Prodromic Inflammatory-Oxidative Stress in Peritoneal Leukocytes of Triple-Transgenic Mice for Alzheimer's Disease.

Inflammatory-oxidative stress is known to be pivotal in the pathobiology of Alzheimer's disease (AD), but the involvement of this stress at the peripheral level in the disease's onset has been scarcely studied. This study investigated the pro-inflammatory profile and oxidative stress parameters in peritoneal leukocytes from female triple-transgenic mice for AD (3xTgAD) and non-transgenic mice (NTg). Peritoneal leukocytes were obtained at 2, 4, 6, 12, and 15 months of age. The concentrations of TNFα, INFγ, IL-1ß, IL-2, IL-6, IL-17, and IL-10 released in cultures without stimuli and mitogen concanavalin A and lipopolysaccharide presence were measured. The concentrations of reduced glutathione (GSH), oxidized glutathione (GSSG), lipid peroxidation, and Hsp70 were also analyzed in the peritoneal cells. Our results showed that although there was a lower release of pro-inflammatory cytokines by 3xTgAD mice, this response was uncontrolled and overstimulated, especially at a prodromal stage at 2 months of age. In addition, there were lower concentrations of GSH in leukocytes from 3xTgAD and higher amounts of lipid peroxides at 2 and 4 months, as well as, at 6 months, a lower concentration of Hsp70. In conclusion, 3xTgAD mice show a worse pro-inflammatory response and higher oxidative stress than NTg mice during the prodromal stages, potentially supporting the idea that Alzheimer's disease could be a consequence of peripheral alteration in the leukocyte inflammation-oxidation state.

In Response to a Punctual Stress Male and Female Tyrosine Hydroxylase Haploinsufficient Mice Show a Deteriorated Behavior, Immunity, and Redox State.

An inadequate stress response is associated with impaired neuroimmunoendocrine communication, increasing morbidity and mortality. Since catecholamines (CA) constitute one of the acute stress response pathways, female mice with an haploinsufficiency of the tyrosine hydroxylase gene (TH-HZ), the main limiting enzyme in CA synthesis, show low CA amounts, exhibiting an impairment of homeostatic systems. The aim of this study was to investigate the effect of a punctual stress in TH-HZ mice, determining the differences with wild-type (WT) mice and those due to sex by restraint with a clamp for 10 min. After restraint, a behavioral battery was performed, and several immune functions, redox state parameters, and CA amounts were evaluated in peritoneal leukocytes. Results show that this punctual stress impaired WT behavior and improved female WT immunity and oxidative stress, whereas in TH-HZ mice, all parameters were impaired. In addition, different responses to stress due to sex were observed, with males having a worse response. In conclusion, this study confirms that a correct CA synthesis is necessary to deal with stress, and that when a positive stress (eustress) occurs, individuals may improve their immune function and oxidative state. Furthermore, it shows that the response to the same stressor is different according to sex.

Social environment improves immune function and redox state in several organs from prematurely aging female mice and increases their lifespan.

Aging is associated with a chronic oxidative stress (increase of oxidants and decrease of antioxidants), which contributes to immunosenescence and therefore shorter longevity. Nevertheless, a positive social network has been related to the adequate maintenance of health and deceleration of aging. Adult prematurely aging mice (PAM) are characterized by their inadequate stress response to a T-maze, showing premature immunosenescence and oxidative stress establishment. These impairments contribute to shorter life spans in comparison to exceptional non-PAM (ENPAM). However, it is not known whether these characteristics of PAM could be prevented by a positive cohabitation. Therefore, the aim of the present work was to determine if the premature immunosenescence and oxidative stress shown by PAM could be avoided by the cohabitation with ENPAM, increasing their life span. Female CD1 PAM and ENPAM were divided into three experimental groups: PAM controls, ENPAM controls and a social environment experimental group, containing in the same cage ENPAM and PAM (proportion 5/2, respectively). After 2 months, mice were sacrificed and spleen, thymus, liver and heart removed. Later, several immune functions as well as oxidative stress parameters were assessed in spleen and thymus leukocytes. Also, several oxidative stress parameters were analyzed in liver and heart. The results showed that PAM, after co-housing with ENPAM, had improved immune functions and redox balance in spleen and thymus leukocytes. This improvement of redox state was also observed in liver and heart. Furthermore, all these positive effects seem to be related to the increased life span of PAM.

Oxidative-Inflammatory Stress in Immune Cells from Adult Mice with Premature Aging.

Oxidative and inflammatory stresses are closely related processes, which contribute to age-associated impairments that affect the regulatory systems such as the immune system and its immunosenescence. Therefore, the aim of this work was to confirm whether an oxidative/inflammatory stress occurs in immune cells from adult mice with premature aging, similar to that shown in leukocytes from chronologically old animals, and if this results in immunosenescence. Several oxidants/antioxidants and inflammatory/anti-inflammatory cytokines were analyzed in peritoneal leukocytes from adult female CD1 mice in two models of premature aging-(a) prematurely aging mice (PAM) and (b) mice with the deletion of a single allele (hemi-zygotic: HZ) of the tyrosine hydroxylase (th) gene (TH-HZ), together with cells from chronologically old animals. Several immune function parameters were also studied in peritoneal phagocytes and lymphocytes. The same oxidants and antioxidants were also analyzed in spleen and thymus leukocytes. The results showed that the immune cells of PAM and TH-HZ mice presented lower values of antioxidant defenses and higher values of oxidants/pro-inflammatory cytokines than cells from corresponding controls, and similar to those in cells from old animals. Moreover, premature immunosenescence in peritoneal leukocytes from both PAM and TH-HZ mice was also observed. In conclusion, adult PAM and TH-HZ mice showed oxidative stress in their immune cells, which would explain their immunosenescence.

Lymphoproliferation Impairment and Oxidative Stress in Blood Cells from Early Parkinson's Disease Patients.

In Parkinson's Disease (PD), the peripheral changes in the functional capacity and redox state of immune cells has been scarcely investigated, especially in the early PD stages. Aging is a risk factor for PD, and the age-related impairment of the immune system, based on a chronic-oxidative stress situation, is involved in the rate of aging. We analyzed several functions in isolated peripheral blood neutrophils and mononuclear cells from PD stage 2 patients, and compared the results to those in healthy elderly and adult controls. Several oxidative stress and damage parameters were studied in whole blood cells. The results showed an impairment of the lymphoproliferative response in stimulated conditions in the PD patients compared with age-matched controls, who also showed typical immunosenescence in comparison with adult individuals. Higher oxidative stress and damage were observed in whole blood cells from PD patients (lower glutathione peroxidase activity, and higher oxidized glutathione and malondialdehyde contents). Our results suggest an accelerated immunosenescence in PD stage 2, and that several of the parameters studied could be appropriate peripheral biomarkers in the early stages of PD.

Quality of life, sleepiness and depressive symptoms in adolescents with insomnia: A cross-sectional study.

OBJECTIVES: To determine the prevalence of insomnia in a sample of Portuguese adolescents and assess its repercussions on HRQoL, daytime sleepiness and depressive symptomatology. DESIGN: We carried out a cross-sectional school-based study evaluating students from Viseu. LOCATION: Students from twenty-six public secondary schools in the county of Viseu, Portugal. PARTICIPANTS: Of 9237 questionnaires distributed, 7581 were collected (82.1%). We excluded from analysis all questionnaires from adolescents younger than 12 or older than 18 years of age (211) and unfilled forms (451). The sample comprised 6919 adolescents, the 7th to 12th grade, from 26 public secondary schools. INTERVENTIONS: None. MEASUREMENTS: Data gathering was done using a self-applied questionnaire. Insomnia was defined based on the Diagnostic and Statistical Manual of Mental Disorders - IV criteria. HRQoL was evaluated with the Quality of Life Health Survey SF-36, depressive symptomatology with BDI-II and daytime sleepiness with the Epworth Sleepiness Scale. RESULTS: Prevalence of insomnia was 8.3% and the prevalence of adolescents with symptoms of insomnia without daytime impairment (disturbed sleepers) was 13.1%. HRQoL was significantly reduced among adolescents with insomnia compared to normal sleepers (p<0.001) and even when compared to disturbed sleepers (p<0.001). There was an increase in daytime sleepiness from normal sleepers to disturbed sleepers and to adolescents with insomnia (p<0.001). There was also an increase in the prevalence and severity of depressive symptoms (p<0.001). CONCLUSIONS: Our results show that insomnia is associated with a significantly lower health related quality of life among adolescents.

Sleep patterns and insomnia among portuguese adolescents: a cross-sectional study.

INTRODUCTION: Inadequate sleep patterns and insomnia are frequently linked and represent common sleep disorders among adolescents. The present study provides data on sleep patterns and insomnia among Portuguese adolescents. MATERIAL E METHODS: In a cross-sectional study we evaluated 6,919 students from the 7th to the 12th grade from twenty-six secondary schools. Data was collected using a self-administered questionnaire. Insomnia was defined based on the Diagnostic and Statistical Manual of Mental Disorders IV criteria and daytime sleepiness was assessed with the Epworth Sleepiness Scale. Sleep patterns evaluated both sleep duration ("insufficient" sleep was defined as < 8 hours per night) and bedtime schedules and regularity. RESULTS: The prevalence of insomnia was 8.3%, insomnia symptoms 21.4% and insufficient sleep 29.3%. All prevalence were higher among girls (P<.001). Average sleep time, on weeknights, was 8:04±1:13 hours. On average adolescents went to bed at 22:18±1:47 hours, took 21 minutes to fall asleep and woke up at 7:15±0:35 hours. Only 6.4% of adolescents stated having a regular bedtime. The majority of adolescents (90.6%) reported having difficulty waking up, 64.7% experienced daytime sleepiness and 53.3% experienced sleep during classes. CONCLUSIONS: There are high prevalence of inadequate sleep patterns, insufficient sleep and insomnia among Portuguese adolescents. Insufficient sleep is associated with sleep patterns and social and behavioural factors. These results add to our knowledge of adolescent sleep worldwide.

Indicators of verbal creative thinking: results of a Delphi panel.

Introduction: Creativity is a fundamental competence that manifests itself in various domains of knowledge, including verbal creativity. The main aim of this study was to identify indicators of verbal creativity for the assessment of three writing tasks. Methods: Sixteen multidisciplinary and international creativity experts participated in a two-stage Delphi panel. The administered questionnaire asked about the measurement or non-measurement of eight indicators of verbal creative thinking in three tasks: problem posing, creative idea generation, and idea improvement. Originality is the most important indicator of creativity. The indicators identified in the first task were fluency, flexibility, originality, elaboration, and sensitivity to problems. The second task measures flexibility, originality, elaboration, opacity, and dynamic integration. In the third task, fluency, flexibility, originality, elaboration, dynamic integration, and refinement of ideas are considered. Results: The results of this study are key to progress in the field of measuring verbal creative thinking. Discussion: The identification of indicators of the construct called verbal creativity allows the determination of its components in order to be able to estimate the creative potential in this specific domain.

Bioavailability of flumequine and diclofenac in mice exposed to a metal-drug chemical cocktail. Evaluation of the protective role of selenium.

BACKGROUND AND PURPOSE: Organisms, including humans, are subjected to the simultaneous action of a wide variety of pollutants, the effects of which should not be considered in isolation, as many synergies and antagonisms have been found between many of them. Therefore, this work proposes an in vivo study to evaluate the effect of certain metal contaminants on the bioavailability and metabolism of pharmacologically active compounds. Because the most frequent entry vector is through ingestion, the influence of the gut microbiota and the possible protective effects of selenium has been additionally evaluated. EXPERIMENTAL APPROACH: A controlled exposure experiment in mammals (Mus musculus) to a "chemical cocktail" consisting of metals and pharmaceuticals (diclofenac and flumequine). The presence of selenium has also been evaluated as an antagonist. Mouse plasma samples were measured by UPLC-QTOF. A targeted search of 48 metabolites was also performed. KEY RESULTS: Metals significantly affected the FMQ plasma levels when the gut microbiota was depleted. Hydroxy FMQ decreased if metals were present. Selenium minimized this decrease. The 3-hydroxy DCF metabolite was not found in any case. Changes in some metabolic pathways are discussed. CONCLUSIONS AND IMPLICATIONS: The presence of metals in the mouse diet as well as the prior treatment of mice with an antibiotic mixture (Abxs), which deplete the gut microbiota, has a decisive effect on the bioavailability and metabolism of the tested pharmaceuticals and dietary selenium minimize some of their effects.

[Improved immunity and mean lifespan in mature mice genetically deficient in catecholamine synthesis after living with wild type for two months]. / Mejoría de la inmunidad y la esperanza de vida en ratones maduros, genéticamente deficientes en la síntesis de catecolaminas, tras convivir con controles durante dos meses.

INTRODUCTION: Mice hemizygous in tyrosine hydroxylase (TH-HZ), the limiting enzyme in catecholamine synthesis, show premature immunosenescence, which in females is associated with a shorter lifespan than the corresponding controls (WT). The coexistence of TH-Hz with WT improves the immune function in both males and females in adulthood. OBJECTIVE: To test whether cohabitation for two months of mature male TH-HZ with WT improves the immune function of the former and whether this impacts the lifespan. MATERIAL AND METHODS: Mature male ICR-CD1 mice (13 ± 1 months) TH-HZ coexisted with WT (2:4 ratio in each cage) for two months. Peritoneal leukocytes were extracted from all animals at baseline, one month, and two months after cohabitation, and macrophage phagocytic capacity, macrophage and lymphocyte chemotaxis, natural killer (NK) antitumor activity, and lymphoproliferative capacity in response to the mitogens concanavalin A and lipopolysaccharide (LPS) were assessed. The animals were maintained under these conditions until their natural death. RESULTS: The TH-HZ, which start, in general, with lower values than the WT in the immune functions studied, improved them after two months of cohabitation, becoming similar to those of the controls. This improvement was already observed in NK activity after one month of cohabitation. The TH-HZ presented lower mean longevity than WT, but when they cohabited with WT, it was similar to the latter. CONCLUSION: The coexistence of TH-HZ male mice with WT mice for two months at mature age improves these genetically modified animals' immune response and longevity.

A Green Solution for the Rehabilitation of Marginal Lands: The Case of Lablab purpureus (L.) Sweet Grown in Technosols.

Reclamation of abandoned mining areas can be a potentially viable solution to tackle three major problems: waste mismanagement, environmental contamination, and growing food demand. This study aims to evaluate the rehabilitation of mining areas into agricultural production areas using integrated biotechnology and combining Technosols with a multipurpose (forage, food, ornamental and medicinal) drought-resistant legume, the Lablab purpureus (L.) Sweet. Two Technosols were prepared by combining gossan waste (GW) from an abandoned mining area with a mix of low-cost organic and inorganic materials. Before and after plant growth, several parameters were analysed, such as soil physicochemical characteristics, nutritional status, bioavailable concentrations of potentially hazardous elements (PHE), soil enzymatic activities, and development and accumulation of PHE in Lablab, among others. Both Technosols improved physicochemical conditions, nutritional status and microbiological activity, and reduced the bioavailability of most PHE (except As) of GW. Lablab thrived in both Technosols and showed PHE accumulation mainly in the roots, with PHE concentrations in the shoots that are safe for cattle and sheep consumption. Thus, this is a potential plant that, in conjunction with Technosols, constitutes a potential integrated biotechnology approach for the conversion of marginal lands, such as abandoned mining areas, into food-production areas.

Ecotoxicological Assessment of Polluted Soils One Year after the Application of Different Soil Remediation Techniques.

The present work evaluated the influence of eight different soil remediation techniques, based on the use of residual materials (gypsum, marble, vermicompost) on the reduction in metal(loid)s toxicity (Cu, Zn, As, Pb and Cd) in a polluted natural area. Selected remediation treatments were applied in a field exposed to real conditions and they were evaluated one year after the application. More specifically, five ecotoxicological tests were carried out using different organisms on either the solid or the aqueous (leachate) fraction of the amended soils. Likewise, the main soil properties and the total, water-soluble and bioavailable metal fractions were determined to evaluate their influence on soil toxicity. According to the toxicity bioassays performed, the response of organisms to the treatments differed depending on whether the solid or the aqueous fraction was used. Our results highlighted that the use of a single bioassay may not be sufficient as an indicator of toxicity pathways to select soil remediation methods, so that the joint determination of metal availability and ecotoxicological response will be determinant for the correct establishment of any remediation technique carried out under natural conditions. Our results indicated that, of the different treatments used, the best technique for the remediation of metal(loid)s toxicity was the addition of marble sludge with vermicompost.

Technosols Derived from Mining, Urban, and Agro-Industrial Waste for the Remediation of Metal(loid)-Polluted Soils: A Microcosm Assay.

This study evaluated the effectiveness of six Technosols designed for the remediation of polluted soils (PS) by metal(loid)s at physicochemical, biological, and ecotoxicological levels and at a microcosm scale. Technosols T1-T6 were prepared by combining PS with a mix of organic and inorganic wastes from mining, urban, and agro-industrial activities. After two months of surface application of Technosols on polluted soils, we analysed the soil properties, metal(loid) concentration in total, soluble and bioavailable fractions, soil enzymatic activities, and the growth responses of Trifolium campestre and Lactuca sativa in both the Technosols and the underlying polluted soils. All Technosols improved the unfavourable conditions of polluted soils by neutralising acidity, increasing the OC, reducing the mobility of most metal(loid)s, and stimulating both the soil enzymatic activities and growths of T. campestre and L. sativa. The origin of organic waste used in the Technosols strongly conditioned the changes induced in the polluted soils; in this sense, the Technosols composed of pruning and gardening vermicompost (T3 and T6) showed greater reductions in toxicity and plant growth than the other Technosols composed with different organic wastes. Thus, these Technosols constitute a potential solution for the remediation of persistent polluted soils that should be applied in large-scale and long-term interventions to reinforce their feasibility as a cost-effective ecotechnology.

Remediation potential of mining, agro-industrial, and urban wastes against acid mine drainage.

Acid mine drainage (AMD) poses serious consequences for human health and ecosystems. Novel strategies for its treatment involve the use of wastes. This paper evaluates the remediation potential of wastes from urban, mining and agro-industrial activities to address acidity and high concentrations of potentially toxic elements (PTE) in AMD. Samples of these waste products were spiked with an artificially prepared AMD, then pH, electrical conductivity (EC), and PTE concentrations in the leachates were measured. The artificial AMD obtained through oxidation of Aznalcóllar's tailing showed an ultra-acid character (pH - 2.89 ± 0.03) and extreme high electrical conductivity (EC - 3.76 ± 0.14 dS m-1). Moreover, most PTE were above maximum regulatory levels in natural and irrigation waters. Wastes studied had a very high acid neutralising capacity, as well as a strong capacity to immobilise PTE. Inorganic wastes, together with vermicompost from pruning, reduced most PTE concentrations by over 95%, while organic wastes retained between 50 and 95%. Thus, a wide range of urban, mining, and agro-industrial wastes have a high potential to be used in the treatment of AMD. This study provides valuable input for the development of new eco-technologies based on the combination of wastes (eg. Technosols, permeable reactive barriers) to remediate degraded environments.

Thalidomide in refractory bleeding due to gastrointestinal angiodysplasias.

OBJECTIVES: to assess the efficacy of thalidomide in the treatment of relapsed or refractory bleeding secondary to gastrointestinal angiodysplasia. MATERIAL AND METHODS: we carried out a prospective study of 12 patients with bleeding due to gastrointestinal angiodysplasia refractory to conventional therapy who were treated with thalidomide. For each patient, we considered: age, sex, underlying disease, previous therapies, dose and duration of thalidomide treatment, evolution of haemoglobin levels and adverse effects of treatment. The data obtained were analysed using descriptive statistics with SPSS v. 16. RESULTS: seven men and 5 women with a mean age of 77 years were included in the present study. Five had some underlying pathology and all of them had received prior endoscopic/octreotide treatment. The dose of thalidomide administered was 200 mg/24 h and the duration of the treatment four months, with the exception of two patients in whom treatment was discontinued because of adverse side effects. Mean haemoglobin concentration before onset of treatment was 6.5 g/dL, at two months it was 11.3 g/dL and at the end of treatment 12.1 g/dL. CONCLUSIONS: thalidomide is an effective treatment in gastrointestinal bleeding due to angiodysplasia, but it was withdrawn due to side effects in 16% of the patients included in our study.

[An exceptional case of choledochocele and pancreas divisum in an elderly man]. / Un caso excepcional de coledococele y páncreas divisum de presentación en el anciano.

Choledochocele belongs to type III biliary cysts in Todani's classification and are considered the least frequent cysts in this class. The usual definition of choledochocele is that of a cystic expansion of the distal intramural portion of the bile duct that protrudes into the duodenal lumen. Endoscopic retrograde cholangiopancreatography (ERCP) is one of the tests of choice both for diagnosis and treatment. We report the case of a 77-year-old patient with chronic epigastric pain, nausea/vomiting and episodes of cholangitis due to a choledochocele. Magnetic resonance cholangiography and other radiological procedures (ultrasound, computed tomography, magnetic resonance) were not diagnostic. ERCP was essential to diagnosis and treatment since this procedure provided the treatment by means of biliary sphincterotomy.

Targeting PTEN Regulation by Post Translational Modifications.

Phosphatidylinositol-3,4,5-triphosphate (PIP3) is a lipidic second messenger present at very low concentrations in resting normal cells. PIP3 levels, though, increase quickly and transiently after growth factor addition, upon activation of phosphatidylinositol 3-kinase (PI3-kinase). PIP3 is required for the activation of intracellular signaling pathways that induce cell proliferation, cell migration, and survival. Given the critical role of this second messenger for cellular responses, PIP3 levels must be tightly regulated. The lipid phosphatase PTEN (phosphatase and tensin-homolog in chromosome 10) is the phosphatase responsible for PIP3 dephosphorylation to PIP2. PTEN tumor suppressor is frequently inactivated in endometrium and prostate carcinomas, and also in glioblastoma, illustrating the contribution of elevated PIP3 levels for cancer development. PTEN biological activity can be modulated by heterozygous gene loss, gene mutation, and epigenetic or transcriptional alterations. In addition, PTEN can also be regulated by post-translational modifications. Acetylation, oxidation, phosphorylation, sumoylation, and ubiquitination can alter PTEN stability, cellular localization, or activity, highlighting the complexity of PTEN regulation. While current strategies to treat tumors exhibiting a deregulated PI3-kinase/PTEN axis have focused on PI3-kinase inhibition, a better understanding of PTEN post-translational modifications could provide new therapeutic strategies to restore PTEN action in PIP3-dependent tumors.

Social environment improves the cytokine profile and lymphoproliferative response in chronologically old and prematurely aging mice.

Among the age-associated changes in the immune system, the most evident is the decrease in proliferative responses of lymphocytes to mitogenic stimuli, which is accompanied by the loss of cytokine network homeostasis. Chronic low-grade inflammatory stress, termed as sterile inflammation, is also observed during aging. In chronologically and prematurely aging mice, cohabitation with adult animals for two months favored improvements in several immune functions. This study aimed to determine whether cohabitation could restore several cytokine networks, improve lymphoproliferative responses to mitogens, and diminish sterile inflammation. Chronologically old mice (76 ± 4 weeks) and prematurely aging mice (33 ± 4 weeks) (PAM and TH-HZ) were cohabited with adults (without premature aging) for two months. Subsequently, lymphoproliferation in both basal (unstimulated) conditions and in the presence of mitogenic stimuli lipopolysaccharide A (LPS) or concanavalin A (ConA) was analyzed in cultures of peritoneal leukocytes for 48 h. Cytokine secretions (IL-1ß, TNF-α, IL-6, IL-10, and IL-17) in these cultures were also evaluated. The results showed that cohabitation restored the levels of these cytokines in old and prematurely aging mice and improved the subsequent lymphoproliferative responses. In addition, this social strategy diminished sterile inflammation and decreased inflammatory stress in unstimulated conditions. Therefore, this strategy seems to be capable of restoring the relevant immune function of lymphocytes and reducing the inflammatory stress, which are the improvements required for an adequate immune response.

PI3Kß-regulated ß-catenin mediates EZH2 removal from promoters controlling primed human ESC stemness and primitive streak gene expression.

The mechanism governing the transition of human embryonic stem cells (hESCs) toward differentiated cells is only partially understood. To explore this transition, the activity and expression of the ubiquitous phosphatidylinositol 3-kinase (PI3Kα and PI3Kß) were modulated in primed hESCs. The study reports a pathway that dismantles the restraint imposed by the EZH2 polycomb repressor on an essential stemness gene, NODAL, and on transcription factors required to trigger primitive streak formation. The primitive streak is the site where gastrulation begins to give rise to the three embryonic cell layers from which all human tissues derive. The pathway involves a PI3Kß non-catalytic action that controls nuclear/active RAC1 levels, activation of JNK (Jun N-terminal kinase) and nuclear ß-catenin accumulation. ß-Catenin deposition at promoters triggers release of the EZH2 repressor, permitting stemness maintenance (through control of NODAL) and correct differentiation by allowing primitive streak master gene expression. PI3Kß epigenetic control of EZH2/ß-catenin might be modulated to direct stem cell differentiation.

Role of NRF2 in Lung Cancer.

The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro-tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action.