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15 pages, 5346 KiB

Open AccessArticle

Melatonin Restores Autophagic Flux by Activating the Sirt3/TFEB Signaling Pathway to Attenuate Doxorubicin-Induced Cardiomyopathy

by Yanyan Ma, Jipeng Ma, Linhe Lu, Xiang Xiong, Yalan Shao, Jun Ren, Jian Yang and Jiankang Liu

Antioxidants 2023, 12(9), 1716; https://doi.org/10.3390/antiox12091716 - 04 Sep 2023

Viewed by 1083

Abstract

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects [...] Read more.

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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15 pages, 2348 KiB

Open AccessArticle

1,3-Butanediol Administration Increases β-Hydroxybutyrate Plasma Levels and Affects Redox Homeostasis, Endoplasmic Reticulum Stress, and Adipokine Production in Rat Gonadal Adipose Tissue

by Giuliana Panico, Gianluca Fasciolo, Vincenzo Migliaccio, Rita De Matteis, Lillà Lionetti, Gaetana Napolitano, Claudio Agnisola, Paola Venditti and Assunta Lombardi

Antioxidants 2023, 12(7), 1471; https://doi.org/10.3390/antiox12071471 - 22 Jul 2023

Viewed by 1426

Abstract

Ketone bodies (KBs) are an alternative energy source under starvation and play multiple roles as signaling molecules regulating energy and metabolic homeostasis. The mechanism by which KBs influence visceral white adipose tissue physiology is only partially known, and our study aimed to shed [...] Read more.

Ketone bodies (KBs) are an alternative energy source under starvation and play multiple roles as signaling molecules regulating energy and metabolic homeostasis. The mechanism by which KBs influence visceral white adipose tissue physiology is only partially known, and our study aimed to shed light on the effects they exert on such tissue. To this aim, we administered 1,3-butanediol (BD) to rats since it rapidly enhances β-hydroxybutyrate serum levels, and we evaluated the effect it induces within 3 h or after 14 days of treatment. After 14 days of treatment, rats showed a decrease in body weight gain, energy intake, gonadal-WAT (gWAT) weight, and adipocyte size compared to the control. BD exerted a pronounced antioxidant effect and directed redox homeostasis toward reductive stress, already evident within 3 h after its administration. BD lowered tissue ROS levels and oxidative damage to lipids and proteins and enhanced tissue soluble and enzymatic antioxidant capacity as well as nuclear erythroid factor-2 protein levels. BD also reduced specific mitochondrial maximal oxidative capacity and induced endoplasmic reticulum stress as well as interrelated processes, leading to changes in the level of adipokines/cytokines involved in inflammation, macrophage infiltration into gWAT, adipocyte differentiation, and lipolysis. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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11 pages, 1286 KiB

Open AccessArticle

NAD+ Biosynthesis Impairment and Acute Kidney Injury after Major Vascular Surgery

by Annmarie I. Mede, Ginger L. Milne, Dawei Wei, Derek K. Smith and Loren E. Smith

Antioxidants 2023, 12(4), 821; https://doi.org/10.3390/antiox12040821 - 28 Mar 2023

Cited by 3 | Viewed by 1270

Abstract

Acute kidney injury (AKI) is a serious complication after vascular surgery. Reduced synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan is associated with an increased risk of AKI in critically ill patients, patients hospitalized with COVID-19, and cardiac surgery patients, and is marked [...] Read more.

Acute kidney injury (AKI) is a serious complication after vascular surgery. Reduced synthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan is associated with an increased risk of AKI in critically ill patients, patients hospitalized with COVID-19, and cardiac surgery patients, and is marked by elevated urinary quinolinate and quinolinate to tryptophan ratios. We measured quinolinate concentrations in vascular surgery patients to determine if impaired NAD+ synthesis was associated with AKI in this patient population. Eight preoperative and eight postoperative vascular surgery patients who developed AKI were selected from a parent study to participate in this single-center case-control study. They were matched with controls who did not develop AKI based on age, sex, BMI, eGFR, hypertension, and diabetes. Urinary quinolinate and tryptophan concentrations were measured at anesthetic induction and on postoperative day one. Two-sided Mann–Whitney U tests were used to compare quinolinate and quinolinate to tryptophan ratios. Multivariate linear regression modeling was used to estimate the relationship between quinolinate and serum creatinine. There was no difference in preoperative or postoperative urine quinolinate concentrations or the preoperative quinolinate to tryptophan ratio between patients that did and did not develop AKI (p = 0.07, 0.50, and 0.32, respectively). However, postoperative quinolinate to tryptophan ratios were higher in AKI patients (p = 0.04). Further, after adjustment for AKI risk factors, higher preoperative quinolinate concentrations and higher postoperative quinolinate to tryptophan ratios were associated with greater postoperative creatinine increases (p = 0.04 and 0.04, respectively). These data suggest that impaired NAD+ synthesis may contribute to AKI development in vascular surgery patients. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 6795 KiB

Open AccessArticle

Schizochytrium spp. Dietary Supplementation Modulates Immune-Oxidative Transcriptional Signatures in Monocytes and Neutrophils of Dairy Goats

by Panagiota Kyriakaki, Alexandros Mavrommatis and Eleni Tsiplakou

Antioxidants 2023, 12(2), 497; https://doi.org/10.3390/antiox12020497 - 16 Feb 2023

Cited by 1 | Viewed by 1243

Abstract

The high propensity of dietary polyunsaturated fatty acids (PUFA) to oxidation can induce a cascade of cellular immune-oxidative imbalances. On the other hand, PUFA, namely docosapentaenoic acid (ω6-DPA) and docosahexaenoic acid (DHA) can exert immunomodulatory effects by suppressing a pro-inflammatory response. Thus, the [...] Read more.

The high propensity of dietary polyunsaturated fatty acids (PUFA) to oxidation can induce a cascade of cellular immune-oxidative imbalances. On the other hand, PUFA, namely docosapentaenoic acid (ω6-DPA) and docosahexaenoic acid (DHA) can exert immunomodulatory effects by suppressing a pro-inflammatory response. Thus, the objective of this study was to investigate the effect of dietary supplementation with Schizochytrium spp. levels, rich in both ω6-DPA and DHA on the transcriptional profiling of genes involved in oxidative homeostasis and innate immunity of dairy goats’ monocytes and neutrophils. Twenty-four dairy goats were divided into four homogeneous sub-groups; the diet of the control group (CON) had no Schizochytrium spp. while those of the treated groups were supplemented daily with 20 (ALG20), 40 (ALG40), and 60 (ALG60) g/goat/day. The mRNA levels of MGST1 in neutrophils were downregulated (p = 0.037), while in monocytes, SOD2 and SOD3 were downregulated (p = 0.010 and p = 0.044, respectively) in ALG60 compared to the CON group. GPX2 mRNA levels were downregulated (p = 0.036) in ALG20 and ALG60 compared to the CON group in neutrophils. NOX1 was upregulated (p = 0.043) in the neutrophiles of ALG60-goats. NOX2 was upregulated (p = 0.042) in the monocytes of ALG40-fed goats, while higher (p = 0.045) levels were also found in the ALG60 group in neutrophils. The mRNA levels of COX2 were downregulated (p = 0.035) in monocytes of the ALG40 and ALG60 groups. The mRNA levels of PTGER2 were also downregulated (p = 0.004) in monocytes of Schizochytrium-fed goats, while in neutrophils, significant downregulation (p = 0.024) was only found for ALG60 compared to the CON group. ALOX5AP mRNA levels were significantly decreased (p = 0.033) in ALG60 compared to the CON group in monocytes. LTA4H mRNA levels were increased (p = 0.015) in ALG60 compared to ALG20 and ALG40 groups in monocytes, while in neutrophils, a significant downregulation (p = 0.028) was observed in ALG20 compared to the CON group. The inclusion of more than 20 g Schizochytrium spp./day in goats’ diet induced imbalances in mechanisms that regulate the antioxidant system, while downregulated the expression of pro-inflammatory pathways in monocytes and neutrophils. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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16 pages, 3217 KiB

Open AccessArticle

Characterization and Preliminary In Vitro Antioxidant Activity of a New Multidrug Formulation Based on the Co-Encapsulation of Rutin and the α-Acylamino-β-Lactone NAAA Inhibitor URB894 within PLGA Nanoparticles

by Agnese Gagliardi, Silvia Voci, Nicola Ambrosio, Massimo Fresta, Andrea Duranti and Donato Cosco

Antioxidants 2023, 12(2), 305; https://doi.org/10.3390/antiox12020305 - 28 Jan 2023

Cited by 3 | Viewed by 1494

Abstract

A biodegradable and biocompatible polymeric matrix made up of poly(d,l-lactide-co-glycolide) (PLGA) was used for the simultaneous delivery of rutin and the (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide derivative (URB894). The goal was to exploit the well-known radical scavenging properties of [...] Read more.

A biodegradable and biocompatible polymeric matrix made up of poly(d,l-lactide-co-glycolide) (PLGA) was used for the simultaneous delivery of rutin and the (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide derivative (URB894). The goal was to exploit the well-known radical scavenging properties of rutin and the antioxidant features recently reported for the molecules belonging to the class of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors, such as URB894. The use of the compounds, both as single agents or in association promoted the development of negatively-charged nanosystems characterized by a narrow size distribution and an average diameter of ~200 nm when 0.2–0.6 mg/mL of rutin or URB894 were used. The obtained multidrug carriers evidenced an entrapment efficiency of ~50% and 40% when 0.4 and 0.6 mg/mL of rutin and URB894 were associated during the sample preparation, respectively. The multidrug formulation evidenced an improved in vitro dose-dependent protective effect against H₂O₂-related oxidative stress with respect to that of the nanosystems containing the active compounds as a single agent, confirming the rationale of using the co-encapsulation approach to obtain a novel antioxidant nanomedicine. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 2199 KiB

Open AccessArticle

DTPA-Bound Planar Catechin with Potent Antioxidant Activity Triggered by Fe³⁺ Coordination

by Kiyoshi Fukuhara, Ikuo Nakanishi, Kohei Imai, Mirei Mizuno, Ken-ichiro Matsumoto and Akiko Ohno

Antioxidants 2023, 12(2), 225; https://doi.org/10.3390/antiox12020225 - 18 Jan 2023

Cited by 1 | Viewed by 1766

Abstract

In diseases related to oxidative stress, accumulation of metal ions at the site of pathogenesis results in the generation of reactive oxygen species (ROS) through the reductive activation of oxygen molecules catalyzed by the metal ions. If these metals can be removed and [...] Read more.

In diseases related to oxidative stress, accumulation of metal ions at the site of pathogenesis results in the generation of reactive oxygen species (ROS) through the reductive activation of oxygen molecules catalyzed by the metal ions. If these metals can be removed and the generated ROS can be strongly scavenged, such diseases can be prevented and treated. Planar catechins exhibit stronger radical scavenging activity than natural catechins and can efficiently scavenge hydroxyl radicals generated by the Fenton reaction without showing pro-oxidant effects, even in the presence of iron ions. Hence, in the current study, we designed a compound in which diethylenetriaminepentaacetic acid (DTPA), a metal chelator, was bound to a planar catechin with enhanced radical scavenging activity by immobilizing the steric structure of a natural catechin to be planar. This compound showed almost no radical scavenging activity due to intramolecular hydrogen bonding of DTPA with the planar catechins; however, when coordinated with Fe³⁺, it showed more potent radical scavenging activity than planar catechins. Owing to its potent antioxidant activity triggered by metal coordination and its inhibition of ROS generation by trapping metal ions, this compound might exert excellent preventive and therapeutic effects against oxidative stress-related diseases. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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19 pages, 4052 KiB

Open AccessArticle

Neuroprotective Effects of Pulicaria incisa Infusion on Human Neuroblastoma Cells and Hippocampal Neurons

by Talya Barak, Oshrat Miller, Sarit Melamed, Zipora Tietel, Moti Harari, Eduard Belausov and Anat Elmann

Antioxidants 2023, 12(1), 32; https://doi.org/10.3390/antiox12010032 - 24 Dec 2022

Cited by 1 | Viewed by 1408

Abstract

Reactive oxygen species (ROS) and oxidative stress increase susceptibility to neurodegeneration and other age-related pathologies. We have previously demonstrated that an infusion prepared from Pulicaria incisa (Pi) has protective, anti-inflammatory, and antioxidative effects in glial cells. However, the neuroprotective activities of [...] Read more.

Reactive oxygen species (ROS) and oxidative stress increase susceptibility to neurodegeneration and other age-related pathologies. We have previously demonstrated that an infusion prepared from Pulicaria incisa (Pi) has protective, anti-inflammatory, and antioxidative effects in glial cells. However, the neuroprotective activities of Pi infusion in cultured neurons and aging mice have never been studied. In the following study, the effects of Pi infusion were explored in a hydrogen peroxide (H₂O₂)-induced oxidative stress model in SH-SY5Y human neuroblastoma cells. Profiling of the infusion by gas chromatography–mass spectrometry identified chlorogenic acid, quercetin, and aucubin as some of its main constituents. H₂O₂-induced ROS accumulation and caspase 3 activity decreased SH-SY5Y viability and were prevented upon the pretreatment of cells with Pi infusion. Additionally, the Pi infusion upregulated cellular levels and the nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2) as well as the phosphorylation of cyclic AMP response element-binding protein (CREB). Aging mice treated daily for 18 months with Pi infusion exhibited reduced neuronal cell death in the hippocampus as compared to age-matched controls. We, therefore, propose Pi infusion as a candidate regulator of oxidative stress in the brain. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 1220 KiB

Open AccessArticle

Effects of In Vitro Digestion on the Antioxidant Activity of Three Phenolic Extracts from Olive Mill Wastewaters

by Dario Mercatante, Diana Ansorena, Agnese Taticchi, Iciar Astiasarán, Maurizio Servili and Maria Teresa Rodriguez-Estrada

Antioxidants 2023, 12(1), 22; https://doi.org/10.3390/antiox12010022 - 22 Dec 2022

Cited by 2 | Viewed by 1660

Abstract

The aim of this study was to assess the impact of in vitro digestion on the antioxidant activity of three extracts rich in phenols (two purified organic extracts (A20, A21) and one powdered extract stabilized with maltodextrins (SP)) obtained from olive mill wastewaters [...] Read more.

The aim of this study was to assess the impact of in vitro digestion on the antioxidant activity of three extracts rich in phenols (two purified organic extracts (A20, A21) and one powdered extract stabilized with maltodextrins (SP)) obtained from olive mill wastewaters (OMWW). The content and composition of phenols and antioxidant activity was determined before and after in vitro digestion. The phenol content of the A20 and A21 samples were higher (>75%) than that of the SP sample before in vitro digestion. After the entire in vitro digestion, 89.3, 76.9, and 50% loss of phenols was found in A20, A21 and SP, respectively. ABTS^•+ and ORAC values decreased during in vitro digestion of A20 and A21 samples, while they remained almost constant in SP. IC₅₀ increased during digestion of A20 and A21, evidencing a loss of antioxidant capacity after the intestinal phase; an opposite IC₅₀ trend was noted in SP, confirming the protective role of maltodextrins. For these reasons, SP represents a promising formulation to be used in the food field. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 4869 KiB

Open AccessArticle

High-Altitude Hypoxia Exposure Induces Iron Overload and Ferroptosis in Adipose Tissue

by Yanfei Zhang, Jinyu Fang, Yingyue Dong, Huiru Ding, Quancheng Cheng, Huaicun Liu, Guoheng Xu and Weiguang Zhang

Antioxidants 2022, 11(12), 2367; https://doi.org/10.3390/antiox11122367 - 29 Nov 2022

Cited by 5 | Viewed by 2203

Abstract

High altitude (HA) has become one of the most challenging environments featuring hypobaric hypoxia, which seriously threatens public health, hence its gradual attraction of public attention over the past decade. The purpose of this study is to investigate the effect of HA hypoxia [...] Read more.

High altitude (HA) has become one of the most challenging environments featuring hypobaric hypoxia, which seriously threatens public health, hence its gradual attraction of public attention over the past decade. The purpose of this study is to investigate the effect of HA hypoxia on iron levels, redox state, inflammation, and ferroptosis in adipose tissue. Here, 40 mice were randomly divided into two groups: the sea-level group and HA hypoxia group (altitude of 5000 m, treatment for 4 weeks). Total iron contents, ferrous iron contents, ROS generation, lipid peroxidation, the oxidative enzyme system, proinflammatory factor secretion, and ferroptosis-related biomarkers were examined, respectively. According to the results, HA exposure increases total iron and ferrous iron levels in both WAT and BAT. Meanwhile, ROS release, MDA, 4-HNE elevation, GSH depletion, as well as the decrease in SOD, CAT, and GSH-Px activities further evidenced a phenotype of redox imbalance in adipose tissue during HA exposure. Additionally, the secretion of inflammatory factors was also significantly enhanced in HA mice. Moreover, the remarkably changed expression of ferroptosis-related markers suggested that HA exposure increased ferroptosis sensitivity in adipose tissue. Overall, this study reveals that HA exposure is capable of inducing adipose tissue redox imbalance, inflammatory response, and ferroptosis, driven in part by changes in iron overload, which is expected to provide novel preventive targets for HA-related illness. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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18 pages, 5256 KiB

Open AccessArticle

The Effect of the Ala16Val Mutation on the Secondary Structure of the Manganese Superoxide Dismutase Mitochondrial Targeting Sequence

by Matic Broz, Veronika Furlan, Samo Lešnik, Marko Jukič and Urban Bren

Antioxidants 2022, 11(12), 2348; https://doi.org/10.3390/antiox11122348 - 27 Nov 2022

Cited by 2 | Viewed by 1807

Abstract

Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. A known single nucleotide polymorphism (SNP) rs4880 on the SOD2 gene, causing a mutation from alanine to valine (Ala16Val) in the primary structure of immature [...] Read more.

Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. A known single nucleotide polymorphism (SNP) rs4880 on the SOD2 gene, causing a mutation from alanine to valine (Ala16Val) in the primary structure of immature MnSOD, has been associated with several types of cancer and other autoimmune diseases. However, no conclusive correlation has been established yet. This study aims to determine the effect of the alanine to valine mutation on the secondary structure of the MnSOD mitochondrial targeting sequence (MTS). A model for each variant of the MTS was prepared and extensively simulated with molecular dynamics simulations using the CHARMM36m force field. The results indicate that the alanine variant of the MTS preserves a uniform α-helical secondary structure favorable for the protein transport into mitochondria, whereas the valine variant quickly breaks down its α-helix. Thus, the alanine MTS represents the more active MnSOD variant, the benefits of which have yet to be determined experimentally. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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19 pages, 4937 KiB

Open AccessArticle

DPP9 as a Potential Novel Mediator in Gastrointestinal Virus Infection

by Ángela del Castillo-Izquierdo, José María Moreno-Navarrete, Jessica Latorre, María Arnoriaga-Rodríguez, Marta Ballanti, Giovanni Monteleone, Omero Alessandro Paoluzi, Geltrude Mingrone, Josep Puig, Rafael Ramos, Josep Garre-Olmo, Mariona Jové, Reinald Pamplona, Manuel Portero-Otín, Joaquim Sol, Philippe Lefebvre, Bart Staels, Massimo Federici, José Manuel Fernández-Real and Jordi Mayneris-Perxachs

Antioxidants 2022, 11(11), 2177; https://doi.org/10.3390/antiox11112177 - 03 Nov 2022

Viewed by 2009

Abstract

Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family. Inhibition of DPP9 has recently been shown to activate the nucleotide-binding domain leucine-rich repeat 1 (NLRP1) inflammasome. NLRP1 is known to bind nucleic acids with high affinity and directly interact [...] Read more.

Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family. Inhibition of DPP9 has recently been shown to activate the nucleotide-binding domain leucine-rich repeat 1 (NLRP1) inflammasome. NLRP1 is known to bind nucleic acids with high affinity and directly interact with double stranded RNA, which plays a key role in viral replication. DPP9 has also recently emerged as a key gene related to lung-inflammation in critical SARS-CoV-2 infection. Importantly, DPP9 activity is strongly dependent on the oxidative status. Here, we explored the potential role of DPP9 in the gastrointestinal tract. We performed transcriptomics analyses of colon (microarray, n = 37) and jejunal (RNA sequencing, n = 31) biopsies from two independent cohorts as well as plasma metabolomics analyses in two independent cohorts (n = 37 and n = 795). The expression of DPP9 in the jejunum, colon, and blood was significantly associated with circulating biomarkers of oxidative stress (uric acid, bilirubin). It was also associated positively with the expression of transcription factors (NRF-2) and genes (SOD, CAT, GPX) encoding for antioxidant enzymes, but negatively with that of genes (XDH, NOX) and transcription factors (NF-KB) involved in ROS-generating enzymes. Gene co-expression patterns associated with DPP9 identified several genes participating in antiviral pathways in both tissues. Notably, DPP9 expression in the colon and plasma was strongly positively associated with several circulating nucleotide catabolites (hypoxanthine, uric acid, 3-ureidopropionic acid) with important roles in the generation of ROS and viral infection, as well as other metabolites related to oxidative stress (Resolvin D1, glutamate-containing dipeptides). Gene-drug enrichment analyses identified artenimol, puromycin, anisomycin, 3-phenyllactic acid, and linezolid as the most promising drugs targeting these DPP9-associated genes. We have identified a novel potential pathogenic mechanism of viral infection in the digestive tract and promising existing drugs that can be repositioned against viral infection. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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21 pages, 7582 KiB

Open AccessArticle

Exogenous L-Glutathione Improves Vitrification Outcomes in Murine Preimplantation Embryos

by Nor-Shahida Abdul Rahman, Nor-Ashikin Mohamed Noor Khan, Zolkapli Eshak, Mimi-Sophia Sarbandi, Aqila-Akmal Mohammad Kamal, Mastura Abd Malek, Fathiah Abdullah, Maizaton Atmadini Abdullah and Fezah Othman

Antioxidants 2022, 11(11), 2100; https://doi.org/10.3390/antiox11112100 - 25 Oct 2022

Cited by 5 | Viewed by 1976

Abstract

Vitrification is an important tool to store surplus embryos in assisted reproductive technology (ART). However, vitrification increases oxidative damage and results in decreased viability. Studies have reported that L-glutathione (GSH) supplementation improves the preimplantation development of murine embryos. Glutathione constitutes the major non-protein [...] Read more.

Vitrification is an important tool to store surplus embryos in assisted reproductive technology (ART). However, vitrification increases oxidative damage and results in decreased viability. Studies have reported that L-glutathione (GSH) supplementation improves the preimplantation development of murine embryos. Glutathione constitutes the major non-protein sulphydryl compound in mammalian cells, which confers protection against oxidative damage. However, the effect of GSH supplementation on embryonic vitrification outcomes has yet to be reported. This study aims to determine whether GSH supplementation in culture media improves in vitro culture and vitrification outcomes, as observed through embryo morphology and preimplantation development. Female BALB/c mice aged 6–8 weeks were superovulated through an intraperitoneal injection of 10 IU of pregnant mare serum gonadotrophin (PMSG), followed by 10 IU of human chorionic gonadotrophin (hCG) 48 h later. The mated mice were euthanized by cervical dislocation 48 h after hCG to harvest embryos. Two-cell embryos were randomly assigned to be cultured in either Group 1 (GSH-free medium), Group 2 (GSH-free medium with vitrification), Group 3 (0.01 mM GSH-supplemented medium), or Group 4 (0.01 mM GSH-supplemented medium with vitrification). Non-vitrified (Groups 1 and 3) and vitrified (Groups 2 and 4) embryos were observed for morphological quality and preimplantation development at 24, 48, 72, and 96 h. In the non-vitrified groups, there were significant increases in the number of Grade-1 blastocysts in GSH cultures (p < 0.05). Similarly, in the vitrified groups, GSH supplementation was also seen to significantly increase blastocyst formation. Exogenous GSH supplementation resulted in a significant increase in intracellular GSH, a release of cytochrome c from mitochondria, and a parallel decrease in intracellular reactive oxygen species (ROS) levels in vitrified eight-cell embryos (p < 0.05). GSH supplementation was shown to upregulate Bcl2 expression and downregulate Bax expression in the vitrified preimplantation embryo group. The action of exogenous GSH was concomitant with an increase in the relative abundance of Gpx1 and Sod1. In conclusion, our study demonstrated the novel use and practical applicability of GSH supplementation for improving embryonic cryotolerance via a decrease in ROS levels and the inhibition of apoptotic events by improvement in oxidative status. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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20 pages, 3762 KiB

Open AccessArticle

Luteolin-Induced Activation of Mitochondrial BK_Ca Channels: Undisclosed Mechanism of Cytoprotection

by Rafał P. Kampa, Lorenzo Flori, Aleksandra Sęk, Jacopo Spezzini, Simone Brogi, Adam Szewczyk, Vincenzo Calderone, Piotr Bednarczyk and Lara Testai

Antioxidants 2022, 11(10), 1892; https://doi.org/10.3390/antiox11101892 - 24 Sep 2022

Cited by 6 | Viewed by 2360

Abstract

Luteolin (LUT) is a well-known flavonoid that exhibits a number of beneficial properties. Among these, it shows cardioprotective effects, as confirmed by numerous studies. However, its effect on mitochondrial potassium channels, the activation of which is related to cytoprotection, as well as on [...] Read more.

Luteolin (LUT) is a well-known flavonoid that exhibits a number of beneficial properties. Among these, it shows cardioprotective effects, as confirmed by numerous studies. However, its effect on mitochondrial potassium channels, the activation of which is related to cytoprotection, as well as on heart ischemia/reperfusion (I/R) damage prevention, has not yet been investigated. The large conductance calcium-regulated potassium channel (mitoBK_Ca) has been identified in both the mitochondria of the vascular endothelial cells, which plays a significant role in the functioning of the cardiovascular system under oxidative stress-related conditions, and in the mitochondria of cardiomyocytes, where it is deeply involved in cardiac protection against I/R injury. Therefore, the aim of this study was to explore the role of the mitoBK_Ca channel in luteolin-induced cytoprotection. A number of in vitro, in vivo, ex vivo and in silico studies have confirmed that luteolin activates this channel in the mitochondria of cardiomyocytes and endothelial cells, which in turn leads to the protection of the endothelium and a significant reduction in the extent of damage resulting from myocardial infarction, where this effect was partially abolished by the mitoBK_Ca channel blocker paxilline. In conclusion, these results suggest that luteolin has cardioprotective effects, at least in part, through the activation of the mitoBK_Ca channel, shedding light on a new putative mechanism of action. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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14 pages, 2706 KiB

Open AccessArticle

Mitochondrial Glrx2 Knockout Augments Acetaminophen-Induced Hepatotoxicity in Mice

by Jing Li, Xuewen Tang, Xing Wen, Xiaoyuan Ren, Huihui Zhang, Yatao Du and Jun Lu

Antioxidants 2022, 11(9), 1643; https://doi.org/10.3390/antiox11091643 - 24 Aug 2022

Cited by 5 | Viewed by 1923

Abstract

Acetaminophen (APAP) is one of the most widely used drugs with antipyretic and analgesic effects, and thus hepatotoxicity from the overdose of APAP becomes one of the most common forms of drug-induced liver injury. The reaction towards thiol molecules, such as GSH by [...] Read more.

Acetaminophen (APAP) is one of the most widely used drugs with antipyretic and analgesic effects, and thus hepatotoxicity from the overdose of APAP becomes one of the most common forms of drug-induced liver injury. The reaction towards thiol molecules, such as GSH by APAP metabolite, N-acetyl-p-benzo-quinonimine (NAPQI), is the main cause of APAP-induced hepatotoxicity. However, the role of many other thiol-related regulators in toxicity caused by APAP is still unclear. Here we have found that knockout of the Glrx2 gene, which encodes mitochondrial glutaredoxin2 (Grx2), sensitized mice to APAP-caused hepatotoxicity. Glrx2 deletion hindered Nrf2-mediated compensatory recovery of thiol-dependent redox systems after acetaminophen challenge, resulting in a more oxidized cellular state with a further decrease in GSH level, thioredoxin reductase activity, and GSH/GSSG ratio. The weakened feedback regulation capacity of the liver led to higher levels of protein glutathionylation and thioredoxin (both Trx1 and Trx2) oxidation in Glrx2^−/− mice. Following the cellular environment oxidation, nuclear translocation of apoptosis-inducing factor (AIF) was elevated in the liver of Glrx2^−/− mice. Taken together, these results demonstrated that mitochondrial Grx2 deficiency deteriorated APAP-induced hepatotoxicity by interrupting thiol-redox compensatory response, enhancing the AIF pathway-mediated oxidative damage. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 5276 KiB

Open AccessArticle

Genetic and Pharmacological Inhibition of GCN2 Ameliorates Hyperglycemia and Insulin Resistance in Type 2 Diabetic Mice

by Juntao Yuan, Fang Li, Xiyue Shen, Junling Gao, Zhuoran Yu, Kai Luo, Bingqing Cui and Zhongbing Lu

Antioxidants 2022, 11(8), 1584; https://doi.org/10.3390/antiox11081584 - 16 Aug 2022

Cited by 2 | Viewed by 2142

Abstract

It is well recognized that there is a strong and complex association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We previously demonstrated that genetic knockout or pharmacological inhibition of general control nondepressible kinase 2 (GCN2), a well-known amino acid [...] Read more.

It is well recognized that there is a strong and complex association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We previously demonstrated that genetic knockout or pharmacological inhibition of general control nondepressible kinase 2 (GCN2), a well-known amino acid sensor, alleviated hepatic steatosis and insulin resistance in obese mice. However, whether GCN2 affects the development of T2D remains unclear. After a high-fat diet (HFD) plus low-dose streptozotocin (STZ) treatments, Gcn2^−/− mice developed less hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress than wild-type (WT) mice. Inhibition of GCN2 by intraperitoneal injection of 3 mg/kg GCN2iB (a specific inhibitor of GCN2) every other day for 6 weeks also ameliorated hyperglycemia, insulin resistance, hepatic steatosis, and oxidative stress in HFD/STZ- and leptin receptor deletion (db/db)-induced T2D mice. Moreover, depletion of hepatic GCN2 in db/db mice by tail vein injection of an AAV8-shGcn2 vector resulted in similar improvement in those metabolic disorders. The protective mechanism of GCN2 inhibition in T2D mice was associated with regulation of the glucose metabolic pathway, repression of lipogenesis genes, and activation of the Nrf2 pathway. Together, our data provide evidence that strategies to inhibit hepatic GCN2 activity may be novel approaches for T2D therapy. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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15 pages, 3585 KiB

Open AccessArticle

Salidroside Ameliorates Radiation Damage by Reducing Mitochondrial Oxidative Stress in the Submandibular Gland

by Yue-Mei Sun, Xin-Yue Wang, Xin-Ru Zhou, Chong Zhang, Ke-Jian Liu, Fu-Yin Zhang and Bin Xiang

Antioxidants 2022, 11(7), 1414; https://doi.org/10.3390/antiox11071414 - 21 Jul 2022

Cited by 4 | Viewed by 1863

Abstract

Radiotherapy for patients with head and neck cancer inevitably causes radiation damage to salivary glands (SGs). Overproduction of reactive oxygen species (ROS) leads to mitochondrial damage and is critical in the pathophysiology of SG radiation damage. However, mitochondrial-targeted treatment is unavailable. Herein, both [...] Read more.

Radiotherapy for patients with head and neck cancer inevitably causes radiation damage to salivary glands (SGs). Overproduction of reactive oxygen species (ROS) leads to mitochondrial damage and is critical in the pathophysiology of SG radiation damage. However, mitochondrial-targeted treatment is unavailable. Herein, both in vitro and in vivo models of radiation-damaged rat submandibular glands (SMGs) were used to investigate the potential role of salidroside in protecting irradiated SGs. Cell morphology was observed with an inverted phase-contrast microscope. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), mitochondrial ROS, mitochondrial membrane potential (MMP), and ATP were measured using relevant kits. The mitochondrial ultrastructure was observed under transmission electron microscopy. Cell apoptosis was determined by Western blot and TUNEL assays. Saliva was measured from Wharton’s duct. We found that salidroside protected SMG cells and tissues against radiation and improved the secretion function. Moreover, salidroside enhanced the antioxidant defense by decreasing MDA, increasing SOD, CAT, and GSH, and scavenging mitochondrial ROS. Furthermore, salidroside rescued the mitochondrial ultrastructure, preserved MMP and ATP, suppressed cytosolic cytochrome c and cleaved caspase 3 expression, and inhibited cell apoptosis. Together, these findings first identify salidroside as a mitochondrial-targeted antioxidant for preventing SG radiation damage. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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16 pages, 2543 KiB

Open AccessArticle

Overexpression of Mitochondrial Ferritin Enhances Blood–Brain Barrier Integrity Following Ischemic Stroke in Mice by Maintaining Iron Homeostasis in Endothelial Cells

by Peina Wang, Qianqian Ren, Mengtong Shi, Yuanyuan Liu, Huiyuan Bai and Yan-Zhong Chang

Antioxidants 2022, 11(7), 1257; https://doi.org/10.3390/antiox11071257 - 26 Jun 2022

Cited by 17 | Viewed by 2960

Abstract

Blood–brain barrier (BBB) breakdown, a characteristic feature of ischemic stroke, contributes to poor patient outcomes. Brain microvascular endothelial cells (BMVECs) are a key component of the BBB and dysfunction or death of these cells following cerebral ischemia reperfusion (I/R) injury can disrupt the [...] Read more.

Blood–brain barrier (BBB) breakdown, a characteristic feature of ischemic stroke, contributes to poor patient outcomes. Brain microvascular endothelial cells (BMVECs) are a key component of the BBB and dysfunction or death of these cells following cerebral ischemia reperfusion (I/R) injury can disrupt the BBB, leading to leukocyte infiltration, brain edema and intracerebral hemorrhage. We previously demonstrated that mitochondrial ferritin (FtMt) can alleviate I/R-induced neuronal ferroptosis by inhibiting inflammation-regulated iron deposition. However, whether FtMt is involved in BBB disruption during cerebral I/R is still unknown. In the present study, we found that FtMt expression in BMVECs is upregulated after I/R and overexpression of FtMt attenuates I/R-induced BBB disruption. Mechanistically, we found that FtMt prevents tight junction loss and apoptosis by inhibiting iron dysregulation and reactive oxygen species (ROS) accumulation in I/R-treated BMVECs. Chelating excess iron with deferoxamine alleviates apoptosis in the brain endothelial cell line bEnd.3 under oxygen glucose deprivation followed by reoxygenation (OGD/R) insult. In summary, our data identify a previously unexplored effect for FtMt in the BBB and provide evidence that iron-mediated oxidative stress in BMVECs is an early cause of BMVECs damage and BBB breakdown in ischemic stroke. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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10 pages, 1161 KiB

Open AccessArticle

The Use of Quercetin to Improve the Antioxidant and Regenerative Properties of Frozen or Cryopreserved Human Amniotic Membrane

by Valeria Purpura, Serena Benedetti, Elena Bondioli, Francesca Scarpellini, Agnese Giacometti, Maria Cristina Albertini and Davide Melandri

Antioxidants 2022, 11(7), 1250; https://doi.org/10.3390/antiox11071250 - 25 Jun 2022

Cited by 2 | Viewed by 1612

Abstract

The biological properties of the human amniotic membrane (HAM) and its characteristic ability to be a reservoir of growth factors promoting wound healing make it an ideal biological dressing for the treatment of different clinical conditions, such as burns and non-healing wounds. However, [...] Read more.

The biological properties of the human amniotic membrane (HAM) and its characteristic ability to be a reservoir of growth factors promoting wound healing make it an ideal biological dressing for the treatment of different clinical conditions, such as burns and non-healing wounds. However, the application of a preservation method on the HAM is required during banking to maintain biological tissue properties and to ensure the release overtime of protein content for its final clinical effectiveness after application on the wound bed. Although cryopreservation and freezing are methods widely used to maintain tissue properties, reactive oxygen species (ROS) are produced within tissue cellular components during their switching from frozen to thawed state. Consequently, these methods can lead to oxidative stress-induced cell injury, affecting tissue regenerative properties and its final clinical effectiveness. Taking advantage of the antioxidant activity of the natural compound quercetin, we used it to improve the antioxidant and regenerative properties of frozen or cryopreserved HAM tissues. In particular, we evaluated the oxidative damage (lipid peroxidation, malondialdehyde) as well as the regenerative/biological properties (bFGF growth factor release, wound healing closure, structure, and viability) of HAM tissue after its application. We identified the effectiveness of quercetin on both preservation methods to reduce oxidative damage, as well as its ability to enhance regenerative properties, while maintaining the unaltered structure and viability of HAM tissue. The use of quercetin described in this study appears able to counteract the side effects of cryopreservation and freezing methods related to oxidative stress, enhancing the regenerative properties of HAM. However, further investigations will need to be performed, starting from these promising results, to identify its beneficial effect when applied on burns or non-healing wounds. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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16 pages, 4304 KiB

Open AccessArticle

Antioxidant Effect of Tyr-Ala Extracted from Zein on INS-1 Cells and Type 2 Diabetes High-Fat-Diet-Induced Mice

by Jinghui Zhai, Yuhua Zhu, Yi Wu, Na Li, Yue Cao, Yi Guo and Li Xu

Antioxidants 2022, 11(6), 1111; https://doi.org/10.3390/antiox11061111 - 02 Jun 2022

Cited by 1 | Viewed by 2292

Abstract

Type 2 diabetes mellitus (T2DM) is associated with an oxidative milieu that often leads to adverse health problems. Bioactive peptides of zein possess outstanding antioxidant activity; however, their effects on hyperglycemia-related oxidative stress remain elusive. In the present study, the dipeptide Tyr-Ala (YA), [...] Read more.

Type 2 diabetes mellitus (T2DM) is associated with an oxidative milieu that often leads to adverse health problems. Bioactive peptides of zein possess outstanding antioxidant activity; however, their effects on hyperglycemia-related oxidative stress remain elusive. In the present study, the dipeptide Tyr-Ala (YA), a functional peptide with typical health benefits, was applied to alleviate oxidative stress in pancreatic islets under hyperglycemic conditions. By detecting viability, antioxidant ability, and insulin secretion in INS-1 cells, YA showed excellent protection of INS-1 cells from H₂O₂ oxidative stress, erasing reactive oxygen species (ROS) and promoting insulin secretion. Moreover, by Western blotting, we found that YA can regulate the PI3K/Akt signaling pathway associated with glycometabolism. After establishing a T2DM mice model, we treated mice with YA and measured glucose, insulin, hemoglobin A1C (HbA1c), total cholesterol (TC), triglyceride (TG), and malonaldehyde (MDA) levels and activities of superoxide dismutase (SOD) and glutathione (GSH) from blood samples. We observed that YA could reduce the production of glucose, insulin, HbA1c, TC, TG, and MDA, in addition to enhancing the activities of SOD and GSH. YA could also repair the function of the kidneys and pancreas of T2DM mice. Along with the decline in fasting blood glucose, the oxidative stress in islets was alleviated in T2DM mice after YA administration. This may improve the health situation of diabetic patients in the future. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 2360 KiB

Open AccessArticle

Curcumin, Polydatin and Quercetin Synergistic Activity Protects from High-Glucose-Induced Inflammation and Oxidative Stress

by Giulia Matacchione, Debora Valli, Andrea Silvestrini, Angelica Giuliani, Jacopo Sabbatinelli, Chiara Giordani, Sofia Coppari, Maria Rita Rippo, Maria Cristina Albertini and Fabiola Olivieri

Antioxidants 2022, 11(6), 1037; https://doi.org/10.3390/antiox11061037 - 24 May 2022

Cited by 8 | Viewed by 2869

Abstract

Chronic hyperglycemia, the diagnostic biomarker of Type 2 Diabetes Mellitus (T2DM), is a condition that fosters oxidative stress and proinflammatory signals, both involved in the promotion of cellular senescence. Senescent cells acquire a proinflammatory secretory phenotype, called SASP, exacerbating and perpetuating the detrimental [...] Read more.

Chronic hyperglycemia, the diagnostic biomarker of Type 2 Diabetes Mellitus (T2DM), is a condition that fosters oxidative stress and proinflammatory signals, both involved in the promotion of cellular senescence. Senescent cells acquire a proinflammatory secretory phenotype, called SASP, exacerbating and perpetuating the detrimental effects of hyperglycemia. Bioactive compounds can exert antioxidant and anti-inflammatory properties. However, the synergistic anti-inflammatory and antioxidant effects of the most extensively investigated natural compounds have not been confirmed yet in senescent cells and in hyperglycemic conditions. Here, we exposed young and replicative senescent HUVEC (yHUVEC and sHUVEC) to a high-glucose (HG) condition (45 mM) and treated them with Polydatin (POL), Curcumin (CUR) and Quercetin (QRC), alone or in combination (MIX), to mirror the anti-inflammatory component OxiDef^TM contained in the novel nutraceutical Glicefen^TM (Mivell, Italy). In both yHUVEC and sHUVEC, the MIX significantly decreased the expression levels of inflammatory markers, such as MCP-1, IL-1β and IL-8, and ROS production. Importantly, in sHUVEC, a synergistic effect of the MIX was observed, suggesting its senomorphic activity. Moreover, the MIX was able to reduce the expression level of RAGE, a receptor involved in the activation of proinflammatory signaling. Overall, our data suggest that the consumption of nutraceuticals containing different natural compounds could be an adjuvant supplement to counteract proinflammatory and pro-oxidative signals induced by both hyperglycemic and senescence conditions. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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22 pages, 2823 KiB

Open AccessArticle

Identification of Modulators of the C. elegans Aryl Hydrocarbon Receptor and Characterization of Transcriptomic and Metabolic AhR-1 Profiles

by Lucie Larigot, Linh-Chi Bui, Marine de Bouvier, Ophélie Pierre, Grégory Pinon, Justine Fiocca, Mohammad Ozeir, Cendrine Tourette, Chris Ottolenghi, Sandrine Imbeaud, Clément Pontoizeau, Benjamin J. Blaise, Aline Chevallier, Céline Tomkiewicz, Béatrice Legrand, Bénédicte Elena-Herrmann, Christian Néri, Vanessa Brinkmann, Pierre Nioche, Robert Barouki, Natascia Ventura, Julien Dairou and Xavier Coumoul Show full author list Hide full author list

Antioxidants 2022, 11(5), 1030; https://doi.org/10.3390/antiox11051030 - 23 May 2022

Cited by 4 | Viewed by 2689

Abstract

The Aryl hydrocarbon Receptor (AhR) is a xenobiotic sensor in vertebrates, regulating the metabolism of its own ligands. However, no ligand has been identified to date for any AhR in invertebrates. In C. elegans, the AhR ortholog, AHR-1, displays physiological functions. [...] Read more.

The Aryl hydrocarbon Receptor (AhR) is a xenobiotic sensor in vertebrates, regulating the metabolism of its own ligands. However, no ligand has been identified to date for any AhR in invertebrates. In C. elegans, the AhR ortholog, AHR-1, displays physiological functions. Therefore, we compared the transcriptomic and metabolic profiles of worms expressing AHR-1 or not and investigated the putative panel of chemical AHR-1 modulators. The metabolomic profiling indicated a role for AHR-1 in amino acids, carbohydrates, and fatty acids metabolism. The transcriptional profiling in neurons expressing AHR-1, identified 95 down-regulated genes and 76 up-regulated genes associated with neuronal and metabolic functions in the nervous system. A gene reporter system allowed us to identify several AHR-1 modulators including bacterial, dietary, or environmental compounds. These results shed new light on the biological functions of AHR-1 in C. elegans and perspectives on the evolution of the AhR functions across species. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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20 pages, 2677 KiB

Open AccessArticle

Phytochemical Characterization, Antioxidant and Anti-Proliferative Properties of Rubia cordifolia L. Extracts Prepared with Improved Extraction Conditions

by Ravikiran B. Humbare, Joyita Sarkar, Anjali A. Kulkarni, Mugdha G. Juwale, Sushil H. Deshmukh, Dinesh Amalnerkar, Manohar Chaskar, Maria C. Albertini, Marco B. L. Rocchi, Swapnil C. Kamble and Seeram Ramakrishna

Antioxidants 2022, 11(5), 1006; https://doi.org/10.3390/antiox11051006 - 20 May 2022

Cited by 4 | Viewed by 2836

Abstract

Rubia cordifolia L. (Rubiaceae) is an important plant in Indian and Chinese medical systems. Extracts prepared from the root, stem and leaf have been used traditionally for the management of various diseases. Some of the known effects are anti-inflammation, neuroprotection, anti-proliferation, immunomodulation and [...] Read more.

Rubia cordifolia L. (Rubiaceae) is an important plant in Indian and Chinese medical systems. Extracts prepared from the root, stem and leaf have been used traditionally for the management of various diseases. Some of the known effects are anti-inflammation, neuroprotection, anti-proliferation, immunomodulation and anti-tumor. A comparative account of the extracts derived from different organs that lead to the identification of the most suitable solvent is lacking. We explored the presence of phytochemicals, antioxidant activity and anti-proliferative properties of a variety of solvent-based extracts of root, and methanol extracts of stem and leaf of R. cordifolia L. The antioxidant potential was determined by DPPH, hydrogen peroxide, nitric oxide and total antioxidant assays. The anti-proliferative nature was evaluated by MTT assay on HeLa, ME-180 and HepG2 cells. The composition of the extracts was determined by UPLC-UV-MS. We found that the root extracts had the presence of higher amounts of antioxidants over the stem and leaf extracts. The root extracts prepared in methanol exhibited the highest cytotoxicity in HepG2 cells. The main compounds identified through UPLC-UV-MS of the methanol extract give credibility to the previous results. Our comprehensive study corroborates the preference given to the root over the stem and leaf for extract preparation. In conclusion, we identified the methanol extract of the root to be the most suited to have bioactivity with anti-cancer potential. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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20 pages, 3037 KiB

Open AccessArticle

Characterization of the Biological Activity of the Ethanolic Extract from the Roots of Cannabis sativa L. Grown in Aeroponics

by Fabio Ferrini, Sabrina Donati Zeppa, Daniele Fraternale, Vittoria Carrabs, Giosuè Annibalini, Giancarlo Verardo, Andrea Gorassini, Maria Cristina Albertini, Tariq Ismail, Carmela Fimognari and Piero Sestili

Antioxidants 2022, 11(5), 860; https://doi.org/10.3390/antiox11050860 - 27 Apr 2022

Cited by 8 | Viewed by 4162

Abstract

Cannabis sativa var. Kompolti, a variety routinely used for food production purposes, is characterized by a low concentration of psychoactive molecules, although containing many other biologically attractive metabolites in all parts of the plant, including the roots. In the present work, we evaluate [...] Read more.

Cannabis sativa var. Kompolti, a variety routinely used for food production purposes, is characterized by a low concentration of psychoactive molecules, although containing many other biologically attractive metabolites in all parts of the plant, including the roots. In the present work, we evaluate the specific biological activities of the roots’ extract from plants cultivated through aeroponics, an affordable and reliable method facilitating the isolation and processing of roots, with the advantage of being suitable for industrial scale-up. Furthermore, aeroponics results in an increased net accumulation of the most biologically attractive constituents (β-sitosterol, friedelin and epi-friedelanol) found in the roots. The ethanolic extract of the aeroponic roots of C. sativa (APEX) and its separate components are studied to evaluate their anti-inflammatory (modulation of the expression level of specific markers upon LPS stimulation in U937 cells, such as IL-6, IL-8, TNF-α, IkB-α, iNOS, IRAK-1 and miR-146a) and antioxidant (in either acellular or cellular settings) activities. The APEX anti-inflammatory and antioxidant capacities are also functionally benchmarked using the wound-healing assay. On the whole, the data obtained show that APEX and its main components showed significant anti-inflammatory and antioxidant activities, which may render the exploitation of roots as a source of natural antioxidants and anti-inflammatory agents highly attractive, with the additional technical and economic advantages of aeroponics compared to soil cultivation. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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20 pages, 3422 KiB

Open AccessArticle

Challenges in Quantifying 8-OHdG and 8-Isoprostane in Exhaled Breath Condensate

by Maud Hemmendinger, Jean-Jacques Sauvain, Nancy B. Hopf, Guillaume Suárez and Irina Guseva Canu

Antioxidants 2022, 11(5), 830; https://doi.org/10.3390/antiox11050830 - 25 Apr 2022

Cited by 5 | Viewed by 1976

Abstract

Exhaled breath condensate (EBC) has attracted substantial interest in the last few years, enabling the assessment of airway inflammation with a non-invasive method. Concentrations of 8-Hydroxydesoxyguanosine (8-OHdG) and 8-isoprostane in EBC have been suggested as candidate biomarkers for lung diseases associated with inflammation [...] Read more.

Exhaled breath condensate (EBC) has attracted substantial interest in the last few years, enabling the assessment of airway inflammation with a non-invasive method. Concentrations of 8-Hydroxydesoxyguanosine (8-OHdG) and 8-isoprostane in EBC have been suggested as candidate biomarkers for lung diseases associated with inflammation and oxidative stress. EBC is a diluted biological matrix and consequently, requires highly sensitive chemical analytic methods (picomolar range) for biomarker quantification. We developed a new liquid chromatography coupled to tandem mass spectrometry method to quantify 8-OHdG and 8-isoprostane in EBC simultaneously. We applied this novel biomarker method in EBC obtained from 10 healthy subjects, 7 asthmatic subjects, and 9 subjects with chronic obstructive pulmonary disease. Both biomarkers were below the limit of detection (LOD) despite the good sensitivity of the chemical analytical method (LOD = 0.5 pg/mL for 8-OHdG; 1 pg/mL for 8-isoprostane). This lack of detection might result from factors affecting EBC collections. These findings are in line with methodological concerns already raised regarding the reliability of EBC collection for quantification of 8-OHdG and 8-isoprostane. Precaution is therefore needed when comparing literature results without considering methodological issues relative to EBC collection and analysis. Loss of analyte during EBC collection procedures still needs to be resolved before using these oxidative stress biomarkers in EBC. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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13 pages, 300 KiB

Open AccessArticle

Pre-Operative Assessment of Micronutrients, Amino Acids, Phospholipids and Oxidative Stress in Bariatric Surgery Candidates

by Thorsten Henning, Bastian Kochlik, Paula Kusch, Matthias Strauss, Viktorija Jurić, Marc Pignitter, Frank Marusch, Tilman Grune and Daniela Weber

Antioxidants 2022, 11(4), 774; https://doi.org/10.3390/antiox11040774 - 13 Apr 2022

Cited by 3 | Viewed by 2315

Abstract

Obesity has been linked to lower concentrations of fat-soluble micronutrients and higher concentrations of oxidative stress markers as well as an altered metabolism of branched chain amino acids and phospholipids. In the context of morbid obesity, the aim of this study was to [...] Read more.

Obesity has been linked to lower concentrations of fat-soluble micronutrients and higher concentrations of oxidative stress markers as well as an altered metabolism of branched chain amino acids and phospholipids. In the context of morbid obesity, the aim of this study was to investigate whether and to which extent plasma status of micronutrients, amino acids, phospholipids and oxidative stress differs between morbidly obese (n = 23) and non-obese patients (n = 13). In addition to plasma, malondialdehyde, retinol, cholesterol and triglycerides were assessed in visceral and subcutaneous adipose tissue in both groups. Plasma γ-tocopherol was significantly lower (p < 0.011) in the obese group while other fat-soluble micronutrients showed no statistically significant differences between both groups. Branched-chain amino acids (all p < 0.008) and lysine (p < 0.006) were significantly higher in morbidly obese patients compared to the control group. Malondialdehyde concentrations in both visceral (p < 0.016) and subcutaneous (p < 0.002) adipose tissue were significantly higher in the morbidly obese group while plasma markers of oxidative stress showed no significant differences between both groups. Significantly lower plasma concentrations of phosphatidylcholine, phosphatidylethanolamine, lyso-phosphatidylethanolamine (all p < 0.05) and their corresponding ether-linked analogs were observed, which were all reduced in obese participants compared to the control group. Pre-operative assessment of micronutrients in patients undergoing bariatric surgery is recommended for early identification of patients who might be at higher risk to develop a severe micronutrient deficiency post-surgery. Assessment of plasma BCAAs and phospholipids in obese patients might help to differentiate between metabolic healthy patients and those with metabolic disorders. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

12 pages, 3670 KiB

Open AccessArticle

α-Acylamino-β-lactone N-Acylethanolamine-hydrolyzing Acid Amidase Inhibitors Encapsulated in PLGA Nanoparticles: Improvement of the Physical Stability and Protection of Human Cells from Hydrogen Peroxide-Induced Oxidative Stress

by Agnese Gagliardi, Roberto Molinaro, Massimo Fresta, Andrea Duranti and Donato Cosco

Antioxidants 2022, 11(4), 686; https://doi.org/10.3390/antiox11040686 - 31 Mar 2022

Cited by 7 | Viewed by 1601

Abstract

N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that preferentially catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide, which has been shown to exhibit neuroprotective and antinociceptive properties by engaging peroxisome proliferator-activated receptor-α. A few potent NAAA inhibitors have [...] Read more.

N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that preferentially catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide, which has been shown to exhibit neuroprotective and antinociceptive properties by engaging peroxisome proliferator-activated receptor-α. A few potent NAAA inhibitors have been developed, including α-acylamino-β-lactone derivatives, which are very strong and effective, but they have limited chemical and plasmatic stability, compromising their use as systemic agents. In the present study, as an example of a molecule belonging to the chemical class of N-(2-oxo-3-oxetanyl)amide NAAA inhibitors, URB866 was entrapped in poly(lactic-co-glycolic acid) nanoparticles in order to increase its physical stability. The data show a monomodal pattern and a significant time- and temperature-dependent stability of the molecule-loaded nanoparticles, which also demonstrated a greater ability to effectively retain the compound. The nanoparticles improved the photostability of URB866 with respect to that of the free molecule and displayed a better antioxidant profile on various cell lines at the molecule concentration of 25 μM. Overall, these results prove that the use of polymeric nanoparticles could be a useful strategy for overcoming the instability of α-acylamino-β-lactone NAAA inhibitors, allowing the maintenance of their characteristics and activity for a longer time. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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30 pages, 4047 KiB

Open AccessArticle

Aryl Hydrocarbon Receptor-Dependent and -Independent Pathways Mediate Curcumin Anti-Aging Effects

by Vanessa Brinkmann, Margherita Romeo, Lucie Larigot, Anne Hemmers, Lisa Tschage, Jennifer Kleinjohann, Alfonso Schiavi, Swantje Steinwachs, Charlotte Esser, Ralph Menzel, Sara Giani Tagliabue, Laura Bonati, Fiona Cox, Niloofar Ale-Agha, Philipp Jakobs, Joachim Altschmied, Judith Haendeler, Xavier Coumoul and Natascia Ventura

Antioxidants 2022, 11(4), 613; https://doi.org/10.3390/antiox11040613 - 23 Mar 2022

Cited by 3 | Viewed by 2829

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols, such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin [...] Read more.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols, such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin across species. Using a combination of in vivo, in vitro, and in silico analyses, we demonstrated that curcumin has AhR-dependent or -independent effects in a context-specific manner. We found that in Caenorhabditis elegans, AhR mediates curcumin-induced lifespan extension, most likely through a ligand-independent inhibitory mechanism related to its antioxidant activity. Curcumin also showed AhR-independent anti-aging activities, such as protection against aggregation-prone proteins and oxidative stress in C. elegans and promotion of the migratory capacity of human primary endothelial cells. These AhR-independent effects are largely mediated by the Nrf2/SKN-1 pathway. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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Review

Jump to: Research

10 pages, 551 KiB

Open AccessReview

Oxidative Stress Is a Concept, Not an Indication for Selective Antioxidant Treatment

by Dov Lichtenberg, Ilya Pinchuk, Eleni Yonassi, Daniela Weber and Tilman Grune

Antioxidants 2023, 12(6), 1188; https://doi.org/10.3390/antiox12061188 - 30 May 2023

Cited by 2 | Viewed by 1355

Abstract

The steady-state redox status is physiologically important and therefore homeostatically maintained. Changes in the status result in signaling (eustress) or oxidative damage (distress). Oxidative stress (OS) is a hard-to-quantitate term that can be estimated only based on different biomarkers. Clinical application of OS, [...] Read more.

The steady-state redox status is physiologically important and therefore homeostatically maintained. Changes in the status result in signaling (eustress) or oxidative damage (distress). Oxidative stress (OS) is a hard-to-quantitate term that can be estimated only based on different biomarkers. Clinical application of OS, particularly for selective antioxidant treatment of people under oxidative stress, requires quantitative evaluation and is limited by the lack of universal biomarkers to describe it. Furthermore, different antioxidants have different effects on the redox state. Hence, as long as we do not have the possibility to determine and quantify OS, therapeutic interventions by the “identify-and-treat” approach cannot be assessed and are, therefore, not likely to be the basis for selective preventive measures against oxidative damage. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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20 pages, 2231 KiB

Open AccessReview

Role of 3-Mercaptopyruvate Sulfurtransferase (3-MST) in Physiology and Disease

by Swetha Pavani Rao, Prakashkumar Dobariya, Harshini Bellamkonda and Swati S. More

Antioxidants 2023, 12(3), 603; https://doi.org/10.3390/antiox12030603 - 01 Mar 2023

Cited by 7 | Viewed by 2933

Abstract

3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well as the cytoplasm. 3-MST mediates the reaction of 3-mercaptopyruvate with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. Hydrogen [...] Read more.

3-mercaptopyruvate sulfurtransferase (3-MST) plays the important role of producing hydrogen sulfide. Conserved from bacteria to Mammalia, this enzyme is localized in mitochondria as well as the cytoplasm. 3-MST mediates the reaction of 3-mercaptopyruvate with dihydrolipoic acid and thioredoxin to produce hydrogen sulfide. Hydrogen sulfide is also produced through cystathionine beta-synthase and cystathionine gamma-lyase, along with 3-MST, and is known to alleviate a variety of illnesses such as cancer, heart disease, and neurological conditions. The importance of cystathionine beta-synthase and cystathionine gamma-lyase in hydrogen sulfide biogenesis is well-described, but documentation of the 3-MST pathway is limited. This account compiles the current state of knowledge about the role of 3-MST in physiology and pathology. Attempts at targeting the 3-MST pathway for therapeutic benefit are discussed, highlighting the potential of 3-MST as a therapeutic target. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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37 pages, 1621 KiB

Open AccessReview

The Chemical Variability, Nutraceutical Value, and Food-Industry and Cosmetic Applications of Citrus Plants: A Critical Review

by Anis Ben Hsouna, Carmen Sadaka, Ivana Generalić Mekinić, Stefania Garzoli, Jaroslava Švarc-Gajić, Francisca Rodrigues, Simone Morais, Manuela M. Moreira, Eduarda Ferreira, Giorgia Spigno, Tanja Brezo-Borjan, Boutheina Ben Akacha, Rania Ben Saad, Cristina Delerue-Matos and Wissem Mnif

Antioxidants 2023, 12(2), 481; https://doi.org/10.3390/antiox12020481 - 14 Feb 2023

Cited by 22 | Viewed by 4950

Abstract

Citrus fruits occupy an important position in the context of the fruit trade, considering that both fresh fruits and processed products are produced on a large scale. Citrus fruits are recognized as an essential component of the human diet, thanks to their high [...] Read more.

Citrus fruits occupy an important position in the context of the fruit trade, considering that both fresh fruits and processed products are produced on a large scale. Citrus fruits are recognized as an essential component of the human diet, thanks to their high content of beneficial nutrients such as vitamins, minerals, terpenes, flavonoids, coumarins and dietary fibers. Among these, a wide range of positive biological activities are attributed to terpenes and flavonoids derivatives. In this review, a list of bibliographic reports (from 2015 onwards) on the phytochemical composition, beneficial effects and potential applications of citrus fruits and their by-products is systematically summarized. In detail, information regarding the nutraceutical and medicinal value closely linked to the presence of numerous bioactive metabolites and their growing use in the food industry and food packaging, also considering any technological strategies such as encapsulation to guarantee their stability over time, were evaluated. In addition, since citrus fruit, as well as its by-products, are interesting alternatives for the reformulation of natural cosmetic products, the sector of the cosmetic industry is also explored. More in-depth knowledge of the latest information in this field will contribute to future conscious use of citrus fruits. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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33 pages, 2059 KiB

Open AccessReview

Honey and Alzheimer’s Disease—Current Understanding and Future Prospects

by Ammara Shaikh, Fairus Ahmad, Seong Lin Teoh, Jaya Kumar and Mohamad Fairuz Yahaya

Antioxidants 2023, 12(2), 427; https://doi.org/10.3390/antiox12020427 - 09 Feb 2023

Cited by 2 | Viewed by 5897

Abstract

Alzheimer’s disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to [...] Read more.

Alzheimer’s disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to be attributed by extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles. Additionally, genetic factors such as abnormality in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2 play a role in the disease. As the current treatment aims to treat the symptoms and to slow the disease progression, there has been a continuous search for new nutraceutical agent or medicine to help prevent and cure AD pathology. In this quest, honey has emerged as a powerful nootropic agent. Numerous studies have demonstrated that the high flavonoids and phenolic acids content in honey exerts its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes the effect of main flavonoid compounds found in honey on the physiological functioning of the central nervous system, and the effect of honey intake on memory and cognition in various animal model. This review provides a new insight on the potential of honey to prevent AD pathology, as well as to ameliorate the damage in the developed AD. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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11 pages, 1084 KiB

Open AccessReview

Oxidative Stress: What Is It? Can It Be Measured? Where Is It Located? Can It Be Good or Bad? Can It Be Prevented? Can It Be Cured?

by Angelo Azzi

Antioxidants 2022, 11(8), 1431; https://doi.org/10.3390/antiox11081431 - 23 Jul 2022

Cited by 21 | Viewed by 3268

Abstract

The meaning, the appropriate usage and the misusage of the terms oxidative stress, oxidative eustress, and oxidative distress have been evaluated. It has been realized that the terms oxidative stress and oxidative damage are often used inappropriately as synonyms. The usage of the [...] Read more.

The meaning, the appropriate usage and the misusage of the terms oxidative stress, oxidative eustress, and oxidative distress have been evaluated. It has been realized that the terms oxidative stress and oxidative damage are often used inappropriately as synonyms. The usage of the term eustress (intended as good stress) is unsuitable to indicate signaling by reactive molecular an event that can be finalistically considered either good or bad, depending on the circumstances. The so defined oxidative distress is an oxidative damage but not an oxidative stress. What is measured and defined as oxidative stress is in fact an oxidative damage. Damaging oxidations and signaling oxidant events (good or bad) can be present, also simultaneously, in different and multiple location of a cell, tissue or body and the measure of an oxidant event in body fluids or tissue specimen can only be the sum of non-separatable events, sometimes of opposite sign. There is no officially approved therapy to prevent or cure oxidative stress or oxidative damage. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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8 pages, 255 KiB

Open AccessReview

What Are the Oxidizing Intermediates in the Fenton and Fenton-like Reactions? A Perspective

by Dan Meyerstein

Antioxidants 2022, 11(7), 1368; https://doi.org/10.3390/antiox11071368 - 14 Jul 2022

Cited by 13 | Viewed by 2495

Abstract

The Fenton and Fenton-like reactions are of major importance due to their role as a source of oxidative stress in all living systems and due to their use in advanced oxidation technologies. For many years, there has been a debate whether the reaction [...] Read more.

The Fenton and Fenton-like reactions are of major importance due to their role as a source of oxidative stress in all living systems and due to their use in advanced oxidation technologies. For many years, there has been a debate whether the reaction of Fe^II(H₂O)₆²⁺ with H₂O₂ yields OH^• radicals or Fe^IV=O_aq. It is now known that this reaction proceeds via the formation of the intermediate complex (H₂O)₅Fe^II(O₂H)⁺/(H₂O)₅Fe^II(O₂H₂)²⁺ that decomposes to form either OH^• radicals or Fe^IV=O_aq, depending on the pH of the medium. The intermediate complex might also directly oxidize a substrate present in the medium. In the presence of Fe^III_aq, the complex Fe^III(OOH)_aq is formed. This complex reacts via Fe^II(H₂O)₆²⁺ + Fe^III(OOH)_aq → Fe^IV=O_aq + Fe^III_aq. In the presence of ligands, the process often observed is L_n(H₂O)_5−nFe^II(O₂H) → L^•⁺ + L_n−1Fe^III_aq. Thus, in the presence of small concentrations of HCO₃⁻ i.e., in biological systems and in advanced oxidation processes—the oxidizing radical formed is CO₃^•⁻. It is evident that, in the presence of other transition metal complexes and/or other ligands, other radicals might be formed. In complexes of the type L_n(H₂O)_5−nM^III/II(O₂H⁻), the peroxide might oxidize the ligand L without oxidizing the central cation M. OH^• radicals are evidently not often formed in Fenton or Fenton-like reactions. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

18 pages, 1769 KiB

Open AccessReview

How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS-CoV-2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism

by Francesco Galli, Giada Marcantonini, Daniela Giustarini, Maria Cristina Albertini, Anna Migni, Linda Zatini, Antimo Gioiello, Ranieri Rossi and Desirée Bartolini

Antioxidants 2022, 11(7), 1366; https://doi.org/10.3390/antiox11071366 - 14 Jul 2022

Cited by 13 | Viewed by 3252

Abstract

SARS-CoV-2 infection can cause a severe respiratory distress syndrome with inflammatory and thrombotic complications, the severity of which increases with patients’ age and presence of comorbidity. The reasons for an age-dependent increase in the risk of severe COVID-19 could be many. These include [...] Read more.

SARS-CoV-2 infection can cause a severe respiratory distress syndrome with inflammatory and thrombotic complications, the severity of which increases with patients’ age and presence of comorbidity. The reasons for an age-dependent increase in the risk of severe COVID-19 could be many. These include defects in the homeostatic processes that control the cellular redox and its pivotal role in sustaining the immuno-inflammatory response to the host and the protection against oxidative stress and tissue degeneration. Pathogens may take advantage of such age-dependent abnormalities. Alterations of the thiol redox balance in the lung tissue and lining fluids may influence the risk of infection, and the host capability to respond to pathogens and to avoid severe complications. SARS-CoV-2, likewise other viruses, such as HIV, influenza, and HSV, benefits in its replication cycle of pro-oxidant conditions that the same viral infection seems to induce in the host cell with mechanisms that remain poorly understood. We recently demonstrated that the pro-oxidant effects of SARS-CoV-2 infection are associated with changes in the cellular metabolism and transmembrane fluxes of Cys and GSH. These appear to be the consequence of an increased use of Cys in viral protein synthesis and to ER stress pathway activation that interfere with transcription factors, as Nrf2 and NFkB, important to coordinate the metabolism of GSH with other aspects of the stress response and with the pro-inflammatory effects of this virus in the host cell. This narrative review article describes these cellular and molecular aspects of SARS-CoV-2 infection, and the role that antivirals and cytoprotective agents such as N-acetyl cysteine may have to limit the cytopathic effects of this virus and to recover tissue homeostasis after infection. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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17 pages, 1067 KiB

Open AccessReview

Oxidative Stress in Type 2 Diabetes: The Case for Future Pediatric Redoxomics Studies

by Stephanie N. Alu, Evan A. Los, George A. Ford and William L. Stone

Antioxidants 2022, 11(7), 1336; https://doi.org/10.3390/antiox11071336 - 07 Jul 2022

Cited by 12 | Viewed by 2524

Abstract

Considerable evidence supports the role of oxidative stress in adult type 2 diabetes (T2D). Due to increasing rates of pediatric obesity, lack of physical activity, and consumption of excess food calories, it is projected that the number of children living with insulin resistance, [...] Read more.

Considerable evidence supports the role of oxidative stress in adult type 2 diabetes (T2D). Due to increasing rates of pediatric obesity, lack of physical activity, and consumption of excess food calories, it is projected that the number of children living with insulin resistance, prediabetes, and T2D will markedly increase with enormous worldwide economic costs. Understanding the factors contributing to oxidative stress and T2D risk may help develop optimal early intervention strategies. Evidence suggests that oxidative stress, triggered by excess dietary fat consumption, causes excess mitochondrial hydrogen peroxide emission in skeletal muscle, alters redox status, and promotes insulin resistance leading to T2D. The pathophysiological events arising from excess calorie-induced mitochondrial reactive oxygen species production are complex and not yet investigated in children. Systems medicine is an integrative approach leveraging conventional medical information and environmental factors with data obtained from “omics” technologies such as genomics, proteomics, and metabolomics. In adults with T2D, systems medicine shows promise in risk assessment and predicting drug response. Redoxomics is a branch of systems medicine focusing on “omics” data related to redox status. Systems medicine with a complementary emphasis on redoxomics can potentially optimize future healthcare strategies for adults and children with T2D. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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26 pages, 3371 KiB

Open AccessReview

Metabolic Adaptation-Mediated Cancer Survival and Progression in Oxidative Stress

by Yongquan Tang, Zhe Zhang, Yan Chen, Siyuan Qin, Li Zhou, Wei Gao and Zhisen Shen

Antioxidants 2022, 11(7), 1324; https://doi.org/10.3390/antiox11071324 - 05 Jul 2022

Cited by 11 | Viewed by 3253

Abstract

Undue elevation of ROS levels commonly occurs during cancer evolution as a result of various antitumor therapeutics and/or endogenous immune response. Overwhelming ROS levels induced cancer cell death through the dysregulation of ROS-sensitive glycolytic enzymes, leading to the catastrophic depression of glycolysis and [...] Read more.

Undue elevation of ROS levels commonly occurs during cancer evolution as a result of various antitumor therapeutics and/or endogenous immune response. Overwhelming ROS levels induced cancer cell death through the dysregulation of ROS-sensitive glycolytic enzymes, leading to the catastrophic depression of glycolysis and oxidative phosphorylation (OXPHOS), which are critical for cancer survival and progression. However, cancer cells also adapt to such catastrophic oxidative and metabolic stresses by metabolic reprograming, resulting in cancer residuality, progression, and relapse. This adaptation is highly dependent on NADPH and GSH syntheses for ROS scavenging and the upregulation of lipolysis and glutaminolysis, which fuel tricarboxylic acid cycle-coupled OXPHOS and biosynthesis. The underlying mechanism remains poorly understood, thus presenting a promising field with opportunities to manipulate metabolic adaptations for cancer prevention and therapy. In this review, we provide a summary of the mechanisms of metabolic regulation in the adaptation of cancer cells to oxidative stress and the current understanding of its regulatory role in cancer survival and progression. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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19 pages, 1826 KiB

Open AccessReview

Antioxidant Therapy in Cancer: Rationale and Progress

by Maochao Luo, Li Zhou, Zhao Huang, Bowen Li, Edouard C. Nice, Jia Xu and Canhua Huang

Antioxidants 2022, 11(6), 1128; https://doi.org/10.3390/antiox11061128 - 08 Jun 2022

Cited by 45 | Viewed by 5195

Abstract

Cancer is characterized by increased oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidants. Enhanced ROS accumulation, as a result of metabolic disturbances and signaling aberrations, can promote carcinogenesis and malignant progression by inducing gene mutations and activating pro-oncogenic signaling, providing [...] Read more.

Cancer is characterized by increased oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidants. Enhanced ROS accumulation, as a result of metabolic disturbances and signaling aberrations, can promote carcinogenesis and malignant progression by inducing gene mutations and activating pro-oncogenic signaling, providing a possible rationale for targeting oxidative stress in cancer treatment. While numerous antioxidants have demonstrated therapeutic potential, their clinical efficacy in cancer remains unproven. Here, we review the rationale for, and recent advances in, pre-clinical and clinical research on antioxidant therapy in cancer, including targeting ROS with nonenzymatic antioxidants, such as NRF2 activators, vitamins, N-acetylcysteine and GSH esters, or targeting ROS with enzymatic antioxidants, such as NOX inhibitors and SOD mimics. In addition, we will offer insights into prospective therapeutic options for improving the effectiveness of antioxidant therapy, which may expand its applications in clinical cancer treatment. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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14 pages, 2026 KiB

Open AccessReview

Oxidation of Polyunsaturated Fatty Acids as a Promising Area of Research in Infertility

by Giulia Collodel, Elena Moretti, Daria Noto, Roberta Corsaro and Cinzia Signorini

Antioxidants 2022, 11(5), 1002; https://doi.org/10.3390/antiox11051002 - 19 May 2022

Cited by 12 | Viewed by 2454

Abstract

In this review, the role of fatty acids (FA) in human pathological conditions, infertility in particular, was considered. FA and FA-derived metabolites modulate cell membrane composition, membrane lipid microdomains and cell signaling. Moreover, such molecules are involved in cell death, immunological responses and [...] Read more.

In this review, the role of fatty acids (FA) in human pathological conditions, infertility in particular, was considered. FA and FA-derived metabolites modulate cell membrane composition, membrane lipid microdomains and cell signaling. Moreover, such molecules are involved in cell death, immunological responses and inflammatory processes. Human health and several pathological conditions are specifically associated with both dietary and cell membrane lipid profiles. The role of FA metabolism in human sperm and spermatogenesis has recently been investigated. Cumulative findings indicate F₂ isoprostanes (oxygenated products from arachidonic acid metabolism) and resolvins (lipid mediators of resolution of inflammation) as promising biomarkers for the evaluation of semen and follicular fluid quality. Advanced knowledge in this field could lead to new scenarios in the treatment of infertility. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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12 pages, 875 KiB

Open AccessReview

Punicalagin Regulates Signaling Pathways in Inflammation-Associated Chronic Diseases

by Jie Xu, Ke Cao, Xuyun Liu, Lin Zhao, Zhihui Feng and Jiankang Liu

Antioxidants 2022, 11(1), 29; https://doi.org/10.3390/antiox11010029 - 24 Dec 2021

Cited by 26 | Viewed by 4750

Abstract

Inflammation is a complex biological defense system associated with a series of chronic diseases such as cancer, arthritis, diabetes, cardiovascular and neurodegenerative diseases. The extracts of pomegranate fruit and peel have been reported to possess health-beneficial properties in inflammation-associated chronic diseases. Punicalagin is [...] Read more.

Inflammation is a complex biological defense system associated with a series of chronic diseases such as cancer, arthritis, diabetes, cardiovascular and neurodegenerative diseases. The extracts of pomegranate fruit and peel have been reported to possess health-beneficial properties in inflammation-associated chronic diseases. Punicalagin is considered to be the major active component of pomegranate extracts. In this review we have focused on recent studies into the therapeutic effects of punicalagin on inflammation-associated chronic diseases and the regulatory roles in NF-κB, MAPK, IL-6/JAK/STAT3 and PI3K/Akt/mTOR signaling pathways. We have concluded that punicalagin may be a promising therapeutic compound in preventing and treating inflammation-associated chronic diseases, although further clinical studies are required. Full article

(This article belongs to the Special Issue The 10th Anniversary of Antioxidants: Past, Present and Future)

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