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Volume 9
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Antioxidants, Volume 9, Issue 8 (August 2020) – 125 articles

Cover Story (view full-size image): The transcription factor NF-E2 p45-related factor 2 (Nrf2) plays a critical role in regulating cellular redox. Contributions of the Nrf2 pathway to organismal homeostasis are seen in many animal studies, raising intense attention towards its clinical promise against an ever-widening range of diseases. Understanding the pharmacokinetic and pharmacodynamic properties of drug candidates relies in part on the use of biomarkers to optimize clinical applications. This review focuses on the mechanistically-linked biomarkers measured in clinical trials with four agents (dimethyl fumarate, bardoxolone methyl, oltipraz, sulforaphane) known to target Nrf2 signaling in animals. While no biomarkers to date excel at defining pharmacodynamic action, it is clear that these four compounds do touch the NRF2 pathway in humans. View this paper
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12 pages, 4828 KiB  
Article
Ablation of Peroxiredoxin V Exacerbates Ischemia/Reperfusion-Induced Kidney Injury in Mice
by Jiyoung Park, Eun Gyeong Lee, Ho Jin Yi, Nam Hee Kim, Sue Goo Rhee and Hyun Ae Woo
Antioxidants 2020, 9(8), 769; https://doi.org/10.3390/antiox9080769 - 18 Aug 2020
Cited by 10 | Viewed by 3140
Abstract
Ischemia/reperfusion (I/R) is one of the major causes of acute kidney injury (AKI) and associated with increased mortality and progression to chronic kidney injury (CKI). Molecular mechanisms underlying I/R injury involve the production and excessive accumulation of reactive oxygen species (ROS). Peroxiredoxin (Prx) [...] Read more.
Ischemia/reperfusion (I/R) is one of the major causes of acute kidney injury (AKI) and associated with increased mortality and progression to chronic kidney injury (CKI). Molecular mechanisms underlying I/R injury involve the production and excessive accumulation of reactive oxygen species (ROS). Peroxiredoxin (Prx) V, a cysteine-dependent peroxidase, is located in the cytosol, mitochondria, and peroxisome and has an intensive ROS scavenging activity. Therefore, we focused on the role of Prx V during I/R-induced AKI using Prx V knockout (KO) mice. Ablation of Prx V augmented tubular damage, apoptosis, and declined renal function. Prx V deletion also showed higher susceptibility to I/R injury with increased markers for oxidative stress, ER stress, and inflammation in the kidney. Overall, these results demonstrate that Prx V protects the kidneys against I/R-induced injury. Full article
(This article belongs to the Special Issue Peroxiredoxin)
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29 pages, 4022 KiB  
Article
Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease
by Razvan Stefan Boiangiu, Marius Mihasan, Dragos Lucian Gorgan, Bogdan Alexandru Stache, Brindusa Alina Petre and Lucian Hritcu
Antioxidants 2020, 9(8), 768; https://doi.org/10.3390/antiox9080768 - 18 Aug 2020
Cited by 15 | Viewed by 4326
Abstract
The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease [...] Read more.
The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions. Full article
(This article belongs to the Special Issue Oxidative Stress and Inflammation in the Nervous System)
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15 pages, 2514 KiB  
Article
The Impact of Formulation on Lutein, Zeaxanthin, and meso-Zeaxanthin Bioavailability: A Randomised Double-Blind Placebo-Controlled Study
by Marina Green-Gomez, Alfonso Prado-Cabrero, Rachel Moran, Tommy Power, Laura G. Gómez-Mascaraque, Jim Stack and John M. Nolan
Antioxidants 2020, 9(8), 767; https://doi.org/10.3390/antiox9080767 - 18 Aug 2020
Cited by 8 | Viewed by 4705
Abstract
Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) have been the focus of research and commercial interest for their applications in human health. Research into formulations to enhance their bioavailability is merited. This 6 month randomised placebo-controlled trial involving 81 healthy volunteers compared [...] Read more.
Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) have been the focus of research and commercial interest for their applications in human health. Research into formulations to enhance their bioavailability is merited. This 6 month randomised placebo-controlled trial involving 81 healthy volunteers compared the bioavailability of different formulations of free L, Z, and MZ in sunflower or omega-3 oil versus L, Z, and MZ diacetates (Ld, Zd, and MZd) in a micromicellar formulation. Fasting serum carotenoids, macular pigment, and skin carotenoid score were analysed at baseline and 6 months. Serum L, Z, and MZ concentrations increased in all active interventions compared to placebo (p < 0.001 to p = 0.008). The diacetate micromicelle formulation exhibited a significantly higher mean response in serum concentrations of Z and MZ compared to the other active interventions (p = 0.002 to 0.019). A micromicellar formulation with solubilised Z and MZ diacetates is a promising technology advancement that enhances the bioavailability of these carotenoids when compared to traditional carotenoid formulations (ISRCTN clinical trial registration number: ISRCTN18206561). Full article
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23 pages, 5441 KiB  
Article
Oxidative Stress Response Is Mediated by Overexpression and Spatiotemporal Regulation of Caveolin-1
by Andreas Goutas, Ioanna Papathanasiou, Evanthia Mourmoura, Konstantinos Tsesmelis, Aspasia Tsezou and Varvara Trachana
Antioxidants 2020, 9(8), 766; https://doi.org/10.3390/antiox9080766 - 18 Aug 2020
Cited by 10 | Viewed by 3051
Abstract
Oxidative stress (OS) has been linked to the aetiology of many diseases including osteoarthritis (OA). Recent studies have shown that caveolin-1—a structural protein of plasma membrane’s caveolae—is upregulated in response to OS. Here, we explore the function of caveolin-1 in chondrocytes derived from [...] Read more.
Oxidative stress (OS) has been linked to the aetiology of many diseases including osteoarthritis (OA). Recent studies have shown that caveolin-1—a structural protein of plasma membrane’s caveolae—is upregulated in response to OS. Here, we explore the function of caveolin-1 in chondrocytes derived from healthy individuals (control) and OA patients that were subjected to exogenous OS. We showed that caveolin-1 was upregulated in response to acute OS in the control, but not in OA chondrocytes. Moreover, OS-induced DNA damage analysis revealed that control cells started repairing the DNA lesions 6 h post-oxidative treatment, while OA cells seemed unable to restore these damages. Importantly, in the control cells, we observed a translocation of caveolin-1 from the membrane/cytoplasm in and out of the nucleus, which coincided with the appearance and restoration of DNA lesions. When caveolin-1 was prevented from translocating to the nucleus, the control cells were unable to repair DNA damage. In OA cells, no such translocation of caveolin-1 was observed, which could account for their inability to repair DNA damage. Taken together, these results provide novel insights considering the role of caveolin-1 in response to OS-induced DNA damage while revealing its implication in the pathophysiology of OA. Full article
(This article belongs to the Special Issue Feature Papers in Antioxidants in 2020)
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20 pages, 1460 KiB  
Review
TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis
by Eiji Yoshihara
Antioxidants 2020, 9(8), 765; https://doi.org/10.3390/antiox9080765 - 18 Aug 2020
Cited by 56 | Viewed by 9288
Abstract
Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity [...] Read more.
Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed. Full article
(This article belongs to the Special Issue Thioredoxin Family Proteins)
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24 pages, 735 KiB  
Review
Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?
by Laura Bordoni and Rosita Gabbianelli
Antioxidants 2020, 9(8), 764; https://doi.org/10.3390/antiox9080764 - 17 Aug 2020
Cited by 24 | Viewed by 6059
Abstract
The maintenance of the mitochondrial function is essential in preventing and counteracting neurodegeneration. In particular, mitochondria of neuronal cells play a pivotal role in sustaining the high energetic metabolism of these cells and are especially prone to oxidative damage. Since overproduction of reactive [...] Read more.
The maintenance of the mitochondrial function is essential in preventing and counteracting neurodegeneration. In particular, mitochondria of neuronal cells play a pivotal role in sustaining the high energetic metabolism of these cells and are especially prone to oxidative damage. Since overproduction of reactive oxygen species (ROS) is involved in the pathogenesis of neurodegeneration, dietary antioxidants have been suggested to counteract the detrimental effects of ROS and to preserve the mitochondrial function, thus slowing the progression and limiting the extent of neuronal cell loss in neurodegenerative disorders. In addition to their role in the redox-system homeostasis, mitochondria are unique organelles in that they contain their own genome (mtDNA), which acts at the interface between environmental exposures and the molecular triggers of neurodegeneration. Indeed, it has been demonstrated that mtDNA (including both genetics and, from recent evidence, epigenetics) might play relevant roles in modulating the risk for neurodegenerative disorders. This mini-review describes the link between the mitochondrial genome and cellular oxidative status, with a particular focus on neurodegeneration; moreover, it provides an overview on potential beneficial effects of antioxidants in preserving mitochondrial functions through the protection of mtDNA. Full article
(This article belongs to the Special Issue Role of Natural Antioxidants on Neuroprotection and Neuroinflammation)
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13 pages, 1704 KiB  
Article
S-Thiolation Targets Albumin in Heart Failure
by Maura Brioschi, Erica Gianazza, Alice Mallia, Beatrice Zoanni, Alessandra Altomare, Alma Martinez Fernandez, Piergiuseppe Agostoni, Giancarlo Aldini and Cristina Banfi
Antioxidants 2020, 9(8), 763; https://doi.org/10.3390/antiox9080763 - 17 Aug 2020
Cited by 18 | Viewed by 3128
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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17 pages, 1380 KiB  
Article
Dietary Lipids Influence Bioaccessibility of Polyphenols from Black Carrots and Affect Microbial Diversity under Simulated Gastrointestinal Digestion
by Chunhe Gu, Hafiz A. R. Suleria, Frank R. Dunshea and Kate Howell
Antioxidants 2020, 9(8), 762; https://doi.org/10.3390/antiox9080762 - 17 Aug 2020
Cited by 33 | Viewed by 4742
Abstract
The bioaccessibility and activity of polyphenols is dependent on their structure and entrapment in the food matrix. While dietary lipids are known to transit into the colon, the impact of different lipids on the microbiome, and their interactions with dietary polyphenols are largely [...] Read more.
The bioaccessibility and activity of polyphenols is dependent on their structure and entrapment in the food matrix. While dietary lipids are known to transit into the colon, the impact of different lipids on the microbiome, and their interactions with dietary polyphenols are largely unknown. Here, we investigated the effect of dietary lipids on the bioaccessibility of polyphenols from purple/black carrots and adaptation of the gut microbiome in a simulated in vitro digestion-fermentation. Coconut oil, sunflower oil, and beef tallow were selected to represent common dietary sources of medium-chain fatty acids (MCFAs), long-chain polyunsaturated fatty acids (PUFAs), and long-chain polysaturated fatty acids (SFAs), respectively. All lipids promoted the bioaccessibility of both anthocyanins and phenolic acids during intestinal digestion with coconut oil exhibiting the greatest protection of anthocyanins. Similar trends were shown in antioxidant assays (2,2-Diphenyl-1-pricrylhydrazyl (DPPH), ferric reducing ability (FRAP), and total phenolic content (TPC)) with higher phytochemical bioactivities observed with the addition of dietary lipids. Most bioactive polyphenols were decomposed during colonic fermentation. Black carrot modulated diversity and composition of a simulated gut microbiome. Dramatic shifts in gut microbiome were caused by coconut oil. Inclusion of sunflower oil improved the production of butyrate, potentially due to the presence of PUFAs. The results show that the impact of polyphenols in the digestive tract should be considered in the context of other components of the diet, particularly lipids. Full article
(This article belongs to the Special Issue Fate of Antioxidants in Gut and Interaction of Gut Metabolites and Gut Microbiota)
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30 pages, 1534 KiB  
Review
Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies
by Yue Ruan, Subao Jiang, Aytan Musayeva and Adrian Gericke
Antioxidants 2020, 9(8), 761; https://doi.org/10.3390/antiox9080761 - 17 Aug 2020
Cited by 56 | Viewed by 4909
Abstract
Many retinal diseases, such as diabetic retinopathy, glaucoma, and age-related macular (AMD) degeneration, are associated with elevated reactive oxygen species (ROS) levels. ROS are important intracellular signaling molecules that regulate numerous physiological actions, including vascular reactivity and neuron function. However, excessive ROS formation [...] Read more.
Many retinal diseases, such as diabetic retinopathy, glaucoma, and age-related macular (AMD) degeneration, are associated with elevated reactive oxygen species (ROS) levels. ROS are important intracellular signaling molecules that regulate numerous physiological actions, including vascular reactivity and neuron function. However, excessive ROS formation has been linked to vascular endothelial dysfunction, neuron degeneration, and inflammation in the retina. ROS can directly modify cellular molecules and impair their function. Moreover, ROS can stimulate the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) causing inflammation and cell death. However, there are various compounds with direct or indirect antioxidant activity that have been used to reduce ROS accumulation in animal models and humans. In this review, we report on the physiological and pathophysiological role of ROS in the retina with a special focus on the vascular system. Moreover, we present therapeutic approaches for individual retinal diseases targeting retinal signaling pathways involving ROS. Full article
(This article belongs to the Special Issue Feature Papers in Antioxidants in 2020)
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16 pages, 995 KiB  
Review
BKCa Channels as Targets for Cardioprotection
by Kalina Szteyn and Harpreet Singh
Antioxidants 2020, 9(8), 760; https://doi.org/10.3390/antiox9080760 - 17 Aug 2020
Cited by 34 | Viewed by 3603
Abstract
The large-conductance calcium- and voltage-activated K+ channel (BKCa) are encoded by the Kcnma1 gene. They are ubiquitously expressed in neuronal, smooth muscle, astrocytes, and neuroendocrine cells where they are known to play an important role in physiological and pathological processes. [...] Read more.
The large-conductance calcium- and voltage-activated K+ channel (BKCa) are encoded by the Kcnma1 gene. They are ubiquitously expressed in neuronal, smooth muscle, astrocytes, and neuroendocrine cells where they are known to play an important role in physiological and pathological processes. They are usually localized to the plasma membrane of the majority of the cells with an exception of adult cardiomyocytes, where BKCa is known to localize to mitochondria. BKCa channels couple calcium and voltage responses in the cell, which places them as unique targets for a rapid physiological response. The expression and activity of BKCa have been linked to several cardiovascular, muscular, and neurological defects, making them a key therapeutic target. Specifically in the heart muscle, pharmacological and genetic activation of BKCa channels protect the heart from ischemia-reperfusion injury and also facilitate cardioprotection rendered by ischemic preconditioning. The mechanism involved in cardioprotection is assigned to the modulation of mitochondrial functions, such as regulation of mitochondrial calcium, reactive oxygen species, and membrane potential. Here, we review the progress made on BKCa channels and cardioprotection and explore their potential roles as therapeutic targets for preventing acute myocardial infarction. Full article
(This article belongs to the Special Issue Antioxidant Therapy in Cardiovascular Medicine: Bench to Bedside)
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16 pages, 684 KiB  
Article
Oxidative Stress and Pro-Inflammatory Status in Patients with Non-Alcoholic Fatty Liver Disease
by Margalida Monserrat-Mesquida, Magdalena Quetglas-Llabrés, Manuela Abbate, Sofía Montemayor, Catalina M. Mascaró, Miguel Casares, Silvia Tejada, Itziar Abete, Maria Angeles Zulet, Josep A. Tur, J. Alfredo Martínez and Antoni Sureda
Antioxidants 2020, 9(8), 759; https://doi.org/10.3390/antiox9080759 - 16 Aug 2020
Cited by 48 | Viewed by 4549
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation, especially triglycerides, in hepatocytes. If the pathology is not properly treated, it can progress to nonalcoholic steatohepatitis (NASH) and continue to fibrosis, cirrhosis or hepatocarcinoma. Objective: The aim of the current [...] Read more.
Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation, especially triglycerides, in hepatocytes. If the pathology is not properly treated, it can progress to nonalcoholic steatohepatitis (NASH) and continue to fibrosis, cirrhosis or hepatocarcinoma. Objective: The aim of the current research was to identify the plasma biomarkers of liver damage, oxidative stress and inflammation that facilitate the early diagnosis of the disease and control its progression. Methods: Antioxidant and inflammatory biomarkers were measured in the plasma of patients diagnosed with NAFLD (n = 100 adults; 40–60 years old) living in the Balearic Islands, Spain. Patients were classified according to the intrahepatic fat content (IFC) measured by magnetic resonance imaging (MRI). Results: Circulating glucose, glycosylated haemoglobin, triglycerides, low-density lipoprotein-cholesterol, aspartate aminotransferase and alanine aminotransferase were higher in patients with an IFC ≥ 2 of NAFLD in comparison to patients with an IFC of 0 and 1. The plasma levels of catalase, irisin, interleukin-6, malondialdehyde, and cytokeratin 18 were higher in stage ≥2 subjects, whereas the resolvin D1 levels were lower. No differences were observed in xanthine oxidase, myeloperoxidase, protein carbonyl and fibroblast growth factor 21 depending on liver status. Conclusion: The current available data show that the severity of NAFLD is associated with an increase in oxidative stress and proinflammatory status. It may be also useful as diagnostic purpose in clinical practice. Full article
(This article belongs to the Special Issue Antioxidants in the Prevention and Treatment of Chronic Diseases)
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15 pages, 1818 KiB  
Article
Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore
by Richard Gordan, Nadezhda Fefelova, Judith K. Gwathmey and Lai-Hua Xie
Antioxidants 2020, 9(8), 758; https://doi.org/10.3390/antiox9080758 - 16 Aug 2020
Cited by 29 | Viewed by 4230
Abstract
Iron (Fe) plays an essential role in many physiological processes. Hereditary hemochromatosis or frequent blood transfusions often cause iron overload (IO), which can lead to cardiomyopathy and arrhythmias; however, the underlying mechanism is not well defined. In the present study, we assess the [...] Read more.
Iron (Fe) plays an essential role in many physiological processes. Hereditary hemochromatosis or frequent blood transfusions often cause iron overload (IO), which can lead to cardiomyopathy and arrhythmias; however, the underlying mechanism is not well defined. In the present study, we assess the hypothesis that IO promotes arrhythmias via reactive oxygen species (ROS) production, mitochondrial membrane potential (∆Ψm) depolarization, and disruption of cytosolic Ca dynamics. In ventricular myocytes isolated from wild type (WT) mice, both cytosolic and mitochondrial Fe levels were elevated following perfusion with the Fe3+/8-hydroxyquinoline (8-HQ) complex. IO promoted mitochondrial superoxide generation (measured using MitoSOX Red) and induced the depolarization of the ΔΨm (measured using tetramethylrhodamine methyl ester, TMRM) in a dose-dependent manner. IO significantly increased the rate of Ca wave (CaW) formation measured in isolated ventricular myocytes using Fluo-4. Furthermore, in ex-vivo Langendorff-perfused hearts, IO increased arrhythmia scores as evaluated by ECG recordings under programmed S1-S2 stimulation protocols. We also carried out similar experiments in cyclophilin D knockout (CypD KO) mice in which the mitochondrial permeability transition pore (mPTP) opening is impaired. While comparable cytosolic and mitochondrial Fe load, mitochondrial ROS production, and depolarization of the ∆Ψm were observed in ventricular myocytes isolated from both WT and CypD KO mice, the rate of CaW formation in isolated cells and the arrhythmia scores in ex-vivo hearts were significantly lower in CypD KO mice compared to those observed in WT mice under conditions of IO. The mPTP inhibitor cyclosporine A (CsA, 1 µM) also exhibited a protective effect. In conclusion, our results suggest that IO induces mitochondrial ROS generation and ∆Ψm depolarization, thus opening the mPTP, thereby promoting CaWs and cardiac arrhythmias. Conversely, the inhibition of mPTP ameliorates the proarrhythmic effects of IO. Full article
(This article belongs to the Special Issue Antioxidant Therapy in Cardiovascular Medicine: Bench to Bedside)
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13 pages, 2532 KiB  
Article
Engineering the Unicellular Alga Phaeodactylum tricornutum for Enhancing Carotenoid Production
by Francesco Manfellotto, Giulio Rocco Stella, Angela Falciatore, Christophe Brunet and Maria Immacolata Ferrante
Antioxidants 2020, 9(8), 757; https://doi.org/10.3390/antiox9080757 - 16 Aug 2020
Cited by 33 | Viewed by 4895
Abstract
Microalgae represent a promising resource for the production of beneficial natural compounds due to their richness in secondary metabolites and easy cultivation. Carotenoids feature among distinctive compounds of many microalgae, including diatoms, which owe their golden color to the xanthophyll fucoxanthin. Carotenoids have [...] Read more.
Microalgae represent a promising resource for the production of beneficial natural compounds due to their richness in secondary metabolites and easy cultivation. Carotenoids feature among distinctive compounds of many microalgae, including diatoms, which owe their golden color to the xanthophyll fucoxanthin. Carotenoids have antioxidant, anti-obesity and anti-inflammatory properties, and there is a considerable market demand for these compounds. Here, with the aim to increase the carotenoid content in the model diatom Phaeodactylum tricornutum, we exploited genetic transformation to overexpress genes involved in the carotenoid biosynthetic pathway. We produced transgenic lines over-expressing simultaneously one, two or three carotenoid biosynthetic genes, and evaluated changes in pigment content with high-performance liquid chromatography. Two triple transformants over-expressing the genes Violaxanthin de-epoxidase (Vde), Vde-related (Vdr) and Zeaxanthin epoxidase 3 (Zep3) showed an accumulation of carotenoids, with an increase in the fucoxanthin content up to four fold. Vde, Vdr and Zep3 mRNA and protein levels in the triple transformants were coherently increased. The exact role of these enzymes in the diatom carotenoid biosynthetic pathway is not completely elucidated nevertheless our strategy successfully modulated the carotenoid metabolism leading to an accumulation of valuable compounds, leading the way toward improved utilization of microalgae in the field of antioxidants. Full article
(This article belongs to the Special Issue From Marine Organisms to High Value Products with Health Benefits)
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18 pages, 2812 KiB  
Article
Theoretical Study of the Iron Complexes with Aminoguanidine: Investigating Secondary Antioxidant Activity
by Guillermo García-Díez and Nelaine Mora-Diez
Antioxidants 2020, 9(8), 756; https://doi.org/10.3390/antiox9080756 - 15 Aug 2020
Cited by 10 | Viewed by 2372
Abstract
A thorough analysis of the thermodynamic stability of various complexes of aminoguanidine (AG) with Fe(III) at a physiological pH is presented. Moreover, the secondary antioxidant activity of AG is studied with respect to its kinetic role in the Fe(III) reduction to Fe(II) when [...] Read more.
A thorough analysis of the thermodynamic stability of various complexes of aminoguanidine (AG) with Fe(III) at a physiological pH is presented. Moreover, the secondary antioxidant activity of AG is studied with respect to its kinetic role in the Fe(III) reduction to Fe(II) when reacting with the superoxide radical anion or ascorbate. Calculations are performed at the M05(SMD)/6-311+G(d,p) level of theory. Solvent effects (water) are taken into account in both geometry optimizations and frequency calculations employing the SMD solvation method. Even though the results of this study show that AG can form an extensive number of stable complexes with Fe(III), none of these can reduce the rate constant of the initial step of the Haber–Weiss cycle when the reducing agent is O2•−. However, when the reductant is the ascorbate anion, AG is capable of reducing the rate constant of this reaction significantly, to the point of inhibiting the production of •OH radicals. In fact, the most stable complex of Fe(III) with AG, having a ∆Gf° of −37.9 kcal/mol, can reduce the rate constant of this reaction by 7.9 × 105 times. Thus, AG possesses secondary antioxidant activity relative to the Fe(III)/Fe(II) reduction with ascorbate, but not with O2•−. Similar results have also been found for AG relative to the Cu(II)/Cu(I) reduction, in agreement with experimental results. Full article
(This article belongs to the Section Natural and Synthetic Antioxidants)
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11 pages, 282 KiB  
Article
Advanced Glycation End Product Accumulation in Subjects with Open-Angle Glaucoma with and without Exfoliation
by Tomoki Shirakami, Mikihiro Yamanaka, Jo Fujihara, Yotaro Matsuoka, Yuko Gohto, Akira Obana and Masaki Tanito
Antioxidants 2020, 9(8), 755; https://doi.org/10.3390/antiox9080755 - 15 Aug 2020
Cited by 12 | Viewed by 3012
Abstract
Advanced glycation end products (AGEs), which are the products of a non-enzymatic reaction between reducing sugars and other macromolecules, are critical in aging, as well as metabolic and degenerative diseases. To assess the involvement of AGEs in glaucoma, skin autofluorescence (sAF) level, which [...] Read more.
Advanced glycation end products (AGEs), which are the products of a non-enzymatic reaction between reducing sugars and other macromolecules, are critical in aging, as well as metabolic and degenerative diseases. To assess the involvement of AGEs in glaucoma, skin autofluorescence (sAF) level, which is a measurement of AGEs’ accumulation, was compared among Japanese patients with glaucoma (316 with primary open-angle glaucoma (PG) and 127 exfoliation syndrome and glaucoma (EG)) and controls (133 nonglaucomatous controls) (mean age 71.6 ± 12.8 years, 254 men and 322 women). The sAF values were estimated from the middle fingertip using a 365 nm light-emitting diode for excitation and detection at 440 nm emission light. The estimated AGE values (arbitrary unit) were 0.56 ± 0.15, 0.56 ± 0.11, and 0.61 ± 0.11 in the control, PG, and EG groups, respectively (p < 0.0001, analysis of variance); and were significantly higher in the EG group than the control (p = 0.0007) and PG (p < 0.0001) groups. After adjustment for various demographic parameters by multivariate analyses, male sex (standard β = 0.23), EG (0.19), and diabetes (0.09) were associated with higher AGE levels; PG (−0.18) and smoking (−0.19) were associated with lower AGE levels. Age, visual acuity, intraocular pressure, glaucoma medications, lens status, and systemic hypertension were not associated with AGEs. The high AGE level in EG suggested that specific oxidation and glycation mechanisms underlie the glaucoma pathogenesis associated with pseudoexfoliation syndrome. Full article
(This article belongs to the Special Issue Oxidative Stress and Inflammation in Health and Diseases)
14 pages, 2355 KiB  
Article
Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis
by Sara La Manna, Laura Lopez-Sanz, Susana Bernal, Luna Jimenez-Castilla, Ignacio Prieto, Giancarlo Morelli, Carmen Gomez-Guerrero and Daniela Marasco
Antioxidants 2020, 9(8), 754; https://doi.org/10.3390/antiox9080754 - 14 Aug 2020
Cited by 12 | Viewed by 3075
Abstract
The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) [...] Read more.
The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that KIR-SOCS1 mimetics can be considered valuable therapeutics in several disorders (e.g., diabetes, neurological disorders and atherosclerosis). Herein, we investigated the antioxidant and atheroprotective effects of PS5, a peptidomimetic of KIR-SOCS1, both in vitro (vascular smooth muscle cells and macrophages) and in vivo (atherosclerosis mouse model) by analyzing gene expression, intracellular O2•− production and atheroma plaque progression and composition. PS5 was revealed to be able to attenuate NADPH oxidase (NOX1 and NOX4) and pro-inflammatory gene expression, to upregulate antioxidant genes and to reduce atheroma plaque size, lipid content and monocyte/macrophage accumulation. These findings confirm that KIR-SOCS1-based drugs could be excellent antioxidant agents to contrast atherosclerosis. Full article
(This article belongs to the Section Natural and Synthetic Antioxidants)
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21 pages, 3904 KiB  
Article
Syk Kinase Inhibitors Synergize with Artemisinins by Enhancing Oxidative Stress in Plasmodium falciparum-Parasitized Erythrocytes
by Ioannis Tsamesidis, Karine Reybier, Giuseppe Marchetti, Maria Carmina Pau, Patrizia Virdis, Claudio Fozza, Francoise Nepveu, Philip S. Low, Francesco Michelangelo Turrini and Antonella Pantaleo
Antioxidants 2020, 9(8), 753; https://doi.org/10.3390/antiox9080753 - 14 Aug 2020
Cited by 19 | Viewed by 3131
Abstract
Although artemisinin-based combination therapies (ACTs) treat Plasmodium falciparum malaria effectively throughout most of the world, the recent expansion of ACT-resistant strains in some countries of the Greater Mekong Subregion (GMS) further increased the interest in improving the effectiveness of treatment and counteracting resistance. [...] Read more.
Although artemisinin-based combination therapies (ACTs) treat Plasmodium falciparum malaria effectively throughout most of the world, the recent expansion of ACT-resistant strains in some countries of the Greater Mekong Subregion (GMS) further increased the interest in improving the effectiveness of treatment and counteracting resistance. Recognizing that (1) partially denatured hemoglobin containing reactive iron (hemichromes) is generated in parasitized red blood cells (pRBC) by oxidative stress, (2) redox-active hemichromes have the potential to enhance oxidative stress triggered by the parasite and the activation of artemisinin to its pharmaceutically active form, and (3) Syk kinase inhibitors block the release of membrane microparticles containing hemichromes, we hypothesized that increasing hemichrome content in parasitized erythrocytes through the inhibition of Syk kinase might trigger a virtuous cycle involving the activation of artemisinin, the enhancement of oxidative stress elicited by activated artemisinin, and a further increase in hemichrome production. We demonstrate here that artemisinin indeed augments oxidative stress within parasitized RBCs and that Syk kinase inhibitors further increase iron-dependent oxidative stress, synergizing with artemisinin in killing the parasite. We then demonstrate that Syk kinase inhibitors achieve this oxidative enhancement by preventing parasite-induced release of erythrocyte-derived microparticles containing redox-active hemichromes. We also observe that Syk kinase inhibitors do not promote oxidative toxicity to healthy RBCs as they do not produce appreciable amounts of hemichromes. Since some Syk kinase inhibitors can be taken daily with minimal side effects, we propose that Syk kinase inhibitors could evidently contribute to the potentiation of ACTs. Full article
(This article belongs to the Special Issue Cellular Oxidative Stress)
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54 pages, 1835 KiB  
Review
Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease
by Alina Podkowińska and Dorota Formanowicz
Antioxidants 2020, 9(8), 752; https://doi.org/10.3390/antiox9080752 - 14 Aug 2020
Cited by 144 | Viewed by 14805
Abstract
Generating reactive oxygen species (ROS) is necessary for both physiology and pathology. An imbalance between endogenous oxidants and antioxidants causes oxidative stress, contributing to vascular dysfunction. The ROS-induced activation of transcription factors and proinflammatory genes increases inflammation. This phenomenon is of crucial importance [...] Read more.
Generating reactive oxygen species (ROS) is necessary for both physiology and pathology. An imbalance between endogenous oxidants and antioxidants causes oxidative stress, contributing to vascular dysfunction. The ROS-induced activation of transcription factors and proinflammatory genes increases inflammation. This phenomenon is of crucial importance in patients with chronic kidney disease (CKD), because atherosclerosis is one of the critical factors of their cardiovascular disease (CVD) and increased mortality. The effect of ROS disrupts the excretory function of each section of the nephron. It prevents the maintenance of intra-systemic homeostasis and leads to the accumulation of metabolic products. Renal regulatory mechanisms, such as tubular glomerular feedback, myogenic reflex in the supplying arteriole, and the renin–angiotensin–aldosterone system, are also affected. It makes it impossible for the kidney to compensate for water–electrolyte and acid–base disturbances, which progress further in the mechanism of positive feedback, leading to a further intensification of oxidative stress. As a result, the progression of CKD is observed, with a spectrum of complications such as malnutrition, calcium phosphate abnormalities, atherosclerosis, and anemia. This review aimed to show the role of oxidative stress and inflammation in renal impairment, with a particular emphasis on its influence on the most common disturbances that accompany CKD. Full article
(This article belongs to the Special Issue Oxidative Stress and Inflammation in Cardiovascular Diseases)
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24 pages, 3059 KiB  
Review
The KEAP1/NRF2 Signaling Pathway in Keratinization
by Yosuke Ishitsuka, Tatsuya Ogawa and Dennis Roop
Antioxidants 2020, 9(8), 751; https://doi.org/10.3390/antiox9080751 - 14 Aug 2020
Cited by 18 | Viewed by 8888
Abstract
Keratinization is a tissue adaptation, but aberrant keratinization is associated with skin disorders such as ichthyoses, atopic dermatitis, psoriasis, and acne. The disease phenotype stems from the interaction between genes and the environment; therefore, an understanding of the adaptation machinery may lead to [...] Read more.
Keratinization is a tissue adaptation, but aberrant keratinization is associated with skin disorders such as ichthyoses, atopic dermatitis, psoriasis, and acne. The disease phenotype stems from the interaction between genes and the environment; therefore, an understanding of the adaptation machinery may lead to a new appreciation of pathomechanisms. The KEAP1/NRF2 signaling pathway mediates the environmental responses of squamous epithelial tissue. The unpredicted outcome of the Keap1-null mutation in mice allowed us to revisit the basic principle of the biological process of keratinization: sulfur metabolism establishes unparalleled cytoprotection in the body wall of terrestrial mammals. We summarize the recent understanding of the KEAP1/NRF2 signaling pathway, which is a thiol-based sensor-effector apparatus, with particular focuses on epidermal differentiation in the context of the gene-environment interaction, the structure/function principles involved in KEAP1/NRF2 signaling, lessons from mouse models, and their pathological implications. This synthesis may provide insights into keratinization, which provides physical insulation and constitutes an essential innate integumentary defense system. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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17 pages, 2236 KiB  
Article
Mitochondrial Activation and Reactive Oxygen-Species Overproduction during Sperm Capacitation are Independent of Glucose Stimuli
by David F. Carrageta, Bárbara Guerra-Carvalho, Mário Sousa, Alberto Barros, Pedro F. Oliveira, Mariana P. Monteiro and Marco G. Alves
Antioxidants 2020, 9(8), 750; https://doi.org/10.3390/antiox9080750 - 14 Aug 2020
Cited by 25 | Viewed by 3972
Abstract
Spermatozoa capacitation is a complex process that requires specific ionic and energetic conditions to support biochemical alterations leading to motility hyperactivation. However, human sperm capacitation is still poorly understood. Herein, we studied the effects of glucose on human sperm capacitation. Healthy men seminal [...] Read more.
Spermatozoa capacitation is a complex process that requires specific ionic and energetic conditions to support biochemical alterations leading to motility hyperactivation. However, human sperm capacitation is still poorly understood. Herein, we studied the effects of glucose on human sperm capacitation. Healthy men seminal samples (n = 55) were submitted to a density gradient centrifugation and incubated in capacitating conditions in the absence or presence of increasing glucose concentrations (0, 5.5, 11, and 22 mM). Viability and total motility were accessed. Phosphotyrosine levels were measured. Mitochondrial activity and endogenous ROS production were evaluated. Oxidative stress-induced damage was analyzed. Culture media was collected and analyzed by 1H-NMR. Our results show that glucose is essential for human sperm capacitation and motility. Notably, we observed that mitochondrial activity increased even in the absence of glucose. This increased mitochondrial activity was followed by a ROS overproduction, although no oxidative stress-induced damage was detected. Our results show that glucose is essential for capacitation but mitochondrial activation is independent from its stimuli. ROS overproduction may take part on a finely regulated signaling pathway that modulates or even activates capacitation. Taken together, our results constitute a paradigm shift on human sperm capacitation physiology. Full article
(This article belongs to the Special Issue Feature Papers in Antioxidants in 2020)
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16 pages, 4672 KiB  
Article
Toxicological Profile of the Pain-Relieving Antioxidant Compound Thioctic Acid in Its Racemic and Enantiomeric Forms
by Elena Lucarini, Elena Trallori, Daniele Tomassoni, Francesco Amenta, Carla Ghelardini, Alessandra Pacini and Lorenzo Di Cesare Mannelli
Antioxidants 2020, 9(8), 749; https://doi.org/10.3390/antiox9080749 - 14 Aug 2020
Cited by 6 | Viewed by 2328
Abstract
Thioctic acid is a multipotent antioxidant compound existing as dextrorotatory (+), eutomer and naturally occurring and levorotatory (−). It has been proven to help fight many pathologies and is sold as racemate. In agreement with studies claiming a greater biopotency of the eutomer [...] Read more.
Thioctic acid is a multipotent antioxidant compound existing as dextrorotatory (+), eutomer and naturally occurring and levorotatory (−). It has been proven to help fight many pathologies and is sold as racemate. In agreement with studies claiming a greater biopotency of the eutomer compared to the levorotatory compound, we recently preclinically and clinically showed that (+) thioctic acid is a pain-reliever as effective as double-dosed racemate. We investigated acute and subchronical toxicity of (+/−) thioctic acid, (−) thioctic acid, (+) thioctic acid and (+) salt thioctic acid on Sprague–Dawley rats. For acute toxicity, compounds were administered intraperitoneally (i.p.) with a single-injection at 125, 240, 360, 480 µmol/kg, then rodents were tested for motorial coordination and minimum lethal dose (LDmin). A subtoxic dose (360 µmol/kg) was administered i.p. for 15 days and we finally evaluated motorial impairment, glycemia, organ toxicity, and apoptosis state. Acutely administered, the highest doses of all thioctic acid compounds negatively affected motorial ability and (−) thioctic acid LDmin resulted higher than the others. Subchronic administrations caused overall body weight loss, motorial impairment, mass loss in some organs. (+/−) and (−) thioctic acid injections enhanced caspase-3 activity in some organs, (−) enantiomer-treated animals displayed more marked organ toxicity signs. Together with our previous study on the biologic role of enantiomers, these data suggest a therapeutic use of (+) enantiomer-based formulations, thus lowering dose and toxicity without affecting the positive effects brought by the drug. Full article
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14 pages, 1649 KiB  
Perspective
The Interaction of the Endogenous Hydrogen Sulfide and Oxytocin Systems in Fluid Regulation and the Cardiovascular System
by Nicole Denoix, Oscar McCook, Sarah Ecker, Rui Wang, Christiane Waller, Peter Radermacher and Tamara Merz
Antioxidants 2020, 9(8), 748; https://doi.org/10.3390/antiox9080748 - 14 Aug 2020
Cited by 9 | Viewed by 3561
Abstract
The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (H2S) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, [...] Read more.
The purpose of this review is to explore the parallel roles and interaction of hydrogen sulfide (H2S) and oxytocin (OT) in cardiovascular regulation and fluid homeostasis. Their interaction has been recently reported to be relevant during physical and psychological trauma. However, literature reports on H2S in physical trauma and OT in psychological trauma are abundant, whereas available information regarding H2S in psychological trauma and OT in physical trauma is much more limited. This review summarizes recent direct and indirect evidence of the interaction of the two systems and their convergence in downstream nitric oxide-dependent signaling pathways during various types of trauma, in an effort to better understand biological correlates of psychosomatic interdependencies. Full article
(This article belongs to the Special Issue Hydrogen Sulfide in Biology)
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15 pages, 3925 KiB  
Article
Oxidative Stress—Part of the Solution or Part of the Problem in the Hypoxic Environment of a Brain Tumor
by Kamil Krawczynski, Jakub Godlewski and Agnieszka Bronisz
Antioxidants 2020, 9(8), 747; https://doi.org/10.3390/antiox9080747 - 14 Aug 2020
Cited by 12 | Viewed by 3164
Abstract
Rapid growth of brain tumors such as glioblastoma often results in oxygen deprivation and the emergence of hypoxic zones. In consequence, the enrichment of reactive oxygen species occurs, harming nonmalignant cells and leading them toward apoptotic cell death. However, cancer cells survive such [...] Read more.
Rapid growth of brain tumors such as glioblastoma often results in oxygen deprivation and the emergence of hypoxic zones. In consequence, the enrichment of reactive oxygen species occurs, harming nonmalignant cells and leading them toward apoptotic cell death. However, cancer cells survive such exposure and thrive in a hypoxic environment. As the mechanisms responsible for such starkly different outcomes are not sufficiently explained, we aimed to explore what transcriptome rearrangements are used by glioblastoma cells in hypoxic areas. Using metadata analysis of transcriptome in different subregions of the glioblastoma retrieved from the Ivy Glioblastoma Atlas Project, we created the reactive oxygen species-dependent map of the transcriptome. This map was then used for the analysis of differential gene expression in the histologically determined cellular tumors and hypoxic zones. The gene ontology analysis cross-referenced with the clinical data from The Cancer Genome Atlas revealed that the metabolic shift is one of the major prosurvival strategies applied by cancer cells to overcome hypoxia-related cytotoxicity. Full article
(This article belongs to the Special Issue Hypoxia-Induced Oxidative Stress in the Brain)
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22 pages, 2121 KiB  
Article
Germination Improves the Polyphenolic Profile and Functional Value of Mung Bean (Vigna radiata L.)
by Garyfallia Kapravelou, Rosario Martínez, Gloria Perazzoli, Cristina Sánchez González, Juan Llopis, Samuel Cantarero, Marie Goua, Giovanna Bermano, Jose Prados, Consolación Melguizo, Pilar Aranda, María López-Jurado and Jesus M. Porres
Antioxidants 2020, 9(8), 746; https://doi.org/10.3390/antiox9080746 - 13 Aug 2020
Cited by 17 | Viewed by 5054
Abstract
The use of legumes as functional foods has gained increasing attention for the prevention and treatment of the so called non-communicable diseases that are highly prevalent worldwide. In this regard, biotechnological approaches for the enhancement of legumes’ nutritional and functional value have been [...] Read more.
The use of legumes as functional foods has gained increasing attention for the prevention and treatment of the so called non-communicable diseases that are highly prevalent worldwide. In this regard, biotechnological approaches for the enhancement of legumes’ nutritional and functional value have been extensively employed. In the present study, the process of germination increased several parameters of mung bean (Vigna radiata L.) functionality, including extract yield, total phenolic content and in vitro antioxidant capacity. In addition, 3-day-germinated mung bean proved to be an interesting source of dietary essential minerals and exhibited a greater variety of polyphenolic compounds compared to raw mung bean. These properties resulted in enhanced cytoprotective features of the 3-day mung bean extracts against radical oxygen species in human colorectal (HT29) and monocyte (U937) cell lines. Moreover, the antiproliferative effects were tested in different colon cancer cell lines, T84 and drug-resistant HCT-18, as well as in a non-tumor colon CCD-18 line. Altogether, our results demonstrate that the germination process improves the mung bean’s nutritional value and its potential as a functional food. Full article
(This article belongs to the Special Issue Antioxidant and Biological Properties of Plant Extracts)
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16 pages, 5142 KiB  
Article
Protective Effect of Low Molecular Weight Peptides from Solenocera crassicornis Head against Cyclophosphamide-Induced Nephrotoxicity in Mice via the Keap1/Nrf2 Pathway
by Shuoqi Jiang, Zhuangwei Zhang, FangFang Huang, Zuisu Yang, Fangmiao Yu, Yunping Tang and Guofang Ding
Antioxidants 2020, 9(8), 745; https://doi.org/10.3390/antiox9080745 - 13 Aug 2020
Cited by 18 | Viewed by 3294
Abstract
The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male [...] Read more.
The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male mice were randomly divided into 5 groups and received either saline or 80 mg/kg body weight (BW) CTX by intraperitoneal injection for 5 days, followed by either saline or SCHPs-F1 (100, 200, and 400 mg/kg BW) by intragastric administration for 15 days. SCHPs-F1 treatment significantly reversed the CTX-induced decreases in the levels of blood urea nitrogen (BUN), creatinine (CRE), and cytochrome P450 (CYP450), as well as the renal histological lesions. Furthermore, the results indicated that SCHPs-F1 potentially alleviated CTX-induced nephrotoxicity through mitigating inflammatory responses, oxidative stress, and apoptosis status of the kidneys, as evidenced by decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and increased levels of total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, overexpression of pro-apoptotic proteins pair B-cell lymphoma-2 (Bcl-2)-associated X (Bax)/Bcl-2, cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 in renal tissues were suppressed by treatment with SCHPs-F1. In addition, the protein levels of the antioxidant factor nuclear factor erythroid-2 related factor 2 (Nrf2) and the expression levels of its downstream target genes heme-oxygenase (HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were stimulated by treatment with SCHPs-F1 in the CTX-induced renal injury model. Taken together, our data suggested that SCHPs-F1 could provide a novel potential strategy in mitigating the nephrotoxicity caused by CTX. Full article
(This article belongs to the Special Issue Keap1/Nrf2 Signaling Pathway)
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20 pages, 4497 KiB  
Article
Gd-Complex of a Rosmarinic Acid Conjugate as an Anti-Inflammatory Theranostic Agent via Reactive Oxygen Species Scavenging
by Hee-Kyung Kim, Seonghwan Hwang, Bokyung Sung, Yeoun-Hee Kim and Yongmin Chang
Antioxidants 2020, 9(8), 744; https://doi.org/10.3390/antiox9080744 - 13 Aug 2020
Cited by 10 | Viewed by 3832
Abstract
Rosmarinic acid (RosA), an important polyphenol, is known for its antioxidant and anti-inflammatory activities. However, its application in theranostics has been rarely reported. Therefore, a new single-molecule anti-inflammatory theranostic compound containing RosA would be of great interest. A gadolinium (Gd) complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic [...] Read more.
Rosmarinic acid (RosA), an important polyphenol, is known for its antioxidant and anti-inflammatory activities. However, its application in theranostics has been rarely reported. Therefore, a new single-molecule anti-inflammatory theranostic compound containing RosA would be of great interest. A gadolinium (Gd) complex of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) and RosA (Gd(DO3A-RosA)(H2O)) was synthesized and examined for use as a single-molecule theranostic agent. Its kinetic stability is comparable to that of clinically used macrocyclic magnetic resonance imaging contrast agents. In addition, its relaxivity is higher than that of structurally analogous Gd-BT-DO3A. This agent was evaluated for inflammatory targeting magnetic resonance contrast and showed strong and prolonged enhancement of imaging in inflamed tissues of mice. The theranostic agent also possesses antioxidant and anti-inflammatory activities, as evidenced by reactive oxygen species scavenging, superoxide dismutase activity, and inflammatory factors. The novel RosA-conjugated Gd complex is a promising theranostic agent for the imaging of inflamed tissues, as well as for the treatment of inflammation and oxidative stress. Full article
(This article belongs to the Special Issue Redox Systems, Oxidative Stress, and Antioxidant Defences in Health and Disease)
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27 pages, 1613 KiB  
Review
ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease
by Dominic S. A. Simpson and Peter L. Oliver
Antioxidants 2020, 9(8), 743; https://doi.org/10.3390/antiox9080743 - 13 Aug 2020
Cited by 431 | Viewed by 19185
Abstract
Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) [...] Read more.
Neurodegenerative disorders, such as Alzheimer’s disease, are a global public health burden with poorly understood aetiology. Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia (DAM) via damage-associated molecular patterns (DAMPs). DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined; thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2 (NOX2) and activation of NOX2 in DAM is associated with DAMP signalling, inflammation and amyloid plaque deposition, especially in the cerebrovasculature. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation; thus intracellular ROS signalling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 (NQO1), is promoted by transcription factor Nrf2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia (LDAM) may also represent a double-edged sword in neurodegenerative disease by sequestering peroxidised lipids in non-pathological ageing but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics. Full article
(This article belongs to the Special Issue Oxidative Stress and Neurodegenerative Disorders)
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18 pages, 1770 KiB  
Review
Hesperidin and SARS-CoV-2: New Light on the Healthy Function of Citrus Fruits
by Paolo Bellavite and Alberto Donzelli
Antioxidants 2020, 9(8), 742; https://doi.org/10.3390/antiox9080742 - 13 Aug 2020
Cited by 144 | Viewed by 26021
Abstract
Among the many approaches to Coronavirus disease 2019 (COVID-19) prevention, the possible role of nutrition has so far been rather underestimated. Foods are very rich in substances, with a potential beneficial effect on health, and some of these could have an antiviral action [...] Read more.
Among the many approaches to Coronavirus disease 2019 (COVID-19) prevention, the possible role of nutrition has so far been rather underestimated. Foods are very rich in substances, with a potential beneficial effect on health, and some of these could have an antiviral action or be important in modulating the immune system and in defending cells from the oxidative stress associated with infection. This short review draws the attention on some components of citrus fruits, and especially of the orange (Citrus sinensis), well known for its vitamin and flavonoid content. Among the flavonoids, hesperidin has recently attracted the attention of researchers, because it binds to the key proteins of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several computational methods, independently applied by different researchers, showed that hesperidin has a low binding energy, both with the coronavirus “spike” protein, and with the main protease that transforms the early proteins of the virus (pp1a and ppa1b) into the complex responsible for viral replication. The binding energy of hesperidin to these important components is lower than that of lopinavir, ritonavir, and indinavir, suggesting that it could perform an effective antiviral action. Furthermore, both hesperidin and ascorbic acid counteract the cell damaging effects of the oxygen free radicals triggered by virus infection and inflammation. There is discussion about the preventive efficacy of vitamin C, at the dose achievable by the diet, but recent reviews suggest that this substance can be useful in the case of strong immune system burden caused by viral disease. Computational methods and laboratory studies support the need to undertake apposite preclinical, epidemiological, and experimental studies on the potential benefits of citrus fruit components for the prevention of infectious diseases, including COVID-19. Full article
(This article belongs to the Special Issue Nutrigenomics and Antioxidant Components of Diet)
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14 pages, 1773 KiB  
Article
Exploring Seminal Plasma GSTM3 as a Quality and In Vivo Fertility Biomarker in Pigs—Relationship with Sperm Morphology
by Marc Llavanera, Ariadna Delgado-Bermúdez, Yentel Mateo-Otero, Lorena Padilla, Xavier Romeu, Jordi Roca, Isabel Barranco and Marc Yeste
Antioxidants 2020, 9(8), 741; https://doi.org/10.3390/antiox9080741 - 12 Aug 2020
Cited by 9 | Viewed by 2892
Abstract
Glutathione S-transferases Mu 3 (GSTM3) is an essential antioxidant enzyme whose presence in sperm has recently been related to sperm cryotolerance, quality and fertility. However, its role in seminal plasma (SP) as a predictor of the same sperm parameters has never been investigated. [...] Read more.
Glutathione S-transferases Mu 3 (GSTM3) is an essential antioxidant enzyme whose presence in sperm has recently been related to sperm cryotolerance, quality and fertility. However, its role in seminal plasma (SP) as a predictor of the same sperm parameters has never been investigated. Herein, cell biology and proteomic approaches were performed to explore the presence, origin and role of SP-GSTM3 as a sperm quality and in vivo fertility biomarker. GSTM3 in SP was quantified using a commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit specific for Sus scrofa, whereas the presence of GSTM3 in testis, epididymis and accessory sex glands was assessed through immunoblotting analysis. Sperm quality and functionality parameters were evaluated in semen samples at 0 and 72 h of liquid-storage, whereas fertility parameters were recorded over a 12-months as farrowing rate and litter size. The presence and concentration of GSTM3 in SP was established for the first time in mammalian species, predominantly synthesized in the epididymis. The present study also evidenced a relationship between SP-GSTM3 and sperm morphology and suggested it is involved in epididymal maturation rather than in ejaculated sperm physiology. Finally, the data reported herein ruled out the role of this antioxidant enzyme as a quality and in vivo fertility biomarker of pig sperm. Full article
(This article belongs to the Special Issue Oxidative Stress, Antioxidants and Male Reproduction)
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34 pages, 1908 KiB  
Review
When It Comes to an End: Oxidative Stress Crosstalk with Protein Aggregation and Neuroinflammation Induce Neurodegeneration
by Patrycja Michalska and Rafael León
Antioxidants 2020, 9(8), 740; https://doi.org/10.3390/antiox9080740 - 12 Aug 2020
Cited by 54 | Viewed by 5641
Abstract
Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals [...] Read more.
Neurodegenerative diseases are characterized by a progressive loss of neurons in the brain or spinal cord that leads to a loss of function of the affected areas. The lack of effective treatments and the ever-increasing life expectancy is raising the number of individuals affected, having a tremendous social and economic impact. The brain is particularly vulnerable to oxidative damage given the high energy demand, low levels of antioxidant defenses, and high levels of metal ions. Driven by age-related changes, neurodegeneration is characterized by increased oxidative stress leading to irreversible neuronal damage, followed by cell death. Nevertheless, neurodegenerative diseases are known as complex pathologies where several mechanisms drive neuronal death. Herein we discuss the interplay among oxidative stress, proteinopathy, and neuroinflammation at the early stages of neurodegenerative diseases. Finally, we discuss the use of the Nrf2-ARE pathway as a potential therapeutic strategy based on these molecular mechanisms to develop transformative medicines. Full article
(This article belongs to the Special Issue Oxidative Stress and Neurodegenerative Disorders)
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