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Oxidative Stress Impact on Protein Synthesis and Protein Degradation Systems in Health and Disease

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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 (15 October 2022) | Viewed by 15508

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Special Issue Editors

Dr. Eftekhar Eftekharpour

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Guest Editor

Department of Physiology and Pathophysiology, Regenerative Medicine Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
Interests: neurodegeneration; oxidative stress; lysosomal autophagy; thioredoxin; laminopathy
Special Issues, Collections and Topics in MDPI journals

Dr. Susan Logue

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Guest Editor

1. Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
2. Research Institute in Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
Interests: cancer biology; cell signalling; endoplasmic reticulum; cellular stress; inflammation; unfolded protein response

Special Issue Information

Dear Colleagues,

Over the past three decades, the role of reactive oxygen/nitrogen species (RO/NS) in cellular signalling has emerged. We now appreciate that RO/NS facilitates rapid and transient alterations of cellular proteins, instigating downstream changes in cell signalling pathways and, ultimately, cellular function. Perturbations in RO/NS regulation, a conditioned referred to as oxidative stress, is both recognised as a driver of cell death and as an emerging contributor to the pathophysiology of many diseases. Therefore, understanding the mechanisms which promote and those that prevent damage initiated by oxidative stress is an important question in biomedical research. Cellular antioxidants, including enzymatic and non-enzymatic systems, are considered the main defence against RO/NS mediated damage. However, we are now beginning to appreciate that stress response pathways such as the unfolded protein response (UPR), ubiquitin protease system (UPS), and lysosomal autophagy help to protect cells from the consequences of oxidative stress. Attempts to regulate such systems can be the remedy for improving human life.

This Special Issue, comprised of primary research and review articles, will focus on oxidative stress and its interaction with protein synthesis and degradation systems in mammalian systems. Contributions focused on understanding the interplay between oxidative stress, cell stress responses and cell death in cancer, ageing and chronic diseases such as neurodegenerative or diabetes will be especially welcomed. As are those focused on harnessing stress response pathways as therapeutic approaches to limit damage initiated by oxidative stress.

Dr. Eftekhar Eftekharpour
Dr. Susan Logue
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

endoplasmic reticulum
lysosome integrity
unfolded protein response
mitophagy
autophagy
oxytosis
ferroptosis
apoptosis
cell stress
cancer

Published Papers (5 papers)

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Research

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29 pages, 10591 KiB

Open AccessArticle

Evolutionary Conserved Short Linear Motifs Provide Insights into the Cellular Response to Stress

by Sergey P. Zavadskiy, Denis S. Gruzdov, Susanna S. Sologova, Alexander A. Terentiev and Nurbubu T. Moldogazieva

Antioxidants 2023, 12(1), 96; https://doi.org/10.3390/antiox12010096 - 30 Dec 2022

Viewed by 2530

Abstract

Short linear motifs (SLiMs) are evolutionarily conserved functional modules of proteins composed of 3 to 10 residues and involved in multiple cellular functions. Here, we performed a search for SLiMs that exert sequence similarity to two segments of alpha-fetoprotein (AFP), a major mammalian embryonic and cancer-associated protein. Biological activities of the peptides, LDSYQCT (AFP_14–20) and EMTPVNPGV (GIP-9), have been previously confirmed under in vitro and in vivo conditions. In our study, we retrieved a vast array of proteins that contain SLiMs of interest from both prokaryotic and eukaryotic species, including viruses, bacteria, archaea, invertebrates, and vertebrates. Comprehensive Gene Ontology enrichment analysis showed that proteins from multiple functional classes, including enzymes, transcription factors, as well as those involved in signaling, cell cycle, and quality control, and ribosomal proteins were implicated in cellular adaptation to environmental stress conditions. These include response to oxidative and metabolic stress, hypoxia, DNA and RNA damage, protein degradation, as well as antimicrobial, antiviral, and immune response. Thus, our data enabled insights into the common functions of SLiMs evolutionary conserved across all taxonomic categories. These SLiMs can serve as important players in cellular adaptation to stress, which is crucial for cell functioning. Full article

(This article belongs to the Special Issue Oxidative Stress Impact on Protein Synthesis and Protein Degradation Systems in Health and Disease)

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24 pages, 12370 KiB

Open AccessArticle

Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

by Phuong Linh Nguyen, Chang Hoon Lee, Heesoon Lee and Jungsook Cho

Antioxidants 2022, 11(1), 117; https://doi.org/10.3390/antiox11010117 - 5 Jan 2022

Cited by 10 | Viewed by 3069

Abstract

Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy. Full article

(This article belongs to the Special Issue Oxidative Stress Impact on Protein Synthesis and Protein Degradation Systems in Health and Disease)

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14 pages, 1022 KiB

Open AccessArticle

Endoplasmic Reticulum Stress Promotes iNOS/NO and Influences Inflammation in the Development of Doxorubicin-Induced Cardiomyopathy

by Ashim K. Bagchi, Akshi Malik, Gauri Akolkar, Davinder S. Jassal and Pawan K. Singal

Antioxidants 2021, 10(12), 1897; https://doi.org/10.3390/antiox10121897 - 26 Nov 2021

Cited by 14 | Viewed by 2552

Abstract

Doxorubicin (Dox) is known to cause heart failure in some cancer patients. Despite extensive studies over the past half century, the subcellular basis of Dox-induced cardiomyopathy (DIC) is still elusive. Earlier, we suggested that Dox causes a delayed activation of unfolded protein response (UPR) which may promote mitochondrial Bax activity leading to cardiomyocyte death. As a follow up, using NO donor, S-Nitroso-N-acetyl-d,l-penicillamine (SNAP), and/or NOS inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), we now show that endoplasmic reticulum (ER) stress promotes inflammation through iNOS/NO-induced TLR2 activation. In vivo Dox treatment increased mitochondrial iNOS to promote ER stress as there was an increase in Bip (Grp78) response, proapoptotic CHOP (DDIT3) and ER-mediated Caspase 12 activation. Increased iNOS activity is associated with an increase in TLR2 and TNF-α receptor associated factor 2 (TRAF2). These two together with NF-κB p105/50 expression and a synergistic support through ER stress, promote inflammatory response in the myocardium leading to cell death and ultimately fostering DIC conditions. In the presence of NOS inhibitor, such detrimental effects of Dox were inhibited, suggesting iNOS/NO as key mediators of Dox-induced inflammatory as well as apoptotic responses. Full article

(This article belongs to the Special Issue Oxidative Stress Impact on Protein Synthesis and Protein Degradation Systems in Health and Disease)

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10 pages, 5103 KiB

Open AccessArticle

Alpha-Ketoglutarate: A Potential Inner Mitochondrial and Cytosolic Protector against Peroxynitrite and Peroxynitrite-Induced Nitration?

by Joachim Greilberger, Michaela Greilberger, Reinhold Wintersteiger, Klaus Zangger and Ralf Herwig

Antioxidants 2021, 10(9), 1501; https://doi.org/10.3390/antiox10091501 - 21 Sep 2021

Cited by 4 | Viewed by 3268

Abstract

The generation of peroxynitrite (ONOO⁻) is associated with several diseases, including atherosclerosis, hypertension, neurodegeneration, cancer, inflammation, and sepsis. Alpha-ketoglutarate (αKG) is a known potential highly antioxidative agent for radical oxidative species such as peroxides. The question arises as to whether αKG is also a potential scavenger of ONOO⁻ and a potential protector against ONOO⁻-mediated nitration of proteins. NMR studies of 1 mM αKG in 100 mM phosphate-buffered saline at pH 7.4 and pH 6.0 were carried out in the presence or absence of a final concentration of 2 mM ONOO⁻. An ONOO⁻–luminol-induced chemiluminescence reaction was used to measure the scavenging function of several concentrations of αKG; quantification of αKG was performed via spectrophotometric enzymatic assay of αKG in the absence or presence of 0, 1, or 2 mM ONOO⁻. The nitration of tyrosine residues on proteins was measured on ONOO⁻-treated bovine serum albumin (BSA) in the presence or absence of 0–24 mM αKG by an ELISA technique using a specific anti-IgG against nitro-tyrosine. The addition of ONOO⁻ to αKG led to the formation of succinic acid and nitrite at pH 7.0, but not at pH 6.0, as αKG was stable against ONOO⁻. The absorbance of enzymatically estimated αKG at the time point of 30 min was significantly lower in favour of ONOO⁻ (1 mM: 0.21 ± 0.03, 2 mM: 0.12 ± 0.05 vs. 0 mM: 0.32 ± 0.02; p < 0.001). The luminol technique showed an inverse logarithmic correlation of the ONOO⁻ and αKG concentrations (y = −2 × 10⁵ ln(x) + 1 × 10⁶; r² = 0.99). The usage of 4 mM αKG showed a significant reduction by nearly half in the chemiluminescence signal (284,456 ± 29,293 cps, p < 0.001) compared to the control (474,401 ± 18,259); for 20 and 200 mM αKG, there were further reductions to 163,546 ± 26,196 cps (p < 0.001) and 12,658 ± 1928 cps (p < 0.001). Nitrated tyrosine residues were estimated using the ELISA technique. A negative linear correlation was obtained by estimating nitrated tyrosine residues in the presence of αKG (r² = 0.94): a reduction by half of nitrated tyrosine was estimated using 12 mM αKG compared to the control (326.1 ± 39.6 nmol vs. 844.5 ± 128.4 nmol; p < 0.001). Full article

(This article belongs to the Special Issue Oxidative Stress Impact on Protein Synthesis and Protein Degradation Systems in Health and Disease)

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Review

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17 pages, 887 KiB

Open AccessReview

Physiological Overview of the Potential Link between the UPS and Ca²⁺ Signaling

by Dongun Lee and Jeong Hee Hong

Antioxidants 2022, 11(5), 997; https://doi.org/10.3390/antiox11050997 - 19 May 2022

Cited by 7 | Viewed by 2511

Abstract

The ubiquitin–proteasome system (UPS) is the main proteolytic pathway by which damaged target proteins are degraded after ubiquitination and the recruit of ubiquitinated proteins, thus regulating diverse physiological functions and the maintenance in various tissues and cells. Ca²⁺ signaling is raised by oxidative or ER stress. Although the basic function of the UPS has been extensively elucidated and has been continued to define its mechanism, the precise relationship between the UPS and Ca²⁺ signaling remains unclear. In the present review, we describe the relationship between the UPS and Ca²⁺ signaling, including Ca²⁺-associated proteins, to understand the end point of oxidative stress. The UPS modulates Ca²⁺ signaling via the degradation of Ca²⁺-related proteins, including Ca²⁺ channels and transporters. Conversely, the modulation of UPS is driven by increases in the intracellular Ca²⁺ concentration. The multifaceted relationship between the UPS and Ca²⁺ plays critical roles in different tissue systems. Thus, we highlight the potential crosstalk between the UPS and Ca²⁺ signaling by providing an overview of the UPS in different organ systems and illuminating the relationship between the UPS and autophagy. Full article

(This article belongs to the Special Issue Oxidative Stress Impact on Protein Synthesis and Protein Degradation Systems in Health and Disease)

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