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Antioxidants and Second Messengers of Free Radicals

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A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (30 June 2018) | Viewed by 72653

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Prof. Dr. Neven Zarkovic

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Laboratory for Oxidative Stress (LabOS), Rudjer Boskovic Institute, Bijenička 54, HR-10000 Zagreb, Croatia
Interests: oxidative stress; growth regulation; cancer; lipid peroxidation; 4-hydroxynonenal (HNE)
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Dear Colleagues,

While research on pathology of oxidative stress has been complemented in recent years by intense studies on redox signaling, there is a lack of general understanding of pathophysiological roles played by reactive aldehydes like malondialdehyde, 4-hydroxynonenal, 4-hydroxyhexenal, acrolein, etc., which are considered also as “second messengers of free radicals”. Being generated mostly by lipid peroxidation, they often form bioactive adducts with macromolecules important for pathophysiology of living cells, thus mimicking the effects of ROS even in the absence of severe oxidative stress. We lack especially understanding on the complex effects of antioxidants that might be active in regulation of toxic and/or hormetic effects of reactive aldehydes.

Therefore, this Special Issue will publish original research papers and reviews on complex aspects of reactive aldehydes and their macromolecular adducts (especially with proteins and nucleic acids) generated during lipid peroxidation and their interference with natural and synthetic antioxidants in physiology of cell and in pathophysiology of various diseases studied by modern bioanalytical methods applied in translational and clinical medicine.

Prof. Dr. Neven Zarkovic
Guest Editor

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Keywords

Reactive aldehydes
Advanced lipoxidation end products (ALEs)
Lipid peroxidation
Stress and age-associated disorders
Metabolomics/lipidomics
Bioactive antioxidants

Published Papers (10 papers)

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Editorial

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4 pages, 147 KiB

Open AccessEditorial

Antioxidants and Second Messengers of Free Radicals

by Neven Zarkovic

Antioxidants 2018, 7(11), 158; https://doi.org/10.3390/antiox7110158 - 06 Nov 2018

Cited by 16 | Viewed by 2948

Abstract

In the recent years, numerous research on the pathology of oxidative stress has been completed by intense studies on redox signaling implementing various experimental models and clinical trials. [...] Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

Research

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14 pages, 1926 KiB

Open AccessArticle

Cell-Type-Specific Modulation of Hydrogen Peroxide Cytotoxicity and 4-Hydroxynonenal Binding to Human Cellular Proteins In Vitro by Antioxidant Aloe vera Extract

by Vera Cesar, Iva Jozić, Lidija Begović, Tea Vuković, Selma Mlinarić, Hrvoje Lepeduš, Suzana Borović Šunjić and Neven Žarković

Antioxidants 2018, 7(10), 125; https://doi.org/10.3390/antiox7100125 - 21 Sep 2018

Cited by 19 | Viewed by 4591

Abstract

Although Aloe vera contains numerous bioactive components, the activity principles of widely used A. vera extracts are uncertain. Therefore, we analyzed the effects of genuine A. vera aqueous extract (AV) on human cells with respect to the effects of hydrogen peroxide (H₂O₂) and 4-hydroxynonenal (HNE). Fully developed A. vera leaves were harvested and analyzed for vitamin C, carotenoids, total soluble phenolic content, and antioxidant capacity. Furthermore, human cervical cancer (HeLa), human microvascular endothelial cells (HMEC), human keratinocytes (HaCat), and human osteosarcoma (HOS) cell cultures were treated with AV extract for one hour after treatment with H₂O₂ or HNE. The cell number and viability were determined using Trypan Blue, and endogenous reactive oxygen species (ROS) production was determined by fluorescence, while intracellular HNE–protein adducts were measured for the first time ever by genuine cell-based HNE–His ELISA. The AV extract expressed strong antioxidant capacities (1.1 mmol of Trolox eq/g fresh weight) and cell-type-specific influence on the cytotoxicity of H₂O₂, as well as on endogenous production of ROS and HNE–protein adducts induced by HNE treatment, while AV itself did not induce production of ROS or HNE–protein adducts at all. This study, for the first time, revealed the importance of HNE for the activity principles of AV. Since HMEC cells were the most sensitive to AV, the effects of AV on microvascular endothelia could be of particular importance for the activity principles of Aloe vera extracts. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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23 pages, 7353 KiB

Open AccessArticle

Antioxidative 1,4-Dihydropyridine Derivatives Modulate Oxidative Stress and Growth of Human Osteoblast-Like Cells In Vitro

by Lidija Milkovic, Tea Vukovic, Neven Zarkovic, Franz Tatzber, Egils Bisenieks, Zenta Kalme, Imanta Bruvere, Zaiga Ogle, Janis Poikans, Astrida Velena and Gunars Duburs

Antioxidants 2018, 7(9), 123; https://doi.org/10.3390/antiox7090123 - 19 Sep 2018

Cited by 23 | Viewed by 4376

Abstract

Oxidative stress has been implicated in pathophysiology of different human stress- and age-associated disorders, including osteoporosis for which antioxidants could be considered as therapeutic remedies as was suggested recently. The 1,4-dihydropyridine (DHP) derivatives are known for their pleiotropic activity, with some also acting as antioxidants. To find compounds with potential antioxidative activity, a group of 27 structurally diverse DHPs, as well as one pyridine compound, were studied. A group of 11 DHPs with 10-fold higher antioxidative potential than of uric acid, were further tested in cell model of human osteoblast-like cells. Short-term combined effects of DHPs and 50 µM H₂O₂ (1-h each), revealed better antioxidative potential of DHPs if administered before a stressor. Indirect 24-h effect of DHPs was evaluated in cells further exposed to mild oxidative stress conditions induced either by H₂O₂ or tert-butyl hydroperoxide (both 50 µM). Cell growth (viability and proliferation), generation of ROS and intracellular glutathione concentration were evaluated. The promotion of cell growth was highly dependent on the concentrations of DHPs used, type of stressor applied and treatment set-up. Thiocarbatone III-1, E2-134-1 III-4, Carbatone II-1, AV-153 IV-1, and Diethone I could be considered as therapeutic agents for osteoporosis although further research is needed to elucidate their bioactivity mechanisms, in particular in respect to signaling pathways involving 4-hydroxynoneal and related second messengers of free radicals. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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18 pages, 3797 KiB

Open AccessArticle

Unbiased Identification of Proteins Covalently Modified by Complex Mixtures of Peroxidized Lipids Using a Combination of Electrophoretic Mobility Band Shift with Mass Spectrometry

by Bernd Gesslbauer, David Kuerzl, Niko Valpatic and Valery N. Bochkov

Antioxidants 2018, 7(9), 116; https://doi.org/10.3390/antiox7090116 - 30 Aug 2018

Cited by 10 | Viewed by 4080

Abstract

Covalent modification of functionally important cell proteins by lipid oxidation products (LOPs) is a known mechanism initiating pathological consequences of oxidative stress. Identification of new proteins covalently modified by electrophilic lipids can be performed by a combination of chemical, immunological, and mass spectrometry-based methods, but requires prior knowledge either on the exact molecular structure of LOPs (e.g., 4-hydroxynonenal) or candidate protein targets. However, under the conditions of oxidative stress in vivo, a complex mixture of proteins (e.g., cytosolic proteome) reacts with a complex mixture of LOPs. Here we describe a method for detection of lipid-modified proteins that does not require an a priori knowledge on the chemical structure of LOPs or identity of target proteins. The method is based on the change of electrophoretic mobility of lipid-modified proteins, which is induced by conformational changes and cross-linking with other proteins. Abnormally migrating proteins are detected by mass spectrometry-based protein peptide sequencing. We applied this method to study effects of oxidized palmitoyl-arachidonoyl-phosphatidylcholine (OxPAPC) on endothelial cells. Several known, but also many new, OxPAPC-binding proteins were identified. We expect that this technically relatively simple method can be widely applied for label-free analysis of lipid-protein interactions in complex protein samples treated with different LOPs. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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21 pages, 2509 KiB

Open AccessArticle

The Effect of Sea Buckthorn (Hippophae rhamnoides L.) Seed Oil on UV-Induced Changes in Lipid Metabolism of Human Skin Cells

by Agnieszka Gęgotek, Anna Jastrząb, Iwona Jarocka-Karpowicz, Marta Muszyńska and Elżbieta Skrzydlewska

Antioxidants 2018, 7(9), 110; https://doi.org/10.3390/antiox7090110 - 23 Aug 2018

Cited by 44 | Viewed by 7799

Abstract

Lipids and proteins of skin cells are the most exposed to harmful ultraviolet (UV) radiation contained in sunlight. There is a growing need for natural compounds that will protect these sensitive molecules from damage, without harmful side effects. The aim of this study was to investigate the effect of sea buckthorn seed oil on the redox balance and lipid metabolism in UV irradiated cells formed different skin layers to examine whether it had a protective effect. Human keratinocytes and fibroblasts were subjected to UVA (ultraviolet type A; 30 J/cm² and 20 J/cm²) or UVB (ultraviolet type B; 60 mJ/cm² and 200 mJ/cm², respectively) radiation and treated with sea buckthorn seed oil (500 ng/mL), and the redox activity was estimated by reactive oxygen species (ROS) generation and enzymatic/non-enzymatic antioxidants activity/level (using electron spin resonance (ESR), high-performance liquid chromatography (HPLC), and spectrophotometry). Lipid metabolism was measured by the level of fatty acids, lipid peroxidation products, endocannabinoids and phospholipase A2 activity (GC/MS (gas chromatography/mass spectrometry), LC/MS (liquid chromatography/mass spectrometry), and spectrophotometry). Also, transcription factor Nrf2 (nuclear erythroid 2-related factor) and its activators/inhibitors, peroxisome proliferator-activated receptors (PPAR) and cannabinoid receptor levels were measured (Western blot). Sea buckthorn oil partially prevents UV-induced ROS generation and enhances the level of non-enzymatic antioxidants such as glutathione (GSH), thioredoxin (Trx) and vitamins E and A. Moreover, it stimulates the activity of Nrf2 leading to enhanced antioxidant enzyme activity. As a result, decreases in lipid peroxidation products (4-hydroxynonenal, 8-isoprostaglandin) and increases in the endocannabinoid receptor levels were observed. Moreover, sea buckthorn oil treatment enhanced the level of phospholipid and free fatty acids, while simultaneously decreasing the cannabinoid receptor expression in UV irradiated keratinocytes and fibroblasts. The main differences in sea buckthorn oil on various skin cell types was observed in the case of PPARs—in keratinocytes following UV radiation PPAR expression was decreased by sea buckthorn oil treatment, while in fibroblasts the reverse effect was observed, indicating an anti-inflammatory effect. With these results, sea buckthorn seed oil exhibited prevention of UV-induced disturbances in redox balance as well as lipid metabolism in skin fibroblasts and keratinocytes, which indicates it is a promising natural compound in skin photo-protection. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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Review

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15 pages, 932 KiB

Open AccessReview

Oxidative Stress in the Male Germline: A Review of Novel Strategies to Reduce 4-Hydroxynonenal Production

by Jessica L. H. Walters, Geoffry N. De Iuliis, Brett Nixon and Elizabeth G. Bromfield

Antioxidants 2018, 7(10), 132; https://doi.org/10.3390/antiox7100132 - 03 Oct 2018

Cited by 36 | Viewed by 7250

Abstract

Germline oxidative stress is intimately linked to several reproductive pathologies including a failure of sperm-egg recognition. The lipid aldehyde 4-hydroxynonenal (4HNE) is particularly damaging to the process of sperm-egg recognition as it compromises the function and the stability of several germline proteins. Considering mature spermatozoa do not have the capacity for de novo protein translation, 4HNE modification of proteins in the mature gametes has uniquely severe consequences for protein homeostasis, cell function and cell survival. In somatic cells, 4HNE overproduction has been attributed to the action of lipoxygenase enzymes that facilitate the oxygenation and degradation of ω-6 polyunsaturated fatty acids (PUFAs). Accordingly, the arachidonate 15-lipoxygenase (ALOX15) enzyme has been intrinsically linked with 4HNE production, and resultant pathophysiology in various complex conditions such as coronary artery disease and multiple sclerosis. While ALOX15 has not been well characterized in germ cells, we postulate that ALOX15 inhibition may pose a new strategy to prevent 4HNE-induced protein modifications in the male germline. In this light, this review focuses on (i) 4HNE-induced protein damage in the male germline and its implications for fertility; and (ii) new methods for the prevention of lipid peroxidation in germ cells. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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14 pages, 895 KiB

Open AccessReview

4-Hydroxynonenal in Redox Homeostasis of Gastrointestinal Mucosa: Implications for the Stomach in Health and Diseases

by Andriy Cherkas and Neven Zarkovic

Antioxidants 2018, 7(9), 118; https://doi.org/10.3390/antiox7090118 - 03 Sep 2018

Cited by 15 | Viewed by 4443

Abstract

Maintenance of integrity and function of the gastric mucosa (GM) requires a high regeneration rate of epithelial cells during the whole life span. The health of the gastric epithelium highly depends on redox homeostasis, antioxidant defense, and activity of detoxifying systems within the cells, as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular, second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in physiological adaptive reactions and signaling, but they are also thought to be implicated in the pathogenesis of numerous gastric diseases. Molecular mechanisms and consequences of increased production of HNE, and its protein adducts, in response to stressors during acute and chronic gastric injury, are well studied. However, several important issues related to the role of HNE in gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, or the relevance of antioxidants for HNE-related redox homeostasis in GM, still need more studies and new comprehensive approaches. In this regard, preclinical studies and clinical intervention trials are required, which should also include the use of state-of-the-art analytical techniques, such as HNE determination by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), as well as modern mass-spectroscopy methods. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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11 pages, 471 KiB

Open AccessReview

Evening Primrose (Oenothera biennis) Biological Activity Dependent on Chemical Composition

by Magdalena Timoszuk, Katarzyna Bielawska and Elżbieta Skrzydlewska

Antioxidants 2018, 7(8), 108; https://doi.org/10.3390/antiox7080108 - 14 Aug 2018

Cited by 82 | Viewed by 16641

Abstract

Evening primrose (Oenothera L.) is a plant belonging to the family Onagraceae, in which the most numerous species is Oenothera biennis. Some plants belonging to the genus Oenothera L. are characterized by biological activity. Therefore, studies were conducted to determine the dependence of biological activity on the chemical composition of various parts of the evening primrose, mainly leaves, stems, and seeds. Common components of all parts of the Oenothera biennis plants are fatty acids, phenolic acids, and flavonoids. In contrast, primrose seeds also contain proteins, carbohydrates, minerals, and vitamins. Therefore, it is believed that the most interesting sources of biologically active compounds are the seeds and, above all, evening primrose seed oil. This oil contains mainly aliphatic alcohols, fatty acids, sterols, and polyphenols. Evening primrose oil (EPO) is extremely high in linoleic acid (LA) (70–74%) and γ-linolenic acid (GLA) (8–10%), which may contribute to the proper functioning of human tissues because they are precursors of anti-inflammatory eicosanoids. EPO supplementation results in an increase in plasma levels of γ-linolenic acid and its metabolite dihomo-γ-linolenic acid (DGLA). This compound is oxidized by lipoxygenase (15-LOX) to 15-hydroxyeicosatrienoic acid (15-HETrE) or, under the influence of cyclooxygenase (COX), DGLA is metabolized to series 1 prostaglandins. These compounds have anti-inflammatory and anti-proliferative properties. Furthermore, 15-HETrE blocks the conversion of arachidonic acid (AA) to leukotriene A₄ (LTA₄) by direct inhibition of 5-LOX. In addition, γ-linolenic acid suppresses inflammation mediators such as interleukin 1β (IL-1β), interleukin 6 (IL-6), and cytokine - tumor necrosis factor α (TNF-α). The beneficial effects of EPO have been demonstrated in the case of atopic dermatitis, psoriasis, Sjögren’s syndrome, asthma, and anti-cancer therapy. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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17 pages, 1258 KiB

Open AccessReview

Lipid Peroxidation-Derived Aldehydes, 4-Hydroxynonenal and Malondialdehyde in Aging-Related Disorders

by Giuseppina Barrera, Stefania Pizzimenti, Martina Daga, Chiara Dianzani, Alessia Arcaro, Giovanni Paolo Cetrangolo, Giulio Giordano, Marie Angele Cucci, Maria Graf and Fabrizio Gentile

Antioxidants 2018, 7(8), 102; https://doi.org/10.3390/antiox7080102 - 30 Jul 2018

Cited by 162 | Viewed by 11007

Abstract

Among the various mechanisms involved in aging, it was proposed long ago that a prominent role is played by oxidative stress. A major way by which the latter can provoke structural damage to biological macromolecules, such as DNA, lipids, and proteins, is by fueling the peroxidation of membrane lipids, leading to the production of several reactive aldehydes. Lipid peroxidation-derived aldehydes can not only modify biological macromolecules, by forming covalent electrophilic addition products with them, but also act as second messengers of oxidative stress, having relatively extended lifespans. Their effects might be further enhanced with aging, as their concentrations in cells and biological fluids increase with age. Since the involvement and the role of lipid peroxidation-derived aldehydes, particularly of 4-hydroxynonenal (HNE), in neurodegenerations, inflammation, and cancer, has been discussed in several excellent recent reviews, in the present one we focus on the involvement of reactive aldehydes in other age-related disorders: osteopenia, sarcopenia, immunosenescence and myelodysplastic syndromes. In these aging-related disorders, characterized by increases of oxidative stress, both HNE and malondialdehyde (MDA) play important pathogenic roles. These aldehydes, and HNE in particular, can form adducts with circulating or cellular proteins of critical functional importance, such as the proteins involved in apoptosis in muscle cells, thus leading to their functional decay and acceleration of their molecular turnover and functionality. We suggest that a major fraction of the toxic effects observed in age-related disorders could depend on the formation of aldehyde-protein adducts. New redox proteomic approaches, pinpointing the modifications of distinct cell proteins by the aldehydes generated in the course of oxidative stress, should be extended to these age-associated disorders, to pave the way to targeted therapeutic strategies, aiming to alleviate the burden of morbidity and mortality associated with these disturbances. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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44 pages, 2684 KiB

Open AccessReview

Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues

by Cristina Anna Gallelli, Silvio Calcagnini, Adele Romano, Justyna Barbara Koczwara, Marialuisa De Ceglia, Donatella Dante, Rosanna Villani, Anna Maria Giudetti, Tommaso Cassano and Silvana Gaetani

Antioxidants 2018, 7(7), 93; https://doi.org/10.3390/antiox7070093 - 18 Jul 2018

Cited by 73 | Viewed by 8618

Abstract

Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts. Full article

(This article belongs to the Special Issue Antioxidants and Second Messengers of Free Radicals)

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