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).

Sex Differences Affect the NRF2 Signaling Pathway in the Early Phase of Liver Steatosis: A High-Fat-Diet-Fed Rat Model Supplemented with Liquid Fructose.

Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis.

Propranolol Promotes Monocyte-to-Macrophage Differentiation and Enhances Macrophage Anti-Inflammatory and Antioxidant Activities by NRF2 Activation.

Adrenergic pathways represent the main channel of communication between the nervous system and the immune system. During inflammation, blood monocytes migrate within tissue and differentiate into macrophages, which polarize to M1 or M2 macrophages with tissue-damaging or -reparative properties, respectively. This study investigates whether the β-adrenergic receptor (β-AR)-blocking drug propranolol modulates the monocyte-to-macrophage differentiation process and further influences macrophages in their polarization toward M1- and M2-like phenotypes.

Natural products as non-covalent and covalent modulators of the KEAP1/NRF2 pathway exerting antioxidant effects.

By controlling several antioxidant and detoxifying genes at the transcriptional level, including NAD(P)H quinone oxidoreductase 1 (NQO1), multidrug resistance-associated proteins (MRPs), UDP-glucuronosyltransferase (UGT), glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, glutathione S-transferase (GST), sulfiredoxin1 (SRXN1), and heme-oxygenase-1 (HMOX1), the KEAP1/NRF2 pathway plays a crucial role in the oxidative stress response. Accordingly, the discovery of modulators of this pathway, activating cellular signaling through NRF2, and targeting the antioxidant response element (ARE) genes is pivotal for the development of effective antioxidant agents. In this context, natural products could represent promising drug candidates for supplementation to provide antioxidant capacity to human cells.

Regulation of Nrf2/Keap1 signaling pathway in cancer drug resistance by galectin-1: cellular and molecular implications.

Oxidative stress is characterized by the deregulation of the redox state in the cells, which plays a role in the initiation of various types of cancers. The activity of galectin-1 (Gal-1) depends on the cell redox state and the redox state of the microenvironment. Gal-1 expression has been related to many different tumor types, as it plays important roles in several processes involved in cancer progression, such as apoptosis, cell migration, adhesion, and immune response.

Nutrition, Physical Activity and Smoking Habit in the Italian General Adult Population: CUORE Project Health Examination Survey 2018-2019.

Background: Tobacco consumption, incorrect nutrition and insufficient physical activity/sedentariness represent modifiable NCDs risk factors in Western countries. To evaluate recent lifestyle indicators in Italy, data from the national Health Examination Survey (HES), implemented in 2018-2019 within the CUORE Project, were assessed.

Methods: Age-sex standardized results from random samples of Italian general population (35-74 years) were reported by sex, age-class, educational level and geographical area.

A Review of the Potential of Nuclear Factor [Erythroid-Derived 2]-like 2 Activation in Autoimmune Diseases.

An autoimmune disease is the consequence of the immune system attacking healthy cells, tissues, and organs by mistake instead of protecting them. Inflammation and oxidative stress (OS) are well-recognized processes occurring in association with acute or chronic impairment of cell homeostasis. The transcription factor Nrf2 (nuclear factor [erythroid-derived 2]-like 2) is of major importance as the defense instrument against OS and alters anti-inflammatory activities related to different pathological states.

Infection Meets Inflammation: N6-Methyladenosine, an Internal Messenger RNA Modification as a Tool for Pharmacological Regulation of Host-Pathogen Interactions.

The significance of internal mRNA modifications for the modulation of transcript stability, for regulation of nuclear export and translation efficiency, and their role in suppressing innate immunity is well documented. Over the years, the molecular complexes involved in the dynamic regulation of the most prevalent modifications have been characterized-we have a growing understanding of how each modification is set and erased, where it is placed, and in response to what cues. Remarkably, internal mRNA modifications, such as methylation, are emerging as an additional layer of regulation of immune cell homeostasis, differentiation, and function.

Increased circulating levels of MIP-1α and CD14 are associated with the presence of severe stenosis and hypoechoic plaques in patients with carotid atherosclerosis.

Objective: Carotid atherosclerosis, a major cause of ischemic cerebrovascular events, is characterized by a pro-inflammatory and pro-oxidant vascular microenvironment. The current risk score models based on traditional risk factors for cardiovascular risk assessment have some limitations. The identification of novel blood biomarkers could be useful to improve patient management.

Alkaloids as Natural NRF2 Inhibitors: Chemoprevention and Cytotoxic Action in Cancer.

Being a controller of cytoprotective actions, inflammation, and mitochondrial function through participating in the regulation of multiple genes in response to stress-inducing endogenous or exogenous stressors, the transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is considered the main cellular defense mechanism to maintain redox balance at cellular and tissue level. While a transient activation of NRF2 protects normal cells under oxidative stress, the hyperactivation of NRF2 in cancer cells may help them to survive and to adapt under oxidative stress. This can be detrimental and related to cancer progression and chemotherapy resistance.

The Double-Edged Sword of Erythrocytes in Health and Disease via Their Adhesiveness.

Their widespread presence throughout the vasculature, coupled with their reactivity, and thereby to their potential to release reactive oxidative species, or to utilize their anti-oxidative capacities, has promoted much discussion of the role(s) of red blood cells (RBCs) in the progression of health or, alternatively, a wide range of disease states. Moreover, these role(s) have been linked to the development of adhesiveness and, in fact, thereby to the essential pathway to their eventual clearance, e.g.

Hemorheological profiles and chronic inflammation markers in transfusion-dependent and non-transfusion- dependent thalassemia.

The rheological properties of blood play an important role in regulating blood flow in micro and macro circulation. In thalassemia syndromes red blood cells exhibit altered hemodynamic properties that facilitate microcirculatory diseases: increased aggregation and reduced deformability, as well as a marked increase in adherence to the vascular endothelial cells. A personalized approach to treating thalassemia patients (transfusions, iron chelation, and splenectomy), has increased patients' life expectancy, however they generally present many complications and several studies have demonstrated the presence of high incidence of thromboembolic events.

Trends of blood pressure, raised blood pressure, hypertension and its control among Italian adults: CUORE Project cross-sectional health examination surveys 1998/2008/2018.

Objectives: To assess in the Italian general adult population the trends of blood pressure (BP) and prevalence of raised BP (RBP), hypertension and its control in order to evaluate population health and care, and the achievement of an RBP 25% relative reduction as recommended by the WHO at population level.

Design: Results comparison of health examination surveys, cross-sectional observational studies based on health examination of randomly selected age and sex stratified samples including residents aged 35-74 years. Data of the 2018/2019 survey were compared with the previous ones collected in 1998/2002 and 2008/2012.

Neuropeptide Y Promotes Human M2 Macrophage Polarization and Enhances p62/SQSTM1-Dependent Autophagy and NRF2 Activation.

Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals.

Nitro-Oxidative Stress and Mitochondrial Dysfunction in Human Cell Lines Exposed to the Environmental Contaminants PFOA and BPA.

Background: Bisphenol A (BPA) and perfluorooctanoic acid (PFOA) are synthetic compounds widely utilized in industrial activities devoted to the production of daily life plastic, metal products, and packaging from which they are able to migrate to food and water. Due to their persistence in the environment, living organisms are chronically exposed to these pollutants. BPA and PFOA have adverse effects on tissues and organs.

NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies.

An Overview of NRF2-Activating Compounds Bearing α,β-Unsaturated Moiety and Their Antioxidant Effects.

The surge of scientific interest in the discovery of Nuclear Factor Erythroid 2 (NFE2)-Related Factor 2 (NRF2)-activating molecules underscores the importance of NRF2 as a therapeutic target especially for oxidative stress. The chemical reactivity and biological activities of several bioactive compounds have been linked to the presence of α,β-unsaturated structural systems. The α,β-unsaturated carbonyl, sulfonyl and sulfinyl functional groups are reportedly the major α,β-unsaturated moieties involved in the activation of the NRF2 signaling pathway.

Ribosomopathies and cancer: pharmacological implications.

Introduction: The ribosome is a ribonucleoprotein organelle responsible for protein synthesis, and its biogenesis is a highly coordinated process that involves many macromolecular components. Any acquired or inherited impairment in ribosome biogenesis or ribosomopathies is associated with the development of different cancers and rare genetic diseases. Interference with multiple steps of protein synthesis has been shown to promote tumor cell death.

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies.

Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses.

Antioxidant Cardioprotection against Reperfusion Injury: Potential Therapeutic Roles of Resveratrol and Quercetin.

Ischemia-reperfusion myocardial damage is a paradoxical tissue injury occurring during percutaneous coronary intervention (PCI) in acute myocardial infarction (AMI) patients. Although this damage could account for up to 50% of the final infarct size, there has been no available pharmacological treatment until now. Oxidative stress contributes to the underlying production mechanism, exerting the most marked injury during the early onset of reperfusion.

Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response.

Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells.

Trends of overweight, obesity and anthropometric measurements among the adult population in Italy: The CUORE Project health examination surveys 1998, 2008, and 2018.

Background/objectives: Obesity is associated with an increased risk of noncommunicable diseases, such as diabetes, coronary heart disease, stroke, cancers, and conditions, including obstructive sleep apnea and osteoarthritis. Obesity is largely preventable, and halting its rise is one of the World Health Organization Global Action Plan for the Prevention of Noncommunicable Diseases targets. This study aimed to assess trends of anthropometric measurements in Italy using the data collected within the CUORE Project health examination surveys (HESs) 1998, 2008, and 2018.