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DNA Damage, Oxidative Stress and Human Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 15279

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Special Issue Editors

Dr. Ana Rita Carlos

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Guest Editor

Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal
Interests: DNA damage; oxidative stress; extracellular matrix; cancer; muscular dystrophy

Prof. Dr. Fernando Antunes

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Guest Editor

Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, 1749-016 Lisboa, Portugal
Interests: redox regulation; systems biology; quantitative redox biology; metabolism

Dr. Isabel M. Pires

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Guest Editor

Faculty of Health Sciences, University of Hull, Hul HU16 7RX, UK
Interests: tumour hypoxia; cancer biology; DNA damage response; radiotherapy

Special Issue Information

Dear Colleagues,

Organisms have evolved a set of mechanisms to cope with a variety of exogenous and endogenous challenges in order to maintain homeostasis. Amongst these mechanisms are DNA damage and oxidative stress responses. DNA damage responses (DDRs) rely on an intricate network that aims at detecting and repairing any damage caused to the DNA. The damage can be caused, for example, by UV radiation, chemotherapeutic drugs, chemicals or endogenous sources including replication fork stalling and reactive oxygen species (ROS). ROS are molecules naturally produced by cells, namely, by NADPH oxidases or by mitochondria during ATP generation via the electron transport chain (ETC). When ROS accumulate in a cell, leading to oxidative stress, they have highly deleterious effects, promoting oxidation of different macromolecules. The deleterious effects of ROS accumulation are countered by different anti-oxidant defense mechanisms, which aim at restoring the homeostasis between ROS production and accumulation.

Several human diseases have been associated with excessive DNA damage and/or oxidative stress, or failure in the respective response mechanisms. These diseases include cancer, metabolic syndrome, neurodegenerative diseases, myopathies and several other pathologies including diseases characterized by genetic defects of DNA repair mechanisms, such as Fanconi anemia, ataxia telangiectasia or Nijmegen breakage syndrome.

For this Special Issue, we invite authors as well as the participants of The COST Action CA20121 to submit novel work or reviews establishing the importance of DNA damage and/or oxidative stress in the pathology of human diseases. This Special Issue aims at shedding new light onto the disease mechanisms that lead to increased DNA damage and oxidative stress, and conversely onto how DNA damage and oxidative stress lead to an increase in disease pathology. Moreover, it aims at highlighting the cross-talk between DNA damage and oxidative stress responses in the context of human diseases.

Dr. Ana Rita Carlos
Prof. Dr. Fernando Antunes
Dr. Isabel M. Pires
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

DNA damage
oxidative stress
human cancer
metabolic syndrome
neurodegenerative disorders
myopathies

Published Papers (5 papers)

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Research

Jump to: Review

26 pages, 4822 KiB

Open AccessArticle

Evaluation of Mitochondrial Function in Blood Samples Shows Distinct Patterns in Subjects with Thyroid Carcinoma from Those with Hyperplasia

by Julia Bernal-Tirapo, María Teresa Bayo Jiménez, Pedro Yuste-García, Isabel Cordova, Ana Peñas, Francisco-Javier García-Borda, Cesar Quintela, Ignacio Prieto, Cristina Sánchez-Ramos, Eduardo Ferrero-Herrero and María Monsalve

Int. J. Mol. Sci. 2023, 24(7), 6453; https://doi.org/10.3390/ijms24076453 - 29 Mar 2023

Cited by 2 | Viewed by 1830

Abstract

Metabolic adaptations are a hallmark of cancer and may be exploited to develop novel diagnostic and therapeutic tools. Only about 50% of the patients who undergo thyroidectomy due to suspicion of thyroid cancer actually have the disease, highlighting the diagnostic limitations of current tools. We explored the possibility of using non-invasive blood tests to accurately diagnose thyroid cancer. We analyzed blood and thyroid tissue samples from two independent cohorts of patients undergoing thyroidectomy at the Hospital Universitario 12 de Octubre (Madrid, Spain). As expected, histological comparisons of thyroid cancer and hyperplasia revealed higher proliferation and apoptotic rates and enhanced vascular alterations in the former. Notably, they also revealed increased levels of membrane-bound phosphorylated AKT, suggestive of enhanced glycolysis, and alterations in mitochondrial sub-cellular distribution. Both characteristics are common metabolic adaptations in primary tumors. These data together with reduced mtDNA copy number and elevated levels of the mitochondrial antioxidant PRX3 in cancer tissue samples suggest the presence of mitochondrial oxidative stress. In plasma, cancer patients showed higher levels of cfDNA and mtDNA. Of note, mtDNA plasma levels inversely correlated with those in the tissue, suggesting that higher death rates were linked to lower mtDNA copy number. In PBMCs, cancer patients showed higher levels of PGC-1α, a positive regulator of mitochondrial function, but this increase was not associated with a corresponding induction of its target genes, suggesting a reduced activity in cancer patients. We also observed a significant difference in the PRDX3/PFKFB3 correlation at the gene expression level, between carcinoma and hyperplasia patients, also indicative of increased systemic metabolic stress in cancer patients. The correlation of mtDNA levels in tissue and PBMCs further stressed the interconnection between systemic and tumor metabolism. Evaluation of the mitochondrial gene ND1 in plasma, PBMCs and tissue samples, suggested that it could be a good biomarker for systemic oxidative metabolism, with ND1/mtDNA ratio positively correlating in PBMCs and tissue samples. In contrast, ND4 evaluation would be informative of tumor development, with ND4/mtDNA ratio specifically altered in the tumor context. Taken together, our data suggest that metabolic dysregulation in thyroid cancer can be monitored accurately in blood samples and might be exploited for the accurate discrimination of cancer from hyperplasia. Full article

(This article belongs to the Special Issue DNA Damage, Oxidative Stress and Human Disease)

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18 pages, 2972 KiB

Open AccessArticle

Altered Blood and Brain Expression of Inflammation and Redox Genes in Alzheimer’s Disease, Common to APP^V717I × TAU^P301L Mice and Patients

by Catalina Anca Cucos, Elena Milanesi, Maria Dobre, Ioana Andreea Musat, Gina Manda and Antonio Cuadrado

Int. J. Mol. Sci. 2022, 23(10), 5799; https://doi.org/10.3390/ijms23105799 - 21 May 2022

Viewed by 2078

Abstract

Despite intensive research, the pathophysiology of Alzheimer’s disease (AD) is still not fully understood, and currently there are no effective treatments. Therefore, there is an unmet need for reliable biomarkers and animal models of AD to develop innovative therapeutic strategies addressing early pathologic events such as neuroinflammation and redox disturbances. The study aims to identify inflammatory and redox dysregulations in the context of AD-specific neuronal cell death and DNA damage, using the APP^V717I× TAU^P301L (AT) mouse model of AD. The expression of 84 inflammatory and 84 redox genes in the hippocampus and peripheral blood of double transgenic AT mice was evaluated against age-matched controls. A distinctive gene expression profile in the hippocampus and the blood of AT mice was identified, addressing DNA damage, apoptosis and thrombosis, complemented by inflammatory factors and receptors, along with ROS producers and antioxidants. Gene expression dysregulations that are common to AT mice and AD patients guided the final selection of candidate biomarkers. The identified inflammation and redox genes, common to AD patients and AT mice, might be valuable candidate biomarkers for preclinical drug development that could be readily translated to clinical trials. Full article

(This article belongs to the Special Issue DNA Damage, Oxidative Stress and Human Disease)

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Review

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18 pages, 1302 KiB

Open AccessReview

NFIXing Cancer: The Role of NFIX in Oxidative Stress Response and Cell Fate

by Vanessa Ribeiro, Susana G. Martins, Ana Sofia Lopes, Sólveig Thorsteinsdóttir, Rita Zilhão and Ana Rita Carlos

Int. J. Mol. Sci. 2023, 24(5), 4293; https://doi.org/10.3390/ijms24054293 - 21 Feb 2023

Cited by 2 | Viewed by 2076

Abstract

NFIX, a member of the nuclear factor I (NFI) family of transcription factors, is known to be involved in muscle and central nervous system embryonic development. However, its expression in adults is limited. Similar to other developmental transcription factors, NFIX has been found to be altered in tumors, often promoting pro-tumorigenic functions, such as leading to proliferation, differentiation, and migration. However, some studies suggest that NFIX can also have a tumor suppressor role, indicating a complex and cancer-type dependent role of NFIX. This complexity may be linked to the multiple processes at play in regulating NFIX, which include transcriptional, post-transcriptional, and post-translational processes. Moreover, other features of NFIX, including its ability to interact with different NFI members to form homodimers or heterodimers, therefore allowing the transcription of different target genes, and its ability to sense oxidative stress, can also modulate its function. In this review, we examine different aspects of NFIX regulation, first in development and then in cancer, highlighting the important role of NFIX in oxidative stress and cell fate regulation in tumors. Moreover, we propose different mechanisms through which oxidative stress regulates NFIX transcription and function, underlining NFIX as a key factor for tumorigenesis. Full article

(This article belongs to the Special Issue DNA Damage, Oxidative Stress and Human Disease)

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17 pages, 1482 KiB

Open AccessReview

Polyphenols as Potent Epigenetics Agents for Cancer

by Peramaiyan Rajendran, Salaheldin Abdelraouf Abdelsalam, Kaviyarasi Renu, Vishnupriya Veeraraghavan, Rebai Ben Ammar and Emad A. Ahmed

Int. J. Mol. Sci. 2022, 23(19), 11712; https://doi.org/10.3390/ijms231911712 - 03 Oct 2022

Cited by 30 | Viewed by 3207

Abstract

Human diseases such as cancer can be caused by aberrant epigenetic regulation. Polyphenols play a major role in mammalian epigenome regulation through mechanisms and proteins that remodel chromatin. In fruits, seeds, and vegetables, as well as food supplements, polyphenols are found. Compounds such as these ones are powerful anticancer agents and antioxidants. Gallic acid, kaempferol, curcumin, quercetin, and resveratrol, among others, have potent anti-tumor effects by helping reverse epigenetic changes associated with oncogene activation and tumor suppressor gene inactivation. The role dietary polyphenols plays in restoring epigenetic alterations in cancer cells with a particular focus on DNA methylation and histone modifications was summarized. We also discussed how these natural compounds modulate gene expression at the epigenetic level and described their molecular targets in cancer. It highlights the potential of polyphenols as an alternative therapeutic approach in cancer since they modulate epigenetic activity. Full article

(This article belongs to the Special Issue DNA Damage, Oxidative Stress and Human Disease)

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45 pages, 10749 KiB

Open AccessReview

Hypochlorous Acid Chemistry in Mammalian Cells—Influence on Infection and Role in Various Pathologies

by Celia María Curieses Andrés, José Manuel Pérez de la Lastra, Celia Andrés Juan, Francisco J. Plou and Eduardo Pérez-Lebeña

Int. J. Mol. Sci. 2022, 23(18), 10735; https://doi.org/10.3390/ijms231810735 - 14 Sep 2022

Cited by 27 | Viewed by 5082

Abstract

This review discusses the formation of hypochlorous acid HOCl and the role of reactive chlorinated species (RCS), which are catalysed by the enzyme myeloperoxidase MPO, mainly located in leukocytes and which in turn contribute to cellular oxidative stress. The reactions of RCS with various organic molecules such as amines, amino acids, proteins, lipids, carbohydrates, nucleic acids, and DNA are described, and an attempt is made to explain the chemical mechanisms of the formation of the various chlorinated derivatives and the data available so far on the effects of MPO, RCS and halogenative stress. Their presence in numerous pathologies such as atherosclerosis, arthritis, neurological and renal diseases, diabetes, and obesity is reviewed and were found to be a feature of debilitating diseases. Full article

(This article belongs to the Special Issue DNA Damage, Oxidative Stress and Human Disease)

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