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Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 53171

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Special Issue Editors

Prof. Dr. Luciano Saso

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Faculty of Pharmacy and Medicine, Sapienza University of Rome, 00185 Rome, Italy
Interests: pharmacology; therapeutic modulators of oxidative stress
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ryszard Amarowicz

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Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland
Interests: analytical chemistry; polymer chemistry; food science
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Prof. Dr. Jasmina Dimitrić Marković

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Faculty of Physical Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia
Interests: antioxidants and oxidative stress in biological systems; modulators of oxidative stress; structural characterization of novel compounds, new ligands, and their transition metal complexes, with potential biological activity; the inhibitory potential of compounds towards major transport proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Reactive oxygen (ROS), nitrogen (RNS), and sulfur (RSS) species are implicated in the pathogenesis of a variety of pathological conditions, including chronic infections, inflammatory disorders, cardiovascular diseases, neurodegenerative diseases, and cancer. Unfortunately, antioxidant therapies have not demonstrated effectiveness in the majority of clinical studies for various reasons that have been reviewed elsewhere. However, modulation of oxidative stress, particularly through regulation of gene transcription via, e.g., activation or inhibition of Nrf2, is considered to be an important strategy for the development of new drugs for some of these pathologies, such as cardiovascular and neoplastic diseases that are resistant to other treatments. The main aim of this Special Issue is to explore aspects of the modulation of oxidative stress using an interdisciplinary approach involving chemical, biological, physiological, pharmaceutical, pharmacological, and physicochemical perspectives. Potential topics include but are not limited to the following:

Synthesis and derivatization of oxidative stress modulators with potential pharmacological applications, and the optimization of their antioxidant properties and bioavailability;
Nonradical scavenging mechanisms of action of oxidative stress modulators, particularly of the Keap1/Nrf2/ARE signaling pathway;
Pharmacokinetics, metabolic pathways, and antioxidant activity of metabolites;
In vitro and in vivo studies on the pharmacological activity of oxidative stress modulators;
Epidemiological and clinical studies on the efficacy of redox therapies;
Relevant biological markers for assessing in vivo antioxidant/pro-oxidant activity and its correlation with clinical efficacy;
Pathological states from the redox point of view
Antioxidants vs. oxidative stress—insights from computation
Predicting protection against oxidative stress—computational strategies
Chemical structure and reactivity of modulators of oxidative stress by means of quantum chemical analysis;
The molecular basis of the antioxidant mechanisms of naturally occurring phytochemicals and their synthetic analogues.

Selected references

Amarowicz R, Pegg RB. Natural antioxidants of plant origin. Adv Food Nutr Res. 2019;90:1‐81
Dimić DS, Marković ZS, Saso L, et al. Synthesis and Characterization of 3-(1-((3,4-Dihydroxyphenethyl)amino)ethylidene)-chroman-2,4-dione as a Potential Antitumor Agent. Oxid Med Cell Longev. 2019;2019:2069250.
Panieri E, Saso L. Potential Applications of NRF2 Inhibitors in Cancer Therapy. Oxid Med Cell Longev. 2019
Telkoparan-Akillilar P, Suzen S, Saso L. Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs. Int J Mol Sci. 2019;20(8):2025.
Sova M, Saso L. Design and development of Nrf2 modulators for cancer chemoprevention and therapy: a review. Drug Des Devel Ther. 2018;12:3181-3197

Prof. Dr. Luciano Saso
Prof. Dr. Ryszard Amarowicz
Prof. Dr. Jasmina Dimitrić Marković
Guest Editor

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17 pages, 3917 KiB

Open AccessArticle

Pharmacological Potentiality of Bioactive Flavonoid against Ketamine Induced Cell Death of PC 12 Cell Lines: An In Vitro Study

by Chintha Venkataramaiah, Bandila Lakshmi Priya, Sholapuri Payani and Jangampalli Adi Pradeepkiran

Antioxidants 2021, 10(6), 934; https://doi.org/10.3390/antiox10060934 - 09 Jun 2021

Cited by 3 | Viewed by 3004

Abstract

During the past few years, there has been exponential growth in the field of ethnopharmacology in the treatment of different human ailments, including neurological disorders. In our previous study, we isolated, characterized, and reported a novel bioactive compound with therapeutic efficacy in vivo, which was used in the current study. This study was designed to investigate the pharmacological effect and therapeutic mechanism of the natural plant compound 3-(3,4-dimethoxy phenyl)-1-(4-methoxy phenyl)prop-2-en-1-one against ketamine-induced toxicity in PC 12 cell lines. Cell death was induced in PC 12 cell lines by incubating with ketamine, and the protection offered by the compound at different concentrations was studied during pretreatment. The therapeutic efficacy was screened through MTT assay, LDH assay, DCF-DA assay, clonogenic assay, RT-PCR, and densitometric analysis. The bioactive compound caused a significant elevation in cell viability up to approximately 80%, down-regulation of cell damage, reduction in free radical damage caused by intracellular reactive oxygen species, and up-regulation of cell survival ability, which was dysregulated during ketamine induction. In addition, RT-PCR analysis of DOPA-related genes suggests that the compound exerted significant inhibition in the expression of these genes, which were overexpressed during ketamine induction. The current findings provide new insight into the neuroprotective mediation of bioactive factors as a prospective therapy for neurological disorders. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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28 pages, 14934 KiB

Open AccessFeature PaperArticle

Natural Chain-Breaking Antioxidants and Their Synthetic Analogs as Modulators of Oxidative Stress

by Vessela D. Kancheva, Maria Antonietta Dettori, Davide Fabbri, Petko Alov, Silvia E. Angelova, Adriana K. Slavova-Kazakova, Paola Carta, Valerii A. Menshov, Olga I. Yablonskaya, Aleksei V. Trofimov, Ivanka Tsakovska and Luciano Saso

Antioxidants 2021, 10(4), 624; https://doi.org/10.3390/antiox10040624 - 19 Apr 2021

Cited by 12 | Viewed by 3527

Abstract

Oxidative stress is associated with the increased production of reactive oxygen species or with a significant decrease in the effectiveness of antioxidant enzymes and nonenzymatic defense. The penetration of oxygen and free radicals in the hydrophobic interior of biological membranes initiates radical disintegration of the hydrocarbon “tails” of the lipids. This process is known as “lipid peroxidation”, and the accumulation of the oxidation products as peroxides and the aldehydes and acids derived from them are often used as a measure of oxidative stress levels. In total, 40 phenolic antioxidants were selected for a comparative study and analysis of their chain-breaking antioxidant activity, and thus as modulators of oxidative stress. This included natural and natural-like ortho-methoxy and ortho-hydroxy phenols, nine of them newly synthesized. Applied experimental and theoretical methods (bulk lipid autoxidation, chemiluminescence, in silico methods such as density functional theory (DFT) and quantitative structure–activity relationship ((Q)SAR) modeling) were used to clarify their structure–activity relationship. Kinetics of non-inhibited and inhibited lipid oxidation in close connection with inhibitor transformation under oxidative stress is considered. Special attention has been paid to chemical reactions resulting in the initiation of free radicals, a key stage of oxidative stress. Effects of substituents in the side chains and in the phenolic ring of hydroxylated phenols and biphenols, and the concentration were discussed. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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16 pages, 37823 KiB

Open AccessArticle

The Unity of Redox and Structural Remodeling of Brown Adipose Tissue in Hypothyroidism

by Marija Aleksic, Andjelika Kalezic, Luciano Saso, Aleksandra Jankovic, Bato Korac and Aleksandra Korac

Antioxidants 2021, 10(4), 591; https://doi.org/10.3390/antiox10040591 - 12 Apr 2021

Cited by 2 | Viewed by 2242

Abstract

Brown adipose tissue (BAT) is important for maintaining whole-body metabolic and energy homeostasis. However, the effects of hypothyroidism, one of the most common diseases worldwide, which increases the risk of several metabolic disorders, on BAT redox and metabolic homeostasis remain mostly unknown. We aimed to investigate the dynamics of protein expression, enzyme activity, and localization of antioxidant defense (AD) enzymes in rat interscapular BAT upon induction of hypothyroidism by antithyroid drug methimazole for 7, 15, and 21 days. Our results showed an increased protein expression of CuZn- and Mn-superoxide dismutase, catalase, glutamyl–cysteine ligase, thioredoxin, total glutathione content, and activity of catalase and thioredoxin reductase in hypothyroid rats, compared to euthyroid control. Concomitant with the increase in AD, newly established nuclear, mitochondrial, and peroxisomal localization of AD enzymes was found. Hypothyroidism also potentiated associations between mitochondria, peroxisomes, and lipid bodies, creating specific structural–functional units. Moreover, hypothyroidism induced protein expression and nuclear translocation of a master regulator of redox-metabolic homeostasis, nuclear factor erythroid 2-related factor 2 (Nrf2), and an increased amount of 4-hydroxynonenal (4-HNE) protein adducts. The results indicate that spatiotemporal overlap in the remodeling of AD is orchestrated by Nrf2, implicating the role of 4-HNE in this process and suggesting the potential mechanism of redox-structural remodeling during BAT adaptation in hypothyroidism. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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18 pages, 2760 KiB

Open AccessArticle

Cyclooxygenase-2 Glycosylation Is Affected by Peroxynitrite in Endothelial Cells: Impact on Enzyme Activity and Degradation

by Sonia Eligini, Susanna Colli, Aida Habib, Giancarlo Aldini, Alessandra Altomare and Cristina Banfi

Antioxidants 2021, 10(3), 496; https://doi.org/10.3390/antiox10030496 - 23 Mar 2021

Cited by 5 | Viewed by 2484

Abstract

The exposure of human endothelial cells to 3-morpholinosydnonimine (SIN-1) induced the expression of cyclooxygenase-2 (COX-2) in a dose- and time-dependent manner. Interestingly, after a prolonged incubation (>8 h) several proteoforms were visualized by Western blot, corresponding to different states of glycosylation of the protein. This effect was specific for SIN-1 that generates peroxynitrite and it was not detected with other nitric oxide-donors. Metabolic labeling experiments using ³⁵S or cycloheximide suggested that the formation of hypoglycosylated COX-2 was dependent on de novo synthesis of the protein rather than the deglycosylation of the native protein. Moreover, SIN-1 reduced the activity of the hexokinase, the enzyme responsible for the first step of glycolysis. The hypoglycosylated COX-2 induced by SIN-1 showed a reduced capacity to generate prostaglandins and the activity was only partially recovered after immunoprecipitation. Finally, hypoglycosylated COX-2 showed a more rapid rate of degradation compared to COX-2 induced by IL-1α and an alteration in the localization with an accumulation mainly detected in the nuclear membrane. Our results have important implication to understand the effect of peroxynitrite on COX-2 expression and activity, and they may help to identify new pharmacological tools direct to increase COX-2 degradation or to inhibit its activity. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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20 pages, 2394 KiB

Open AccessArticle

Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases

by Daniel Chavarria, Ophelie Da Silva, Sofia Benfeito, Sandra Barreiro, Jorge Garrido, Fernando Cagide, Pedro Soares, Fernando Remião, Xavier Brazzolotto, Florian Nachon, Paulo J. Oliveira, José Dias and Fernanda Borges

Antioxidants 2021, 10(2), 329; https://doi.org/10.3390/antiox10020329 - 23 Feb 2021

Cited by 10 | Viewed by 3034

Abstract

Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP⁺) conjugates (compounds 2–5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC₅₀ values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2–5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2–5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2–5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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14 pages, 1714 KiB

Open AccessArticle

Acute Kidney Injury is Associated with Lowered Plasma-Free Thiol Levels

by Lisanne Boekhoud, Jacqueline Koeze, Elisabeth C. van der Slikke, Arno R. Bourgonje, Jill Moser, Jan G. Zijlstra, Anneke C. Muller Kobold, Marian L. C. Bulthuis, Matijs van Meurs, Harry van Goor and Hjalmar R. Bouma

Antioxidants 2020, 9(11), 1135; https://doi.org/10.3390/antiox9111135 - 16 Nov 2020

Cited by 9 | Viewed by 2591

Abstract

Acute kidney injury (AKI) is associated with the abrupt loss of kidney function. Oxidative stress plays an important role in the pathophysiology of AKI. Free thiols (R-SH) are crucial components of the extracellular antioxidant machinery and reliably reflect systemic oxidative stress. Lower levels of thiols represent higher levels of oxidative stress. In this preliminary study, we hypothesized that plasma-free thiols are associated with AKI upon admission to the intensive care unit (ICU). In this study, 301 critically ill patients were included. Plasma samples were taken upon admission, and albumin-adjusted plasma-free thiols were determined. Albumin-adjusted plasma-free thiols were lower in patients with AKI (n = 43, median (interquartile range) 7.28 µmol/g (3.52, 8.95)) compared to patients without AKI (8.50 μmol/g (5.82, 11.28); p < 0.05) upon admission to the ICU. Higher age (B = −0.72), higher levels of neutrophil gelatinase-associated lipocalin (B = −0.002), creatinine (B = −0.01) and lower serum albumin (B = 0.47) were associated with lower free thiol levels. Further, albumin-adjusted free thiol levels were significantly reduced in patients with sepsis (8.30 (5.52–10.64) µmol/g) compared to patients without sepsis (6.95 (3.72–8.92) µmol/g; p < 0.05). Together, albumin-adjusted plasma-free thiols were significantly reduced in patients with AKI and patients with sepsis compared with patients without AKI and sepsis. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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16 pages, 1562 KiB

Open AccessArticle

Synthesis, In Vitro Antioxidant Properties and Distribution of a New Cyanothiophene-Based Phenolic Compound in Olive Oil-In-Water Emulsions

by Sonia Losada-Barreiro, Matej Sova, Janez Mravljak, Luciano Saso and Carlos Bravo-Díaz

Antioxidants 2020, 9(7), 623; https://doi.org/10.3390/antiox9070623 - 16 Jul 2020

Cited by 2 | Viewed by 2359

Abstract

We synthesized and determined the antioxidant activity and distribution of a new cyanothiophene-based compound, N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-3,5-dihydroxybenzamide (SIM-53B), in intact stripped olive oil-in-water emulsion. The in vitro antioxidant properties of SIM-53B were evaluated and compared to those for Trolox and resveratrol. Addition of an emulsifier (Tween 20) creates a narrow region, the aqueous–oil interface, and the distribution of SIM-53B can be described by two partition constants: P_W^I (between aqueous/interfacial regions) and P_O^I (between oil/interfacial regions). The effects of emulsifier concentration expressed in terms of the volume fraction, Φ_I, and O/W ratio were also evaluated on its distribution. SIM-53B is predominantly distributed (>90%) in the interfacial region of 1:9 (O/W) olive oil-in-water emulsions at the lowest emulsifier volume fraction (Φ_I = 0.005) and only a small fraction is located in the aqueous (<5%) and the oil (<5%) regions. Besides, the concentration of SIM-53B in the interfacial region of the emulsions is ~170–190-fold higher than the stoichiometric concentration, emphasizing the compartmentalization effects. Results suggest that the emulsifier volume fraction is a key parameter that may modulate significantly its concentration in the interface. Our study suggests that cyanothiophene-based compounds may be interesting additives for potential lipid protection in biomembranes or other lipid-based systems. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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16 pages, 2093 KiB

Open AccessReview

Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

by Daniel Muñoz-Reyes, Ana I. Morales and Marta Prieto

Antioxidants 2021, 10(6), 909; https://doi.org/10.3390/antiox10060909 - 03 Jun 2021

Cited by 18 | Viewed by 3514

Abstract

Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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19 pages, 920 KiB

Open AccessReview

Pharmacological Protection against Ischemia-Reperfusion Injury by Regulating the Nrf2-Keap1-ARE Signaling Pathway

by Bercis Imge Ucar, Gulberk Ucar, Sarmistha Saha, Brigitta Buttari, Elisabetta Profumo and Luciano Saso

Antioxidants 2021, 10(6), 823; https://doi.org/10.3390/antiox10060823 - 21 May 2021

Cited by 60 | Viewed by 6056

Abstract

Ischemia/reperfusion (I/R) injury is associated with substantial clinical implications, including a wide range of organs such as the brain, kidneys, lungs, heart, and many others. I/R injury (IRI) occurs due to the tissue injury following the reestablishment of blood supply to ischemic tissues, leading to enhanced aseptic inflammation and stimulation of oxidative stress via reactive oxygen and nitrogen species (ROS/RNS). Since ROS causes membrane lipids’ peroxidation, triggers loss of membrane integrity, denaturation of proteins, DNA damage, and cell death, oxidative stress plays a critical part in I/R pathogenesis. Therefore, ROS regulation could be a promising therapeutic strategy for IRI. In this context, Nrf2 (NF-E2-related factor 2) is a transcription factor that regulates the expression of several factors involved in the cellular defense against oxidative stress and inflammation, including heme oxygenase-1 (HO-1). Numerous studies have shown the potential role of the Nrf2/HO-1 pathway in IRI; thus, we will review the molecular aspects of Nrf2/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response element (ARE) signaling pathway in I/R, and we will also highlight the recent insights into targeting this pathway as a promising therapeutic strategy for preventing IRI. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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13 pages, 1105 KiB

Open AccessReview

Current Perspective of Hydrogen Sulfide as a Novel Gaseous Modulator of Oxidative Stress in Glaucoma

by Yuan Feng, Verena Prokosch and Hanhan Liu

Antioxidants 2021, 10(5), 671; https://doi.org/10.3390/antiox10050671 - 26 Apr 2021

Cited by 8 | Viewed by 2666

Abstract

Glaucoma is a group of diseases characterized by the progressive loss of retinal ganglion cells and their axons. Elevated intraocular pressure (IOP) is the main clinical manifestation of glaucoma. Despite being in the focus of the studies for decades, the characteristic and the exact pathology of neurodegeneration in glaucoma remains unclear. Oxidative stress is believed to be one of the main risk factors in neurodegeneration, especially its damage to the retinal ganglion cells. Hydrogen sulfide (H₂S), the recently recognized gas signaling molecule, plays a pivotal role in the nervous system, vascular system, and immune system. It has also shown properties in regulating oxidative stress through different pathways in vivo. In this review, we summarize the distribution and the properties of H₂S within the eye with an emphasis on its role in modulating oxidative stress in glaucoma. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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15 pages, 1293 KiB

Open AccessReview

Zebrafish as a Useful Model to Study Oxidative Stress-Linked Disorders: Focus on Flavonoids

by Francesco Abbate, Alessandro Maugeri, Rosaria Laurà, Maria Levanti, Michele Navarra, Santa Cirmi and Antonino Germanà

Antioxidants 2021, 10(5), 668; https://doi.org/10.3390/antiox10050668 - 25 Apr 2021

Cited by 20 | Viewed by 5000

Abstract

The zebrafish is considered one of the most versatile experimental animal models. The transparency of the embryos, the small size, the rapid development and the homology with higher vertebrates have made the zebrafish a valuable model also for drug screening. Its use is closely related for the determination of bioactivity, toxicity and off-target side effects of novel drug candidates, which also allows a thorough evaluation of new targets; thus, it may represent a suitable model for drug screening and the optimization of novel candidates. Flavonoids are polyphenolic compounds widely present in fruits, vegetables and cereals. Polyphenols are important for both plants and humans, considering their involvement in defense mechanisms, particularly against oxidative stress. They protect plants from biotic and abiotic stressors and prevent or treat oxidative-based human diseases. For these reasons, polyphenols are used as nutraceuticals, functional foods and supplements by the pharmaceutical industry. Therefore, the most relevant findings on zebrafish as a useful experimental model to study oxidative stress-linked disorders, focusing on the biological activities of flavonoids, are here summarized and reviewed. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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25 pages, 2234 KiB

Open AccessReview

Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury

by José Lillo-Moya, Catalina Rojas-Solé, Diego Muñoz-Salamanca, Emiliano Panieri, Luciano Saso and Ramón Rodrigo

Antioxidants 2021, 10(5), 667; https://doi.org/10.3390/antiox10050667 - 25 Apr 2021

Cited by 89 | Viewed by 6633

Abstract

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. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on the use of radical trapping antioxidants (RTAs), such as liproxstatin-1 (Lip-1). Hence, it is necessary to develop novel strategies to prevent cardiac IRI, thus improving the clinical outcome in patients with ischemic heart disease. The present review analyses the role of ferroptosis inhibition to prevent heart IRI, with special reference to Lip-1 as a promising drug in this clinicopathological context. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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20 pages, 1007 KiB

Open AccessReview

The Role of Toxic Metals and Metalloids in Nrf2 Signaling

by Aleksandra Buha, Katarina Baralić, Danijela Djukic-Cosic, Zorica Bulat, Alexey Tinkov, Emiliano Panieri and Luciano Saso

Antioxidants 2021, 10(5), 630; https://doi.org/10.3390/antiox10050630 - 21 Apr 2021

Cited by 31 | Viewed by 3507

Abstract

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. Their ability to induce reactive oxygen species (ROS) production through direct and indirect actions and cause oxidative stress has been documented in various organs. Taking into account that Nrf2 signaling represents an important pathway in maintaining antioxidant balance, recent research indicates that it can play a dual role depending on the specific biological context. On one side, Nrf2 represents a potential crucial protective mechanism in metal-induced toxicity, but on the other hand, it can also be a trigger of metal-induced carcinogenesis under conditions of prolonged exposure and continuous activation. Thus, this review aims to summarize the state-of-the-art knowledge regarding the functional interrelation between the toxic metals and Nrf2 signaling. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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24 pages, 1171 KiB

Open AccessReview

Anti-Viral Potential and Modulation of Nrf2 by Curcumin: Pharmacological Implications

by Mahdie Rahban, Mehran Habibi-Rezaei, Mansoureh Mazaheri, Luciano Saso and Ali A. Moosavi-Movahedi

Antioxidants 2020, 9(12), 1228; https://doi.org/10.3390/antiox9121228 - 04 Dec 2020

Cited by 45 | Viewed by 4887

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that maintains the cell’s redox balance state and reduces inflammation in different adverse stresses. Under the oxidative stress, Nrf2 is separated from Kelch-like ECH-associated protein 1 (Keap1), which is a key sensor of oxidative stress, translocated to the nucleus, interacts with the antioxidant response element (ARE) in the target gene, and then activates the transcriptional pathway to ameliorate the cellular redox condition. Curcumin is a yellow polyphenolic curcuminoid from Curcuma longa (turmeric) that has revealed a broad spectrum of bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Curcumin significantly increases the nuclear expression levels and promotes the biological effects of Nrf2 via the interaction with Cys151 in Keap1, which makes it a marvelous therapeutic candidate against a broad range of oxidative stress-related diseases, including type 2 diabetes (T2D), neurodegenerative diseases (NDs), cardiovascular diseases (CVDs), cancers, viral infections, and more recently SARS-CoV-2. Currently, the multifactorial property of the diseases and lack of adequate medical treatment, especially in viral diseases, result in developing new strategies to finding potential drugs. Curcumin potentially opens up new views as possible Nrf2 activator. However, its low bioavailability that is due to low solubility and low stability in the physiological conditions is a significant challenge in the field of its efficient and effective utilization in medicinal purposes. In this review, we summarized recent studies on the potential effect of curcumin to activate Nrf2 as the design of potential drugs for a viral infection like SARS-Cov2 and acute and chronic inflammation diseases in order to improve the cells’ protection. Full article

(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects 2021)

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