Hepato-renal toxicity of low dose metal(oid)s mixture in real-life risk simulation in rats: Effects on Nrf2/HO-1 signalling and redox status.

The understanding that humans are exposed to a low level of toxic metals and metalloids in their lifetime has resulted in a shift in scientific and regulatory perspectives from the traditional evaluation of single metal toxicity to complex mixtures, relevant to real-life exposure. Therefore, the aim of this study was to examine the impact of real-life, 90-days exposure to mixture of toxic metal(oid)s, Cd, Pb, Ni, Cr, As and Hg, on the nuclear factor erythroid 2-related factor 2 and hemoxygenase-1 (Nrf2/HO-1) signalling and redox status by assessing total sulfhydryl groups (SH), glutathione (GSH), superoxide dismutase activity (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) in the liver and kidney of Wistar rats. Animals (20 males and 20 females) were randomized in 2 control and 6 treated groups that received by oral gavage mixture of metal(oid)s solutions in doses that reflect blood metal(oid) levels determined in previous human biomonitoring study as benchmark dose (F/M _BMD), median (F/M _MED), and 95th percentile (F/M _95).

Modulation of NRF2: Biological Dualism in Cancer, Targets and Possible Therapeutic Applications.

The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) system is a master regulator of redox homeostasis and cell adaptation to a variety of exogenous and endogenous stressors. Accumulating evidence from the last decade indicates that the impairment of the redox balance leads to oxidative stress (OS), a common alteration occurring in many human acute and chronic inflammatory diseases, such as cancer, diabetes, neurodegeneration, and metabolic disorders, and aging. Being located at the intersection of crucial signaling pathways, NRF2 can influence several cellular functions, which extend beyond the maintenance of the redox balance and include cellular metabolism, proteostasis, mitochondrial function and inflammation.

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 modulator of skin cells protection against vitiligo, psoriasis, and cancer.

The skin represents a physical barrier between the organism and the environment that has evolved to confer protection against biological, chemical, and physical insults. The inner layer, known as dermis, is constituted by connective tissue and different types of immune cells whereas the outer layer, the epidermis, is composed by different layers of keratinocytes and an abundant number of melanocytes, localized in the stratum basale of the epidermis. Oxidative stress is a common alteration of inflammatory skin disorders such as vitiligo, dermatitis, or psoriasis but can also play a causal role in skin carcinogenesis and tumor progression.

NRF2 and Mitochondrial Function in Cancer and Cancer Stem Cells.

The NRF2-KEAP1 system is a fundamental component of the cellular response that controls a great variety of transcriptional targets that are mainly involved in the regulation of redox homeostasis and multiple cytoprotective mechanisms that confer adaptation to the stress conditions. The pleiotropic response orchestrated by NRF2 is particularly relevant in the context of oncogenic activation, wherein this transcription factor acts as a key driver of tumor progression and cancer cells' resistance to treatment. For this reason, NRF2 has emerged as a promising therapeutic target in cancer cells, stimulating extensive research aimed at the identification of natural, as well as chemical, NRF2 inhibitors.

Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis.

Angiogenesis, the active formation of new blood vessels from pre-existing ones, is a complex and demanding biological process that plays an important role in physiological as well as pathological settings. Recent evidence supports cell metabolism as a critical regulator of angiogenesis. However, whether and how cell metabolism regulates endothelial growth factor receptor levels and nucleotide synthesis remains elusive.

PFAS Molecules: A Major Concern for the Human Health and the Environment.

Per- and polyfluoroalkyl substances (PFAS) are a group of over 4700 heterogeneous compounds with amphipathic properties and exceptional stability to chemical and thermal degradation. The unique properties of PFAS compounds has been exploited for almost 60 years and has largely contributed to their wide applicability over a vast range of industrial, professional and non-professional uses. However, increasing evidence indicate that these compounds represent also a serious concern for both wildlife and human health as a result of their ubiquitous distribution, their extreme persistence and their bioaccumulative potential.

Joint Cardioprotective Effect of Vitamin C and Other Antioxidants against Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention.

Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by AMI, particularly during the reperfusion phase. Numerous attempts based on antioxidant treatments, aimed to reduce the oxidative injury of cardiac tissue, have failed in achieving an effective therapy for these patients.

Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury.

Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention.

Regulatory Role of Nrf2 Signaling Pathway in Wound Healing Process.

Wound healing involves a series of cellular events in damaged cells and tissues initiated with hemostasis and finally culminating with the formation of a fibrin clot. However, delay in the normal wound healing process during pathological conditions due to reactive oxygen species, inflammation and immune suppression at the wound site represents a medical challenge. So far, many therapeutic strategies have been developed to improve cellular homeostasis and chronic wounds in order to accelerate wound repair.

The Role of Toxic Metals and Metalloids in Nrf2 Signaling.

Nuclear factor erythroid 2-related factor 2 (Nrf2), an emerging regulator of cellular resistance to oxidants, serves as one of the key defensive factors against a range of pathological processes such as oxidative damage, carcinogenesis, as well as various harmful chemicals, including metals. An increase in human exposure to toxic metals via air, food, and water has been recently observed, which is mainly due to anthropogenic activities. The relationship between environmental exposure to heavy metals, particularly cadmium (Cd), lead (Pb), mercury (Hg), and nickel (Ni), as well as metaloid arsenic (As), and transition metal chromium (Cr), and the development of various human diseases has been extensively investigated.

Therapeutic Targeting of the NRF2 Signaling Pathway in Cancer.

Cancer is one of the most fatal diseases with an increasing incidence and mortality all over the world. Thus, there is an urgent need for novel therapies targeting major cancer-related pathways. Nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative modulator Kelch-like ECH-associated protein 1 (KEAP1) are main players of the cellular defense mechanisms against internal and external cell stressors.

Involvement of NRF2 in Breast Cancer and Possible Therapeutical Role of Polyphenols and Melatonin.

Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to neurodegenerative diseases and cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor and reported as one of the most important oxidative stress regulators.

Short overview on the relevance of microRNA-reactive oxygen species (ROS) interactions and lipid peroxidation for modulation of oxidative stress-mediated signalling pathways in cancer treatment.

Objectives: Modulation of oxidative stress-mediated signalling pathways is constantly getting more attention as a valuable therapeutic strategy in cancer treatment. Although complexity of redox signalling pathways might represent a major hurdle, the development of advanced -omics technologies allow thorough studies on cancer-specific biology, which is essential to elucidate the impact of these signalling pathways in cancer cells. The scope of our review is to provide updated information about recent developments in cancer treatment.

Inhibition of the NRF2/KEAP1 Axis: A Promising Therapeutic Strategy to Alter Redox Balance of Cancer Cells.

The nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) pathway is a crucial and highly conserved defensive system that is required to maintain or restore the intracellular homeostasis in response to oxidative, electrophilic, and other types of stress conditions. The tight control of NRF2 function is maintained by a complex network of biological interactions between positive and negative regulators that ultimately ensure context-specific activation, culminating in the NRF2-driven transcription of cytoprotective genes. Recent studies indicate that deregulated NRF2 activation is a frequent event in malignant tumors, wherein it is associated with metabolic reprogramming, increased antioxidant capacity, chemoresistance, and poor clinical outcome.

An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation.

Inflammation is a key driver in many pathological conditions such as allergy, cancer, Alzheimer's disease, and many others, and the current state of available drugs prompted researchers to explore new therapeutic targets. In this context, accumulating evidence indicates that the transcription factor Nrf2 plays a pivotal role controlling the expression of antioxidant genes that ultimately exert anti-inflammatory functions. Nrf2 and its principal negative regulator, the E3 ligase adaptor Kelch-like ECH- associated protein 1 (Keap1), play a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation.

Ellagic Acid-Derived Urolithins as Modulators of Oxidative Stress.

Oxidative stress is a state of excess of prooxidative species relative to the antioxidant defenses (enzymatic and nonenzymatic) in a living organism. The consequence of this imbalance is damage of the major cellular macromolecules (carbohydrates, lipids, proteins, and DNA), which further leads to a gradual loss of tissue and organ function. It has been shown that oxidative stress plays an important role in the pathogenesis of many chronic diseases (cardiovascular, metabolic, and neurodegenerative diseases and cancer) and in the process of aging.

The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives.

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review.

Potential Applications of NRF2 Modulators in Cancer Therapy.

The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation.

The Interaction of Flavonols with Membrane Components: Potential Effect on Antioxidant Activity.

Flavonols are the most widely distributed class of dietary flavonoids with a wide range of pharmacological properties due to their potent lipid peroxidation inhibition activity. The permeability and orientation of these compounds in lipid bilayers can provide an understanding of their antioxidant and lipid-peroxidation inhibition activity based on their structures at the molecular level. For this purpose, we studied antioxidant activity and atomic-scale molecular dynamics simulations of 3-hydroxyflavone (fisetin), 5-hydroxyflavone (apigenin) and 3,5-hydroxyflavone (morin) in palmitoyloleylphosphatidylcholine (POPC) membrane models with 0 mol% and 40 mol% cholesterol concentration.

Potential Applications of NRF2 Inhibitors in Cancer Therapy.

The NRF2/KEAP1 pathway represents one of the most important cell defense mechanisms against exogenous or endogenous stressors. Indeed, by increasing the expression of several cytoprotective genes, the transcription factor NRF2 can shelter cells and tissues from multiple sources of damage including xenobiotic, electrophilic, metabolic, and oxidative stress. Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis.

Data on metabolic-dependent antioxidant response in the cardiovascular tissues of living zebrafish under stress conditions.

In this article we used transgenic zebrafish lines that express compartment-specific isoforms of the roGFP2-Orp1 and Grx1-roGFP2 biosensors, described in Panieri et al (2017) [1], to test the contribute of the pentose phosphate pathway and of the glutathione biosynthesis in the antioxidant capacity of myocardial and endothelial cells in vivo. The transgenic zebrafish embryos were subdued to metabolic inhibition and subsequently challenged with H2O2 or the redox-cycling agent menadione to respectively mimic acute or chronic oxidative stress. Confocal time-lapse recordings were performed to follow the compartmentalized HO and E changes in the cardiovascular tissues of zebrafish embryos at 48 h post fertilization.

Real-time quantification of subcellular HO and glutathione redox potential in living cardiovascular tissues.

Detecting and measuring the dynamic redox events that occur in vivo is a prerequisite for understanding the impact of oxidants and redox events in normal and pathological conditions. These aspects are particularly relevant in cardiovascular tissues wherein alterations of the redox balance are associated with stroke, aging, and pharmacological intervention. An ambiguous aspect of redox biology is how redox events occur in subcellular organelles including mitochondria, and nuclei.

PPFIA1 drives active α5β1 integrin recycling and controls fibronectin fibrillogenesis and vascular morphogenesis.

Basolateral polymerization of cellular fibronectin (FN) into a meshwork drives endothelial cell (EC) polarity and vascular remodelling. However, mechanisms coordinating α5β1 integrin-mediated extracellular FN endocytosis and exocytosis of newly synthesized FN remain elusive. Here we show that, on Rab21-elicited internalization, FN-bound/active α5β1 is recycled to the EC surface.

ROS signaling and redox biology in endothelial cells.

The purpose of this review is to provide an overview of redox mechanisms, sources and antioxidants that control signaling events in ECs. In particular, we describe which molecules are involved in redox signaling and how they influence the relationship between ECs and other vascular component with regard to angiogenesis. Recent and new tools to investigate physiological ROS signaling will be also discussed.