Editor's Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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Article
N-Acetylcysteine Inhibits Platelet Function through the Regeneration of the Non-Oxidative Form of Albumin
Antioxidants 2022, 11(3), 445; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11030445 - 23 Feb 2022
Abstract
N-acetylcysteine (NAC) is able to break down protein disulfides, generating free thiols. This mechanism occurs on mixed disulfides of albumin (HSA) to form mercaptoalbumin (HMA), the main antioxidant species in the plasma. Circulating HSA exists in two main forms: the reduced form [...] Read more.
N-acetylcysteine (NAC) is able to break down protein disulfides, generating free thiols. This mechanism occurs on mixed disulfides of albumin (HSA) to form mercaptoalbumin (HMA), the main antioxidant species in the plasma. Circulating HSA exists in two main forms: the reduced form (HMA), and the oxidized forms, whose predominant modification is cystenylation (HSA-Cys). Increased levels of oxidized HSA have been detected in several diseases associated with oxidative stress. This study showed that NAC inhibits platelet aggregation by restoring HMA. In addition, the regeneration of HMA by NAC inhibits platelet functions such as intracellular calcium mobilization, reactive oxygen species generation, arachidonic acid metabolites synthesis, and adhesion to the collagen matrix. In our conditions, the exposure of platelets to NAC did not increase GSH levels. However, the inhibition of platelet aggregation was also detected following treatment of platelet-rich plasma with GSH, which, similarly to NAC, reduced HSA-Cys levels. Furthermore, this study showed that cysteine, another compound able to restore HMA by reducing the HSA-Cys content, inhibited platelet aggregation to a similar extent as NAC. The results obtained in this study suggest a new mechanism by which NAC can modulate platelet activation and suggest its possible use as an antiplatelet drug in conditions associated with oxidative stress. Full article
(This article belongs to the Special Issue Oxidative Stress and Inflammation in Cardiovascular Diseases II)
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Article
Attenuation of Polycyclic Aromatic Hydrocarbon (PAH)-Mediated Pulmonary DNA Adducts and Cytochrome P450 (CYP)1B1 by Dietary Antioxidants, Omega-3 Fatty Acids, in Mice
Antioxidants 2022, 11(1), 119; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010119 - 05 Jan 2022
Abstract
Numerous human and animal studies have reported positive correlation between carcinogen-DNA adduct levels and cancer occurrence. Therefore, attenuation of DNA adduct levels would be expected to suppress tumorigenesis. In this investigation, we report that the antioxidants omega 3-fatty acids, which are constituents of [...] Read more.
Numerous human and animal studies have reported positive correlation between carcinogen-DNA adduct levels and cancer occurrence. Therefore, attenuation of DNA adduct levels would be expected to suppress tumorigenesis. In this investigation, we report that the antioxidants omega 3-fatty acids, which are constituents of fish oil (FO), significantly decreased DNA adduct formation by polycyclic aromatic hydrocarbons (PAHs). B6C3F1 male mice were fed an FO or corn oil (CO) diet, or A/J male mice were pre-fed with omega-3 fatty acids eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA). While the B6C3F1 mice were administered two doses of a mixture of seven carcinogenic PAHs including benzo(a)pyrene (BP), the A/J mice were treated i.p. with pure benzo[a]pyrene (BP). Animals were euthanized after 1, 3, or 7 d after PAH treatment. DNA adduct levels were measured by the 32P-postlabeling assay. Our results showed that DNA adduct levels in the lungs of mice 7 d after treatment were significantly decreased in the FO or EPA/DHA groups compared with the CO group. Interestingly, both qPCR and Western blot analyses revealed that FO, DHA and EPA/DHA significantly decreased the expression of cytochrome P450 (CYP) 1B1. CYP1B1 plays a critical role in the metabolic activation of BP to DNA-reactive metabolites. qPCR also showed that the expression of some metabolic and DNA repair genes was induced by BP and inhibited by FO or omega-3 fatty acids in liver, but not lung. Our results suggest that a combination of mechanism entailing CYP1B1 inhibition and the modulation of DNA repair genes contribute to the attenuation of PAH-mediated carcinogenesis by omega 3 fatty acids. Full article
(This article belongs to the Special Issue Antioxidants and Lung Diseases)
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Article
AGEs and sRAGE Variations at Different Timepoints in Patients with Chronic Kidney Disease
Antioxidants 2021, 10(12), 1994; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10121994 - 15 Dec 2021
Cited by 3
Abstract
Patients with chronic kidney disease (CKD) are affected by enhanced oxidative stress and chronic inflammation, and these factors may contribute to increase advanced glycation end-products (AGEs). In this study we quantified AGEs and soluble receptors for AGE (sRAGE) isoforms and evaluated the association [...] Read more.
Patients with chronic kidney disease (CKD) are affected by enhanced oxidative stress and chronic inflammation, and these factors may contribute to increase advanced glycation end-products (AGEs). In this study we quantified AGEs and soluble receptors for AGE (sRAGE) isoforms and evaluated the association between their variations and eGFR at baseline and after 12 months. We evaluated 64 patients. AGEs were quantified by fluorescence intensity using a fluorescence spectrophotometer, and sRAGE by ELISA. Median age was 81 years, male patients accounted for 70%, 63% were diabetic, and eGFR was 27 ± 10 mL/min/1.73 m2. At follow up, sRAGE isoforms underwent a significant decrement (1679 [1393;2038] vs. 1442 [1117;2102], p < 0.0001), while AGEs/sRAGE ratios were increased (1.77 ± 0.92 vs. 2.24 ± 1.34, p = 0.004). Although AGEs and AGEs/sRAGE ratios were inversely related with eGFR, their basal values as well their variations did not show a significant association with eGFR changes. In a cohort of patients with a stable clinical condition at 1 year follow-up, AGEs/sRAGE was associated with renal function. The lack of association with eGFR suggests that other factors can influence its increase. In conclusion, AGEs/sRAGE can be an additional risk factor for CKD progression over a longer time, but its role as a prognostic tool needs further investigation. Full article
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Article
Investigating the Drought and Salinity Effect on the Redox Components of Sulla coronaria (L.) Medik
Antioxidants 2021, 10(7), 1048; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10071048 - 29 Jun 2021
Cited by 10
Abstract
For the Mediterranean region, climate models predict an acceleration of desertification processes, thus threatening agriculture. The present work aimed to investigate the effect of drought and salinity on Sulla coronaria (L.) Medik., a Mediterranean forage legume, for understanding plant defence systems activated by [...] Read more.
For the Mediterranean region, climate models predict an acceleration of desertification processes, thus threatening agriculture. The present work aimed to investigate the effect of drought and salinity on Sulla coronaria (L.) Medik., a Mediterranean forage legume, for understanding plant defence systems activated by these stressors. In detail, we focused our attention on the variations on the plant redox status. Plants were subjected to suboptimal watering and irrigation with sodium chloride (NaCl) solutions. The same salt treatment was applied for in vitro tests on seedlings. Water content did not change after treatments. Salt negatively influenced seed germination and seedling development, but it did not affect photosynthesis parameters, contrary to what was observed in adult plants. Proline concentration increased in all samples, while abscisic acid level increased exclusively in seedlings. NaCl caused accumulation of superoxide anion in plants and seedlings and hydrogen peroxide only in seedlings; nevertheless, lipid peroxidation was not detected. Total phenolics, glutathione, expression level, and activity of antioxidant enzymes were assayed, revealing a complex antiradical molecular response, depending on the type of stress and development stage. Our results confirm Sulla as a drought- and salt-tolerant species and highlight its ability to counteract oxidative stress. This evidence suggests a key role for the redox components, as signal transduction messengers, in Sulla acclimation to desertification. Finally, plants and seedlings showed different acclimation capacity to salinity, revealing a greater genomic plasticity for seedlings. Full article
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Article
Nitric Oxide Regulates Plant Growth, Physiology, Antioxidant Defense, and Ion Homeostasis to Confer Salt Tolerance in the Mangrove Species, Kandelia obovata
Antioxidants 2021, 10(4), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10040611 - 16 Apr 2021
Cited by 14
Abstract
Facultative halophyte Kandelia obovata plants were exposed to mild (1.5% NaCl) and severe (3% NaCl) salt stress with or without sodium nitroprusside (SNP; 100 µM; a NO donor), hemoglobin (Hb, 100 µM; a NO scavenger), or Nω-nitro-L-arginine methyl ester (L-NAME, 100 µM; a [...] Read more.
Facultative halophyte Kandelia obovata plants were exposed to mild (1.5% NaCl) and severe (3% NaCl) salt stress with or without sodium nitroprusside (SNP; 100 µM; a NO donor), hemoglobin (Hb, 100 µM; a NO scavenger), or Nω-nitro-L-arginine methyl ester (L-NAME, 100 µM; a NO synthase inhibitor). The plants were significantly affected by severe salt stress. They showed decreases in seedling growth, stomatal conductance, intercellular CO2 concentration, SPAD value, photosynthetic rate, transpiration rate, water use efficiency, and disrupted antioxidant defense systems, overproduction of reactive oxygen species, and visible oxidative damage. Salt stress also induced ion toxicity and disrupted nutrient homeostasis, as indicated by elevated leaf and root Na+ contents, decreased K+ contents, lower K+/Na+ ratios, and decreased Ca contents while increasing osmolyte (proline) levels. Treatment of salt-stressed plants with SNP increased endogenous NO levels, reduced ion toxicity, and improved nutrient homeostasis while further increasing Pro levels to maintain osmotic balance. SNP treatment also improved gas exchange parameters and enhanced antioxidant enzymes’ activities (catalase, ascorbate peroxidase, monodehydroascorbate reductase, and dehydroascorbate reductase). Treatment with Hb and l-NAME reversed these beneficial SNP effects and exacerbated salt damage, confirming that SNP promoted stress recovery and improved plant growth under salt stress. Full article
(This article belongs to the Special Issue Approaches in Enhancing Antioxidant Defense in Plants)
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Article
Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits
Antioxidants 2021, 10(4), 574; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10040574 - 08 Apr 2021
Cited by 4
Abstract
Recent studies have shown that carbonyl stress is a causative factor of schizophrenia, categorized as carbonyl stress-related schizophrenia (CS-SCZ). However, the correlation between carbonyl stress and the pathogenesis of this disease is not well established. In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient [...] Read more.
Recent studies have shown that carbonyl stress is a causative factor of schizophrenia, categorized as carbonyl stress-related schizophrenia (CS-SCZ). However, the correlation between carbonyl stress and the pathogenesis of this disease is not well established. In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient mice (KO/VB6 (-) mice), which are susceptible to methylglyoxal (MGO)-induced oxidative damages, were used as a CS-SCZ model to analyze MGO-modified protein and the carbonyl stress status in the brain. A comparison between Wild/VB6(+) mice and KO/VB6(−) mice for accumulated carbonyl proteins levels, with several advanced glycation end products (AGEs) in the brain, revealed that carbonyl protein levels with the Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl) ornithine (MG-H1) moiety were significantly increased in the hippocampus, prefrontal cortex, striatum, cerebral cortex, and brainstem regions of the brain in KO/VB6(−) mice. Moreover, two-dimensional electrophoresis and Liquid chromatography-tandem mass spectrometry analysis showed MG-H1-modified arginine residues in mitochondrial creatine kinase, beta-adrenergic receptor kinase 1, and T-complex protein in the hippocampus region of KO/VB6(−) mice, but not in Wild/VB6(+) mice. In particular, MG-H1 modification of mitochondrial creatine kinase was quite notable. These results suggest that further studies focusing on MG-H1-modified and accumulated proteins in the hippocampus may reveal the onset mechanism of CS-SCZ induced by MGO-induced oxidative damages. Full article
(This article belongs to the Section Health Outcomes of Antioxidants and Oxidative Stress)
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Article
Label-Free Quantitative Proteomic Analysis of Nitrogen Starvation in Arabidopsis Root Reveals New Aspects of H2S Signaling by Protein Persulfidation
Antioxidants 2021, 10(4), 508; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10040508 - 24 Mar 2021
Cited by 12
Abstract
Hydrogen sulfide (H2S)-mediated signaling pathways regulate many physiological and pathophysiological processes in mammalian and plant systems. The molecular mechanism by which hydrogen sulfide exerts its action involves the posttranslational modification of cysteine residues to form a persulfidated thiol motif. We developed [...] Read more.
Hydrogen sulfide (H2S)-mediated signaling pathways regulate many physiological and pathophysiological processes in mammalian and plant systems. The molecular mechanism by which hydrogen sulfide exerts its action involves the posttranslational modification of cysteine residues to form a persulfidated thiol motif. We developed a comparative and label-free quantitative proteomic analysis approach for the detection of endogenous persulfidated proteins in N-starved Arabidopsis thaliana roots by using the tag-switch method. In this work, we identified 5214 unique proteins from root tissue that were persulfidated, 1674 of which were quantitatively analyzed and found to show altered persulfidation levels in vivo under N deprivation. These proteins represented almost 13% of the entire annotated proteome in Arabidopsis. Bioinformatic analysis revealed that persulfidated proteins were involved in a wide range of biological functions, regulating important processes such as primary metabolism, plant responses to stresses, growth and development, RNA translation and protein degradation. Quantitative mass spectrometry analysis allowed us to obtain a comprehensive view of hydrogen sulfide signaling via changes in the persulfidation levels of key protein targets involved in ubiquitin-dependent protein degradation and autophagy, among others. Full article
(This article belongs to the Special Issue Plant and Human Sulfur Biology)
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Article
Allysine and α-Aminoadipic Acid as Markers of the Glyco-Oxidative Damage to Human Serum Albumin under Pathological Glucose Concentrations
Antioxidants 2021, 10(3), 474; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030474 - 17 Mar 2021
Cited by 3
Abstract
Understanding the molecular basis of the disease is of the utmost scientific interest as it contributes to the development of targeted strategies of prevention, diagnosis, and therapy. Protein carbonylation is a typical feature of glyco-oxidative stress and takes place in health disorders such [...] Read more.
Understanding the molecular basis of the disease is of the utmost scientific interest as it contributes to the development of targeted strategies of prevention, diagnosis, and therapy. Protein carbonylation is a typical feature of glyco-oxidative stress and takes place in health disorders such as diabetes. Allysine as well as its oxidation product, the α-amino adipic acid (α-AA) have been found to be markers of diabetes risk whereas little is known about the chemistry involved in its formation under hyperglycemic conditions. To provide insight into this issue, human serum albumin was incubated in the presence of FeCl3 (25 μM) and increasing glucose concentrations for 32 h at 37 °C. These concentrations were selected to simulate (i) physiological fasting plasma concentration (4 mM), (ii) pathological pre-diabetes fasting plasma concentration (8 mM), and pathological diabetes fasting plasma concentration (12 mM) of glucose. While both allysine and α-AA were found to increase with increasing glucose concentrations, the carboxylic acid was only detected at pathological glucose concentrations and appeared to be a more reliable indicator of glyco-oxidative stress. The underlying chemical mechanisms of lysine glycation as well as of the depletion of tryptophan and formation of fluorescent and colored advanced glycation products are discussed. Full article
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Article
A Workflow towards the Reproducible Identification and Quantitation of Protein Carbonylation Sites in Human Plasma
Antioxidants 2021, 10(3), 369; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030369 - 01 Mar 2021
Cited by 5
Abstract
Protein carbonylation, a marker of excessive oxidative stress, has been studied in the context of multiple human diseases related to oxidative stress. The variety of post-translational carbonyl modifications (carbonyl PTMs) and their low concentrations in plasma challenge their reproducible identification and quantitation. However, [...] Read more.
Protein carbonylation, a marker of excessive oxidative stress, has been studied in the context of multiple human diseases related to oxidative stress. The variety of post-translational carbonyl modifications (carbonyl PTMs) and their low concentrations in plasma challenge their reproducible identification and quantitation. However, carbonyl-specific biotinylated derivatization tags (e.g., aldehyde reactive probe, ARP) allow for targeting carbonyl PTMs by enriching proteins and peptides carrying these modifications. In this study, an oxidized human serum albumin protein model (OxHSA) and plasma from a healthy donor were derivatized with ARP, digested with trypsin, and enriched using biotin-avidin affinity chromatography prior to nano reversed-phase chromatography coupled online to electrospray ionization tandem mass spectrometry with travelling wave ion mobility spectrometry (nRPC-ESI-MS/MS-TWIMS). The presented workflow addresses several analytical challenges by using ARP-specific fragment ions to reliably identify ARP peptides. Furthermore, the reproducible recovery and relative quantitation of ARP peptides were validated. Human serum albumin (HSA) in plasma was heavily modified by a variety of direct amino acid oxidation products and adducts from reactive carbonyl species (RCS), with most RCS modifications being detected in six hotspots, i.e., Lys10, Lys190, Lys199, Lys281, Lys432, and Lys525 of mature HSA. Full article
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Article
In-Depth AGE and ALE Profiling of Human Albumin in Heart Failure: Ex Vivo Studies
Antioxidants 2021, 10(3), 358; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030358 - 27 Feb 2021
Cited by 4
Abstract
Advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), particularly carboxymethyl-lysine (CML), have been largely proposed as factors involved in the establishment and progression of heart failure (HF). Despite this evidence, the current literature lacks the comprehensive identification and characterization of the plasma [...] Read more.
Advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), particularly carboxymethyl-lysine (CML), have been largely proposed as factors involved in the establishment and progression of heart failure (HF). Despite this evidence, the current literature lacks the comprehensive identification and characterization of the plasma AGEs/ALEs involved in HF (untargeted approach). This work provides the first ex vivo high-resolution mass spectrometry (HR-MS) profiling of AGEs/ALEs occurring in human serum albumin (HSA), the most abundant protein in plasma, characterized by several nucleophilic sites and thus representing the main protein substrate for AGE/ALE formation. A set of AGE/ALE adducts in pooled HF-HSA samples was defined, and a semi-quantitative analysis was carried out in order to finally select those presenting in increased amounts in the HF samples with respect to the control condition. These adducts were statistically confirmed by monitoring their content in individual HF samples by applying a targeted approach. Selected AGEs/ALEs proved to be mostly CML derivatives on Lys residues (i.e., CML-Lys12, CML-Lys378, CML-Lys402), and one deoxy-fructosyl derivative on the Lys 389 (DFK-Lys 389). The nature of CML adducts was finally confirmed using immunological methods and in vitro production of such adducts further confirmed by mass spectrometry. Full article
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Article
Selenium-Binding Protein 1 (SELENBP1) Supports Hydrogen Sulfide Biosynthesis and Adipogenesis
Antioxidants 2021, 10(3), 361; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10030361 - 27 Feb 2021
Cited by 13
Abstract
Hydrogen sulfide (H2S), a mammalian gasotransmitter, is involved in the regulation of a variety of fundamental processes including intracellular signaling, cellular bioenergetics, cell proliferation, and cell differentiation. Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently considered the [...] Read more.
Hydrogen sulfide (H2S), a mammalian gasotransmitter, is involved in the regulation of a variety of fundamental processes including intracellular signaling, cellular bioenergetics, cell proliferation, and cell differentiation. Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently considered the three principal mammalian H2S-generating enzymes. However, recently, a fourth H2S-producing enzyme, selenium-binding-protein 1 (SELENBP1), has also been identified. The cellular regulatory role(s) of SELENBP1 are incompletely understood. The current study investigated whether SELENBP1 plays a role in the regulation of adipocyte differentiation in vitro. 3T3-L1 preadipocytes with or without SELENBP1 knock-down were subjected to differentiation-inducing conditions, and H2S production, cellular lipid accumulation, cell proliferation, and mitochondrial activity were quantified. Adipocyte differentiation was associated with an upregulation of H2S biosynthesis. SELENBP1 silencing decreased cellular H2S levels, suppressed the expression of the three “classical” H2S-producing enzymes (CBS, CSE, and 3-MST) and significantly suppressed adipocyte differentiation. Treatment of SELENBP1 knock-down cells with the H2S donor GYY4137 partially restored lipid accumulation, increased cellular H2S levels, and exerted a bell-shaped effect on cellular bioenergetics (enhancement at 1 and 3 mM, and inhibition at 6 mM). We conclude that SELENBP1 in adipocytes (1) contributes to H2S biosynthesis and (2) acts as an endogenous stimulator of adipocyte differentiation. Full article
(This article belongs to the Special Issue Hydrogen Sulfide in Biology)
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Article
Overexpression of the Golden SNP-Carrying Orange Gene Enhances Carotenoid Accumulation and Heat Stress Tolerance in Sweetpotato Plants
Antioxidants 2021, 10(1), 51; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10010051 - 04 Jan 2021
Cited by 12
Abstract
Carotenoids function as photosynthetic accessory pigments, antioxidants, and vitamin A precursors. We recently showed that transgenic sweetpotato calli overexpressing the mutant sweetpotato (Ipomoea batatas [L.] Lam) Orange gene (IbOr-R96H), which carries a single nucleotide polymorphism responsible for Arg [...] Read more.
Carotenoids function as photosynthetic accessory pigments, antioxidants, and vitamin A precursors. We recently showed that transgenic sweetpotato calli overexpressing the mutant sweetpotato (Ipomoea batatas [L.] Lam) Orange gene (IbOr-R96H), which carries a single nucleotide polymorphism responsible for Arg to His substitution at amino acid position 96, exhibited dramatically higher carotenoid content and abiotic stress tolerance than calli overexpressing the wild-type IbOr gene (IbOr-WT). In this study, we generated transgenic sweetpotato plants overexpressing IbOr-R96H under the control of the cauliflower mosaic virus (CaMV) 35S promoter via Agrobacterium-mediated transformation. The total carotenoid contents of IbOr-R96H storage roots (light-orange flesh) and IbOr-WT storage roots (light-yellow flesh) were 5.4–19.6 and 3.2-fold higher, respectively, than those of non-transgenic (NT) storage roots (white flesh). The β-carotene content of IbOr-R96H storage roots was up to 186.2-fold higher than that of NT storage roots. In addition, IbOr-R96H plants showed greater tolerance to heat stress (47 °C) than NT and IbOr-WT plants, possibly because of higher DPPH radical scavenging activity and ABA contents. These results indicate that IbOr-R96H is a promising strategy for developing new sweetpotato cultivars with improved carotenoid contents and heat stress tolerance. Full article
(This article belongs to the Special Issue Antioxidant Defenses in Plants)
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Article
Histone Carbonylation Is a Redox-Regulated Epigenomic Mark That Accumulates with Obesity and Aging
Antioxidants 2020, 9(12), 1210; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121210 - 01 Dec 2020
Cited by 4
Abstract
Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and [...] Read more.
Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that histones are avidly modified by 4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (ob/ob) and high-fat feeding models of obesity. Proteomic evaluation of in vitro 4-HNE- modified histones led to the identification of both Michael and Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy hexenal (4-HHE) and 10 sites of 4-HNE histone modification in visceral adipose tissue. In summary, these results characterize adipose histone carbonylation as a redox-linked epigenomic mark associated with metabolic disease and aging. Full article
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Article
Anti-inflammatory and Anti-oxidant Activity of Hidrox® in Rotenone-Induced Parkinson’s Disease in Mice
Antioxidants 2020, 9(9), 824; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090824 - 03 Sep 2020
Cited by 66
Abstract
Background: In developed countries, the extension of human life is increasingly accompanied by a progressive increase in neurodegenerative diseases, most of which do not yet have effective therapy but only symptomatic treatments. In recent years, plant polyphenols have aroused considerable interest in the [...] Read more.
Background: In developed countries, the extension of human life is increasingly accompanied by a progressive increase in neurodegenerative diseases, most of which do not yet have effective therapy but only symptomatic treatments. In recent years, plant polyphenols have aroused considerable interest in the scientific community. The mechanisms currently hypothesized for the pathogenesis of Parkinson’s disease (PD) are neuroinflammation, oxidative stress and apoptosis. Hydroxytyrosol (HT), the main component of Hidrox® (HD), has been shown to have some of the highest free radical evacuation and anti-inflammatory activities. Here we wanted to study the role of HD on the neurobiological and behavioral alterations induced by rotenone. Methods: A study was conducted in which mice received HD (10 mg/kg, i.p.) concomitantly with rotenone (5 mg/kg, o.s.) for 28 days. Results: Locomotor activity, catalepsy, histological damage and several characteristic markers of the PD, such as the dopamine transporter (DAT) content, tyrosine hydroxylase (TH) and accumulation of α-synuclein, have been evaluated. Moreover, we observed the effects of HD on oxidative stress, neuroinflammation, apoptosis and inflammasomes. Taken together, the results obtained highlight HD’s ability to reduce the loss of dopaminergic neurons and the damage associated with it by counteracting the three main mechanisms of PD pathogenesis. Conclusion: HD is subject to fewer regulations than traditional drugs to improve patients’ brain health and could represent a promising nutraceutical choice to prevent PD. Full article
(This article belongs to the Special Issue Dietary Antioxidants for Modulating the Aging Processes)
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Article
S-Thiolation Targets Albumin in Heart Failure
Antioxidants 2020, 9(8), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9080763 - 17 Aug 2020
Cited by 8
Abstract
Human serum albumin (HSA) is associated with several physiological functions, such as maintaining oncotic pressure and microvascular integrity, among others. It also represents the major and predominant antioxidant in plasma due to the presence of the Cys34 sulfhydryl group. In this study, we [...] Read more.
Human serum albumin (HSA) is associated with several physiological functions, such as maintaining oncotic pressure and microvascular integrity, among others. It also represents the major and predominant antioxidant in plasma due to the presence of the Cys34 sulfhydryl group. In this study, we assessed qualitative and quantitative changes in HSA in patients with heart failure (HF) and their relationship with the severity of the disease. We detected by means of mass spectrometry a global decrease of the HSA content in the plasma of HF patients in respect to control subjects, a significant increase of thio-HSA with a concomitant decrease in the reduced form of albumin. Cysteine and, at a lesser extent, homocysteine represent the most abundant thiol bound to HSA. A strong inverse correlation was also observed between cysteine-HSA and peak VO2/kg, an index of oxygen consumption associated with HF severity. Moreover, in HL-1 cardiomyocytes incubated with H2O2, we showed a significant decrease of cell viability in cells treated with thio-HSA in respect to restored native-HSA. In conclusion, we found for the first time that S-thiolation of albumin is increased in the plasma of HF patients and induced changes in the structure and antioxidant function of HSA, likely contributing to HF progression. Full article
(This article belongs to the Section Aberrant Oxidation of Biomolecules)
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Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells
Antioxidants 2020, 9(8), 682; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9080682 - 29 Jul 2020
Cited by 14
Abstract
Ferroptosis, a recently discovered form of iron-dependent cell death, requires an increased level of lipid-reactive oxygen species (ROS). Ferritinophagy, a ferritin degradation pathway, depends on a selective autophagic cargo receptor (NCOA4). By screening various types of natural compounds, formosanin C (FC) was identified [...] Read more.
Ferroptosis, a recently discovered form of iron-dependent cell death, requires an increased level of lipid-reactive oxygen species (ROS). Ferritinophagy, a ferritin degradation pathway, depends on a selective autophagic cargo receptor (NCOA4). By screening various types of natural compounds, formosanin C (FC) was identified as a novel ferroptosis inducer, characterized by attenuations of FC-induced viability inhibition and lipid ROS formation in the presence of ferroptosis inhibitor. FC also induced autophagic flux, evidenced by preventing autophagic marker LC3-II degradation and increasing yellow LC3 puncta in tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) transfected cells when combined with autophagic flux inhibitor. It is noteworthy that FC-induced ferroptosis and autophagic flux were stronger in HepG2 cells expressing higher NCOA4 and lower ferritin heavy chain 1 (FTH1) levels, agreeing with the results of gene expression analysis using CTRP and PRISM, indicating that FTH1 expression level exhibited a significant negative correlation with the sensitivity of the cells to a ferroptosis inducer. Confocal and electron microscopy confirmed the pronounced involvement of ferritinophagy in FC-induced ferroptosis in the cells with elevated NCOA4. Since ferroptosis is a non-apoptotic form of cell death, our data suggest FC has chemotherapeutic potential against apoptosis-resistant HCC with a higher NCOA4 expression via ferritinophagy. Full article
(This article belongs to the Special Issue Oxidative stress and Applied Biology)
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Article
Polyphenols Attenuate Highly-Glycosylated Haemoglobin-Induced Damage in Human Peritoneal Mesothelial Cells
Antioxidants 2020, 9(7), 572; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9070572 - 01 Jul 2020
Cited by 2
Abstract
We investigated the cytoprotective role of the dietary polyphenols on putative damage induced by Amadori adducts in Human Peritoneal Mesothelial Cells (HPMCs). Increased accumulation of early products of non-enzymatic protein glycation—Amadori adducts—in the peritoneal dialysis fluid due to their high glucose, induces severe [...] Read more.
We investigated the cytoprotective role of the dietary polyphenols on putative damage induced by Amadori adducts in Human Peritoneal Mesothelial Cells (HPMCs). Increased accumulation of early products of non-enzymatic protein glycation—Amadori adducts—in the peritoneal dialysis fluid due to their high glucose, induces severe damage in mesothelial cells during peritoneal dialysis. Dietary polyphenols reportedly have numerous health benefits in various diseases and have been used as an efficient antioxidant in the context of several oxidative stress-related pathologies. HPMCs isolated from different patients were exposed to Amadori adducts (highly glycated haemoglobin, at physiological concentrations), and subsequently treated with several polyphenols, mostly presented in our Mediterranean diet. We studied several Amadori-induced effects in pro-apoptotic and oxidative stress markers, as well as the expression of several pro-inflammatory genes (nuclear factor-kappaB, NF-kB; inducible Nitric Oxide synthetase, iNOS), different caspase-activities, level of P53 protein or production of different reactive oxygen species in the presence of different polyphenols. In fact, cytoprotective agents such as dietary polyphenols may represent an alternate approach to protect mesothelial cells from the cytotoxicity of Amadori adducts. The interference with the Amadori adducts-triggered mechanisms could represent a therapeutic tool to reduce complications associated with peritoneal dialysis in the peritoneum, helping to maintain peritoneal membrane function longer in patients undergoing peritoneal dialysis. Full article
(This article belongs to the Special Issue Effect of Antioxidant Therapy on Oxidative Stress In Vivo)
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Article
Protective Effects of Myricetin on Benzo[a]pyrene-Induced 8-Hydroxy-2′-Deoxyguanosine and BPDE-DNA Adduct
Antioxidants 2020, 9(5), 446; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9050446 - 21 May 2020
Cited by 11
Abstract
Benzo[a]pyrene (B[a]P), a group 1 carcinogen, induces mutagenic DNA adducts. Myricetin is present in many natural foods with diverse biological activities, such as anti-oxidative and anti-cancer activities. The aim of this study was to investigate the protective effects of myricetin against B[a]P-induced toxicity. [...] Read more.
Benzo[a]pyrene (B[a]P), a group 1 carcinogen, induces mutagenic DNA adducts. Myricetin is present in many natural foods with diverse biological activities, such as anti-oxidative and anti-cancer activities. The aim of this study was to investigate the protective effects of myricetin against B[a]P-induced toxicity. Treatment of B[a]P induced cytotoxicity on HepG2 cells, whereas co-treatment of myricetin with B[a]P reduced the formation of the B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE)-DNA adduct, which recovered cell viability. Furthermore, we found a protective effect of myricetin against B[a]P-induced genotoxicity in rats, via myricetin-induced inhibition of 8-hydroxy-2′-deoxyguanosine (8-OHdG) and BPDE-DNA adduct formation in the liver, kidney, colon, and stomach tissue. This inhibition was more prominent in the liver than in other tissues. Correspondingly, myricetin regulated the phase I and II enzymes that inhibit B[a]P metabolism and B[a]P metabolites conjugated with DNA by reducing and inducing CYP1A1 and glutathione S-transferase (GST) expression, respectively. Taken together, this showed that myricetin attenuated B[a]P-induced genotoxicity via regulation of phase I and II enzymes. Our results suggest that myricetin is anti-genotoxic, and prevents oxidative DNA damage and BPDE-DNA adduct formation via regulation of phase I and II enzymes. Full article
(This article belongs to the Special Issue Oxidative Stress Modulators and Functional Foods)
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Article
Melatonin Enhances Palladium-Nanoparticle-Induced Cytotoxicity and Apoptosis in Human Lung Epithelial Adenocarcinoma Cells A549 and H1229
Antioxidants 2020, 9(4), 357; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9040357 - 24 Apr 2020
Cited by 13
Abstract
Palladium nanoparticles (PdNPs) are increasingly being used in medical and biological applications due to their unique physical and chemical properties. Recent evidence suggests that these nanoparticles can act as both a pro-oxidant and as an antioxidant. Melatonin (MLT), which also shows pro- and [...] Read more.
Palladium nanoparticles (PdNPs) are increasingly being used in medical and biological applications due to their unique physical and chemical properties. Recent evidence suggests that these nanoparticles can act as both a pro-oxidant and as an antioxidant. Melatonin (MLT), which also shows pro- and antioxidant properties, can enhance the efficacy of chemotherapeutic agents when combined with anticancer drugs. Nevertheless, studies regarding the molecular mechanisms underlying the anticancer effects of PdNPs and MLT in cancer cells are still lacking. Therefore, we aimed to investigate the potential toxicological and molecular mechanisms of PdNPs, MLT, and the combination of PdNPs with MLT in A549 lung epithelial adenocarcinoma cells. We evaluated cell viability, cell proliferation, cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis in cells treated with different concentrations of PdNPs and MLT. PdNPs and MLT induced cytotoxicity, which was confirmed by leakage of lactate dehydrogenase, increased intracellular protease, and reduced membrane integrity. Oxidative stress increased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), protein carbonyl content (PCC), lipid hydroperoxide (LHP), and 8-isoprostane. Combining PdNPs with MLT elevated the levels of mitochondrial dysfunction by decreasing mitochondrial membrane potential (MMP), ATP content, mitochondrial number, and expression levels of the main regulators of mitochondrial biogenesis. Additionally, PdNPs and MLT induced apoptosis and oxidative DNA damage due to accumulation of 4-hydroxynonenal (HNE), 8-oxo-2′-deoxyguanosine (8-OhdG), and 8-hydroxyguanosine (8-OHG). Finally, PdNPs and MLT increased mitochondrially mediated stress and apoptosis, which was confirmed by the increased expression levels of apoptotic genes. To our knowledge, this is the first study demonstrating the effects of combining PdNPs and MLT in human lung cancer cells. These findings provide valuable insights into the molecular mechanisms involved in PdNP- and MLT-induced toxicity, and it may be that this combination therapy could be a potential effective therapeutic approach. This combination effect provides information to support the clinical evaluation of PdNPs and MLT as a suitable agents for lung cancer treatment, and the combined effect provides therapeutic value, as non-toxic concentrations of PdNPs and MLT are more effective, better tolerated, and show less adverse effects. Finally, this study suggests that MLT could be used as a supplement in nano-mediated combination therapies used to treat lung cancer. Full article
(This article belongs to the Section ROS, RNS and RSS)
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Article
Inactivation of Carbonyl-Detoxifying Enzymes by H2O2 Is a Trigger to Increase Carbonyl Load for Initiating Programmed Cell Death in Plants
Antioxidants 2020, 9(2), 141; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9020141 - 06 Feb 2020
Cited by 10
Abstract
H2O2-induced programmed cell death (PCD) of tobacco Bright Yellow-2 (BY-2) cells is mediated by reactive carbonyl species (RCS), degradation products of lipid peroxides, which activate caspase-3-like protease (C3LP). Here, we investigated the mechanism of RCS accumulation in the H [...] Read more.
H2O2-induced programmed cell death (PCD) of tobacco Bright Yellow-2 (BY-2) cells is mediated by reactive carbonyl species (RCS), degradation products of lipid peroxides, which activate caspase-3-like protease (C3LP). Here, we investigated the mechanism of RCS accumulation in the H2O2-induced PCD of BY-2 cells. The following biochemical changes were observed in 10-min response to a lethal dose (1.0 mM) of H2O2, but they did not occur in a sublethal dose (0.5 mM) of H2O2. (1) The C3LP activity was increased twofold. (2) The intracellular levels of RCS, i.e., 4-hydroxy-(E)-hexenal and 4-hydroxy-(E)-nonenal (HNE), were increased 1.2–1.5-fold. (3) The activity of a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent carbonyl reductase, scavenging HNE, and n-hexanal was decreased. Specifically, these are the earliest events leading to PCD. The proteasome inhibitor MG132 suppressed the H2O2-induced PCD, indicating that the C3LP activity of the β1 subunit of the 20S proteasome was responsible for PCD. The addition of H2O2 to cell-free protein extract inactivated the carbonyl reductase. Taken together, these results suggest a PCD-triggering mechanism in which H2O2 first inactivates a carbonyl reductase(s), allowing RCS levels to rise, and eventually leads to the activation of the C3LP activity of 20S proteasome. The carbonyl reductase thus acts as an ROS sensor for triggering PCD. Full article
(This article belongs to the Special Issue Oxidative Stress in Plant)
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Article
Serratia marcescens BM1 Enhances Cadmium Stress Tolerance and Phytoremediation Potential of Soybean Through Modulation of Osmolytes, Leaf Gas Exchange, Antioxidant Machinery, and Stress-Responsive Genes Expression
Antioxidants 2020, 9(1), 43; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9010043 - 04 Jan 2020
Cited by 49
Abstract
The heavy metal contamination in plant-soil environment has increased manifold recently. In order to reduce the harmful effects of metal stress in plants, the application of beneficial soil microbes is gaining much attention. In the present research, the role of Serratia marcescens BM1 [...] Read more.
The heavy metal contamination in plant-soil environment has increased manifold recently. In order to reduce the harmful effects of metal stress in plants, the application of beneficial soil microbes is gaining much attention. In the present research, the role of Serratia marcescens BM1 in enhancing cadmium (Cd) stress tolerance and phytoremediation potential of soybean plants, was investigated. Exposure of soybean plants to two Cd doses (150 and 300 µM) significantly reduced plant growth, biomass, gas exchange attributes, nutrients uptake, antioxidant capacity, and the contents of chlorophyll, total phenolics, flavonoids, soluble sugars, and proteins. Additionally, Cd induced the stress levels of Cd, proline, glycine betaine, hydrogen peroxide, malondialdehyde, antioxidant enzymes (i.e., catalase, CAT; ascorbate peroxidase, APX; superoxide dismutase, SOD; peroxidise, POD), and the expression of stress-related genes (i.e., APX, CAT, Fe-SOD, POD, CHI, CHS, PHD2, VSO, NR, and P5CS) in soybean leaves. On the other hand, inoculation of Cd-stressed soybean plants with Serratia marcescens BM1 significantly enhanced the plant growth, biomass, gas exchange attributes, nutrients uptake, antioxidant capacity, and the contents of chlorophyll, total phenolics, flavonoids, soluble sugars, and proteins. Moreover, Serratia marcescens BM1 inoculation reduced the levels of cadmium and oxidative stress markers, but significantly induced the activities of antioxidant enzymes and the levels of osmolytes and stress-related genes expression in Cd-stressed plants. The application of 300 µM CdCl2 and Serratia marcescens triggered the highest expression levels of stress-related genes. Overall, this study suggests that inoculation of soybean plants with Serratia marcescens BM1 promotes phytoremediation potential and Cd stress tolerance by modulating the photosynthetic attributes, osmolytes biosynthesis, antioxidants machinery, and the expression of stress-related genes. Full article
(This article belongs to the Special Issue Oxidative Stress in Plant)
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Review

Review
Protein Oxidation in Muscle Foods: A Comprehensive Review
Antioxidants 2022, 11(1), 60; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11010060 - 28 Dec 2021
Cited by 7
Abstract
Muscle foods and their products are a fundamental part of the human diet. The high protein content found in muscle foods, as well as the high content of essential amino acids, provides an appropriate composition to complete the nutritional requirements of humans. However, [...] Read more.
Muscle foods and their products are a fundamental part of the human diet. The high protein content found in muscle foods, as well as the high content of essential amino acids, provides an appropriate composition to complete the nutritional requirements of humans. However, due to their special composition, they are susceptible to oxidative degradation. In this sense, proteins are highly susceptible to oxidative reactions. However, in contrast to lipid oxidation, which has been studied in depth for decades, protein oxidation of muscle foods has been investigated much less. Moreover, these reactions have an important influence on the quality of muscle foods, from physico-chemical, techno-functional, and nutritional perspectives. In this regard, the loss of essential nutrients, the impairment of texture, water-holding capacity, color and flavor, and the formation of toxic substances are some of the direct consequences of protein oxidation. The loss of quality for muscle foods results in consumer rejection and substantial levels of economic losses, and thus the control of oxidative processes is of vital importance for the food industry. Nonetheless, the complexity of the reactions involved in protein oxidation and the many different factors that influence these reactions make the mechanisms of protein oxidation difficult to fully understand. Therefore, the present manuscript reviews the fundamental mechanisms of protein oxidation, the most important oxidative reactions, the main factors that influence protein oxidation, and the currently available analytical methods to quantify compounds derived from protein oxidation reactions. Finally, the main effects of protein oxidation on the quality of muscle foods, both from physico-chemical and nutritional points of view, are also discussed. Full article
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Review
Mitophagy and Oxidative Stress: The Role of Aging
Antioxidants 2021, 10(5), 794; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10050794 - 17 May 2021
Cited by 15
Abstract
Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species [...] Read more.
Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer’s and Parkinson’s diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria. Full article
(This article belongs to the Special Issue Regulation of Autophagy under Stress)
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Review
Functions of ROS in Macrophages and Antimicrobial Immunity
Antioxidants 2021, 10(2), 313; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020313 - 19 Feb 2021
Cited by 53
Abstract
Reactive oxygen species (ROS) are a chemically defined group of reactive molecules derived from molecular oxygen. ROS are involved in a plethora of processes in cells in all domains of life, ranging from bacteria, plants and animals, including humans. The importance of ROS [...] Read more.
Reactive oxygen species (ROS) are a chemically defined group of reactive molecules derived from molecular oxygen. ROS are involved in a plethora of processes in cells in all domains of life, ranging from bacteria, plants and animals, including humans. The importance of ROS for macrophage-mediated immunity is unquestioned. Their functions comprise direct antimicrobial activity against bacteria and parasites as well as redox-regulation of immune signaling and induction of inflammasome activation. However, only a few studies have performed in-depth ROS analyses and even fewer have identified the precise redox-regulated target molecules. In this review, we will give a brief introduction to ROS and their sources in macrophages, summarize the versatile roles of ROS in direct and indirect antimicrobial immune defense, and provide an overview of commonly used ROS probes, scavengers and inhibitors. Full article
(This article belongs to the Special Issue Reactive Oxygen Species in Different Biological Processes)
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Review
Abiotic Stress and Reactive Oxygen Species: Generation, Signaling, and Defense Mechanisms
Antioxidants 2021, 10(2), 277; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox10020277 - 11 Feb 2021
Cited by 74
Abstract
Climate change is an invisible, silent killer with calamitous effects on living organisms. As the sessile organism, plants experience a diverse array of abiotic stresses during ontogenesis. The relentless climatic changes amplify the intensity and duration of stresses, making plants dwindle to survive. [...] Read more.
Climate change is an invisible, silent killer with calamitous effects on living organisms. As the sessile organism, plants experience a diverse array of abiotic stresses during ontogenesis. The relentless climatic changes amplify the intensity and duration of stresses, making plants dwindle to survive. Plants convert 1–2% of consumed oxygen into reactive oxygen species (ROS), in particular, singlet oxygen (1O2), superoxide radical (O2•–), hydrogen peroxide (H2O2), hydroxyl radical (OH), etc. as a byproduct of aerobic metabolism in different cell organelles such as chloroplast, mitochondria, etc. The regulatory network comprising enzymatic and non-enzymatic antioxidant systems tends to keep the magnitude of ROS within plant cells to a non-damaging level. However, under stress conditions, the production rate of ROS increases exponentially, exceeding the potential of antioxidant scavengers instigating oxidative burst, which affects biomolecules and disturbs cellular redox homeostasis. ROS are similar to a double-edged sword; and, when present below the threshold level, mediate redox signaling pathways that actuate plant growth, development, and acclimatization against stresses. The production of ROS in plant cells displays both detrimental and beneficial effects. However, exact pathways of ROS mediated stress alleviation are yet to be fully elucidated. Therefore, the review deposits information about the status of known sites of production, signaling mechanisms/pathways, effects, and management of ROS within plant cells under stress. In addition, the role played by advancement in modern techniques such as molecular priming, systems biology, phenomics, and crop modeling in preventing oxidative stress, as well as diverting ROS into signaling pathways has been canvassed. Full article
(This article belongs to the Special Issue Approaches in Enhancing Antioxidant Defense in Plants)
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Review
Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases
Antioxidants 2020, 9(12), 1292; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9121292 - 17 Dec 2020
Cited by 26
Abstract
Oxidative stress plays a key role in many physiological and pathological conditions. The intracellular oxidative homeostasis is tightly regulated by the reactive oxygen species production and the intracellular defense mechanisms. Increased oxidative stress could alter lipid, DNA, and protein, resulting in cellular inflammation [...] Read more.
Oxidative stress plays a key role in many physiological and pathological conditions. The intracellular oxidative homeostasis is tightly regulated by the reactive oxygen species production and the intracellular defense mechanisms. Increased oxidative stress could alter lipid, DNA, and protein, resulting in cellular inflammation and programmed cell death. Evidences show that oxidative stress plays an important role in the progression of various cardiovascular diseases, such as atherosclerosis, heart failure, cardiac arrhythmia, and ischemia-reperfusion injury. There are a number of therapeutic options to treat oxidative stress-associated cardiovascular diseases. Well known antioxidants, such as nutritional supplements, as well as more novel antioxidants have been studied. In addition, novel therapeutic strategies using miRNA and nanomedicine are also being developed to treat various cardiovascular diseases. In this article, we provide a detailed description of oxidative stress. Then, we will introduce the relationship between oxidative stress and several cardiovascular diseases. Finally, we will focus on the clinical implications of oxidative stress in cardiovascular diseases. Full article
(This article belongs to the Special Issue Oxidative stress and Applied Biology)
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Review
The Advanced Lipoxidation End-Product Malondialdehyde-Lysine in Aging and Longevity
Antioxidants 2020, 9(11), 1132; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111132 - 15 Nov 2020
Cited by 20
Abstract
The nonenzymatic adduction of malondialdehyde (MDA) to the protein amino groups leads to the formation of malondialdehyde-lysine (MDALys). The degree of unsaturation of biological membranes and the intracellular oxidative conditions are the main factors that modulate MDALys formation. The low concentration of this [...] Read more.
The nonenzymatic adduction of malondialdehyde (MDA) to the protein amino groups leads to the formation of malondialdehyde-lysine (MDALys). The degree of unsaturation of biological membranes and the intracellular oxidative conditions are the main factors that modulate MDALys formation. The low concentration of this modification in the different cellular components, found in a wide diversity of tissues and animal species, is indicative of the presence of a complex network of cellular protection mechanisms that avoid its cytotoxic effects. In this review, we will focus on the chemistry of this lipoxidation-derived protein modification, the specificity of MDALys formation in proteins, the methodology used for its detection and quantification, the MDA-lipoxidized proteome, the metabolism of MDA-modified proteins, and the detrimental effects of this protein modification. We also propose that MDALys is an indicator of the rate of aging based on findings which demonstrate that (i) MDALys accumulates in tissues with age, (ii) the lower the concentration of MDALys the greater the longevity of the animal species, and (iii) its concentration is attenuated by anti-aging nutritional and pharmacological interventions. Full article
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Review
Are Flavonoids Effective Antioxidants in Plants? Twenty Years of Our Investigation
Antioxidants 2020, 9(11), 1098; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111098 - 09 Nov 2020
Cited by 45
Abstract
Whether flavonoids play significant antioxidant roles in plants challenged by photooxidative stress of different origin has been largely debated over the last few decades. A critical review of the pertinent literature and our experimentation as well, based on a free-of-scale approach, support an [...] Read more.
Whether flavonoids play significant antioxidant roles in plants challenged by photooxidative stress of different origin has been largely debated over the last few decades. A critical review of the pertinent literature and our experimentation as well, based on a free-of-scale approach, support an important antioxidant function served by flavonoids in plants exposed to a wide range of environmental stressors, the significance of which increases with the severity of stress. On the other side, some questions need conclusive answers when the putative antioxidant functions of plant flavonoids are examined at the level of both the whole-cell and cellular organelles. This partly depends upon a conclusive, robust, and unbiased definition of “a plant antioxidant”, which is still missing, and the need of considering the subcellular re-organization that occurs in plant cells in response to severe stress conditions. This likely makes our deterministic-based approach unsuitable to unveil the relevance of flavonoids as antioxidants in extremely complex biological systems, such as a plant cell exposed to an ever-changing stressful environment. This still poses open questions about how to measure the occurred antioxidant action of flavonoids. Our reasoning also evidences the need of contemporarily evaluating the changes in key primary and secondary components of the antioxidant defense network imposed by stress events of increasing severity to properly estimate the relevance of the antioxidant functions of flavonoids in an in planta situation. In turn, this calls for an in-depth analysis of the sub-cellular distribution of primary and secondary antioxidants to solve this still intricate matter. Full article
(This article belongs to the Special Issue Antioxidant Defenses in Plants)
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Review
ROS and NO Regulation by Melatonin Under Abiotic Stress in Plants
Antioxidants 2020, 9(11), 1078; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9111078 - 03 Nov 2020
Cited by 24
Abstract
Abiotic stress in plants is an increasingly common problem in agriculture, and thus, studies on plant treatments with specific compounds that may help to mitigate these effects have increased in recent years. Melatonin (MET) application and its role in mitigating the negative effects [...] Read more.
Abiotic stress in plants is an increasingly common problem in agriculture, and thus, studies on plant treatments with specific compounds that may help to mitigate these effects have increased in recent years. Melatonin (MET) application and its role in mitigating the negative effects of abiotic stress in plants have become important in the last few years. MET, a derivative of tryptophan, is an important plant-related response molecule involved in the growth, development, and reproduction of plants, and the induction of different stress factors. In addition, MET plays a protective role against different abiotic stresses such as salinity, high/low temperature, high light, waterlogging, nutrient deficiency and stress combination by regulating both the enzymatic and non-enzymatic antioxidant defense systems. Moreover, MET interacts with many signaling molecules, such as reactive oxygen species (ROS) and nitric oxide (NO), and participates in a wide variety of physiological reactions. It is well known that NO produces S-nitrosylation and NO2-Tyr of important antioxidant-related proteins, with this being an important mechanism for maintaining the antioxidant capacity of the AsA/GSH cycle under nitro-oxidative conditions, as extensively reviewed here under different abiotic stress conditions. Lastly, in this review, we show the coordinated actions between NO and MET as a long-range signaling molecule, regulating many responses in plants, including plant growth and abiotic stress tolerance. Despite all the knowledge acquired over the years, there is still more to know about how MET and NO act on the tolerance of plants to abiotic stresses. Full article
(This article belongs to the Special Issue Antioxidant Defenses in Plants)
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Review
Oxidative Stress in Cardiovascular Diseases
Antioxidants 2020, 9(9), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090864 - 14 Sep 2020
Cited by 74
Abstract
Reactive oxygen species (ROS) are subcellular messengers in signal transductions pathways with both beneficial and deleterious roles. ROS are generated as a by-product of mitochondrial respiration or metabolism or by specific enzymes such as superoxide dismutases, glutathione peroxidase, catalase, peroxiredoxins, and myeloperoxidases. Under [...] Read more.
Reactive oxygen species (ROS) are subcellular messengers in signal transductions pathways with both beneficial and deleterious roles. ROS are generated as a by-product of mitochondrial respiration or metabolism or by specific enzymes such as superoxide dismutases, glutathione peroxidase, catalase, peroxiredoxins, and myeloperoxidases. Under physiological conditions, the low levels of ROS production are equivalent to their detoxification, playing a major role in cellular signaling and function. In pathological situations, particularly atherosclerosis or hypertension, the release of ROS exceeds endogenous antioxidant capacity, leading to cell death. At cardiovascular levels, oxidative stress is highly implicated in myocardial infarction, ischemia/reperfusion, or heart failure. Here, we will first detail the physiological role of low ROS production in the heart and the vessels. Indeed, ROS are able to regulate multiple cardiovascular functions, such as cell proliferation, migration, and death. Second, we will investigate the implication of oxidative stress in cardiovascular diseases. Then, we will focus on ROS produced by NAPDH oxidase or during endothelial or mitochondrial dysfunction. Given the importance of oxidative stress at the cardiovascular level, antioxidant therapies could be a real benefit. In the last part of this review, we will detail the new therapeutic strategies potentially involved in cardiovascular protection and currently under study. Full article
(This article belongs to the Special Issue Oxidative Stress in Vascular Pathophysiology)
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Review
Melatonin-Induced Water Stress Tolerance in Plants: Recent Advances
Antioxidants 2020, 9(9), 809; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9090809 - 01 Sep 2020
Cited by 34
Abstract
Water stress (drought and waterlogging) is severe abiotic stress to plant growth and development. Melatonin, a bioactive plant hormone, has been widely tested in drought situations in diverse plant species, while few studies on the role of melatonin in waterlogging stress conditions have [...] Read more.
Water stress (drought and waterlogging) is severe abiotic stress to plant growth and development. Melatonin, a bioactive plant hormone, has been widely tested in drought situations in diverse plant species, while few studies on the role of melatonin in waterlogging stress conditions have been published. In the current review, we analyze the biostimulatory functions of melatonin on plants under both drought and waterlogging stresses. Melatonin controls the levels of reactive oxygen and nitrogen species and positively changes the molecular defense to improve plant tolerance against water stress. Moreover, the crosstalk of melatonin and other phytohormones is a key element of plant survival under drought stress, while this relationship needs further investigation under waterlogging stress. In this review, we draw the complete story of water stress on both sides—drought and waterlogging—through discussing the previous critical studies under both conditions. Moreover, we suggest several research directions, especially for waterlogging, which remains a big and vague piece of the melatonin and water stress puzzle. Full article
(This article belongs to the Special Issue Approaches in Enhancing Antioxidant Defense in Plants)
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Review
Squalene: More than a Step toward Sterols
Antioxidants 2020, 9(8), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9080688 - 02 Aug 2020
Cited by 18
Abstract
Squalene (SQ) is a natural triterpene widely distributed in nature. It is a metabolic intermediate of the sterol biosynthetic pathway and represents a possible target in different metabolic and oxidative stress-related disorders. Growing interest has been focused on SQ’s antioxidant properties, derived from [...] Read more.
Squalene (SQ) is a natural triterpene widely distributed in nature. It is a metabolic intermediate of the sterol biosynthetic pathway and represents a possible target in different metabolic and oxidative stress-related disorders. Growing interest has been focused on SQ’s antioxidant properties, derived from its chemical structure. Strong evidence provided by ex vivo models underline its scavenging activity towards free radicals, whereas only a few studies have highlighted its effect in cellular models of oxidative stress. Given the role of unbalanced free radicals in both the onset and progression of several cardiovascular diseases, an in depth evaluation of SQ’s contribution to antioxidant defense mechanisms could represent a strategic approach in dealing with these pathological conditions. At present experimental results overall show a double-edged sword role of squalene in cardiovascular diseases and its function has to be better elucidated in order to establish intervention lines focused on its features. This review aims to summarize current knowledge about endogenous and exogenous sources of SQ and to point out the controversial role of SQ in cardiovascular physiology. Full article
(This article belongs to the Special Issue Redox and Nitrosative Signaling and Stress)
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Review
Reactive Oxygen Species and Antioxidant Defense in Plants under Abiotic Stress: Revisiting the Crucial Role of a Universal Defense Regulator
Antioxidants 2020, 9(8), 681; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9080681 - 29 Jul 2020
Cited by 411
Abstract
Global climate change and associated adverse abiotic stress conditions, such as drought, salinity, heavy metals, waterlogging, extreme temperatures, oxygen deprivation, etc., greatly influence plant growth and development, ultimately affecting crop yield and quality, as well as agricultural sustainability in general. Plant cells produce [...] Read more.
Global climate change and associated adverse abiotic stress conditions, such as drought, salinity, heavy metals, waterlogging, extreme temperatures, oxygen deprivation, etc., greatly influence plant growth and development, ultimately affecting crop yield and quality, as well as agricultural sustainability in general. Plant cells produce oxygen radicals and their derivatives, so-called reactive oxygen species (ROS), during various processes associated with abiotic stress. Moreover, the generation of ROS is a fundamental process in higher plants and employs to transmit cellular signaling information in response to the changing environmental conditions. One of the most crucial consequences of abiotic stress is the disturbance of the equilibrium between the generation of ROS and antioxidant defense systems triggering the excessive accumulation of ROS and inducing oxidative stress in plants. Notably, the equilibrium between the detoxification and generation of ROS is maintained by both enzymatic and nonenzymatic antioxidant defense systems under harsh environmental stresses. Although this field of research has attracted massive interest, it largely remains unexplored, and our understanding of ROS signaling remains poorly understood. In this review, we have documented the recent advancement illustrating the harmful effects of ROS, antioxidant defense system involved in ROS detoxification under different abiotic stresses, and molecular cross-talk with other important signal molecules such as reactive nitrogen, sulfur, and carbonyl species. In addition, state-of-the-art molecular approaches of ROS-mediated improvement in plant antioxidant defense during the acclimation process against abiotic stresses have also been discussed. Full article
(This article belongs to the Special Issue Antioxidant Defenses in Plants)
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Review
Redox Imbalances in Ageing and Metabolic Alterations: Implications in Cancer and Cardiac Diseases. An Overview from the Working Group of Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology (SIC)
Antioxidants 2020, 9(7), 641; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9070641 - 21 Jul 2020
Cited by 10
Abstract
Metabolic syndrome (MetS) is a well established risk factor for cardiovascular (CV) diseases. In addition, several studies indicate that MetS correlates with the increased risk of cancer in adults. The mechanisms linking MetS and cancer are not fully understood. Several risk factors involved [...] Read more.
Metabolic syndrome (MetS) is a well established risk factor for cardiovascular (CV) diseases. In addition, several studies indicate that MetS correlates with the increased risk of cancer in adults. The mechanisms linking MetS and cancer are not fully understood. Several risk factors involved in MetS are also cancer risk factors, such as the consumption of high calorie-food or high fat intake, low fibre intake, and sedentary lifestyle. Other common aspects of both cancer and MetS are oxidative stress and inflammation. In addition, some anticancer treatments can induce cardiotoxicity, including, for instance, left ventricular (LV) dysfunction and heart failure (HF), endothelial dysfunction and hypertension. In this review, we analyse several aspects of MetS, cancer and cardiotoxicity from anticancer drugs. In particular, we focus on oxidative stress in ageing, cancer and CV diseases, and we analyse the connections among CV risk factors, cancer and cardiotoxicity from anticancer drugs. Full article
(This article belongs to the Special Issue Redox and Nitrosative Signaling and Stress)
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Review
The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19
Antioxidants 2020, 9(7), 624; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9070624 - 16 Jul 2020
Cited by 68
Abstract
The novel COVID-19 pandemic is affecting the world’s population differently: mostly in the presence of conditions such as aging, diabetes and hypertension the virus triggers a lethal cytokine storm and patients die from acute respiratory distress syndrome, whereas in many cases the disease [...] Read more.
The novel COVID-19 pandemic is affecting the world’s population differently: mostly in the presence of conditions such as aging, diabetes and hypertension the virus triggers a lethal cytokine storm and patients die from acute respiratory distress syndrome, whereas in many cases the disease has a mild or even asymptomatic progression. A common denominator in all conditions associated with COVID-19 appears to be the impaired redox homeostasis responsible for reactive oxygen species (ROS) accumulation; therefore, levels of glutathione (GSH), the key anti-oxidant guardian in all tissues, could be critical in extinguishing the exacerbated inflammation that triggers organ failure in COVID-19. The present review provides a biochemical investigation of the mechanisms leading to deadly inflammation in severe COVID-19, counterbalanced by GSH. The pathways competing for GSH are described to illustrate the events concurring to cause a depletion of endogenous GSH stocks. Drawing on evidence from literature that demonstrates the reduced levels of GSH in the main conditions clinically associated with severe disease, we highlight the relevance of restoring GSH levels in the attempt to protect the most vulnerable subjects from severe symptoms of COVID-19. Finally, we discuss the current data about the feasibility of increasing GSH levels, which could be used to prevent and subdue the disease. Full article
(This article belongs to the Special Issue ROS and COVID)
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Review
Hydrogen Sulfide: From a Toxic Molecule to a Key Molecule of Cell Life
Antioxidants 2020, 9(7), 621; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9070621 - 15 Jul 2020
Cited by 40
Abstract
Hydrogen sulfide (H2S) has always been considered toxic, but a huge number of articles published more recently showed the beneficial biochemical properties of its endogenous production throughout all regna. In this review, the participation of H2S in many [...] Read more.
Hydrogen sulfide (H2S) has always been considered toxic, but a huge number of articles published more recently showed the beneficial biochemical properties of its endogenous production throughout all regna. In this review, the participation of H2S in many physiological and pathological processes in animals is described, and its importance as a signaling molecule in plant systems is underlined from an evolutionary point of view. H2S quantification methods are summarized and persulfidation is described as the underlying mechanism of action in plants, animals and bacteria. This review aims to highlight the importance of its crosstalk with other signaling molecules and its fine regulation for the proper function of the cell and its survival. Full article
(This article belongs to the Special Issue Hydrogen Sulfide in Biology)
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Review
An Update on Mitochondrial Reactive Oxygen Species Production
Antioxidants 2020, 9(6), 472; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9060472 - 02 Jun 2020
Cited by 52
Abstract
Mitochondria are quantifiably the most important sources of superoxide (O2●−) and hydrogen peroxide (H2O2) in mammalian cells. The overproduction of these molecules has been studied mostly in the contexts of the pathogenesis of human diseases and [...] Read more.
Mitochondria are quantifiably the most important sources of superoxide (O2●−) and hydrogen peroxide (H2O2) in mammalian cells. The overproduction of these molecules has been studied mostly in the contexts of the pathogenesis of human diseases and aging. However, controlled bursts in mitochondrial ROS production, most notably H2O2, also plays a vital role in the transmission of cellular information. Striking a balance between utilizing H2O2 in second messaging whilst avoiding its deleterious effects requires the use of sophisticated feedback control and H2O2 degrading mechanisms. Mitochondria are enriched with H2O2 degrading enzymes to desensitize redox signals. These organelles also use a series of negative feedback loops, such as proton leaks or protein S-glutathionylation, to inhibit H2O2 production. Understanding how mitochondria produce ROS is also important for comprehending how these organelles use H2O2 in eustress signaling. Indeed, twelve different enzymes associated with nutrient metabolism and oxidative phosphorylation (OXPHOS) can serve as important ROS sources. This includes several flavoproteins and respiratory complexes I-III. Progress in understanding how mitochondria generate H2O2 for signaling must also account for critical physiological factors that strongly influence ROS production, such as sex differences and genetic variances in genes encoding antioxidants and proteins involved in mitochondrial bioenergetics. In the present review, I provide an updated view on how mitochondria budget cellular H2O2 production. These discussions will focus on the potential addition of two acyl-CoA dehydrogenases to the list of ROS generators and the impact of important phenotypic and physiological factors such as tissue type, mouse strain, and sex on production by these individual sites. Full article
(This article belongs to the Special Issue Redox and Nitrosative Signaling and Stress)
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Review
Diet and Mental Health: Review of the Recent Updates on Molecular Mechanisms
Antioxidants 2020, 9(4), 346; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9040346 - 23 Apr 2020
Cited by 70
Abstract
Over the last decades, there has been a substantial increase in the prevalence of mental health disorders, including an increased prevalence of depression, anxiety, cognitive, and sleep disorders. Diet and its bioactive components have been recognized among the modifiable risk factors, possibly influencing [...] Read more.
Over the last decades, there has been a substantial increase in the prevalence of mental health disorders, including an increased prevalence of depression, anxiety, cognitive, and sleep disorders. Diet and its bioactive components have been recognized among the modifiable risk factors, possibly influencing their pathogenesis. This review aimed to summarize molecular mechanisms underlying the putative beneficial effects toward brain health of different dietary factors, such as micro- and macronutrient intake and habits, such as feeding time and circadian rhythm. The role of hormonal homeostasis in the context of glucose metabolism and adiponectin regulation and its impact on systemic and neuro-inflammation has also been considered and deepened. In addition, the effect of individual bioactive molecules exerting antioxidant activities and acting as anti-inflammatory agents, such as omega-3 fatty acids and polyphenols, considered beneficial for the central nervous system via modulation of adult neurogenesis, synaptic and neuronal plasticity, and microglia activation has been summarized. An overview of the regulation of the gut–brain axis and its effect on the modulation of systemic inflammation and oxidative stress has been provided. Finally, the impact of bioactive molecules on inflammation and oxidative stress and its association with brain health has been summarized. Full article
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Review
Molecular Mechanism of Oxidation of P700 and Suppression of ROS Production in Photosystem I in Response to Electron-Sink Limitations in C3 Plants
Antioxidants 2020, 9(3), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9030230 - 11 Mar 2020
Cited by 27
Abstract
Photosynthesis fixes CO2 and converts it to sugar, using chemical-energy compounds of both NADPH and ATP, which are produced in the photosynthetic electron transport system. The photosynthetic electron transport system absorbs photon energy to drive electron flow from Photosystem II (PSII) to [...] Read more.
Photosynthesis fixes CO2 and converts it to sugar, using chemical-energy compounds of both NADPH and ATP, which are produced in the photosynthetic electron transport system. The photosynthetic electron transport system absorbs photon energy to drive electron flow from Photosystem II (PSII) to Photosystem I (PSI). That is, both PSII and PSI are full of electrons. O2 is easily reduced to a superoxide radical (O2) at the reducing side, i.e., the acceptor side, of PSI, which is the main production site of reactive oxygen species (ROS) in photosynthetic organisms. ROS-dependent inactivation of PSI in vivo has been reported, where the electrons are accumulated at the acceptor side of PSI by artificial treatments: exposure to low temperature and repetitive short-pulse (rSP) illumination treatment, and the accumulated electrons flow to O2, producing ROS. Recently, my group found that the redox state of the reaction center of chlorophyll P700 in PSI regulates the production of ROS: P700 oxidation suppresses the production of O2 and prevents PSI inactivation. This is why P700 in PSI is oxidized upon the exposure of photosynthesis organisms to higher light intensity and/or low CO2 conditions, where photosynthesis efficiency decreases. In this study, I introduce a new molecular mechanism for the oxidation of P700 in PSI and suppression of ROS production from the robust relationship between the light and dark reactions of photosynthesis. The accumulated protons in the lumenal space of the thylakoid membrane and the accumulated electrons in the plastoquinone (PQ) pool drive the rate-determining step of the P700 photo-oxidation reduction cycle in PSI from the photo-excited P700 oxidation to the reduction of the oxidized P700, thereby enhancing P700 oxidation. Full article
(This article belongs to the Special Issue Oxidative Stress in Plant)
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Review
Potential Applications of NRF2 Modulators in Cancer Therapy
Antioxidants 2020, 9(3), 193; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9030193 - 25 Feb 2020
Cited by 59
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Modulators of Oxidative Stress: Chemical and Pharmacological Aspects)
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Review
Polyphenols from Food and Natural Products: Neuroprotection and Safety
Antioxidants 2020, 9(1), 61; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9010061 - 10 Jan 2020
Cited by 87
Abstract
Polyphenols are naturally occurring micronutrients that are present in many food sources. Besides being potent antioxidants, these molecules may also possess anti-inflammatory properties. Many studies have highlighted their potential role in the prevention and treatment of various pathological conditions connected to oxidative stress [...] Read more.
Polyphenols are naturally occurring micronutrients that are present in many food sources. Besides being potent antioxidants, these molecules may also possess anti-inflammatory properties. Many studies have highlighted their potential role in the prevention and treatment of various pathological conditions connected to oxidative stress and inflammation (e.g., cancer, and cardiovascular and neurodegenerative disorders). Neurodegenerative diseases are globally one of the main causes of death and represent an enormous burden in terms of human suffering, social distress, and economic costs. Recent data expanded on the initial antioxidant-based mechanism of polyphenols’ action by showing that they are also able to modulate several cell-signaling pathways and mediators. The proposed benefits of polyphenols, either as protective/prophylactic substances or as therapeutic molecules, may be achieved by the consumption of a natural polyphenol-enriched diet, by their use as food supplements, or with formulations as pharmaceutical drugs/nutraceuticals. It has also been proved that the health effects of polyphenols depend on the consumed amount and their bioavailability. However, their overconsumption may raise safety concerns due to the accumulation of high levels of these molecules in the organism, particularly if we consider the loose regulatory legislation regarding the commercialization and use of food supplements. This review addresses the main beneficial effects of food polyphenols, and focuses on neuroprotection and the safety issues related to overconsumption. Full article
(This article belongs to the Special Issue Botanical Antioxidants and Neurological Diseases)
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