10th Anniversary of Antioxidants—Aberrant and Signaling Oxidation of Biomolecules

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Aberrant Oxidation of Biomolecules".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 54636

Special Issue Editors

Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milan, Italy
Interests: reactive carbonyls species; advanced glycation end products (AGEs); advanced lipoxidation end products (ALEs); sequestering agents; protein adducts
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutical Sciences, University of Milan, Via Luigi Mangiagalli 25, 20133 Milan, Italy
Interests: liquid chromatography; reactive carbonyl species; spectrometry
Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20122 Milan, Italy
Interests: medicinal chemistry; lipid peroxidation; antioxidant activity

Special Issue Information

Dear Colleagues,

Biomolecule oxidation involves covalent modifications and occurs both by direct and indirect reaction mechanisms; the direct oxidation is mediated by reactive oxygen species (ROS), the indirect by secondary by-products of oxidative stress, such as lipid-peroxidation break-down products, which covalently adduct the biomolecules.

In vitro and in vivo evidence indicates that biomolecule oxidation is involved in the onset and propagation of several diseases, including cardiovascular and neurological disorders. The damaging effect can be mediated by several mechanisms, including a direct dysregulating effect of the target biomolecule, oligomerization, and epitope formation.

Most recently, it has been found that besides inducing a damaging effect, protein oxidation, in some circumstances, can exert a beneficial effect by stimulating the Nrf2-antioxidant response element signaling pathway; Nrf2 activation controls the expression of genes whose protein products enhance cellular antioxidant capacity and are involved in the detoxication and elimination of reactive oxidants and electrophilic agents.

Based on the above-mentioned premises, the aim of the Special Issue is to collect research and review papers focusing on the damaging and signaling processes induced by oxidized proteins. Papers on the following topics, among others, are welcome: methodological papers on cutting edge analytical approaches for the identification, characterization, and quantification of oxidized biomolecules in different biological samples, including plant, animal and human specimens; OMICs approaches (genomic, proteomic, metabolomic, and lipidomic) to investigate the effect of oxidized biomolecules on cellular pathways; in vitro and in vivo studies on cell signaling evoked by oxidized biomolecules; cellular mechanisms for degradation and removal of oxidized proteins and their regulation; and oxidized biomolecules as drug target and medicinal chemistry approaches for their regulation.

Prof. Dr. Giancarlo Aldini
Dr. Alessandra Altomare
Dr. Giovanna Baron
Guest Editors

Manuscript Submission Information

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Published Papers (15 papers)

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Research

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15 pages, 1662 KiB  
Article
Carnosinase-1 Knock-Out Reduces Kidney Fibrosis in Type-1 Diabetic Mice on High Fat Diet
by Tilman Pfeffer, Charlotte Wetzel, Philip Kirschner, Maria Bartosova, Tanja Poth, Constantin Schwab, Gernot Poschet, Johanna Zemva, Ruben Bulkescher, Ivan Damgov, Christian Thiel, Sven F. Garbade, Kristina Klingbeil, Verena Peters and Claus Peter Schmitt
Antioxidants 2023, 12(6), 1270; https://doi.org/10.3390/antiox12061270 - 14 Jun 2023
Cited by 1 | Viewed by 1294
Abstract
Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice (Cndp1-KO) and wild-type littermates (WT) on a [...] Read more.
Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice (Cndp1-KO) and wild-type littermates (WT) on a normal diet (ND) and high fat diet (HFD) (n = 10/group), with streptozocin (STZ)-induced type-1 diabetes (n = 21–23/group), were studied for 32 weeks. Independent of diet, Cndp1-KO mice had 2- to 10-fold higher kidney anserine and carnosine concentrations than WT mice, but otherwise a similar kidney metabolome; heart, liver, muscle and serum anserine and carnosine concentrations were not different. Diabetic Cndp1-KO mice did not differ from diabetic WT mice in energy intake, body weight gain, blood glucose, HbA1c, insulin and glucose tolerance with both diets, whereas the diabetes-related increase in kidney advanced glycation end-product and 4-hydroxynonenal concentrations was prevented in the KO mice. Tubular protein accumulation was lower in diabetic ND and HFD Cndp1-KO mice, interstitial inflammation and fibrosis were lower in diabetic HFD Cndp1-KO mice compared to diabetic WT mice. Fatalities occurred later in diabetic ND Cndp1-KO mice versus WT littermates. Independent of systemic glucose homeostasis, increased kidney anserine and carnosine concentrations reduce local glycation and oxidative stress in type-1 diabetic mice, and mitigate interstitial nephropathy in type-1 diabetic mice on HFD. Full article
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26 pages, 2172 KiB  
Article
Ellagic Acid Triggers the Necrosis of Differentiated Human Enterocytes Exposed to 3-Nitro-Tyrosine: An MS-Based Proteomic Study
by Silvia Díaz-Velasco, Josué Delgado, Fernando J. Peña and Mario Estévez
Antioxidants 2022, 11(12), 2485; https://doi.org/10.3390/antiox11122485 - 17 Dec 2022
Cited by 1 | Viewed by 1324
Abstract
To study the molecular basis of the toxicological effect of a dietary nitrosated amino acid, namely, 3-nitrotyrosine (3-NT), differentiated human enterocytes were exposed to dietary concentrations of this species (200 μM) and analyzed for flow cytometry, protein oxidation markers and MS-based proteomics. The [...] Read more.
To study the molecular basis of the toxicological effect of a dietary nitrosated amino acid, namely, 3-nitrotyrosine (3-NT), differentiated human enterocytes were exposed to dietary concentrations of this species (200 μM) and analyzed for flow cytometry, protein oxidation markers and MS-based proteomics. The possible protective role of a dietary phytochemical, ellagic acid (EA) (200 μM), was also tested. The results revealed that cell viability was significantly affected by exposure to 3-NT, with a concomitant significant increase in necrosis (p < 0.05). 3-NT affected several biological processes, such as histocompatibility complex class II (MHC class II), and pathways related to type 3 metabotropic glutamate receptors binding. Addition of EA to 3-NT-treated cells stimulated the toxicological effects of the latter by reducing the abundance of proteins involved in mitochondrial conformation. These results emphasize the impact of dietary nitrosated amino acids in intestinal cell physiology and warn about the potential negative effects of ellagic acid when combined with noxious metabolites. Full article
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14 pages, 1385 KiB  
Article
Quantitative Determination of 2-Oxo-Imidazole-Containing Dipeptides by High-Performance Liquid Chromatography/Tandem Mass Spectrometry
by Somei Komae, Shingo Kasamatsu, Koji Uchida and Hideshi Ihara
Antioxidants 2022, 11(12), 2401; https://doi.org/10.3390/antiox11122401 - 02 Dec 2022
Cited by 3 | Viewed by 15897
Abstract
2-Oxo-imidazole-containing dipeptides (2-oxo-IDPs), novel imidazole-containing dipeptide (IDP) derivatives, exhibit a much higher antioxidant capacity than that of IDPs. However, quantitative methods have only been developed for IDPs, and methods for the quantitative analysis of 2-oxo-IDPs are needed. In this study, we developed methods [...] Read more.
2-Oxo-imidazole-containing dipeptides (2-oxo-IDPs), novel imidazole-containing dipeptide (IDP) derivatives, exhibit a much higher antioxidant capacity than that of IDPs. However, quantitative methods have only been developed for IDPs, and methods for the quantitative analysis of 2-oxo-IDPs are needed. In this study, we developed methods for the quantitative analysis of 2-oxo-IDPs by high-performance liquid chromatography with online electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) coupled with a stable isotope dilution method. First, we prepared stable isotope-labeled IDP and 2-oxo-IDP standards for MS analyses. Next, using these standards, we established highly sensitive, selective, and absolute quantitative analysis methods for five IDPs and five 2-oxo-IDPs by HPLC-ESI-MS/MS, achieving a limit of detection in the fmol range. Finally, we applied the method to various types of meat, such as beef, pork, chicken, and whale meat, demonstrating the detection of both IDPs and 2-oxo-IDPs. Furthermore, we provide the first evidence for the endogenous production of 2-oxo-balenine in meats. The methods developed in this study enable the detection of trace levels of 2-oxo-IDPs in biological samples and could be helpful for understanding the biological relevance of 2-oxo-IDPs. Full article
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17 pages, 4606 KiB  
Article
Copper Depletion Strongly Enhances Ferroptosis via Mitochondrial Perturbation and Reduction in Antioxidative Mechanisms
by Fan Li, Xiaojing Wu, Hongli Liu, Mengqi Liu, Zhengkai Yue, Zhenyu Wu, Lei Liu and Fuchang Li
Antioxidants 2022, 11(11), 2084; https://doi.org/10.3390/antiox11112084 - 22 Oct 2022
Cited by 11 | Viewed by 3290
Abstract
Copper serves as a co-factor for a host of metalloenzymes, particularly cytochrome c oxidase (COX). Although it is known that impaired COX function can lead to the excessive accumulation of reactive oxygen species (ROS), the mechanisms underlying how copper depletion leads to cell [...] Read more.
Copper serves as a co-factor for a host of metalloenzymes, particularly cytochrome c oxidase (COX). Although it is known that impaired COX function can lead to the excessive accumulation of reactive oxygen species (ROS), the mechanisms underlying how copper depletion leads to cell damage are poorly understood. Here, we have investigated the role of copper depletion during ferroptosis. The bathocuproinedisulfonic (BCS) treatment depolarized the mitochondrial membrane potential, increased the total cellular ROS levels, stimulated oxidative stress, and reduced the glutathione levels. Moreover, the depletion of copper limited the protein expression of glutathione peroxidase 4 (GPX4), which is the only enzyme that is known to prevent lipid peroxidation. Furthermore, we found that copper depletion decreased the sensitivity of the dermal papilla cells (DPCs) to erastin (an inducer of ferroptosis), and the ferroptosis inhibitor ferrostatin-1 (Fer-1) partially prevented BCS-mediated cell death. Overall, these findings establish a direct link between copper and ferroptosis; BCS-mediated copper depletion strongly enhances ferroptosis via mitochondrial perturbation and a reduction in antioxidative mechanisms. Full article
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11 pages, 1036 KiB  
Article
N-Acetylcysteine Regenerates In Vivo Mercaptoalbumin
by Alessandra Anna Altomare, Maura Brioschi, Sonia Eligini, Alice Bonomi, Beatrice Zoanni, Ada Iezzi, Costantino Jemos, Benedetta Porro, Yuri D’Alessandra, Anna Guarino, Emanuela Omodeo Salè, Giancarlo Aldini, Piergiuseppe Agostoni and Cristina Banfi
Antioxidants 2022, 11(9), 1758; https://doi.org/10.3390/antiox11091758 - 06 Sep 2022
Cited by 2 | Viewed by 1430
Abstract
Human serum albumin (HSA) represents the most abundant plasma protein, with relevant antioxidant activity due to the presence of the sulfhydryl group on cysteine at position 34 (Cys34), the latter being one of the major target sites for redox-dependent modifications leading to the [...] Read more.
Human serum albumin (HSA) represents the most abundant plasma protein, with relevant antioxidant activity due to the presence of the sulfhydryl group on cysteine at position 34 (Cys34), the latter being one of the major target sites for redox-dependent modifications leading to the formation of mixed disulfide linkages with low molecular weight thiols. Thiolated forms of HSA (Thio-HSA) may be useful as markers of an unbalanced redox state and as a potential therapeutic target. Indeed, we have previously reported that albumin Cys34 can be regenerated in vitro by N-Acetylcysteine (NAC) through a thiol-disulfide breaking mechanism, with a full recovery of the HSA antioxidant and antiplatelet activities. With this case study, we aimed to assess the ability of NAC to regenerate native mercaptoalbumin (HSA-SH) and the plasma antioxidant capacity in subjects with redox unbalance, after oral and intravenous administration. A placebo-controlled crossover study, single-blinded, was performed on six hypertensive subjects, randomized into two groups, on a one-to-one basis with NAC (600 mg/die) or a placebo, orally and intravenously administered. Albumin isoforms, HSA-SH, Thio-HSA, and glutathione levels were evaluated by means of mass spectrometry. The plasma antioxidant activity was assessed by a fluorimetric assay. NAC, orally administered, significantly decreased the Thio-HSA levels in comparison with the pre-treatment conditions (T0), reaching the maximal effect after 60 min (−24.7 ± 8%). The Thio-HSA reduction was accompanied by a concomitant increase in the native HSA-SH levels (+6.4 ± 2%). After intravenous administration of NAC, a significant decrease of the Thio-HSA with respect to the pre-treatment conditions (T0) was observed, with a maximal effect after 30 min (−68.9 ± 10.6%) and remaining significant even after 6 h. Conversely, no effect on the albumin isoforms was detected with either the orally or the intravenously administered placebo treatments. Furthermore, the total antioxidant activity of the plasma significantly increased after NAC infusion with respect to the placebo (p = 0.0089). Interestingly, we did not observe any difference in terms of total glutathione corrected for hemoglobin, ruling out any effect of NAC on the intracellular glutathione and supporting its role as a disulfide-breaking agent. This case study confirms the in vitro experiments and demonstrates for the first time that NAC is able to regenerate mercaptoalbumin in vivo, allowing us to hypothesize that the recovery of Cys34 content can modulate in vivo oxidative stress and, hopefully, have an effect in oxidative-based diseases. Full article
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26 pages, 7185 KiB  
Article
Low Concentrations of Oxidized Phospholipids Increase Stress Tolerance of Endothelial Cells
by Christina Mauerhofer, Taras Afonyushkin, Olga V. Oskolkova, Klara Hellauer, Bernd Gesslbauer, Jasmin Schmerda, Yunbo Ke, Andreas Zimmer, Anna A. Birukova, Konstantin G. Birukov and Valery Bochkov
Antioxidants 2022, 11(9), 1741; https://doi.org/10.3390/antiox11091741 - 01 Sep 2022
Cited by 1 | Viewed by 1833
Abstract
Oxidized phospholipids (OxPLs) are generated by enzymatic or autooxidation of esterified polyunsaturated fatty acids (PUFAs) residues. OxPLs are present in circulation and atherosclerotic plaques where they are thought to induce predominantly proinflammatory and toxic changes in endothelial (ECs) and other cell types. Unexpectedly, [...] Read more.
Oxidized phospholipids (OxPLs) are generated by enzymatic or autooxidation of esterified polyunsaturated fatty acids (PUFAs) residues. OxPLs are present in circulation and atherosclerotic plaques where they are thought to induce predominantly proinflammatory and toxic changes in endothelial (ECs) and other cell types. Unexpectedly, we found that low concentrations of OxPLs were not toxic but protected ECs from stress induced by serum deprivation or cytostatic drugs. The protective effect was observed in ECs obtained from different vessels and was monitored using a variety of readouts based on different biological and chemical principles. Analysis of the structure–activity relationship identified oxidized or missing fatty acid residue (OxPLs or Lyso-PLs, respectively) as a prerequisite for the protective action of a PL. Protective OxPLs or Lyso-PLs acquired detergent-like properties and formed in solution aggregates <10 nm in diameter (likely micelles), which were in striking contrast with large aggregates (>1000 nm, likely multilayer liposomes) produced by nonoxidized precursor PLs. Because surfactants, OxPLs, and Lyso-PLs are known to extract membrane cholesterol, we tested if this effect might trigger the protection of endothelial cells. The protective action of OxPLs and Lyso-PLs was inhibited by cotreatment with cholesterol and mimicked by cholesterol-binding beta-cyclodextrin but not inactive α-cyclodextrin. Wide-scale mRNA expression analysis in four types of ECs showed the induction of genes encoding for heat shock proteins (HSPs) and secreted prosurvival peptides and proteins. Inducers of HSPs, chemical chaperones, and pure prosurvival factors mimicked the protective action of OxPLs/Lyso-PLs. We hypothesize that oxidation changes the physicochemical properties of PLs, thus promoting membrane cholesterol redistribution or extraction leading to the expression of intra- and extracellular prosurvival factors. Full article
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11 pages, 1422 KiB  
Article
The Burden of Impaired Serum Albumin Antioxidant Properties and Glyco-Oxidation in Coronary Heart Disease Patients with and without Type 2 Diabetes Mellitus
by Francesco Piarulli, Cristina Banfi, Maura Brioschi, Alessandra Altomare, Eugenio Ragazzi, Chiara Cosma, Giovanni Sartore and Annunziata Lapolla
Antioxidants 2022, 11(8), 1501; https://doi.org/10.3390/antiox11081501 - 30 Jul 2022
Cited by 3 | Viewed by 1894
Abstract
Human serum albumin (HSA) has an important antioxidant activity due to the presence of the reduced cysteine at position 34, which represents the most abundant free thiol in the plasma. In oxidative-based diseases, HSA undergoes S-thiolation (THIO-HSA) with changes in the antioxidant function [...] Read more.
Human serum albumin (HSA) has an important antioxidant activity due to the presence of the reduced cysteine at position 34, which represents the most abundant free thiol in the plasma. In oxidative-based diseases, HSA undergoes S-thiolation (THIO-HSA) with changes in the antioxidant function of albumin that could contribute to the progression of the disease. The aim of this study was to verify, for the first time, the different burdens of THIO-HSA, glycated HSA (GLY-HSA), and advanced glycation end products (AGE) accumulation both in type 2 diabetes mellitus (T2DM) patients and in non-diabetic patients, with or without coronary heart disease (CHD). In this study, we assessed the presence of modified forms of HSA, THIO-HSA, and GLY-HSA by means of mass spectrometry in 33 patients with both T2DM and CHD, in 31 patients with T2DM and without CHD, in 30 patients without diabetes with a history of CHD, and 27 subjects without diabetes and CHD. All the patients’ anthropometric and clinical data were recorded including age, sex, duration of diabetes, body mass index (BMI), blood pressure, and history of CHD defined with anamnestic data. Metabolic parameters, such as fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipids, pentosidine, AGE, receptor for advanced glycation end-products (RAGE) and its soluble form (sRAGE), were measured. AGE and pentosidine are significantly higher in T2DM patients with and without CHD with respect to non-diabetic patients with CHD and control subjects. RAGE levels are significantly higher in T2DM patients with respect to non-diabetic patients, and among T2DM patients, the group with CHD showed significantly higher RAGE levels than those without CHD (217 ± 171 pg/mL and 140 ± 61 pg/mL, respectively). Albumin isoforms discriminate between non-diabetic patients with CHD and T2DM patients with and without CHD and control subjects, with GLY-HSA levels higher in T2DM with and without CHD, and THIO-HSA higher in CHD patients without T2DM. Finally, we demonstrated that the oxidized forms of HSA can increase the expression of the inflammatory cytokine Tumor Necrosis Factor-alpha (TNFα) in monocytic cells. In patients with CHD, GLY-HSA and THIO-HSA have a different prevalent distribution, the first one prevailing in patients with T2DM and the second one in patients without T2DM. These findings suggest that albumin quality and homeostasis balance between glyco-oxidation and thiolation might have an impact on the antioxidant defense system in cardiovascular diseases. Full article
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19 pages, 2294 KiB  
Article
Doxorubicin Induces Bone Loss by Increasing Autophagy through a Mitochondrial ROS/TRPML1/TFEB Axis in Osteoclasts
by Hyun-Jung Park, Sun-Young Yoon, Jung-Nam Park, Jae-Hee Suh and Hye-Seon Choi
Antioxidants 2022, 11(8), 1476; https://doi.org/10.3390/antiox11081476 - 28 Jul 2022
Cited by 7 | Viewed by 2082
Abstract
Doxorubicin (DOX), a widely used chemotherapeutic agent, has been linked to an increased risk of bone damage in human patients and induces bone loss in mice. DOX induces autophagy, which contributes to bone homeostasis and excess autophagy in osteoclasts (OCs), resulting in bone [...] Read more.
Doxorubicin (DOX), a widely used chemotherapeutic agent, has been linked to an increased risk of bone damage in human patients and induces bone loss in mice. DOX induces autophagy, which contributes to bone homeostasis and excess autophagy in osteoclasts (OCs), resulting in bone loss. We hypothesized that DOX-induced bone loss is caused by the induction of autophagy in OCs. In vitro, DOX significantly increased the area of OCs and bone resorption activity, whereas it decreased OC number through apoptosis. DOX enhanced the level of LC3II and acidic vesicular organelles-containing cells in OCs, whereas an autophagy inhibitor, 3-methyladenine (3-MA), reversed these, indicating that enhanced autophagy was responsible for the effects of DOX. Increased mitochondrial reactive oxygen species (mROS) by DOX oxidized transient receptor potential mucolipin 1 (TRPML1) on the lysosomal membrane, which led to nuclear localization of transcription factor EB (TFEB), an autophagy-inducing transcription factor. In vivo, micro-computerized tomography analysis revealed that the injection of 3-MA reversed DOX-induced bone loss, and tartrate-resistant acid phosphatase staining showed that 3-MA reduced the area of OCs on the bone surface, which was enhanced upon DOX administration. Collectively, DOX-induced bone loss is at least partly attributable to autophagy upregulation in OCs via an mROS/TRPML1/TFEB axis. Full article
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19 pages, 3466 KiB  
Article
Measurement of Tetrahydrobiopterin in Animal Tissue Samples by HPLC with Electrochemical Detection—Protocol Optimization and Pitfalls
by Ksenija Vujacic-Mirski, Matthias Oelze, Ivana Kuntic, Marin Kuntic, Sanela Kalinovic, Huige Li, Jacek Zielonka, Thomas Münzel and Andreas Daiber
Antioxidants 2022, 11(6), 1182; https://doi.org/10.3390/antiox11061182 - 16 Jun 2022
Cited by 3 | Viewed by 2080
Abstract
Tetrahydrobiopterin (BH4) is an essential cofactor of all nitric oxide synthase isoforms, thus determination of BH4 levels can provide important mechanistic insight into diseases. We established a protocol for high-performance liquid chromatography/electrochemical detection (HPLC/ECD)-based determination of BH4 in tissue samples. We first determined [...] Read more.
Tetrahydrobiopterin (BH4) is an essential cofactor of all nitric oxide synthase isoforms, thus determination of BH4 levels can provide important mechanistic insight into diseases. We established a protocol for high-performance liquid chromatography/electrochemical detection (HPLC/ECD)-based determination of BH4 in tissue samples. We first determined the optimal storage and work-up conditions for authentic BH4 and its oxidation product dihydrobiopterin (BH2) under various conditions (pH, temperature, presence of antioxidants, metal chelators, and storage time). We then applied optimized protocols for detection of BH4 in tissues of septic (induced by lipopolysaccharide [LPS]) rats. BH4 standards in HCl are stabilized by addition of 1,4-dithioerythritol (DTE) and diethylenetriaminepentaacetic acid (DTPA), while HCl was sufficient for BH2 standard stabilization. Overnight storage of BH4 standard solutions at room temperature in HCl without antioxidants caused complete loss of BH4 and the formation of BH2. We further optimized the protocol to separate ascorbate and the BH4 tissue sample and found a significant increase in BH4 in the heart and kidney as well as higher BH4 levels by trend in the brain of septic rats compared to control rats. These findings correspond to reports on augmented nitric oxide and BH4 levels in both animals and patients with septic shock. Full article
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13 pages, 9063 KiB  
Article
Simple and Sensitive Method for the Quantitative Determination of Lipid Hydroperoxides by Liquid Chromatography/Mass Spectrometry
by Chongsheng Liang, Siddabasave Gowda B. Gowda, Divyavani Gowda, Toshihiro Sakurai, Iku Sazaki, Hitoshi Chiba and Shu-Ping Hui
Antioxidants 2022, 11(2), 229; https://doi.org/10.3390/antiox11020229 - 25 Jan 2022
Cited by 3 | Viewed by 3701
Abstract
Lipid hydroperoxides (LOOH) are the initial products of the peroxidation of unsaturated lipids and play a crucial role in lipid oxidation due to their ability to decompose into free radicals and cause adverse effects on human health. Thus, LOOHs are commonly considered biomarkers [...] Read more.
Lipid hydroperoxides (LOOH) are the initial products of the peroxidation of unsaturated lipids and play a crucial role in lipid oxidation due to their ability to decompose into free radicals and cause adverse effects on human health. Thus, LOOHs are commonly considered biomarkers of oxidative stress-associated pathological conditions. Despite their importance, the sensitive and selective analytical method for determination is limited, due to their low abundance, poor stability, and low ionizing efficiency. To overcome these limitations, in this study, we chemically synthesized eight fatty acid hydroperoxides (FAOOH), including FA 18:1-OOH, FA 18:2-OOH, FA 18:3-OOH, FA 20:4-OOH, FA 20:5-OOH, FA 22:1-OOH, FA 22:6-OOH as analytes, and FA 19:1-OOH as internal standard. Then, they were chemically labeled with 2-methoxypropene (2-MxP) to obtain FAOOMxP by one-step derivatization (for 10 min). A selected reaction monitoring assisted targeted analytical method was developed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). The MxP-labelling improved the stability and enhanced the ionization efficiency in positive mode. Application of reverse-phase chromatography allowed coelution of analytes and internal standards with a short analysis time of 6 min. The limit of detection and quantification for FAOOH ranged from 0.1–1 pmol/µL and 1–2.5 pmol/µL, respectively. The method was applied to profile total FAOOHs in chemically oxidized human serum samples (n = 5) and their fractions of low and high-density lipoproteins (n = 4). The linoleic acid hydroperoxide (FA 18:2-OOH) and oleic acid hydroperoxide (FA 18:1-OOH) were the most abundant FAOOHs in human serum and lipoproteins. Overall, our validated LC-MS/MS methodology features enhanced detection and rapid separation that enables facile quantitation of multiple FAOOHs, therefore providing a valuable tool for determining the level of lipid peroxidation with potential diagnostic applications. Full article
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Review

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21 pages, 6753 KiB  
Review
Accelerated AGEing: The Impact of Advanced Glycation End Products on the Prognosis of Chronic Kidney Disease
by Elena Dozio, Lara Caldiroli, Paolo Molinari, Giuseppe Castellano, Nicholas Walter Delfrate, Massimiliano Marco Corsi Romanelli and Simone Vettoretti
Antioxidants 2023, 12(3), 584; https://doi.org/10.3390/antiox12030584 - 26 Feb 2023
Cited by 6 | Viewed by 2656
Abstract
Advanced glycation end products (AGEs) are aging products. In chronic kidney disease (CKD), AGEs accumulate due to the increased production, reduced excretion, and the imbalance between oxidant/antioxidant capacities. CKD is therefore a model of aging. The aim of this review is to summarize [...] Read more.
Advanced glycation end products (AGEs) are aging products. In chronic kidney disease (CKD), AGEs accumulate due to the increased production, reduced excretion, and the imbalance between oxidant/antioxidant capacities. CKD is therefore a model of aging. The aim of this review is to summarize the present knowledge of AGEs in CKD onset and progression, also focusing on CKD-related disorders (cardiovascular diseases, sarcopenia, and nutritional imbalance) and CKD mortality. The role of AGEs as etiopathogenetic molecules, as well as potential markers of disease progression and/or therapeutic targets, will be discussed. Full article
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14 pages, 2182 KiB  
Review
Post-Translational Modifications Evoked by Reactive Carbonyl Species in Ultraviolet-A-Exposed Skin: Implication in Fibroblast Senescence and Skin Photoaging
by Anne Negre-Salvayre and Robert Salvayre
Antioxidants 2022, 11(11), 2281; https://doi.org/10.3390/antiox11112281 - 18 Nov 2022
Cited by 4 | Viewed by 2194
Abstract
Photoaging is an accelerated form of aging resulting from skin exposure to ultraviolet (UV) radiation. UV-A radiation deeply penetrates the dermis and triggers the generation of reactive oxygen species (ROS) which promotes damage to DNA, lipids and proteins. Lipid peroxidation results from the [...] Read more.
Photoaging is an accelerated form of aging resulting from skin exposure to ultraviolet (UV) radiation. UV-A radiation deeply penetrates the dermis and triggers the generation of reactive oxygen species (ROS) which promotes damage to DNA, lipids and proteins. Lipid peroxidation results from the oxidative attack of polyunsaturated fatty acids which generate a huge amount of lipid peroxidation products, among them reactive carbonyl species (RCS) such as α, β-unsaturated hydroxyalkenals (e.g., 4-hydroxynonenal), acrolein or malondialdehyde. These highly reactive agents form adducts on free NH2 groups and thiol residues on amino acids in proteins and can also modify DNA and phospholipids. The accumulation of RCS-adducts leads to carbonyl stress characterized by progressive cellular and tissular dysfunction, inflammation and toxicity. RCS-adducts are formed in the dermis of skin exposed to UV-A radiation. Several RCS targets have been identified in the dermis, such as collagen and elastin in the extracellular matrix, whose modification could contribute to actinic elastosis lesions. RCS-adducts may play a role in fibroblast senescence via the modification of histones, and the sirtuin SIRT1, leading to an accumulation of acetylated proteins. The cytoskeleton protein vimentin is modified by RCS, which could impair fibroblast motility. A better identification of protein modification and carbonyl stress in the dermis may help to develop new treatment approaches for preventing photoaging. Full article
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22 pages, 3712 KiB  
Review
Mutual Regulation between Redox and Hypoxia-Inducible Factors in Cardiovascular and Renal Complications of Diabetes
by Carla Iacobini, Martina Vitale, Jonida Haxhi, Carlo Pesce, Giuseppe Pugliese and Stefano Menini
Antioxidants 2022, 11(11), 2183; https://doi.org/10.3390/antiox11112183 - 04 Nov 2022
Cited by 10 | Viewed by 2519
Abstract
Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and [...] Read more.
Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes. Full article
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18 pages, 1847 KiB  
Review
Antioxidative and Anti-Inflammatory Activity of Ascorbic Acid
by Agnieszka Gęgotek and Elżbieta Skrzydlewska
Antioxidants 2022, 11(10), 1993; https://doi.org/10.3390/antiox11101993 - 07 Oct 2022
Cited by 49 | Viewed by 7988
Abstract
Ascorbic acid, as a one of the basic exogenous vitamins, occurs in the body in the form of ascorbate, known for its strong antioxidant and anti-inflammatory properties. The presented review shows not only the importance of ascorbate as a free radical scavenger but [...] Read more.
Ascorbic acid, as a one of the basic exogenous vitamins, occurs in the body in the form of ascorbate, known for its strong antioxidant and anti-inflammatory properties. The presented review shows not only the importance of ascorbate as a free radical scavenger but also summarizes its antioxidant action based on other mechanisms, including the activation of intracellular antioxidant systems and its effect on the NFκB/TNFα pathway and apoptosis. Ascorbate interacts with small-molecule antioxidants, including tocopherol, glutathione, and thioredoxin; it can also stimulate biosynthesis and the activation of antioxidant enzymes, such as superoxide dismutase, catalase, or glutathione peroxidase. Moreover, ascorbate promotes the activity of transcription factors (Nrf2, Ref-1, AP-1), which enables the expression of genes encoding antioxidant proteins. Additionally, it supports the action of other exogenous antioxidants, mainly polyphenols. In this regard, both DNA, proteins, and lipids are protected against oxidation, leading to an inflammatory reaction and even cell death. Although ascorbate has strong antioxidant properties, it can also have pro-oxidant effects in the presence of free transition metals. However, its role in the prevention of DNA mutation, inflammation, and cell apoptosis, especially in relation to cancer cells, is controversial. Full article
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21 pages, 856 KiB  
Review
Extracellular Vesicles and Cancer Therapy: Insights into the Role of Oxidative Stress
by Jenni Ho, Luksana Chaiswing and Daret K. St. Clair
Antioxidants 2022, 11(6), 1194; https://doi.org/10.3390/antiox11061194 - 17 Jun 2022
Cited by 10 | Viewed by 2792
Abstract
Oxidative stress plays a significant role in cancer development and cancer therapy, and is a major contributor to normal tissue injury. The unique characteristics of extracellular vesicles (EVs) have made them potentially useful as a diagnostic tool in that their molecular content indicates [...] Read more.
Oxidative stress plays a significant role in cancer development and cancer therapy, and is a major contributor to normal tissue injury. The unique characteristics of extracellular vesicles (EVs) have made them potentially useful as a diagnostic tool in that their molecular content indicates their cell of origin and their lipid membrane protects the content from enzymatic degradation. In addition to their possible use as a diagnostic tool, their role in how normal and diseased cells communicate is of high research interest. The most exciting area is the association of EVs, oxidative stress, and pathogenesis of numerous diseases. However, the relationship between oxidative stress and oxidative modifications of EVs is still unclear, which limits full understanding of the clinical potential of EVs. Here, we discuss how EVs, oxidative stress, and cancer therapy relate to one another; how oxidative stress can contribute to the generation of EVs; and how EVs’ contents reveal the presence of oxidative stress. We also point out the potential promise and limitations of using oxidatively modified EVs as biomarkers of cancer and tissue injury with a focus on pediatric oncology patients. Full article
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