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Special Issue "DNA Damage and Repair in Degenerative Diseases 2014"

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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".

Deadline for manuscript submissions: closed (31 December 2014)

Special Issue Editor

Guest Editor
Prof. Guillermo T. Sáez

Department of Biochemistry and Molecular Biology, Faculty of Medicine and Odontology-INCLIVA, Service of Clinical Analysis, University Hospital Dr. Peset, University of Valencia, Avda. Blasco Ibañez 15, Valencia, Spain
E-Mail
Phone: +34 963864160
Fax: +34 96 386 4101
Interests: Oxidative stress-induced DNA damage and repair and its repair mechanisms in cardiometabolic and cancer diseases.

Special Issue Information

Dear Colleagues,

There is extensive experimental evidence supporting the role of Reactive Oxygen Species (ROS)-induced oxidative stress (OS) as an emerging and plausible mechanism underlying the pathophysiology of an extent and variable number of degenerative diseases. Almost all cell macromolecules are susceptible of ROS attacks. However, the molecular architecture of nucleic acids seems to be especially attractive for free radical species, such as the hydroxyl radical (·OH). The rate of DNA damage is relatively important due to the high frequency of impacts (105/cells/day) in eukaryotic organisms. Such rates immediately induce one to think of the dramatic consequences but-for the existence of an efficient and continuous DNA repair mechanism.

Maintaining genomic integrity is one of the most important objectives for plant and animal species. DNA is not only protected against potential aggressive factors, but is linked to a complex and effective repair machinery. These measures enable life-forms to avoid accumulating nucleotide damage and sequence errors. The plethora of different molecular mechanisms that help cells respond to DNA damage emphasizes the biological relevance of such repair processes. DNA damage response (DDR) must therefore be carefully reviewed and understood so as to better understand and interpret the symptoms and pathophysiology of degenerative diseases.

The mutagenic base, 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), is one of the most abundant byproducts of DNA oxidation. 8-oxo-dG has been proposed as both an excellent marker of DNA damage and as an indicator of the degree and clinical progress of degenerative diseases (including cardiometabolic ones and cancer). In light of this, the European Standard Committee for Oxidative DNA Damage (ESCODD and ESCULA) has recognized the need to arrive at “best methods” for measuring 8-Oxo-DG in DNA and urine.

Lesions in genomic DNA are known to be the etiology of many diseases, including neurodegeneration and tumor development. Unstable DNA molecules may no longer be able to coordinate regulatory orders from the nucleus to the cytoplasm, and may therefore cause such aforementioned ailments. A similar conclusion applies to mitochondrial DNA, which is the origin of an important number of rare diseases. Mitochondria are highly susceptible to DNA mutations from ROS. Moreover, the mitochondrial DNA repair system is less sophisticated and efficient (such that mitochondrial DNA has a higher replication error rate). However, mitochondria are also involved in signaling both the nucleus and the cytoplasm; in so doing, mitochondria enhance the development of cellular adaptation.

The DNA damage theory of aging remains a powerful one. Mammalian tissues clearly accumulate different types of DNA damage with age, which may eventually have profound implications on the equilibrium between cell survival and death. DNA damage induces different cell-intrinsic checkpoints (p53, retinoblastoma, p16, p19, p21 etc.), which play a pivotal role in the control of cell proliferation, differentiation, and/or senescence and aging. A decline in stem cell function results in abnormal tissue homeostasis and repair. An increase of such abnormalities may lead to a malignant transformation phenotype.

We now know that cells respond to the injury of their genetic material not only with the DNA repair response, but also with maneuvers that help them adapt to hostile and difficult environments (e.g., those that present free radicals and/or lack of appropriate antioxidants). These adjustment mechanisms are extremely advantageous for the maintenance of cellular homeostasis and integrity. Technological and scientific advances in the field of DNA damage and repair allow one to look forward to the emergence of new diagnostic and therapeutic strategies that may be useful for better managing rare and degenerative diseases.

Prof. Guillermo T. Sáez
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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 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 1600 CHF (Swiss Francs).

Keywords

  • DNA damage
  • DNA repair
  • 8-oxo-dG
  • degenerative diseases
  • antioxidants signal transduction
  • oxidative stress
  • byproducts
  • cardiovascular
  • neurogeneration
  • cancer
  • metabolic diseases

Related Special Issues

Published Papers (16 papers)

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Research

Jump to: Review

Open AccessCommunication Understanding Xeroderma Pigmentosum Complementation Groups Using Gene Expression Profiling after UV-Light Exposure
Int. J. Mol. Sci. 2015, 16(7), 15985-15996; doi:10.3390/ijms160715985
Received: 28 April 2015 / Revised: 31 May 2015 / Accepted: 29 June 2015 / Published: 14 July 2015
Cited by 2 | PDF Full-text (1762 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations
[...] Read more.
Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessArticle Polymorphism of the DNA Base Excision Repair Genes in Keratoconus
Int. J. Mol. Sci. 2014, 15(11), 19682-19699; doi:10.3390/ijms151119682
Received: 5 August 2014 / Revised: 8 October 2014 / Accepted: 16 October 2014 / Published: 29 October 2014
Cited by 2 | PDF Full-text (720 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Keratoconus (KC) is a degenerative corneal disorder for which the exact pathogenesis is not yet known. Oxidative stress is reported to be associated with this disease. The stress may damage corneal biomolecules, including DNA, and such damage is primarily removed by base excision
[...] Read more.
Keratoconus (KC) is a degenerative corneal disorder for which the exact pathogenesis is not yet known. Oxidative stress is reported to be associated with this disease. The stress may damage corneal biomolecules, including DNA, and such damage is primarily removed by base excision repair (BER). Variation in genes encoding BER components may influence the effectiveness of corneal cells to cope with oxidative stress. In the present work we genotyped 5 polymorphisms of 4 BER genes in 284 patients and 353 controls. The A/A genotype of the c.–1370T>A polymorphism of the DNA polymerase γ (POLG) gene was associated with increased occurrence of KC, while the A/T genotype was associated with decreased occurrence of KC. The A/G genotype and the A allele of the c.1196A>G polymorphism of the X-ray repair cross-complementing group 1 (XRCC1) were associated with increased, and the G/G genotype and the G allele, with decreased KC occurrence. Also, the C/T and T as well as C/C genotypes and alleles of the c.580C>T polymorphism of the same gene displayed relationship with KC occurrence. Neither the g.46438521G>C polymorphism of the Nei endonuclease VIII-like 1 (NEIL1) nor the c.2285T>C polymorphism of the poly(ADP-ribose) polymerase-1 (PARP-1) was associated with KC. In conclusion, the variability of the XRCC1 and POLG genes may play a role in KC pathogenesis and determine the risk of this disease. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessCommunication Localization of MLH3 at the Centrosomes
Int. J. Mol. Sci. 2014, 15(8), 13932-13937; doi:10.3390/ijms150813932
Received: 10 June 2014 / Revised: 7 July 2014 / Accepted: 4 August 2014 / Published: 11 August 2014
Cited by 1 | PDF Full-text (1504 KB) | HTML Full-text | XML Full-text
Abstract
Mutations in human DNA mismatch repair (MMR) genes are commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC). MLH1 protein heterodimerizes with PMS2, PMS1, and MLH3 to form MutLα, MutLβ, and MutLγ, respectively. We reported recently stable expression of GFP-linked MLH3 in human cell
[...] Read more.
Mutations in human DNA mismatch repair (MMR) genes are commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC). MLH1 protein heterodimerizes with PMS2, PMS1, and MLH3 to form MutLα, MutLβ, and MutLγ, respectively. We reported recently stable expression of GFP-linked MLH3 in human cell lines. Monitoring these cell lines during the cell cycle using live cell imaging combined with confocal microscopy, we detected accumulation of MLH3 at the centrosomes. Fluorescence recovery after photobleaching (FRAP) revealed high mobility and fast exchange rates at the centrosomes as it has been reported for other DNA repair proteins. MLH3 may have a role in combination with other repair proteins in the control of centrosome numbers. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

Review

Jump to: Research

Open AccessReview Nucleotide Salvage Deficiencies, DNA Damage and Neurodegeneration
Int. J. Mol. Sci. 2015, 16(5), 9431-9449; doi:10.3390/ijms16059431
Received: 2 January 2015 / Revised: 16 March 2015 / Accepted: 3 April 2015 / Published: 27 April 2015
Cited by 2 | PDF Full-text (873 KB) | HTML Full-text | XML Full-text
Abstract
Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP) produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated
[...] Read more.
Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP) produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated DNA damage because nucleotide imbalance can lead to mitochondrial depletion due to low replication fidelity. Failure to maintain nucleotide balance due to genetic defects can result in infantile death; however there is great variability in clinical presentation for particular diseases. This review compares genetic diseases that result from defects in specific nucleotide salvage enzymes and a signaling kinase that activates nucleotide salvage after DNA damage exposure. These diseases include Lesch-Nyhan syndrome, mitochondrial depletion syndromes, and ataxia telangiectasia. Although treatment options are available to palliate symptoms of these diseases, there is no cure. The conclusions drawn from this review include the critical role of guanine nucleotides in preventing neurodegeneration, the limitations of animals as disease models, and the need to further understand nucleotide imbalances in treatment regimens. Such knowledge will hopefully guide future studies into clinical therapies for genetic diseases. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia
Int. J. Mol. Sci. 2015, 16(3), 6183-6201; doi:10.3390/ijms16036183
Received: 21 January 2015 / Revised: 4 March 2015 / Accepted: 9 March 2015 / Published: 17 March 2015
Cited by 7 | PDF Full-text (806 KB) | HTML Full-text | XML Full-text
Abstract
In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to
[...] Read more.
In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview The Actin Depolymerizing Factor (ADF)/Cofilin Signaling Pathway and DNA Damage Responses in Cancer
Int. J. Mol. Sci. 2015, 16(2), 4095-4120; doi:10.3390/ijms16024095
Received: 22 December 2014 / Revised: 26 January 2015 / Accepted: 9 February 2015 / Published: 13 February 2015
Cited by 4 | PDF Full-text (1768 KB) | HTML Full-text | XML Full-text
Abstract
The actin depolymerizing factor (ADF)/cofilin protein family is essential for actin dynamics, cell division, chemotaxis and tumor metastasis. Cofilin-1 (CFL-1) is a primary non-muscle isoform of the ADF/cofilin protein family accelerating the actin filamental turnover in vitro and in vivo. In response
[...] Read more.
The actin depolymerizing factor (ADF)/cofilin protein family is essential for actin dynamics, cell division, chemotaxis and tumor metastasis. Cofilin-1 (CFL-1) is a primary non-muscle isoform of the ADF/cofilin protein family accelerating the actin filamental turnover in vitro and in vivo. In response to environmental stimulation, CFL-1 enters the nucleus to regulate the actin dynamics. Although the purpose of this cytoplasm-nucleus transition remains unclear, it is speculated that the interaction between CFL-1 and DNA may influence various biological responses, including DNA damage repair. In this review, we will discuss the possible involvement of CFL-1 in DNA damage responses (DDR) induced by ionizing radiation (IR), and the implications for cancer radiotherapy. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview Effects of Atmospheric Pressure Plasmas on Isolated and Cellular DNA—A Review
Int. J. Mol. Sci. 2015, 16(2), 2971-3016; doi:10.3390/ijms16022971
Received: 7 November 2014 / Revised: 14 January 2015 / Accepted: 15 January 2015 / Published: 29 January 2015
Cited by 15 | PDF Full-text (3217 KB) | HTML Full-text | XML Full-text
Abstract
Atmospheric Pressure Plasma (APP) is being used widely in a variety of biomedical applications. Extensive research in the field of plasma medicine has shown the induction of DNA damage by APP in a dose-dependent manner in both prokaryotic and eukaryotic systems. Recent evidence
[...] Read more.
Atmospheric Pressure Plasma (APP) is being used widely in a variety of biomedical applications. Extensive research in the field of plasma medicine has shown the induction of DNA damage by APP in a dose-dependent manner in both prokaryotic and eukaryotic systems. Recent evidence suggests that APP-induced DNA damage shows potential benefits in many applications, such as sterilization and cancer therapy. However, in several other applications, such as wound healing and dentistry, DNA damage can be detrimental. This review reports on the extensive investigations devoted to APP interactions with DNA, with an emphasis on the critical role of reactive species in plasma-induced damage to DNA. The review consists of three main sections dedicated to fundamental knowledge of the interactions of reactive oxygen species (ROS)/reactive nitrogen species (RNS) with DNA and its components, as well as the effects of APP on isolated and cellular DNA in prokaryotes and eukaryotes. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview BRCA1 and p53 Tumor Suppressor Molecules in Alzheimer’s Disease
Int. J. Mol. Sci. 2015, 16(2), 2879-2892; doi:10.3390/ijms16022879
Received: 29 October 2014 / Revised: 20 November 2014 / Accepted: 20 January 2015 / Published: 28 January 2015
Cited by 4 | PDF Full-text (801 KB) | HTML Full-text | XML Full-text
Abstract
Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disorder, however, the precise molecular events that control the
[...] Read more.
Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer’s disease. Alzheimer’s disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer’s disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer’s disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer’s disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview Autophagy in DNA Damage Response
Int. J. Mol. Sci. 2015, 16(2), 2641-2662; doi:10.3390/ijms16022641
Received: 15 December 2014 / Accepted: 12 January 2015 / Published: 23 January 2015
Cited by 17 | PDF Full-text (1469 KB) | HTML Full-text | XML Full-text
Abstract
DNA damage response (DDR) involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood,
[...] Read more.
DNA damage response (DDR) involves DNA repair, cell cycle regulation and apoptosis, but autophagy is also suggested to play a role in DDR. Autophagy can be activated in response to DNA-damaging agents, but the exact mechanism underlying this activation is not fully understood, although it is suggested that it involves the inhibition of mammalian target of rapamycin complex 1 (mTORC1). mTORC1 represses autophagy via phosphorylation of the ULK1/2–Atg13–FIP200 complex thus preventing maturation of pre-autophagosomal structures. When DNA damage occurs, it is recognized by some proteins or their complexes, such as poly(ADP)ribose polymerase 1 (PARP-1), Mre11–Rad50–Nbs1 (MRN) complex or FOXO3, which activate repressors of mTORC1. SQSTM1/p62 is one of the proteins whose levels are regulated via autophagic degradation. Inhibition of autophagy by knockout of FIP200 results in upregulation of SQSTM1/p62, enhanced DNA damage and less efficient damage repair. Mitophagy, one form of autophagy involved in the selective degradation of mitochondria, may also play role in DDR. It degrades abnormal mitochondria and can either repress or activate apoptosis, but the exact mechanism remains unknown. There is a need to clarify the role of autophagy in DDR, as this process may possess several important biomedical applications, involving also cancer therapy. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Figures

Open AccessReview Oxidative Stress, Bone Marrow Failure, and Genome Instability in Hematopoietic Stem Cells
Int. J. Mol. Sci. 2015, 16(2), 2366-2385; doi:10.3390/ijms16022366
Received: 19 December 2014 / Revised: 6 January 2015 / Accepted: 16 January 2015 / Published: 22 January 2015
Cited by 8 | PDF Full-text (1223 KB) | HTML Full-text | XML Full-text
Abstract
Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases
[...] Read more.
Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview Potential Relationship between Inadequate Response to DNA Damage and Development of Myelodysplastic Syndrome
Int. J. Mol. Sci. 2015, 16(1), 966-989; doi:10.3390/ijms16010966
Received: 5 November 2014 / Accepted: 22 December 2014 / Published: 5 January 2015
Cited by 2 | PDF Full-text (1177 KB) | HTML Full-text | XML Full-text
Abstract
Hematopoietic stem cells (HSCs) are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC
[...] Read more.
Hematopoietic stem cells (HSCs) are responsible for the continuous regeneration of all types of blood cells, including themselves. To ensure the functional and genomic integrity of blood tissue, a network of regulatory pathways tightly controls the proliferative status of HSCs. Nevertheless, normal HSC aging is associated with a noticeable decline in regenerative potential and possible changes in other functions. Myelodysplastic syndrome (MDS) is an age-associated hematopoietic malignancy, characterized by abnormal blood cell maturation and a high propensity for leukemic transformation. It is furthermore thought to originate in a HSC and to be associated with the accrual of multiple genetic and epigenetic aberrations. This raises the question whether MDS is, in part, related to an inability to adequately cope with DNA damage. Here we discuss the various components of the cellular response to DNA damage. For each component, we evaluate related studies that may shed light on a potential relationship between MDS development and aberrant DNA damage response/repair. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview The Anticancer Drug Ellipticine Activated with Cytochrome P450 Mediates DNA Damage Determining Its Pharmacological Efficiencies: Studies with Rats, Hepatic Cytochrome P450 Reductase Null (HRN™) Mice and Pure Enzymes
Int. J. Mol. Sci. 2015, 16(1), 284-306; doi:10.3390/ijms16010284
Received: 19 October 2014 / Accepted: 17 December 2014 / Published: 25 December 2014
Cited by 2 | PDF Full-text (1019 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Ellipticine is a DNA-damaging agent acting as a prodrug whose pharmacological efficiencies and genotoxic side effects are dictated by activation with cytochrome P450 (CYP). Over the last decade we have gained extensive experience in using pure enzymes and various animal models that helped
[...] Read more.
Ellipticine is a DNA-damaging agent acting as a prodrug whose pharmacological efficiencies and genotoxic side effects are dictated by activation with cytochrome P450 (CYP). Over the last decade we have gained extensive experience in using pure enzymes and various animal models that helped to identify CYPs metabolizing ellipticine. In this review we focus on comparison between the in vitro and in vivo studies and show a necessity of both approaches to obtain valid information on CYP enzymes contributing to ellipticine metabolism. Discrepancies were found between the CYP enzymes activating ellipticine to 13-hydroxy- and 12-hydroxyellipticine generating covalent DNA adducts and those detoxifying this drug to 9-hydroxy- and 7-hydroellipticine in vitro and in vivo. In vivo, formation of ellipticine-DNA adducts is dependent not only on expression levels of CYP3A, catalyzing ellipticine activation in vitro, but also on those of CYP1A that oxidize ellipticine in vitro mainly to the detoxification products. The finding showing that cytochrome b5 alters the ratio of ellipticine metabolites generated by CYP1A1/2 and 3A4 explained this paradox. Whereas the detoxification of ellipticine by CYP1A and 3A is either decreased or not changed by cytochrome b5, activation leading to ellipticine-DNA adducts increased considerably. We show that (I) the pharmacological effects of ellipticine mediated by covalent ellipticine-derived DNA adducts are dictated by expression levels of CYP1A, 3A and cytochrome b5, and its own potency to induce these enzymes in tumor tissues, (II) animal models, where levels of CYPs are either knocked out or induced are appropriate to identify CYPs metabolizing ellipticine in vivo, and (III) extrapolation from in vitro data to the situation in vivo is not always possible, confirming the need for these animal models. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview Oxidative Stress and Its Significant Roles in Neurodegenerative Diseases and Cancer
Int. J. Mol. Sci. 2015, 16(1), 193-217; doi:10.3390/ijms16010193
Received: 4 October 2014 / Accepted: 5 December 2014 / Published: 24 December 2014
Cited by 47 | PDF Full-text (1609 KB) | HTML Full-text | XML Full-text
Abstract
Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and
[...] Read more.
Reactive oxygen and nitrogen species have been implicated in diverse pathophysiological conditions, including inflammation, neurodegenerative diseases and cancer. Accumulating evidence indicates that oxidative damage to biomolecules including lipids, proteins and DNA, contributes to these diseases. Previous studies suggest roles of lipid peroxidation and oxysterols in the development of neurodegenerative diseases and inflammation-related cancer. Our recent studies identifying and characterizing carbonylated proteins reveal oxidative damage to heat shock proteins in neurodegenerative disease models and inflammation-related cancer, suggesting dysfunction in their antioxidative properties. In neurodegenerative diseases, DNA damage may not only play a role in the induction of apoptosis, but also may inhibit cellular division via telomere shortening. Immunohistochemical analyses showed co-localization of oxidative/nitrative DNA lesions and stemness markers in the cells of inflammation-related cancers. Here, we review oxidative stress and its significant roles in neurodegenerative diseases and cancer. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
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Open AccessReview The Emerging Nexus of Active DNA Demethylation and Mitochondrial Oxidative Metabolism in Post-Mitotic Neurons
Int. J. Mol. Sci. 2014, 15(12), 22604-22625; doi:10.3390/ijms151222604
Received: 15 September 2014 / Revised: 12 November 2014 / Accepted: 28 November 2014 / Published: 5 December 2014
Cited by 3 | PDF Full-text (1926 KB) | HTML Full-text | XML Full-text
Abstract
The variable patterns of DNA methylation in mammals have been linked to a number of physiological processes, including normal embryonic development and disease pathogenesis. Active removal of DNA methylation, which potentially regulates neuronal gene expression both globally and gene specifically, has been recently
[...] Read more.
The variable patterns of DNA methylation in mammals have been linked to a number of physiological processes, including normal embryonic development and disease pathogenesis. Active removal of DNA methylation, which potentially regulates neuronal gene expression both globally and gene specifically, has been recently implicated in neuronal plasticity, learning and memory processes. Model pathways of active DNA demethylation involve ten-eleven translocation (TET) methylcytosine dioxygenases that are dependent on oxidative metabolites. In addition, reactive oxygen species (ROS) and oxidizing agents generate oxidative modifications of DNA bases that can be removed by base excision repair proteins. These potentially link the two processes of active DNA demethylation and mitochondrial oxidative metabolism in post-mitotic neurons. We review the current biochemical understanding of the DNA demethylation process and discuss its potential interaction with oxidative metabolism. We then summarise the emerging roles of both processes and their interaction in neural plasticity and memory formation and the pathophysiology of neurodegeneration. Finally, possible therapeutic approaches for neurodegenerative diseases are proposed, including reprogramming therapy by global DNA demethylation and mitohormesis therapy for locus-specific DNA demethylation in post-mitotic neurons. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
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Open AccessReview The Role of 8-Oxoguanine DNA Glycosylase-1 in Inflammation
Int. J. Mol. Sci. 2014, 15(9), 16975-16997; doi:10.3390/ijms150916975
Received: 7 August 2014 / Revised: 9 September 2014 / Accepted: 16 September 2014 / Published: 23 September 2014
Cited by 15 | PDF Full-text (2443 KB) | HTML Full-text | XML Full-text
Abstract
Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular levels of reactive oxygen species (ROS) at the site of exposure. ROS not only function as intracellular signaling entities, but also induce damage to cellular molecules including DNA. Among the several dozen
[...] Read more.
Many, if not all, environmental pollutants/chemicals and infectious agents increase intracellular levels of reactive oxygen species (ROS) at the site of exposure. ROS not only function as intracellular signaling entities, but also induce damage to cellular molecules including DNA. Among the several dozen ROS-induced DNA base lesions generated in the genome, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant because of guanine’s lowest redox potential among DNA bases. In mammalian cells, 8-oxoG is repaired by the 8-oxoguanine DNA glycosylase-1 (OGG1)-initiated DNA base excision repair pathway (OGG1–BER). Accumulation of 8-oxoG in DNA has traditionally been associated with mutagenesis, as well as various human diseases and aging processes, while the free 8-oxoG base in body fluids is one of the best biomarkers of ongoing pathophysiological processes. In this review, we discuss the biological significance of the 8-oxoG base and particularly the role of OGG1–BER in the activation of small GTPases and changes in gene expression, including those that regulate pro-inflammatory chemokines/cytokines and cause inflammation. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
Open AccessReview Antioxidative Dietary Compounds Modulate Gene Expression Associated with Apoptosis, DNA Repair, Inhibition of Cell Proliferation and Migration
Int. J. Mol. Sci. 2014, 15(9), 16226-16245; doi:10.3390/ijms150916226
Received: 16 June 2014 / Revised: 21 July 2014 / Accepted: 27 August 2014 / Published: 15 September 2014
Cited by 10 | PDF Full-text (2618 KB) | HTML Full-text | XML Full-text
Abstract
Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation
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Many dietary compounds are known to have health benefits owing to their antioxidative and anti-inflammatory properties. To determine the molecular mechanism of these food-derived compounds, we analyzed their effect on various genes related to cell apoptosis, DNA damage and repair, oxidation and inflammation using in vitro cell culture assays. This review further tests the hypothesis proposed previously that downstream products of COX-2 (cyclooxygenase-2) called electrophilic oxo-derivatives induce antioxidant responsive elements (ARE), which leads to cell proliferation under antioxidative conditions. Our findings support this hypothesis and show that cell proliferation was inhibited when COX-2 was down-regulated by polyphenols and polysaccharides. Flattened macrophage morphology was also observed following the induction of cytokine production by polysaccharides extracted from viili, a traditional Nordic fermented dairy product. Coix lacryma-jobi (coix) polysaccharides were found to reduce mitochondrial membrane potential and induce caspase-3- and 9-mediated apoptosis. In contrast, polyphenols from blueberries were involved in the ultraviolet-activated p53/Gadd45/MDM2 DNA repair system by restoring the cell membrane potential. Inhibition of hypoxia-inducible factor-1 by saponin extracts of ginsenoside (Ginsen) and Gynostemma and inhibition of S100A4 by coix polysaccharides inhibited cancer cell migration and invasion. These observations suggest that antioxidants and changes in cell membrane potential are the major driving forces that transfer signals through the cell membrane into the cytosol and nucleus, triggering gene expression, changes in cell proliferation and the induction of apoptosis or DNA repair. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)

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