEAP1. However, NRF2 activation was sufficient to recover cell viability and redox homeostasis. This study identifies NRF2 as a putative target in precision medicine for the therapy of ALS patients harboring C9orf72 expansion repeats.

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. Virtual reality (VR) setups can track the movement of the head and other body parts in order to create the sensation of immersion in the virtual environment. Using this tracking position information, a CROM assessment can be performed using a VR setup that may be carried out autonomously from the user's home. The objectives of this study were to develop a VR experience that could be used to perform a CROM assessment, and to evaluate the intra-rater and inter-rater reliability of the CROM measures guided by this VR experience. To the best of our knowledge, a study of this type has not been carried out before. Materials & Methods: A total of 30 asymptomatic adults were assessed using a VR device (HTC Vive Pro Eye™). Two raters provided support with the VR setup, and the participants were guided by the VR experience as they performed the movements. Each rater tested each subject twice, in random order. In addition to a head-mounted display (HMD), a tracker located on the subject's back was used to measure trunk compensatory movements. The CROM was estimated using only the HMD position and this measurement was corrected using the tracker data. The mean and standard deviation were calculated to characterize the CROM. To evaluate the reliability, the interclass correlation coefficients (ICC) were calculated for intra-rater and inter-rater analysis. The standard error of measurement and minimum detectable change were also calculated. The usability of the VR system was measured using the Spanish version of the System Usability Scale. Results: The mean CROM values in each axis of movement were compatible with those described in the literature. ICC values ranged between 0.86 and 0.96 in the intra-rater analysis and between 0.83 and 0.97 in the inter-rater analysis; these values were between good and excellent. When applying the correction of the trunk movements, both the intra-rater and inter-rater ICC values slightly worsened except in the case of the lateral flexion movement, where they slightly improved. The usability score of the CROM assessment/VR system was 86 points, which is an excellent usability score. Conclusion: The reliability of the measurements and the usability of the system indicate that a VR setup can be used to assess CROM. The reliability of the VR setup can be affected by slippage of the HMD or tracker. Both slippage errors are additive, i.e., only when the sum of these two errors is less than the compensatory movement do the measurements improve when considering the tracker data.

An inhibitor of interaction between the transcription factor NRF2 and the E3 ubiquitin ligase adapter ß-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 ß-TrCP, the non-canonical repressor of NRF2, has not been considered yet. After in silico screening of ∼1 million compounds, we now describe a novel small molecule, PHAR, that selectively inhibits the interaction between ß-TrCP and the phosphodegron in transcription factor NRF2. PHAR upregulates NRF2-target genes such as Hmox1, Nqo1, Gclc, Gclm and Aox1, in a KEAP1-independent, but ß-TrCP dependent manner, breaks the ß-TrCP/NRF2 interaction in the cell nucleus, and inhibits the ß-TrCP-mediated in vitro ubiquitination of NRF2. PHAR attenuates hydrogen peroxide induced oxidative stress and, in lipopolysaccharide-treated macrophages, it downregulates the expression of inflammatory genes Il1b, Il6, Cox2, Nos2. In mice, PHAR selectively targets the liver and greatly attenuates LPS-induced liver inflammation as indicated by a reduction in the gene expression of the inflammatory cytokines Il1b, TNf, and Il6, and in F4/80-stained liver resident macrophages. Thus, PHAR offers a still unexplored alternative to current NRF2 activators by acting as a ß-TrCP/NRF2 interaction inhibitor that may have a therapeutic value against undesirable inflammation.

Whole Blood Expression Pattern of Inflammation and Redox Genes in Mild Alzheimer's Disease.

BACKGROUND: Although Alzheimer's disease (AD) is associated with alterations of the central nervous system, this disease has an echo in blood that might represent a valuable source of biomarkers for improved diagnosis, prognosis and for monitoring drug response. METHODS: We performed a targeted transcriptomics study on 38 mild Alzheimer's disease (AD) patients and 38 matched controls for evaluating the expression levels of 136 inflammation and 84 redox genes in whole blood. Patients were diagnosed as mild AD based on altered levels of total TAU, phospho-TAU and Abeta(1-42) in cerebrospinal fluid, and Abeta(1-40), Abeta(1-42) and total TAU levels in plasma. Whenever possible, blood and brain comparisons were made using public datasets. RESULTS: We found 48 inflammation and 34 redox genes differentially expressed in the blood of AD patients vs controls (FC >1.5, p < 0.01), out of which 22 pro-inflammatory and 12 redox genes exhibited FC >2 and p < 0.001. Receiver operating characteristic (ROC) analysis identified nine inflammation and seven redox genes that discriminated between AD patients and controls (area under the curve >0.9). Correlations of the dysregulated inflammation and redox transcripts indicated that RELA may regulate several redox genes including DUOX1 and GSR. Based on the gene expression profile, we have found that the master regulators of inflammation and redox homeostasis, NFκB and NRF2, were significantly disturbed in the blood of AD patients, as well as several zinc finger and helix-loop-helix transcription factors. CONCLUSION: The selected inflammation and redox genes might be useful biomarkers for monitoring anti-inflammatory therapy in mild AD.

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. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.

Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications.

Parkinson's disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.

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. The strategy provides robust cytoprotection by restoring redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19.

Parent engagement in an original and culturally adapted evidence-based parenting program, Legacy for Children™.

Legacy for Children™ (Legacy) is an evidence-based program focused on promoting sensitive, responsive parenting for socioeconomically disadvantaged families. Legacy has recently been culturally and linguistically adapted for Spanish-monolingual Latino families and is being piloted in partnership with an early childhood education program. We conducted a mixed methods study to identify barriers and facilitators to engagement, using program monitoring data sources from both participant and group leader perspectives. We conducted qualitative analyses of open-ended data to identify distinct barriers (e.g., employment challenges, health-related challenges and appointments) and facilitators (e.g., other mothers in group, interest in program topics) to engagement that emerged across English and Spanish language curriculum versions; curriculum-specific barriers and facilitators were also documented. We interpret these findings in light of quantitative data on measures of engagement, showing that participants in the Spanish curriculum evidenced comparable levels of parent-group leader relationship quality relative to the English group, and higher levels of parent's group support/connectedness and overall satisfaction. These results offer promising considerations for optimizing families' engagement in parenting programs in the context of early care and education settings.

Legado para los Niños™ (Legado) es un programa basado en la evidencia que se centra en promover una crianza sensible y susceptible para familias con desventajas socioeconómicas. Recientemente, Legado se ha adaptado cultural y lingüísticamente para familias Latinas en las que sólo se habla español, y está siendo puesto en práctica experimental en asociación con un programa de educación en la temprana niñez. Llevamos a cabo un estudio con una variedad mixta de métodos para identificar obstáculos y promotores para ser incluidos usando recursos de información de la supervisión del programa provenientes de las perspectivas tanto de participantes como de líderes de grupo. Realizamos análisis cuantitativos de información no limitada de antemano para identificar diferentes obstáculos (v.g. dificultades de empleo, dificultades y citas relacionadas con la salud) y promotores (v.g. otras madres en el grupo, interés en los temas del programa) para ser incluidos los cuales surgieron a lo largo de las versiones curriculares del inglés y del español; también se documentaron los obstáculos y promotores relacionados con el currículo específico. Interpretamos estos resultados a la luz de la información cuantitativa sobre medidas de participación, mostrando que los participantes en el currículo en español demostraron comparables niveles de calidad de la relación progenitor-líder de grupo en relación con el grupo de inglés, y más altos niveles de apoyo del grupo a los progenitores y satisfacción en general. Estos resultados ofrecen consideraciones prometedoras para lograr una óptima participación de las familias en programas de crianza en el contexto de escenarios de cuidado y educación tempranos.

Le programme Legacy for ChildrenTM (Legacy) est un programme factuel se concentrant sur la promotion d'une parentage sensible et réactif pour des familles de milieu socioéconomique défavorisé. Legacy a récemment été culturellement et linguistiquement adapté aux familles Latino américaines, en espagnol, et se trouve testé en partenariat avec un programme éducatif de la petite enfance. Nous avons procédé à une étude au moyen de méthodes mixtes afin d'identifier les barrières qui existent et freinent l'engagement, ainsi que ce qui facilite l'engagement, en utilisant des sources de données d'évaluation du programme à la fois de la perspective des participants et du leader de groupe. Nous avons fait des analyses qualitatives de données ouvertes afin d'identifier des barrières précises (i.e. les défis du chômage, les défis liés à la santé et aux rendez-vous) et les aspects facilitateurs (i.e. autres mères dans le groupe, intérêt pour les sujets du programme) pour l'engagement qui ont émergé au travers des deux versions, la version en anglais et la version en espagnol. Les barrières tenant au curriculum et aux facilitateurs ont aussi été répertoriées. Nous avons interprété ces résultats à la lumière de données quantitatives sur des mesures d'engagement, montrant que les personnes participant au curriculum espagnol faisaient preuve de niveaux comparables de qualité de la relation parent-meneur de groupe que le groupe anglais, et de niveaux plus élevés de soutien/connexion et de satisfaction générale du groupe parent. Ces résultats offrent des considérations prometteuses pour l'optimisation de l'engagement des familles dans des programmes de parentage dans le contexte du soin précoce et de l'éducation de la petite enfance.

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

Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, 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). On the other hand, the oxidation of the catechols to the corresponding quinones my elicit alterations in proteins and DNA that raise safety concerns. This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer.

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. Moreover, NRF2 and TAZ protein levels also correlated in immunohistochemical tissue arrays of glioblastomas. Genetic knock-down of NRF2 decreased, while NRF2 overexpression or chemical activation with sulforaphane, increased TAZ transcript and protein levels. Mechanistically, we identified several NRF2-regulated functional enhancers in the regulatory region of WWTR1. The relevance of the new NRF2/TAZ axis in tumorigenesis was demonstrated in subcutaneous and intracranial grafts. Thus, intracranial inoculation of NRF2-depleted glioma stem cells did not develop tumors as determined by magnetic resonance imaging. Forced TAZ overexpression partly rescued both stem cell growth in neurospheres and tumorigenicity. Hence, NRF2 not only enables tumor cells to be competent to proliferate but it also propels tumorigenesis by activating the TAZ-mediated Hippo transcriptional program.

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. However, challenges regarding target specificity, pharmacodynamic properties, efficacy and safety remain.