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Antioxidants
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Protein Oxidative Modification in Brain function, Brain Ageing and Neurological...
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Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 17271

Special Issue Editors

Dr. Mattéa J. Finelli

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Guest Editor
Biodiscovery Institute, University Park, Nottingham NG7 2RD, UK
Interests: neurodegenerative disease; oxidative stress; nitrosative stress; proteomics; metabolomics; stem cell-derived cellular models; neurosciences
Special Issues, Collections and Topics in MDPI journals
Dr. Andreia N. Carvalho

E-Mail Website
Guest Editor
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
Interests: mitochondria; mitochondrial dysfunction; oxidative stress; neurodegenerative disease; neurosciences
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Reactive oxygen and nitrogen species (RONS) are molecules produced by the cellular energy metabolism, which drive the oxidoreduction (redox)-mediated signalling of the cells. Redox signalling plays an important role in the homeostatic control of several molecular pathways and in cell function, particularly changes in the redox status of Cysteine and other amino acid residues of proteins, which are extremely susceptible to reversible and irreversible oxidation by RONS. These changes can lead to redox-post-translational modifications (redox-PTMs) in proteins, which can directly affect protein structure, activity and function, ultimately impacting a multitude of biological functions.

Mitochondrial dysfunction and excessive RONS levels can give rise to oxidative and nitrosative stresses, and aberrant redox-PTMs (i.e., redox PTMs on lowly-reactive residues, and/or the addition of excessiveor irreversible redox-PTMs that may have oxidative damaging effects on proteins). Oxidative and nitrosative stresses and aberrant redox-PTMs are well-established contributors to a plethora of diseases, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and motor neuron diseases; however, the underlying mechanisms are not fully understood.

In this Special Issue, we invite original research articles and review articles related to the roles of the redox-PTMs-mediated signalling in modulating protein structure and activity, and brain function in health, ageing and neurological conditions.

We welcome studies exploring the mechanisms underlying the redox signalling mediated by redox-PTMs in the brain, as well as the therapeutic potential of modulating redox signalling and/or redox-PTMs in cells to treat neurological diseases (e.g., using small molecules or compounds). Manuscripts presenting new methods to study redox signalling mediated by redox-PTMs at the cellular and/or molecular levels (e.g., proteomics, RONS probes, etc) will also be considered.

This Special Issue aims to provide an overview of the field of redox biology and highlight the latest developments in the field, with a particular focus on redox signalling mediated by redox-PTMs of proteins and its role in the mammalian nervous system.

Dr. Mattéa J. Finelli
Dr. Andreia N. Carvalho
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein oxidative modifications
  • post-translational modifications
  • S-glutathionylation
  • S-nitrosylation/S-nitrosation
  • persulfidation
  • redox signalling
  • oxidative and nitrosative stresses
  • cysteine oxidation
  • antioxidants
  • redox-based pharmacological/therapeutic approaches
  • mitochondrial dysfunction
  • mitochondria-targeted molecules
  • brain function and ageing
  • neurological/neurodegenerative diseases
  • proteomics

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Published Papers (8 papers)

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Research

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17 pages, 4061 KiB  
Article
Valproic Acid Causes Redox-Regulated Post-Translational Protein Modifications That Are Dependent upon P19 Cellular Differentiation States
by Ted B. Piorczynski, Jouber Calixto, Haley C. Henry, Kelli England, Susannah Cowley, Jackson M. Hansen, Jonathon T. Hill and Jason M. Hansen
Antioxidants 2024, 13(5), 560; https://doi.org/10.3390/antiox13050560 - 1 May 2024
Viewed by 1761
Abstract
Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often [...] Read more.
Valproic acid (VPA) is a common anti-epileptic drug and known neurodevelopmental toxicant. Although the exact mechanism of VPA toxicity remains unknown, recent findings show that VPA disrupts redox signaling in undifferentiated cells but has little effect on fully differentiated neurons. Redox imbalances often alter oxidative post-translational protein modifications and could affect embryogenesis if developmentally critical proteins are targeted. We hypothesize that VPA causes redox-sensitive post-translational protein modifications that are dependent upon cellular differentiation states. Undifferentiated P19 cells and P19-derived neurons were treated with VPA alone or pretreated with D3T, an inducer of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway, prior to VPA exposure. Undifferentiated cells treated with VPA alone exhibited an oxidized glutathione redox couple and increased overall protein oxidation, whereas differentiated neurons were protected from protein oxidation via increased S-glutathionylation. Pretreatment with D3T prevented the effects of VPA exposure in undifferentiated cells. Taken together, our findings support redox-sensitive post-translational protein alterations in undifferentiated cells as a mechanism of VPA-induced developmental toxicity and propose NRF2 activation as a means to preserve proper neurogenesis. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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20 pages, 3877 KiB  
Article
Influence of Redox and Dopamine Regulation in Cocaine-Induced Phenotypes Using Drosophila
by Ana Filošević Vujnović, Marko Rubinić, Ivona Starčević and Rozi Andretić Waldowski
Antioxidants 2023, 12(4), 933; https://doi.org/10.3390/antiox12040933 - 14 Apr 2023
Cited by 3 | Viewed by 2358
Abstract
Reactive Oxidative Species (ROS) are produced during cellular metabolism and their amount is finely regulated because of negative consequences that ROS accumulation has on cellular functioning and survival. However, ROS play an important role in maintaining a healthy brain by participating in cellular [...] Read more.
Reactive Oxidative Species (ROS) are produced during cellular metabolism and their amount is finely regulated because of negative consequences that ROS accumulation has on cellular functioning and survival. However, ROS play an important role in maintaining a healthy brain by participating in cellular signaling and regulating neuronal plasticity, which led to a shift in our understanding of ROS from being solely detrimental to having a more complex role in the brain. Here we use Drosophila melanogaster to investigate the influence of ROS on behavioral phenotypes induced by single or double exposure to volatilized cocaine (vCOC), sensitivity and locomotor sensitization (LS). Sensitivity and LS depend on glutathione antioxidant defense. Catalase activity and hydrogen peroxide (H2O2) accumulation play a minor role, but their presence is necessary in dopaminergic and serotonergic neurons for LS. Feeding flies the antioxidant quercetin completely abolishes LS confirming the permissive role of H2O2 in the development of LS. This can only partially be rescued by co-feeding H2O2 or the dopamine precursor 3,4-dihydroxy-L-phenylalanine (L-DA) showing coordinate and similar contribution of dopamine and H2O2. Genetic versatility of Drosophila can be used as a tool for more precise dissection of temporal, spatial and transcriptional events that regulate behaviors induced by vCOC. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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Review

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27 pages, 1149 KiB  
Review
Oxidative Cysteine Post Translational Modifications Drive the Redox Code Underlying Neurodegeneration and Amyotrophic Lateral Sclerosis
by Anna Percio, Michela Cicchinelli, Domiziana Masci, Mariagrazia Summo, Andrea Urbani and Viviana Greco
Antioxidants 2024, 13(8), 883; https://doi.org/10.3390/antiox13080883 - 23 Jul 2024
Viewed by 1391
Abstract
Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the “redoxome” encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for [...] Read more.
Redox dysregulation, an imbalance between oxidants and antioxidants, is crucial in the pathogenesis of various neurodegenerative diseases. Within this context, the “redoxome” encompasses the network of redox molecules collaborating to maintain cellular redox balance and signaling. Among these, cysteine-sensitive proteins are fundamental for this homeostasis. Due to their reactive thiol groups, cysteine (Cys) residues are particularly susceptible to oxidative post-translational modifications (PTMs) induced by free radicals (reactive oxygen, nitrogen, and sulfur species) which profoundly affect protein functions. Cys-PTMs, forming what is referred to as “cysteinet” in the redox proteome, are essential for redox signaling in both physiological and pathological conditions, including neurodegeneration. Such modifications significantly influence protein misfolding and aggregation, key hallmarks of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and notably, amyotrophic lateral sclerosis (ALS). This review aims to explore the complex landscape of cysteine PTMs in the cellular redox environment, elucidating their impact on neurodegeneration at protein level. By investigating specific cysteine-sensitive proteins and the regulatory networks involved, particular emphasis is placed on the link between redox dysregulation and ALS, highlighting this pathology as a prime example of a neurodegenerative disease wherein such redox dysregulation is a distinct hallmark. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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33 pages, 2151 KiB  
Review
Protein Oxidative Modifications in Neurodegenerative Diseases: From Advances in Detection and Modelling to Their Use as Disease Biomarkers
by Sandra I. Anjo, Zhicheng He, Zohaib Hussain, Aruba Farooq, Alan McIntyre, Charles A. Laughton, Andreia Neves Carvalho and Mattéa J. Finelli
Antioxidants 2024, 13(6), 681; https://doi.org/10.3390/antiox13060681 - 31 May 2024
Cited by 2 | Viewed by 1348
Abstract
Oxidation–reduction post-translational modifications (redox-PTMs) are chemical alterations to amino acids of proteins. Redox-PTMs participate in the regulation of protein conformation, localization and function, acting as signalling effectors that impact many essential biochemical processes in the cells. Crucially, the dysregulation of redox-PTMs of proteins [...] Read more.
Oxidation–reduction post-translational modifications (redox-PTMs) are chemical alterations to amino acids of proteins. Redox-PTMs participate in the regulation of protein conformation, localization and function, acting as signalling effectors that impact many essential biochemical processes in the cells. Crucially, the dysregulation of redox-PTMs of proteins has been implicated in the pathophysiology of numerous human diseases, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This review aims to highlight the current gaps in knowledge in the field of redox-PTMs biology and to explore new methodological advances in proteomics and computational modelling that will pave the way for a better understanding of the role and therapeutic potential of redox-PTMs of proteins in neurodegenerative diseases. Here, we summarize the main types of redox-PTMs of proteins while providing examples of their occurrence in neurodegenerative diseases and an overview of the state-of-the-art methods used for their detection. We explore the potential of novel computational modelling approaches as essential tools to obtain insights into the precise role of redox-PTMs in regulating protein structure and function. We also discuss the complex crosstalk between various PTMs that occur in living cells. Finally, we argue that redox-PTMs of proteins could be used in the future as diagnosis and prognosis biomarkers for neurodegenerative diseases. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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24 pages, 886 KiB  
Review
Protein Oxidation in Aging and Alzheimer’s Disease Brain
by Rukhsana Sultana and D. Allan Butterfield
Antioxidants 2024, 13(5), 574; https://doi.org/10.3390/antiox13050574 - 7 May 2024
Cited by 4 | Viewed by 1747
Abstract
Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen [...] Read more.
Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate metabolism, synaptic transmission, cellular energetics, etc., of both MCI and AD brains compared to the controls. Some proteins were found to be common targets of oxidation and were observed during the early stages of AD, suggesting that those changes might be critical in the onset of symptoms and/or formation of the pathological hallmarks of AD. Further studies are required to fully elucidate the role of protein oxidation and nitration in the progression and pathogenesis of AD. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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36 pages, 5451 KiB  
Review
A Combinational Therapy for Preventing and Delaying the Onset of Alzheimer’s Disease: A Focus on Probiotic and Vitamin Co-Supplementation
by Omme Fatema Sultana, Raksa Andalib Hia and P. Hemachandra Reddy
Antioxidants 2024, 13(2), 202; https://doi.org/10.3390/antiox13020202 - 5 Feb 2024
Cited by 9 | Viewed by 3254
Abstract
Alzheimer’s disease is a progressive neurodegenerative disorder with a complex etiology, and effective interventions to prevent or delay its onset remain a global health challenge. In recent years, there has been growing interest in the potential role of probiotic and vitamin supplementation as [...] Read more.
Alzheimer’s disease is a progressive neurodegenerative disorder with a complex etiology, and effective interventions to prevent or delay its onset remain a global health challenge. In recent years, there has been growing interest in the potential role of probiotic and vitamin supplementation as complementary strategies for Alzheimer’s disease prevention. This review paper explores the current scientific literature on the use of probiotics and vitamins, particularly vitamin A, D, E, K, and B-complex vitamins, in the context of Alzheimer’s disease prevention and management. We delve into the mechanisms through which probiotics may modulate gut–brain interactions and neuroinflammation while vitamins play crucial roles in neuronal health and cognitive function. The paper also examines the collective impact of this combinational therapy on reducing the risk factors associated with Alzheimer’s disease, such as oxidative stress, inflammation, and gut dysbiosis. By providing a comprehensive overview of the existing evidence and potential mechanisms, this review aims to shed light on the promise of probiotic and vitamin co-supplementation as a multifaceted approach to combat Alzheimer’s disease, offering insights into possible avenues for future research and clinical application. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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15 pages, 1809 KiB  
Review
Regulation of Ras Signaling by S-Nitrosylation
by Sónia Simão, Rafaela Ribeiro Agostinho, Antonio Martínez-Ruiz and Inês Maria Araújo
Antioxidants 2023, 12(8), 1562; https://doi.org/10.3390/antiox12081562 - 4 Aug 2023
Cited by 4 | Viewed by 1879
Abstract
Ras are a family of small GTPases that function as signal transduction mediators and are involved in cell proliferation, migration, differentiation and survival. The significance of Ras is further evidenced by the fact that Ras genes are among the most mutated oncogenes in [...] Read more.
Ras are a family of small GTPases that function as signal transduction mediators and are involved in cell proliferation, migration, differentiation and survival. The significance of Ras is further evidenced by the fact that Ras genes are among the most mutated oncogenes in different types of cancers. After translation, Ras proteins can be targets of post-translational modifications (PTM), which can alter the intracellular dynamics of the protein. In this review, we will focus on how S-nitrosylation of Ras affects the way these proteins interact with membranes, its cellular localization, and its activity. S-Nitrosylation occurs when a nitrosyl moiety of nitric oxide (NO) is covalently attached to a thiol group of a cysteine residue in a target protein. In Ras, the conserved Cys118 is the most surface-exposed Cys and the preferable residue for NO action, leading to the initiation of transduction events. Ras transduces the mitogen-activated protein kinases (MAPK), the phosphoinositide-3 kinase (PI3K) and the RalGEF cellular pathways. S-Nitrosylation of elements of the RalGEF cascade remains to be identified. On the contrary, it is well established that several components of the MAPK and PI3K pathways, as well as different proteins associated with these cascades, can be modified by S-nitrosylation. Overall, this review presents a better understanding of Ras S-nitrosylation, increasing the knowledge on the dynamics of these proteins in the presence of NO and the underlying implications in cellular signaling. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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16 pages, 1023 KiB  
Review
Oxidative Stress in Obstructive Sleep Apnea Syndrome: Putative Pathways to Hearing System Impairment
by Pierluigi Mastino, Davide Rosati, Giulia de Soccio, Martina Romeo, Daniele Pentangelo, Stefano Venarubea, Marco Fiore, Piero Giuseppe Meliante, Carla Petrella, Christian Barbato and Antonio Minni
Antioxidants 2023, 12(7), 1430; https://doi.org/10.3390/antiox12071430 - 15 Jul 2023
Cited by 6 | Viewed by 2328
Abstract
Introduction: OSAS is a disease that affects 2% of men and 4% of women of middle age. It is a major health public problem because untreated OSAS could lead to cardiovascular, metabolic, and cerebrovascular complications. The more accepted theory relates to oxidative stress [...] Read more.
Introduction: OSAS is a disease that affects 2% of men and 4% of women of middle age. It is a major health public problem because untreated OSAS could lead to cardiovascular, metabolic, and cerebrovascular complications. The more accepted theory relates to oxidative stress due to intermittent hypoxia, which leads, after an intense inflammatory response through multiple pathways, to endothelial damage. The objective of this study is to demonstrate a correlation between OSAS and hearing loss, the effect of the CPAP on hearing function, and if oxidative stress is also involved in the damaging of the hearing system. Methods: A review of the literature has been executed. Eight articles have been found, where seven were about the correlation between OSAS and the hearing system, and only one was about the CPAP effects. It is noted that two of the eight articles explored the theory of oxidative stress due to intermittent hypoxia. Results: All studies showed a significant correlation between OSAS and hearing function (p < 0.05).Conclusions: Untreated OSAS affects the hearing system at multiple levels. Oxidative stress due to intermittent hypoxia is the main pathogenetic mechanism of damage. CPAP has no effects (positive or negative) on hearing function. More studies are needed, with the evaluation of extended high frequencies, the execution of vocal audiometry in noisy environments, and the evaluation of potential biomarkers due to oxidative stress. Full article
(This article belongs to the Special Issue Protein Oxidative Modification in Brain function, Brain Ageing and Neurological Diseases)
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