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Special Issue "Redox Signaling in Biology and Patho-Biology"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (30 December 2013)

Special Issue Editor

Guest Editor
Dr. Gregor Drummen

Cellular Stress and Ageing Program, Bionanoscience and Bioimaging Program, BNS, 33647 Bielefeld, Germany
Interests: quantum dots; bionanotechnology; two-photon fluorescence imaging; cellular imaging; fluorescence microscopy; cancer; cell signaling; oxidative stress; lipids and biomembranes; lipid peroxidation; antioxidants; renal pathobiology

Special Issue Information

Dear Colleagues,

Molecular oxygen is one of those fundamental and essential elements to ensure life and survival of most organisms on the third rock from the sun. Through this molecule, efficient formation of the energy molecule and genetic building block ATP is possible and thus allows the organism to perform work (the thermodynamical definition thereof). However, it is the same molecular oxygen that threatens aerobic life on this planet, because of its potential for radical formation (it is a biradical, although Pauli restricted). From molecular oxygen derived species, Reactive Oxygen Species (ROS), have long been implicated in a multitude of diseases, but not until the discovery that nitric oxide is an essential signaling molecule has the view of the all destructive ROS changed to include normal biological function. Redox signaling has become an important field of research in the biological and biomedical sciences. The importance of these mechanisms that influence genes and thus cell function, but might also involve epigenetic modifications, is clear; the mechanisms themselves are still largely intangible.

This special issue calls for contributions, original research, mini and full reviews, commentaries, educational papers, and perspectives that address the progress and current standing in redox signaling biology. These include, but are not limited to:

  • molecular aspects of reactive species involved in redox signaling
  • antioxidants, and other redox-dependent processes
  • redox-based therapeutics and impact on health care

Other aspects of oxidative stress, please submit to the separate issue on Oxidative Stress and Ageing in IJMS

Dr. Gregor Drummen
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).

Published Papers (28 papers)

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Research

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Open AccessArticle Block of the Mevalonate Pathway Triggers Oxidative and Inflammatory Molecular Mechanisms Modulated by Exogenous Isoprenoid Compounds
Int. J. Mol. Sci. 2014, 15(4), 6843-6856; doi:10.3390/ijms15046843
Received: 28 February 2014 / Revised: 3 April 2014 / Accepted: 4 April 2014 / Published: 22 April 2014
Cited by 9 | PDF Full-text (1583 KB) | HTML Full-text | XML Full-text
Abstract
Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the [...] Read more.
Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessArticle A Preliminary X-ray Study of Murine Tnfaip8/Oxi-α
Int. J. Mol. Sci. 2014, 15(3), 4523-4530; doi:10.3390/ijms15034523
Received: 28 January 2014 / Revised: 6 March 2014 / Accepted: 7 March 2014 / Published: 14 March 2014
PDF Full-text (413 KB) | HTML Full-text | XML Full-text
Abstract
Tnfaip8/oxidative stress regulated gene-α (Oxi-α) is a novel protein expressed specifically in brain dopaminergic neurons and its over-expression has been reported to protect dopaminergic cells against OS-induced cell death. In this study, murine C165S mutant Tnfaip8/Oxi-α has been crystallized and X-ray data [...] Read more.
Tnfaip8/oxidative stress regulated gene-α (Oxi-α) is a novel protein expressed specifically in brain dopaminergic neurons and its over-expression has been reported to protect dopaminergic cells against OS-induced cell death. In this study, murine C165S mutant Tnfaip8/Oxi-α has been crystallized and X-ray data have been collected to 1.8 Å using synchrotron radiation. The crystal belonged to the primitive orthorhombic space group P21212, with unit-cell parameters a = 66.9, b = 72.3, c = 93.5 Å. A full structural determination is under way in order to provide insights into the structure-function relationships of this protein. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Dynamin-Related Protein 1 Inhibitors Protect against Ischemic Toxicity through Attenuating Mitochondrial Ca2+ Uptake from Endoplasmic Reticulum Store in PC12 Cells
Int. J. Mol. Sci. 2014, 15(2), 3172-3185; doi:10.3390/ijms15023172
Received: 7 January 2014 / Revised: 25 January 2014 / Accepted: 27 January 2014 / Published: 21 February 2014
Cited by 3 | PDF Full-text (1733 KB) | HTML Full-text | XML Full-text
Abstract
Intracellular calcium homeostasis disorder and mitochondrial dysfunction are involved in many acute and chronic brain diseases, including ischemic brain injury. An imbalance in mitochondrial fission and fusion is one of the most important structural abnormalities found in a large number of mitochondrial [...] Read more.
Intracellular calcium homeostasis disorder and mitochondrial dysfunction are involved in many acute and chronic brain diseases, including ischemic brain injury. An imbalance in mitochondrial fission and fusion is one of the most important structural abnormalities found in a large number of mitochondrial dysfunction related diseases. Here, we investigated the effects of mitochondrial division inhibitor A (mdivi A) and mdivi B, two small molecule inhibitors of mitochondrial fission protein dunamin-related protein 1 (Drp-1), in neuronal injury induced by oxygen-glucose deprivation (OGD) in PC12 cells. We found that mdivi A and mdivi B inhibited OGD-induced neuronal injury through attenuating apoptotic cell death. These two inhibitors also preserved mitochondrial function, as evidenced by reduced reactive oxygen species (ROS) generation and cytochrome c release, as well as prevented loss of mitochondrial membrane potential (MMP). Moreover, mdivi A and mdivi B significantly suppressed mitochondrial Ca2+ uptake, but had no effect on cytoplasmic Ca2+ after OGD injury. The results of calcium imaging and immunofluorescence staining showed that Drp-1 inhibitors attenuated endoplasmic reticulum (ER) Ca2+ release and prevented ER morphological changes induced by OGD. These results demonstrate that Drp-1 inhibitors protect against ischemic neuronal injury through inhibiting mitochondrial Ca2+ uptake from the ER store and attenuating mitochondrial dysfunction. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Dominant Repression by Arabidopsis Transcription Factor MYB44 Causes Oxidative Damage and Hypersensitivity to Abiotic Stress
Int. J. Mol. Sci. 2014, 15(2), 2517-2537; doi:10.3390/ijms15022517
Received: 11 December 2013 / Revised: 17 January 2014 / Accepted: 28 January 2014 / Published: 13 February 2014
Cited by 5 | PDF Full-text (1735 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In any living species, stress adaptation is closely linked with major changes of the gene expression profile. As a substrate protein of the rapidly stress-induced mitogen-activated protein kinase MPK3, Arabidopsis transcription factor MYB44 likely acts at the front line of stress-induced re-programming. [...] Read more.
In any living species, stress adaptation is closely linked with major changes of the gene expression profile. As a substrate protein of the rapidly stress-induced mitogen-activated protein kinase MPK3, Arabidopsis transcription factor MYB44 likely acts at the front line of stress-induced re-programming. We recently characterized MYB44 as phosphorylation-dependent positive regulator of salt stress signaling. Molecular events downstream of MYB44 are largely unknown. Although MYB44 binds to the MBSII element in vitro, it has no discernible effect on MBSII-driven reporter gene expression in plant co-transfection assays. This may suggest limited abundance of a synergistic co-regulator. MYB44 carries a putative transcriptional repression (Ethylene responsive element binding factor-associated Amphiphilic Repression, EAR) motif. We employed a dominant repressor strategy to gain insights into MYB44-conferred stress resistance. Overexpression of a MYB44-REP fusion markedly compromised salt and drought stress tolerance—the opposite was seen in MYB44 overexpression lines. MYB44-mediated resistance likely results from induction of tolerance-enhancing, rather than from repression of tolerance-diminishing factors. Salt stress-induced accumulation of destructive reactive oxygen species is efficiently prevented in transgenic MYB44, but accelerated in MYB44-REP lines. Furthermore, heterologous overexpression of MYB44-REP caused tissue collapse in Nicotiana. A mechanistic model of MAPK-MYB-mediated enhancement in the antioxidative capacity and stress tolerance is proposed. Genetic engineering of MYB44 variants with higher trans-activating capacity may be a means to further raise stress resistance in crops. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessArticle A Novel Thylakoid Ascorbate Peroxidase from Jatrophacurcas Enhances Salt Tolerance in Transgenic Tobacco
Int. J. Mol. Sci. 2014, 15(1), 171-185; doi:10.3390/ijms15010171
Received: 16 October 2013 / Revised: 10 December 2013 / Accepted: 13 December 2013 / Published: 24 December 2013
Cited by 4 | PDF Full-text (2435 KB) | HTML Full-text | XML Full-text
Abstract
Ascorbate peroxidase (APX) plays an important role in the metabolism of hydrogen peroxide in higher plants. In the present study, a novel APX gene (JctAPX) was cloned from Jatropha curcas L. The deduced amino acid sequence was similar to that [...] Read more.
Ascorbate peroxidase (APX) plays an important role in the metabolism of hydrogen peroxide in higher plants. In the present study, a novel APX gene (JctAPX) was cloned from Jatropha curcas L. The deduced amino acid sequence was similar to that of APX of some other plant species. JctAPX has a chloroplast transit peptide and was localized to the chloroplasts by analysis with a JctAPX-green fluorescent protein (GFP) fusion protein. Quantitative polymerase chain reaction (qPCR) analysis showed that JctAPX was constitutively expressed in different tissues from J. curcas and was upregulated by NaCl stress. To characterize its function in salt tolerance, the construct p35S: JctAPX was created and successfully introduced into tobacco by Agrobacterium-mediated transformation. Compared with wild type (WT), the transgenic plants exhibited no morphological abnormalities in the no-stress condition. However, under 200 mM NaCl treatment, JctAPX over-expressing plants showed increased tolerance to salt during seedling establishment and growth. In addition, the transgenic lines showed higher chlorophyll content and APX activity, which resulted in lower H2O2 content than WT when subjected to 400 mM NaCl stress. These results suggest that the increased APX activity in the chloroplasts from transformed plants increased salt tolerance by enhancing reactive oxygen species (ROS)-scavenging capacity under short-term NaCl stress conditions. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Involvement of Calcium-Mediated Reactive Oxygen Species in Inductive GRP78 Expression by Geldanamycin in 9L Rat Brain Tumor Cells
Int. J. Mol. Sci. 2013, 14(9), 19169-19185; doi:10.3390/ijms140919169
Received: 24 July 2013 / Revised: 19 August 2013 / Accepted: 9 September 2013 / Published: 18 September 2013
Cited by 3 | PDF Full-text (1421 KB) | HTML Full-text | XML Full-text
Abstract
Treatment with geldanamycin (GA) leads to an increase in [Ca2+]c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA-exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [...] Read more.
Treatment with geldanamycin (GA) leads to an increase in [Ca2+]c and the production of reactive oxygen species (ROS) in rat brain tumor 9L RBT cells. GA-exerted calcium signaling was blocked by BAPTA/AM and EGTA. The effect of GA on [Ca2+]c was significantly reduced in the presence of thapsigargin (TG) and ruthenium red (RR). GA-induced GRP78 expression is significantly decreased in the presence of BAPTA/AM, EGTA and RR, suggesting that the calcium influx from the extracellular space and intracellular calcium store oscillations are contributed to by the calcium mobilization and GRP78 expression induced by GA. The induced GRP78 expression is sensitive to added U73122 and Ro-31-8425, pinpointing the involvement of phospholipase C (PLC) and protein kinase C (PKC) in GA-induced endoplasmic reticulum (ER) stress. The antioxidants N-acetylcysteine (NAC), BAPTA/AM, EGTA and H7 also have significant inhibitory effects on ROS generation. Finally, neither H7 nor NAC was able to affect the calcium response elicited by GA. Our results suggest that the causal signaling cascade during GA-inducted GRP78 expression occurs via a pathway that connects PLC to cytoplasmic calcium increase, PKC activation and, then, finally, ROS generation. Our data provides new insights into the influence of GA on ER stress response in 9L RBT cells. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Insulin-Dependent H2O2 Production Is Higher in Muscle Fibers of Mice Fed with a High-Fat Diet
Int. J. Mol. Sci. 2013, 14(8), 15740-15754; doi:10.3390/ijms140815740
Received: 1 June 2013 / Revised: 20 July 2013 / Accepted: 24 July 2013 / Published: 29 July 2013
Cited by 5 | PDF Full-text (877 KB) | HTML Full-text | XML Full-text
Abstract
Insulin resistance is defined as a reduced ability of insulin to stimulate glucose utilization. C57BL/6 mice fed with a high-fat diet (HFD) are a model of insulin resistance. In skeletal muscle, hydrogen peroxide (H2O2) produced by NADPH oxidase [...] Read more.
Insulin resistance is defined as a reduced ability of insulin to stimulate glucose utilization. C57BL/6 mice fed with a high-fat diet (HFD) are a model of insulin resistance. In skeletal muscle, hydrogen peroxide (H2O2) produced by NADPH oxidase 2 (NOX2) is involved in signaling pathways triggered by insulin. We evaluated oxidative status in skeletal muscle fibers from insulin-resistant and control mice by determining H2O2 generation (HyPer probe), reduced-to-oxidized glutathione ratio and NOX2 expression. After eight weeks of HFD, insulin-dependent glucose uptake was impaired in skeletal muscle fibers when compared with control muscle fibers. Insulin-resistant mice showed increased insulin-stimulated H2O2 release and decreased reduced-to-oxidized glutathione ratio (GSH/GSSG). In addition, p47phox and gp91phox (NOX2 subunits) mRNA levels were also high (~3-fold in HFD mice compared to controls), while protein levels were 6.8- and 1.6-fold higher, respectively. Using apocynin (NOX2 inhibitor) during the HFD feeding period, the oxidative intracellular environment was diminished and skeletal muscle insulin-dependent glucose uptake restored. Our results indicate that insulin-resistant mice have increased H2O2 release upon insulin stimulation when compared with control animals, which appears to be mediated by an increase in NOX2 expression. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessArticle CD44 Is Associated with the Aggressive Phenotype of Nasopharyngeal Carcinoma through Redox Regulation
Int. J. Mol. Sci. 2013, 14(7), 13266-13281; doi:10.3390/ijms140713266
Received: 13 May 2013 / Revised: 18 June 2013 / Accepted: 19 June 2013 / Published: 26 June 2013
Cited by 9 | PDF Full-text (795 KB) | HTML Full-text | XML Full-text
Abstract
Recent studies have shown that cancer stem-like cells (CSCs) within a tumor have the capacity for self-renewal and differentiation, and are associated with an aggressive phenotype and therapeutic resistance. Studies have also associated tumor progression with alterations in the levels of intracellular [...] Read more.
Recent studies have shown that cancer stem-like cells (CSCs) within a tumor have the capacity for self-renewal and differentiation, and are associated with an aggressive phenotype and therapeutic resistance. Studies have also associated tumor progression with alterations in the levels of intracellular reactive oxygen species (ROS). In this study, we cultured nasopharyngeal carcinoma (NPC) CSCs in conditions that allowed sphere formation. The resulting sphere cells displayed stemness properties, characteristics of the epithelial–mesenchymal transition (EMT), and increased expression of the CSC surface marker CD44. We further evaluated the association between CD44 expression and EMT marker expression, and any correlation with redox status, in these CSCs. We showed that the EMT in sphere cells is associated with the upregulation of CD44 expression and increased ROS generation, which might promote NPC aggressiveness. We also identified the coexpression of CD44 with the EMT marker N-cadherin in sphere cells, and downregulated CD44 expression after the addition of the antioxidant N-acetyl cysteine. Our results indicate that CD44 plays a role in the EMT phenotype of CSCs in NPC, and suggest its involvement in EMT-associated ROS production. These findings might facilitate the development of a novel therapy for the prevention of NPC recurrence and metastasis. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessArticle A Differential Redox Regulation of the Pathways Metabolizing Glyceraldehyde-3-Phosphate Tunes the Production of Reducing Power in the Cytosol of Plant Cells
Int. J. Mol. Sci. 2013, 14(4), 8073-8092; doi:10.3390/ijms14048073
Received: 10 January 2013 / Revised: 2 March 2013 / Accepted: 7 March 2013 / Published: 12 April 2013
Cited by 10 | PDF Full-text (1037 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Adaptation to aerobic life leads organisms to sense reactive oxygen species and use the signal for coordination of the entire metabolism. Glycolysis in plants is a particular network where specific steps, like oxidation of glyceraldehydes-3-phosphate (Ga3P), are critical in order for it [...] Read more.
Adaptation to aerobic life leads organisms to sense reactive oxygen species and use the signal for coordination of the entire metabolism. Glycolysis in plants is a particular network where specific steps, like oxidation of glyceraldehydes-3-phosphate (Ga3P), are critical in order for it to function. The triose-phosphate can be converted into 3-phosphoglycerate through the phosphorylating Ga3P dehydrogenase (Ga3PDHase, EC 1.2.1.12) producing ATP and NADH, or via the non-phosphorylating enzyme (np-Ga3PDHase; EC 1.2.1.9) generating NADPH. In this work we found redox regulation to be a posttranslational mechanism allowing the fine-tuning of the triose-phosphate fate. Both enzymes were inactivated after oxidation by reactive oxygen and nitrogen species. Kinetic studies determined that Ga3PDHase is marked (63-fold) more sensitive to oxidants than np-Ga3PDHase. Thioredoxin-h reverted the oxidation of both enzymes (although with differences between them), suggesting a physiological redox regulation. The results support a metabolic scenario where the cytosolic triose-phosphate dehydrogenases are regulated under changeable redox conditions. This would allow coordinate production of NADPH or ATP through glycolysis, with oxidative signals triggering reducing power synthesis in the cytosol. The NADPH increment would favor antioxidant responses to cope with the oxidative situation, while the thioredoxin system would positively feedback NADPH production by maintaining np-Ga3PDHase at its reduced active state. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Frataxin Deficiency Leads to Reduced Expression and Impaired Translocation of NF-E2-Related Factor (Nrf2) in Cultured Motor Neurons
Int. J. Mol. Sci. 2013, 14(4), 7853-7865; doi:10.3390/ijms14047853
Received: 1 March 2013 / Revised: 29 March 2013 / Accepted: 2 April 2013 / Published: 10 April 2013
Cited by 8 | PDF Full-text (600 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative stress has been implicated in the pathogenesis of Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein responsible of iron homeostasis. Under conditions of oxidative stress, the activation of the transcription factor NF-E2-related factor [...] Read more.
Oxidative stress has been implicated in the pathogenesis of Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein responsible of iron homeostasis. Under conditions of oxidative stress, the activation of the transcription factor NF-E2-related factor (Nrf2) triggers the antioxidant cellular response by inducing antioxidant response element (ARE) driven genes. Increasing evidence supports a role for the Nrf2-ARE pathway in neurodegenerative diseases. In this study, we analyzed the expression and the distribution of Nrf2 in silenced neurons for frataxin gene. Decreased Nrf2 mRNA content and a defective activation after treatment with pro-oxidants have been evidenced in frataxin-silenced neurons by RT-PCR and confocal microscopy. The loss of Nrf2 in FRDA may greatly enhance the cellular susceptibility to oxidative stress and make FRDA neurons more vulnerable to injury. Our findings may help to focus on this promising target, especially in its emerging role in the neuroprotective response. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessArticle Protein Tyrosine Nitration and Thiol Oxidation by Peroxynitrite—Strategies to Prevent These Oxidative Modifications
Int. J. Mol. Sci. 2013, 14(4), 7542-7570; doi:10.3390/ijms14047542
Received: 31 December 2012 / Revised: 11 March 2013 / Accepted: 18 March 2013 / Published: 8 April 2013
Cited by 14 | PDF Full-text (1855 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The reaction product of nitric oxide and superoxide, peroxynitrite, is a potent biological oxidant. The most important oxidative protein modifications described for peroxynitrite are cysteine-thiol oxidation and tyrosine nitration. We have previously demonstrated that intrinsic heme-thiolate (P450)-dependent enzymatic catalysis increases the nitration [...] Read more.
The reaction product of nitric oxide and superoxide, peroxynitrite, is a potent biological oxidant. The most important oxidative protein modifications described for peroxynitrite are cysteine-thiol oxidation and tyrosine nitration. We have previously demonstrated that intrinsic heme-thiolate (P450)-dependent enzymatic catalysis increases the nitration of tyrosine 430 in prostacyclin synthase and results in loss of activity which contributes to endothelial dysfunction. We here report the sensitive peroxynitrite-dependent nitration of an over-expressed and partially purified human prostacyclin synthase (3.3 μM) with an EC50 value of 5 μM. Microsomal thiols in these preparations effectively compete for peroxynitrite and block the nitration of other proteins up to 50 μM peroxynitrite. Purified, recombinant PGIS showed a half-maximal nitration by 10 μM 3-morpholino sydnonimine (Sin-1) which increased in the presence of bicarbonate, and was only marginally induced by freely diffusing NO2-radicals generated by a peroxidase/nitrite/hydrogen peroxide system. Based on these observations, we would like to emphasize that prostacyclin synthase is among the most efficiently and sensitively nitrated proteins investigated by us so far. In the second part of the study, we identified two classes of peroxynitrite scavengers, blocking either peroxynitrite anion-mediated thiol oxidations or phenol/tyrosine nitrations by free radical mechanisms. Dithiopurines and dithiopyrimidines were highly effective in inhibiting both reaction types which could make this class of compounds interesting therapeutic tools. In the present work, we highlighted the impact of experimental conditions on the outcome of peroxynitrite-mediated nitrations. The limitations identified in this work need to be considered in the assessment of experimental data involving peroxynitrite. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Comparative Analysis of Serum (Anti)oxidative Status Parаmeters in Healthy Persons
Int. J. Mol. Sci. 2013, 14(3), 6106-6115; doi:10.3390/ijms14036106
Received: 31 December 2012 / Revised: 5 March 2013 / Accepted: 7 March 2013 / Published: 18 March 2013
Cited by 14 | PDF Full-text (204 KB) | HTML Full-text | XML Full-text
Abstract
Five antioxidant and two oxidative stress assays were applied to serum samples of 43 healthy males. The antioxidant tests showed different inter-assay correlations. A very good correlation of 0.807 was observed between the ferric reducing ability of plasma (FRAP) and total antioxidant [...] Read more.
Five antioxidant and two oxidative stress assays were applied to serum samples of 43 healthy males. The antioxidant tests showed different inter-assay correlations. A very good correlation of 0.807 was observed between the ferric reducing ability of plasma (FRAP) and total antioxidant status (TAS) assay and also a fair correlation of 0.501 between the biological antioxidant potential (BAP) and TAS assay. There was no statistically significant correlation between the BAP and FRAP assay. The anti-oxidant assays have a high correlation with uric acid, especially the TAS (0.922) and FRAP assay (0.869). The BAP assay has a much lower and no statistically significant correlation with uric acid (0.302), which makes BAP more suitable for the antioxidant status. The total thiol assay showed no statistically significant correlation with uric acid (0.114). The total thiol assay, which is based on a completely different principle, showed a good and statistically significant correlation with the BAP assay (0.510) and also to the TAS assay, but to a lower and not significant extent (0.279) and not with the FRAP assay (−0.008). The oxy-adsorbent test (OXY) assay has no correlation with any of the other assays tested. The oxidative stress assays, reactive oxygen metabolites (ROM) and total oxidant status (TOS), based on a different principle, do not show a statistically significant correlation with the serum samples in this study. Both assays showed a negative, but not significant, correlation with the antioxidant assays. In conclusion, the ROM, TOS, BAP and TTP assays are based on different principles and will have an additional value when a combination of these assays will be applied in large-scale population studies. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Global Gene Expression Profiling Reveals Functional Importance of Sirt2 in Endothelial Cells under Oxidative Stress
Int. J. Mol. Sci. 2013, 14(3), 5633-5649; doi:10.3390/ijms14035633
Received: 19 December 2012 / Revised: 22 February 2013 / Accepted: 28 February 2013 / Published: 11 March 2013
Cited by 9 | PDF Full-text (456 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The NAD+-dependent deacetylases Sirt1 and Sirt2 mediate cellular stress responses and are highly expressed in vascular endothelial cells. In contrast to the well-documented protective actions of Sirt1, the role of endothelial Sirt2 remains unknown. Using cDNA microarray and PCR validation, [...] Read more.
The NAD+-dependent deacetylases Sirt1 and Sirt2 mediate cellular stress responses and are highly expressed in vascular endothelial cells. In contrast to the well-documented protective actions of Sirt1, the role of endothelial Sirt2 remains unknown. Using cDNA microarray and PCR validation, we examined global gene expression changes in response to Sirt2 knock down in primary human umbilical vein endothelial cells under oxidative stress. We found that Sirt2 knock down changed expression of 340 genes, which are mainly involved in cellular processes including actin binding, cellular amino acid metabolic process, transmembrane receptor protein serine/threonine kinase signaling, ferrous iron transport, protein transport and localization, cell morphogenesis, and functions associated with endosome membrane and the trans-Golgi network. These genes and associated functions were largely non-overlapping with those altered by Sirt1 knock down. Moreover, we showed that pharmacological inhibition of Sirt2 attenuated oxidant-induced cell toxicity in endothelial cells. These suggest that Sirt2 is functionally important in endothelial cells under oxidative stress, and may have a primarily distinct role as compared to Sirt1. Our results may provide a basis for future studies aiming to dissect the specific signaling pathway(s) that mediates specific Sirt2 functions in endothelial cells. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Cyclic Stretch Induces Inducible Nitric Oxide Synthase and Soluble Guanylate Cyclase in Pulmonary Artery Smooth Muscle Cells
Int. J. Mol. Sci. 2013, 14(2), 4334-4348; doi:10.3390/ijms14024334
Received: 31 December 2012 / Revised: 12 February 2013 / Accepted: 17 February 2013 / Published: 21 February 2013
Cited by 6 | PDF Full-text (581 KB) | HTML Full-text | XML Full-text
Abstract
In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express [...] Read more.
In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express inducible nitric oxide synthase (iNOS), and while iNOS expression increases during late gestation, little is known about how cyclic stretch impacts this pathway. In this study, PASMC were subjected to cyclic stretch of 20% amplitude and frequency of 1 Hz for 24 h and compared to control cells maintained under static conditions. Cyclic stretch significantly increased cytosolic oxidative stress as compared to static cells (62.9 ± 5.9% vs. 33.3 ± 5.7% maximal oxidation), as measured by the intracellular redox sensor roGFP. Cyclic stretch also increased sGCβ protein expression (2.5 ± 0.9-fold), sGC activity (1.5 ± 0.2-fold) and cGMP levels (1.8 ± 0.2-fold), as well as iNOS mRNA and protein expression (3.0 ± 0.9 and 2.6 ± 0.7-fold, respectively) relative to control cells. An antioxidant, recombinant human superoxide dismutase (rhSOD), significantly decreased stretch-induced cytosolic oxidative stress, but did not block stretch-induced sGC activity. Inhibition of iNOS with 1400 W or an iNOS-specific siRNA inhibited stretch-induced sGC activity by 30% and 68% respectively vs. static controls. In conclusion, cyclic stretch increases sGC expression and activity in an iNOS-dependent manner in PASMC from fetal lambs. The mechanism that produces iNOS and sGC upregulation is not yet known, but we speculate these effects represent an early compensatory mechanism to counteract the effects of stretch-induced oxidative stress. A better understanding of the interplay between these two distinct pathways could provide key insights into future avenues to treat infants with pulmonary hypertension. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle The Environmental Pollutant Cadmium Promotes Influenza Virus Replication in MDCK Cells by Altering Their Redox State
Int. J. Mol. Sci. 2013, 14(2), 4148-4162; doi:10.3390/ijms14024148
Received: 27 December 2012 / Revised: 4 February 2013 / Accepted: 6 February 2013 / Published: 19 February 2013
Cited by 9 | PDF Full-text (2561 KB) | HTML Full-text | XML Full-text
Abstract
Cadmium (Cd) is a toxic heavy metal that is considered an environmental contaminant. Several sources of human exposure to Cd, including employment in primary metal industries, production of certain batteries, foods, soil and cigarette smoke, are known. Its inhalation has been related [...] Read more.
Cadmium (Cd) is a toxic heavy metal that is considered an environmental contaminant. Several sources of human exposure to Cd, including employment in primary metal industries, production of certain batteries, foods, soil and cigarette smoke, are known. Its inhalation has been related to different respiratory diseases and toxic effects, among which alterations of the physiological redox state in individuals exposed to the metal have been described. Host-cell redox changes characteristic of oxidative stress facilitate the progression of viral infection through different mechanisms. In this paper, we have demonstrated that pre-treatment with CdCl2 of MDCK cells increased influenza virus replication in a dose-dependent manner. This phenomenon was related to increased viral protein expression (about 40% compared with untreated cells). The concentration of CdCl2, able to raise the virus titer, also induced oxidative stress. The addition of two antioxidants, a glutathione (GSH) derivative or the GSH precursor, N-acetyl-L-cysteine, to Cd pre-treated and infected cells restored the intracellular redox state and significantly inhibited viral replication. In conclusion, our data demonstrate that Cd-induced oxidative stress directly increases the ability of influenza virus to replicate in the host-cell, thus suggesting that exposure to heavy metals, such as this, could be a risk factor for individuals exposed to a greater extent to the contaminant, resulting in increased severity of virus-induced respiratory diseases. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessArticle Phenotypic Identification of the Redox Dye Methylene Blue as an Antagonist of Heat Shock Response Gene Expression in Metastatic Melanoma Cells
Int. J. Mol. Sci. 2013, 14(2), 4185-4202; doi:10.3390/ijms14024185
Received: 5 January 2013 / Revised: 24 January 2013 / Accepted: 29 January 2013 / Published: 19 February 2013
Cited by 5 | PDF Full-text (1647 KB) | HTML Full-text | XML Full-text
Abstract
Repurposing approved and abandoned non-oncological drugs is an alternative developmental strategy for the identification of anticancer therapeutics that has recently attracted considerable attention. Due to the essential role of the cellular heat shock response in cytoprotection through the maintenance of proteostasis and [...] Read more.
Repurposing approved and abandoned non-oncological drugs is an alternative developmental strategy for the identification of anticancer therapeutics that has recently attracted considerable attention. Due to the essential role of the cellular heat shock response in cytoprotection through the maintenance of proteostasis and suppression of apoptosis, small molecule heat shock response antagonists can be harnessed for targeted induction of cytotoxic effects in cancer cells. Guided by gene expression array analysis and a phenotypic screen interrogating a collection of 3,7-diamino-phenothiazinium derivatives, we have identified the redox-drug methylene blue (MB), used clinically for the infusional treatment of methemoglobinemia, as a negative modulator of heat shock response gene expression in human metastatic melanoma cells. MB-treatment blocked thermal (43 °C) and pharmacological (celastrol, geldanamycin) induction of heat shock response gene expression, suppressing Hsp70 (HSPA1A) and Hsp27 (HSPB1) upregulation at the mRNA and protein level. MB sensitized melanoma cells to the apoptogenic activity of geldanamycin, an Hsp90 antagonist known to induce the counter-regulatory upregulation of Hsp70 expression underlying cancer cell resistance to geldanamycin chemotherapy. Similarly, MB-cotreatment sensitized melanoma cells to other chemotherapeutics (etoposide, doxorubicin). Taken together, these data suggest feasibility of repurposing the non-oncological redox drug MB as a therapeutic heat shock response antagonist for cancer cell chemosensitization. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessArticle Identification of Oxidative Stress Related Proteins as Biomarkers for Lung Cancer and Chronic Obstructive Pulmonary Disease in Bronchoalveolar Lavage
Int. J. Mol. Sci. 2013, 14(2), 3440-3455; doi:10.3390/ijms14023440
Received: 24 December 2012 / Revised: 23 January 2013 / Accepted: 31 January 2013 / Published: 6 February 2013
Cited by 11 | PDF Full-text (851 KB) | HTML Full-text | XML Full-text
Abstract
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved [...] Read more.
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. Cigarette smoke causes oxidative stress and an inflammatory response in lung cells, which in turn may be involved in COPD and lung cancer development. The aim of this study was to identify differential proteomic profiles related to oxidative stress response that were potentially involved in these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC, and control (neither COPD nor LC). Proteins were separated into spots by two dimensional polyacrylamide gel electrophoresis (2D-PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 16 oxidative stress regulatory proteins were differentially expressed in BAL samples from LC and/or COPD patients as compared with the control group. A distinct proteomic reactive oxygen species (ROS) protein signature emerged that characterized lung cancer and COPD. In conclusion, our findings highlight the role of the oxidative stress response proteins in the pathogenic pathways of both diseases, and provide new candidate biomarkers and predictive tools for LC and COPD diagnosis. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Review

Jump to: Research

Open AccessReview Defective Homocysteine Metabolism: Potential Implications for Skeletal Muscle Malfunction
Int. J. Mol. Sci. 2013, 14(7), 15074-15091; doi:10.3390/ijms140715074
Received: 27 May 2013 / Revised: 24 June 2013 / Accepted: 11 July 2013 / Published: 18 July 2013
Cited by 20 | PDF Full-text (274 KB) | HTML Full-text | XML Full-text
Abstract
Hyperhomocysteinemia (HHcy) is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy) metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular [...] Read more.
Hyperhomocysteinemia (HHcy) is a systemic medical condition and has been attributed to multi-organ pathologies. Genetic, nutritional, hormonal, age and gender differences are involved in abnormal homocysteine (Hcy) metabolism that produces HHcy. Homocysteine is an intermediate for many key processes such as cellular methylation and cellular antioxidant potential and imbalances in Hcy production and/or catabolism impacts gene expression and cell signaling including GPCR signaling. Furthermore, HHcy might damage the vagus nerve and superior cervical ganglion and affects various GPCR functions; therefore it can impair both the parasympathetic and sympathetic regulation in the blood vessels of skeletal muscle and affect long-term muscle function. Understanding cellular targets of Hcy during HHcy in different contexts and its role either as a primary risk factor or as an aggravator of certain disease conditions would provide better interventions. In this review we have provided recent Hcy mediated mechanistic insights into different diseases and presented potential implications in the context of reduced muscle function and integrity. Overall, the impact of HHcy in various skeletal muscle malfunctions is underappreciated; future studies in this area will provide deeper insights and improve our understanding of the association between HHcy and diminished physical function. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessReview Obesity-Associated Oxidative Stress: Strategies Finalized to Improve Redox State
Int. J. Mol. Sci. 2013, 14(5), 10497-10538; doi:10.3390/ijms140510497
Received: 16 February 2013 / Revised: 18 April 2013 / Accepted: 6 May 2013 / Published: 21 May 2013
Cited by 51 | PDF Full-text (631 KB) | HTML Full-text | XML Full-text
Abstract
Obesity represents a major risk factor for a plethora of severe diseases, including diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and cancer. It is often accompanied by an increased risk of mortality and, in the case of non-fatal health problems, the quality [...] Read more.
Obesity represents a major risk factor for a plethora of severe diseases, including diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and cancer. It is often accompanied by an increased risk of mortality and, in the case of non-fatal health problems, the quality of life is impaired because of associated conditions, including sleep apnea, respiratory problems, osteoarthritis, and infertility. Recent evidence suggests that oxidative stress may be the mechanistic link between obesity and related complications. In obese patients, antioxidant defenses are lower than normal weight counterparts and their levels inversely correlate with central adiposity; obesity is also characterized by enhanced levels of reactive oxygen or nitrogen species. Inadequacy of antioxidant defenses probably relies on different factors: obese individuals may have a lower intake of antioxidant- and phytochemical-rich foods, such as fruits, vegetables, and legumes; otherwise, consumption of antioxidant nutrients is normal, but obese individuals may have an increased utilization of these molecules, likewise to that reported in diabetic patients and smokers. Also inadequate physical activity may account for a decreased antioxidant state. In this review, we describe current concepts in the meaning of obesity as a state of chronic oxidative stress and the potential interventions to improve redox balance. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessReview Targeting the Redox Balance in Inflammatory Skin Conditions
Int. J. Mol. Sci. 2013, 14(5), 9126-9167; doi:10.3390/ijms14059126
Received: 1 March 2013 / Revised: 10 April 2013 / Accepted: 16 April 2013 / Published: 26 April 2013
Cited by 20 | PDF Full-text (359 KB) | HTML Full-text | XML Full-text
Abstract
Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular [...] Read more.
Reactive oxygen species (ROS) can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic) antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessReview Mitochondria and Reactive Oxygen Species: Physiology and Pathophysiology
Int. J. Mol. Sci. 2013, 14(3), 6306-6344; doi:10.3390/ijms14036306
Received: 10 January 2013 / Revised: 8 March 2013 / Accepted: 11 March 2013 / Published: 19 March 2013
Cited by 33 | PDF Full-text (1223 KB) | HTML Full-text | XML Full-text
Abstract
The air that we breathe contains nearly 21% oxygen, most of which is utilized by mitochondria during respiration. While we cannot live without it, it was perceived as a bane to aerobic organisms due to the generation of reactive oxygen and nitrogen [...] Read more.
The air that we breathe contains nearly 21% oxygen, most of which is utilized by mitochondria during respiration. While we cannot live without it, it was perceived as a bane to aerobic organisms due to the generation of reactive oxygen and nitrogen metabolites by mitochondria and other cellular compartments. However, this dogma was challenged when these species were demonstrated to modulate cellular responses through altering signaling pathways. In fact, since this discovery of a dichotomous role of reactive species in immune function and signal transduction, research in this field grew at an exponential pace and the pursuit for mechanisms involved began. Due to a significant number of review articles present on the reactive species mediated cell death, we have focused on emerging novel pathways such as autophagy, signaling and maintenance of the mitochondrial network. Despite its role in several processes, increased reactive species generation has been associated with the origin and pathogenesis of a plethora of diseases. While it is tempting to speculate that anti-oxidant therapy would protect against these disorders, growing evidence suggests that this may not be true. This further supports our belief that these reactive species play a fundamental role in maintenance of cellular and tissue homeostasis. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessReview Cadmium-Induced Pathologies: Where Is the Oxidative Balance Lost (or Not)?
Int. J. Mol. Sci. 2013, 14(3), 6116-6143; doi:10.3390/ijms14036116
Received: 24 December 2012 / Revised: 4 February 2013 / Accepted: 20 February 2013 / Published: 18 March 2013
Cited by 44 | PDF Full-text (717 KB) | HTML Full-text | XML Full-text
Abstract
Over the years, anthropogenic factors have led to cadmium (Cd) accumulation in the environment causing various health problems in humans. Although Cd is not a Fenton-like metal, it induces oxidative stress in various animal models via indirect mechanisms. The degree of Cd-induced [...] Read more.
Over the years, anthropogenic factors have led to cadmium (Cd) accumulation in the environment causing various health problems in humans. Although Cd is not a Fenton-like metal, it induces oxidative stress in various animal models via indirect mechanisms. The degree of Cd-induced oxidative stress depends on the dose, duration and frequency of Cd exposure. Also the presence or absence of serum in experimental conditions, type of cells and their antioxidant capacity, as well as the speciation of Cd are important determinants. At the cellular level, the Cd-induced oxidative stress either leads to oxidative damage or activates signal transduction pathways to initiate defence responses. This balance is important on how different organ systems respond to Cd stress and ultimately define the pathological outcome. In this review, we highlight the Cd-induced oxidant/antioxidant status as well as the damage versus signalling scenario in relation to Cd toxicity. Emphasis is addressed to Cd-induced pathologies of major target organs, including a section on cell proliferation and carcinogenesis. Furthermore, attention is paid to Cd-induced oxidative stress in undifferentiated stem cells, which can provide information for future therapies in preventing Cd-induced pathologies. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessReview The Role of Metallothionein in Oxidative Stress
Int. J. Mol. Sci. 2013, 14(3), 6044-6066; doi:10.3390/ijms14036044
Received: 14 January 2013 / Revised: 14 February 2013 / Accepted: 20 February 2013 / Published: 15 March 2013
Cited by 81 | PDF Full-text (1712 KB) | HTML Full-text | XML Full-text
Abstract
Free radicals are chemical particles containing one or more unpaired electrons, which may be part of the molecule. They cause the molecule to become highly reactive. The free radicals are also known to play a dual role in biological systems, as they [...] Read more.
Free radicals are chemical particles containing one or more unpaired electrons, which may be part of the molecule. They cause the molecule to become highly reactive. The free radicals are also known to play a dual role in biological systems, as they can be either beneficial or harmful for living systems. It is clear that there are numerous mechanisms participating on the protection of a cell against free radicals. In this review, our attention is paid to metallothioneins (MTs) as small, cysteine-rich and heavy metal-binding proteins, which participate in an array of protective stress responses. The mechanism of the reaction of metallothioneins with oxidants and electrophilic compounds is discussed. Numerous reports indicate that MT protects cells from exposure to oxidants and electrophiles, which react readily with sulfhydryl groups. Moreover, MT plays a key role in regulation of zinc levels and distribution in the intracellular space. The connections between zinc, MT and cancer are highlighted. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessReview Interplay between Hepatitis C Virus and Redox Cell Signaling
Int. J. Mol. Sci. 2013, 14(3), 4705-4721; doi:10.3390/ijms14034705
Received: 17 January 2013 / Revised: 13 February 2013 / Accepted: 17 February 2013 / Published: 26 February 2013
Cited by 6 | PDF Full-text (242 KB) | HTML Full-text | XML Full-text
Abstract
Hepatitis C virus (HCV) infects approximately 3% of the world’s population. Currently licensed treatment of HCV chronic infection with pegylated-interferon-α and ribavirin, is not fully effective against all HCV genotypes and is associated to severe side effects. Thus, development of novel therapeutics [...] Read more.
Hepatitis C virus (HCV) infects approximately 3% of the world’s population. Currently licensed treatment of HCV chronic infection with pegylated-interferon-α and ribavirin, is not fully effective against all HCV genotypes and is associated to severe side effects. Thus, development of novel therapeutics and identification of new targets for treatment of HCV infection is necessary. Current opinion is orienting to target antiviral drug discovery to the host cell pathways on which the virus relies, instead of against viral structures. Many intracellular signaling pathways manipulated by HCV for its own replication are finely regulated by the oxido-reductive (redox) state of the host cell. At the same time, HCV induces oxidative stress that has been found to affect both virus replication as well as progression and severity of HCV infection. A dual role, positive or negative, for the host cell oxidized conditions on HCV replication has been reported so far. This review examines current information about the effect of oxidative stress on HCV life cycle and the main redox-regulated intracellular pathways activated during HCV infection and involved in its replication. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessReview Annexin A2: The Importance of Being Redox Sensitive
Int. J. Mol. Sci. 2013, 14(2), 3568-3594; doi:10.3390/ijms14023568
Received: 6 January 2013 / Revised: 30 January 2013 / Accepted: 31 January 2013 / Published: 7 February 2013
Cited by 13 | PDF Full-text (1002 KB) | HTML Full-text | XML Full-text
Abstract
Hydrogen peroxide (H2O2) is an important second messenger in cellular signal transduction. H2O2-dependent signalling regulates many cellular processes, such as proliferation, differentiation, migration and apoptosis. Nevertheless, H2O2 is an oxidant and [...] Read more.
Hydrogen peroxide (H2O2) is an important second messenger in cellular signal transduction. H2O2-dependent signalling regulates many cellular processes, such as proliferation, differentiation, migration and apoptosis. Nevertheless, H2O2 is an oxidant and a major contributor to DNA damage, protein oxidation and lipid peroxidation, which can ultimately result in cell death and/or tumourigenesis. For this reason, cells have developed complex antioxidant systems to scavenge ROS. Recently, our laboratory identified the protein, annexin A2, as a novel cellular redox regulatory protein. Annexin A2 possesses a reactive cysteine residue (Cys-8) that is readily oxidized by H2O2 and subsequently reduced by the thioredoxin system, thereby enabling annexin A2 to participate in multiple redox cycles. Thus, a single molecule of annexin A2 can inactivate several molecules of H2O2. In this report, we will review the studies detailing the reactivity of annexin A2 thiols and the importance of these reactive cysteine(s) in regulating annexin A2 structure and function. We will also focus on the recent reports that establish novel functions for annexin A2, namely as a protein reductase and as a cellular redox regulatory protein. We will further discuss the importance of annexin A2 redox regulatory function in disease, with a particular focus on tumour progression. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessReview NADPH Oxidase Biology and the Regulation of Tyrosine Kinase Receptor Signaling and Cancer Drug Cytotoxicity
Int. J. Mol. Sci. 2013, 14(2), 3683-3704; doi:10.3390/ijms14023683
Received: 24 December 2012 / Revised: 28 January 2013 / Accepted: 31 January 2013 / Published: 7 February 2013
Cited by 20 | PDF Full-text (477 KB) | HTML Full-text | XML Full-text
Abstract
The outdated idea that reactive oxygen species (ROS) are only dangerous products of cellular metabolism, causing toxic and mutagenic effects on cellular components, is being replaced by the view that ROS have several important functions in cell signaling. In aerobic organisms, ROS [...] Read more.
The outdated idea that reactive oxygen species (ROS) are only dangerous products of cellular metabolism, causing toxic and mutagenic effects on cellular components, is being replaced by the view that ROS have several important functions in cell signaling. In aerobic organisms, ROS can be generated from different sources, including the mitochondrial electron transport chain, xanthine oxidase, myeloperoxidase, and lipoxygenase, but the only enzyme family that produces ROS as its main product is the NADPH oxidase family (NOX enzymes). These transfer electrons from NADPH (converting it to NADP) to oxygen to make O2•−. Due to their stability, the products of NADPH oxidase, hydrogen peroxide, and superoxide are considered the most favorable ROS to act as signaling molecules. Transcription factors that regulate gene expression involved in carcinogenesis are modulated by NADPH oxidase, and it has emerged as a promising target for cancer therapies. The present review discusses the mechanisms by which NADPH oxidase regulates signal transduction pathways in view of tyrosine kinase receptors, which are pivotal to regulating the hallmarks of cancer, and how ROS mediate the cytotoxicity of several cancer drugs employed in clinical practice. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
Open AccessReview Oxidative Folding in the Mitochondrial Intermembrane Space in Human Health and Disease
Int. J. Mol. Sci. 2013, 14(2), 2916-2927; doi:10.3390/ijms14022916
Received: 21 December 2012 / Revised: 21 January 2013 / Accepted: 23 January 2013 / Published: 30 January 2013
Cited by 5 | PDF Full-text (279 KB) | HTML Full-text | XML Full-text
Abstract
Oxidative folding in the mitochondrial intermembrane space (IMS) is a key cellular event associated with the folding and import of a large and still undetermined number of proteins. This process is catalyzed by an oxidoreductase, Mia40 that is able to recognize substrates [...] Read more.
Oxidative folding in the mitochondrial intermembrane space (IMS) is a key cellular event associated with the folding and import of a large and still undetermined number of proteins. This process is catalyzed by an oxidoreductase, Mia40 that is able to recognize substrates with apparently little or no homology. Following substrate oxidation, Mia40 is reduced and must be reoxidized by Erv1/Alr1 that consequently transfers the electrons to the mitochondrial respiratory chain. Although our understanding of the physiological relevance of this process is still limited, an increasing number of pathologies are being associated with the impairment of this pathway; especially because oxidative folding is fundamental for several of the proteins involved in defense against oxidative stress. Here we review these aspects and discuss recent findings suggesting that oxidative folding in the IMS is modulated by the redox state of the cell. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)
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Open AccessReview Disease Progression Mediated by Egr-1 Associated Signaling in Response to Oxidative Stress
Int. J. Mol. Sci. 2012, 13(10), 13104-13117; doi:10.3390/ijms131013104
Received: 2 August 2012 / Revised: 4 October 2012 / Accepted: 9 October 2012 / Published: 12 October 2012
Cited by 15 | PDF Full-text (239 KB) | HTML Full-text | XML Full-text
Abstract
When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the [...] Read more.
When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the initiation and/or to the progression of atherosclerosis, tumors or pulmonary hypertension; diseases that are decisively furthered by the presence of oxidizing agents. Redox sensitive genes, like the zinc finger transcription factor early growth response 1 (Egr-1), play a pivotal role in the pathophysiology of these diseases. Apart from inducing apoptosis, signaling partners like the MEK/ERK pathway or the protein kinase C (PKC) can activate salvage programs such as cell proliferation that do not ameliorate, but rather worsen their outcome. Here, we review the currently available data on Egr-1 related signal transduction cascades in response to oxidative stress in the progression of epidemiologically significant diseases. Knowing the molecular pathways behind the pathology will greatly enhance our ability to identify possible targets for the development of new therapeutic strategies. Full article
(This article belongs to the Special Issue Redox Signaling in Biology and Patho-Biology)

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