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. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2

Extracts from the Mediterranean Food Plants Carthamus lanatus, Cichorium intybus, and Cichorium spinosum Enhanced GSH Levels and Increased Nrf2 Expression in Human Endothelial Cells

The Mediterranean diet is considered to prevent several diseases. In the present study, the antioxidant properties of six extracts from Mediterranean plant foods were assessed. The extracts’ chemical composition analysis showed that the total polyphenolic content ranged from 56 to 408 GAE mg/g dw of extract. The major polyphenols identified in the extracts were quercetin,luteolin, caftaric acid, caffeoylquinic acid isomers, and cichoric acid. The extracts showed in vitro high scavenging potencyagainst ABTS•+and O2•−radicals and reducing power activity. Also, the extracts inhibited peroxyl radical-induced cleavage ofDNA plasmids. The three most potent extracts, Cichorium intybus, Carthamus lanatus, and Cichorium spinosum, inhibited OH•-induced mutations in Salmonella typhimurium TA102 cells. Moreover, C. intybus ,C. lanatus, and C. spinosum extracts increased the antioxidant molecule glutathione (GSH) by 33.4, 21.5, and 10.5% at 50μg/ml, respectively, in human endothelialEA.hy926 cells.C. intybusextract was also shown to induce in endothelial cells the transcriptional expression of Nrf2 (the majortranscription factor of antioxidant genes), as well as of antioxidant genes GCLC, GSR, NQO1, and HMOX1. In conclusion, theresults suggested that extracts from edible plants may prevent diseases associated especially with endothelium damag

Study of redox status in farm animals products

Οne οf the main challenges οf tοday's sοciety is the develοpment οf the livestοck sectοr by imprοving the cοnditiοns οf animal husbandry and ensuring the prοductiοn οf high quality prοducts. In recent years it has been οbserved that the intensive grοwth rates οf farm animals have led tο the emergence οf several pathοlοgical cοnditiοns in which οxidative stress is invοlved. It is therefοre understοοd that thrοugh the οverall well-being οf animals can increase their prοductivity, prοduct quality and therefοre imprοve their cοmmercial value and eliminate cοnsumer cοncerns abοut prοduct quality. In view οf all the abοve, the impοrtance οf investigating οxidative stress markers in the tissues and prοducts οf farm animals becοmes clear. In the present dissertatiοn the levels οf redοx status in the tissues οf 144 small ruminants (48 goats and 96 sheep) and 38 cattle as well as in the blοοd and milk οf 40 dοmestic dairy sheep were evaluated. Τhe sheep and gοats belοnged tο the fοllοwing three main grοups: dοmestic gοat breed, fat-tailed sheep (Chios breed) and thin-tailed sheep breed. Τhe cattle belοnged tο the Limοusin, Charοlaise and Simmental breeds, while the dοmestic dairy sheep belοng tο the Greek breed Karagοuniki, and tο the French breed Lacaune. Τhe analysis included variables οf develοpmental stage, breed and sex. Τissues used in the analysis include: blοοd, liver, diaphragm, quadriceps and psοas majοr. Τhe samples measured indicatοrs related tο antiοxidant capacity, οxidative damage tο lipids and prοteins, as well as the effect οn the antiοxidant system οf cell cultures. Αt the same time, a cοrrelatiοn analysis was perfοrmed in οrder tο investigate predictοrs οf antiοxidant capacity and quality οf meat in the blοοd οf the respective animals. Τhe results shοwed statistically significant changes in the different variables taken intο accοunt in the analysis, particularly demοnstrating the fragile redοx equilibrium at critical periοds οf farm animals such as weaning. In additiοn, the variable οf the breed seems tο play a decisive rοle in the levels οf redοx status οf the animals as evidenced by the predοminance in the antiοxidant prοfile οf Limοusin, fat-tailed sheep breed and Karagοuniki dairy breed.Based οn the abοve, it is emerged the need for investigating further the basic levels οf redοx status indicatοrs οf farm animals and their subsequent identificatiοn as a predictοr οf meat quality with new innοvative methοds. The research in this field will contribute, οn the οne hand, to increase the value οf meat and οn the οther hand to the welfare οf farm animals but will alsο be an incentive fοr the further develοpment οf the livestοck sectοr.Μια από τις βασικές προκλήσεις της σημερινής κοινωνίας είναι η ανάπτυξη του κτηνοτροφικού τομέα μέσω της βελτίωσης των συνθηκών εκτροφής των ζώων αλλά και της διασφάλισης παραγωγής προϊόντων υψηλής ποιότητας. Τα τελευταία χρόνια έχει παρατηρηθεί πως οι εντατικοί ρυθμοί ανάπτυξης των παραγωγικών ζώων έχουν οδηγήσει στην εμφάνιση αρκετών παθολογικών καταστάσεων στις οποίες εμπλέκεται το οξειδωτικό στρες. Εξάλλου, φαίνεται πως διαμέσου της βελτίωσης της ευζωίας των ζώων μπορεί να επιτευχθεί αύξηση στην παραγωγικότητα τους, στην ποιότητα των παραγόμενων προϊόντων και επομένως βελτίωση της εμπορικής τους αξίας αλλά και άμβλυνση των προβληματισμών που διακατέχουν τους καταναλωτές σχετικά με την ποιότητα των προϊόντων ζωικής προέλευσης. Στο πλαίσιο αυτό θα μπορούσε να συνεισφέρει η διερεύνηση διαφόρων δεικτών οξειδωτικού στρες στους ιστούς και τα προϊόντα των παραγωγικών ζώων. Για τον σκοπό αυτό, στην παρούσα διατριβή αξιολογήθηκαν τα επίπεδα οξειδοαναγωγικής κατάστασης στους ιστούς 144 μικρών μηρυκαστικών (48 αιγών και 96 προβάτων) και 38 βοοειδών καθώς και στο αίμα και γάλα 40 εγχώριων γαλακτοπαραγωγικών προβάτων. Τα μικρά μηρυκαστικά ανήκαν στις εξής τρεις κύριες ομάδες: εγχώρια φυλή αιγών, πλατύουρη φυλή προβάτων (Χίου), λεπτόουρη φυλή προβάτων. Τα βοοειδή ανήκαν στις φυλές Limοusin, Charοlaise και Simmental, ενώ τα εγχώρια γαλακτοπαραγωγικά πρόβατα ανήκαν σε μια αμιγώς ελληνική φυλή, την Καραγκούνικη, και στην γαλλική Lacaune. Στην ανάλυση συμπεριλήφθηκαν οι μεταβλητές: (α) στάδιο ανάπτυξης, (β) φυλή και (γ) φύλο. Στους ιστούς που αναλύθηκαν συγκαταλέχθηκαν οι εξής: αίμα, ήπαρ, ψοΐτης μυς, τετρακέφαλος μυς και διάφραγμα. Στα δείγματα μετρήθηκαν δείκτες που σχετίζονται με την αντιοξειδωτική ικανότητα, την οξειδωτική καταστροφή σε λιπίδια και πρωτεΐνες, καθώς και η επίδρασή τους στο αντιοξειδωτικό σύστημα κυτταροκαλλιεργειών. Ταυτόχρονα έγινε ανάλυση συσχέτισης προκειμένου να διερευνηθούν πιθανοί δείκτες πρόβλεψης της αντιοξειδωτικής ικανότητας στο αίμα και της ποιότητας του κρέατος των αντίστοιχων ζώων. Τα αποτελέσματα έδειξαν, στατιστικά σημαντικές μεταβολές στις διαφορετικές μεταβλητές που λήφθηκαν υπόψιν στην ανάλυση, καταδεικνύοντας ιδιαίτερα την ευαίσθητη οξειδοαναγωγική ισορροπία σε κρίσιμες περιόδους των παραγωγικών ζώων όπως είναι ο απογαλακτισμός. Επιπλέον η μεταβλητή ‘φυλή’ φαίνεται ότι διαδραματίζει καθοριστικό ρόλο στα επίπεδα οξειδοαναγωγικής κατάστασης των ζώων όπως φάνηκε στη φυλή Limousin, στην παχύ-ουρη φυλή προβάτων και στην Καραγκούνικη γαλακτοπαραγωγική φυλή αφού παρατηρήθηκε ενίσχυση του αντιοξειδωτικού προφίλ αυτών των φυλών. Με βάση τα παραπάνω, αναδεικνύεται η ανάγκη περαιτέρω διερεύνησης των βασικών επιπέδων των δεικτών οξειδοαναγωγικής κατάστασης των παραγωγικών ζώων και η επακόλουθη ταυτοποίηση τους ως δείκτης πρόβλεψης για την ποιότητα του κρέατος και του γάλακτος με νέες καινοτόμες μεθόδους. Η έρευνα σ’ αυτόν τον τομέα θα συμβάλλει αφενός στην αύξηση της προστιθέμενης αξίας του κρέατος και του γάλακτος και αφετέρου στην ευζωία των παραγωγικών ζώων, αλλά και θα αποτελέσει κίνητρο για την περαιτέρω ανάπτυξη του κτηνοτροφικού κλάδου

ROS and COVID

In recent years, the pandemic of coronavirus disease 19 (COVID-19), an infectious disease caused by variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has indisputably emerged as the predominant public health issue [...

Reconceptualization of Hormetic Responses in the Frame of Redox Toxicology

Cellular adaptive mechanisms emerging after exposure to low levels of toxic agents or stressful stimuli comprise an important biological feature that has gained considerable scientific interest. Investigations of low-dose exposures to diverse chemical compounds signify the non-linear mode of action in the exposed cell or organism at such dose levels in contrast to the classic detrimental effects induced at higher ones, a phenomenon usually referred to as hormesis. The resulting phenotype is a beneficial effect that tests our physiology within the limits of our homeostatic adaptations. Therefore, doses below the region of adverse responses are of particular interest and are specified as the hormetic gain zone. The manifestation of redox adaptations aiming to prevent from disturbances of redox homeostasis represent an area of particular interest in hormetic responses, observed after exposure not only to stressors but also to compounds of natural origin, such as phytochemicals. Findings from previous studies on several agents demonstrate the heterogeneity of the specific zone in terms of the molecular events occurring. Major factors deeply involved in these biphasic phenomena are the bioactive compound per se, the dose level, the duration of exposure, the cell, tissue or even organ exposed to and, of course, the biomarker examined. In the end, the molecular fate is a complex toxicological event, based on beneficial and detrimental effects, which, however, are poorly understood to date

Reconceptualization of Hormetic Responses in the Frame of Redox Toxicology

Cellular adaptive mechanisms emerging after exposure to low levels of toxic agents or stressful stimuli comprise an important biological feature that has gained considerable scientific interest. Investigations of low-dose exposures to diverse chemical compounds signify the non-linear mode of action in the exposed cell or organism at such dose levels in contrast to the classic detrimental effects induced at higher ones, a phenomenon usually referred to as hormesis. The resulting phenotype is a beneficial effect that tests our physiology within the limits of our homeostatic adaptations. Therefore, doses below the region of adverse responses are of particular interest and are specified as the hormetic gain zone. The manifestation of redox adaptations aiming to prevent from disturbances of redox homeostasis represent an area of particular interest in hormetic responses, observed after exposure not only to stressors but also to compounds of natural origin, such as phytochemicals. Findings from previous studies on several agents demonstrate the heterogeneity of the specific zone in terms of the molecular events occurring. Major factors deeply involved in these biphasic phenomena are the bioactive compound per se, the dose level, the duration of exposure, the cell, tissue or even organ exposed to and, of course, the biomarker examined. In the end, the molecular fate is a complex toxicological event, based on beneficial and detrimental effects, which, however, are poorly understood to date

Patients Undergoing Surgery for Hip Fractures Suffer from Severe Oxidative Stress as Compared to Patients with Hip Osteoarthritis Undergoing Total Hip Arthroplasty

Hip fractures are associated with the highest degree of morbidity and mortality of all fractures in elderly patients and pose a major risk for subsequent fractures. Patients with hip fractures also present accelerated bone turnover despite early stable fracture fixation and early mobilization. We aimed to evaluate oxidative stress in two groups of patients (25 patients each, matched for age, side, and BMI) who underwent internal fixation of hip fractures and total hip arthroplasty for hip osteoarthritis. Blood samples were taken from all patients during admission, the day of surgery, the 4th postoperative day, and the 15th postoperative day. Reduced (GSH) and oxidized (GSSG) glutathione, GSH/GSSG, catalase (CAT), thiobarbituric acid reactive substances (TBARS), protein carbonyls (PC), and total antioxidant capacity (TAC) as a widely used battery of redox biomarkers were recorded from blood samples. Patients with hip fractures who undergo fixation surgery, compared to those with hip osteoarthritis, suffer significant oxidative stress with an active but insufficient first line of oxidative defense, an intensive first line reaction, a very active second line of oxidative defense, and a low plasma antioxidant capacity. Surgery worsened already present lipid- and protein-related tissue damage. The severe oxidative stress observed may explain high morbidity and mortality rates and high bone turnover status, as well as the high incidence of refractures. Furthermore, the question of whether antioxidant therapy measures should be introduced in the management of hip fracture patients is raised

The Importance of Redox Status in the Frame of Lifestyle Approaches and the Genetics of the Lung Innate Immune Molecules, SP-A1 and SP-A2, on Differential Outcomes of COVID-19 Infection

The pandemic of COVID-19 is of great concern to the scientific community. This mainly affects the elderly and people with underlying diseases. People with obesity are more likely to experience unpleasant disease symptoms and increased mortality. The severe oxidative environment that occurs in obesity due to chronic inflammation permits viral activation of further inflammation leading to severe lung disease. Lifestyle affects the levels of inflammation and oxidative stress. It has been shown that a careful diet rich in antioxidants, regular exercise, and fasting regimens, each and/or together, can reduce the levels of inflammation and oxidative stress and strengthen the immune system as they lead to weight loss and activate cellular antioxidant mechanisms and reduce oxidative damage. Thus, a lifestyle change based on the three pillars: antioxidants, exercise, and fasting could act as a proactive preventative measure against the adverse effects of COVID-19 by maintaining redox balance and well-functioning immunity. Moreover, because of the observed diversity in the expression of COVID-19 inflammation, the role of genetics of innate immune molecules, surfactant protein A (SP-A)1 and SP-A2, and their differential impact on the local lung microenvironment and host defense is reviewed as genetics may play a major role in the diverse expression of the disease

Antioxidant and DNA-Protective Activity of an Extract Originated from Kalamon Olives Debittering

Table olives are a major component of the Mediterranean diet and are associated with many beneficial biological activities, which are mainly related to their phenolic compounds. Olive fruit debittering process defines the quantitative and qualitative composition of table olives in biophenols. The aim of the present study was to evaluate the in vitro antioxidant capacity and DNA-protective activity of an extract originated from brine samples, according to the Greek style debbitering process of Kalamon olive fruits. The main phenolic components determined in the brine extract were hydroxytyrosol (HT), verbascoside (VERB) and tyrosol (T). The in vitro cell-free assays showed strong radical scavenging capacity from the extract, therefore antioxidant potential. At cellular level, human endothelial cells (EA.hy296) and murine myoblasts (C2C12) were treated with non-cytotoxic concentrations of the brine extract and the redox status was assessed by measuring glutathione (GSH), reactive oxygen species (ROS) and lipid peroxidation levels (TBARS). Our results show cell type specific response, exerting a hormetic reflection at endothelial cells. Finally, in both cell lines, pre-treatment with brine extract protected from H2O2-induced DNA damage. In conclusion, this is the first holistic approach highlighted table olive wastewaters from Kalamon- Greek style debittering process, as valuable source of bioactive compounds, which could have interesting implications for the development of new products in food or other industries

Antioxidant and Neuroprotective Effect of a Grape Pomace Extract on Oxaliplatin-Induced Peripheral Neuropathy in Rats: Biochemical, Behavioral and Histopathological Evaluation

Oxaliplatin is a widely used chemotherapeutic agent. Despite its many beneficial aspects in fighting many malignancies, it shares an aversive effect of neuropathy. Many substances have been used to limit this oxaliplatin-driven neuropathy in patients. This study evaluates the neuroprotective role of a grape pomace extract (GPE) into an oxaliplatin induced neuropathy in rats. For this reason, following the delivery of the substance into the animals prior to or simultaneously with oxaliplatin, their performance was evaluated by behavioral tests. Blood tests were also performed for the antioxidant activity of the extract, along with a histological and pathological evaluation of dorsal root ganglion (DRG) cells as the major components of the neuropathy. All behavioral tests were corrected following the use of the grape pomace. Oxidative stressors were also limited with the use of the extract. Additionally, the morphometrical analysis of the DRG cells and their immunohistochemical phenotype revealed the fidelity of the animal model and the changes into the parvalbumin and GFAP concentration indicative of the neuroprotective role of the pomace. In conclusion, the grape pomace extract with its antioxidant properties alleviates the harmful effects of the oxaliplatin induced chronic neuropathy in rats