Oxidative Medicine and Cellular Longevity http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice Tue, 05 May 2015 13:28:22 +0000 http://www.hindawi.com/journals/omcl/2015/605208/ The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT pathways. Ashok Kumar Pandurangan, Salmiah Ismail, Zeinab Saadatdoust, and Norhaizan Mohd. Esa Copyright © 2015 Ashok Kumar Pandurangan et al. All rights reserved. Sirtuin Functions in Female Fertility: Possible Role in Oxidative Stress and Aging Tue, 05 May 2015 12:50:50 +0000 http://www.hindawi.com/journals/omcl/2015/659687/ In search for strategies aimed at preventing oxidative threat to female fertility, a possible role of sirtuins has emerged. Sirtuins (silent information regulator 2 (Sir2) proteins), NAD+ dependent enzymes with deacetylase and/or mono-ADP-ribosyltransferase activity, are emerging as key antiaging molecules and regulators in many diseases. Recently, a crucial role for SIRT1 and SIRT3, the main components of sirtuin family, as sensors and guardians of the redox state in oocytes, granulosa cells, and early embryos has emerged. In this context, the aim of the present review is to summarize current knowledge from research papers on the role of sirtuins in female fertility with particular emphasis on the impairment of SIRT1 signalling with oocyte aging. On this basis, the authors wish to build up a framework to promote research on the possible role of sirtuins as targets for future strategies for female fertility preservation. Carla Tatone, Giovanna Di Emidio, Maurizio Vitti, Michela Di Carlo, Silvano Santini Jr., Anna Maria D’Alessandro, Stefano Falone, and Fernanda Amicarelli Copyright © 2015 Carla Tatone et al. All rights reserved. Thiosemicarbazone p-Substituted Acetophenone Derivatives Promote the Loss of Mitochondrial , GSH Depletion, and Death in K562 Cells Tue, 05 May 2015 08:15:49 +0000 http://www.hindawi.com/journals/omcl/2015/394367/ A series of thiosemicarbazone (TSC) p-substituted acetophenone derivatives were synthesized and chemically characterized. The p-substituents appended to the phenyl group of the TSC structures were hydrogen, fluor, chlorine, methyl, and nitro, producing compounds named TSC-H, TSC-F, TSC-Cl, TSC-Me, and TSC-NO2, respectively. The TSC compounds were evaluated for their capacity to induce mitochondrial permeability, to deplete mitochondrial thiol content, and to promote cell death in the K562 cell lineage using flow cytometry and fluorescence microscopy. TSC-H, TSC-F, and TSC-Cl exhibited a bell-shaped dose-response curve for the induction of apoptosis in K562 cells due to the change from apoptosis to necrosis as the principal mechanism of cell death at the highest tested doses. TSC-Me and TSC-NO2 exhibited a typical dose-response profile, with a half maximal effective concentration of approximately 10 µM for cell death. Cell death was also evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which revealed lower toxicity of these compounds for peripheral blood mononuclear cells than for K562 cells. The possible mechanisms leading to cell death are discussed based on the observed effects of the new TSC compounds on the cellular thiol content and on mitochondrial bioenergetics. Felipe S. Pessoto, Cesar H. Yokomizo, Tatiana Prieto, Cleverton S. Fernandes, Alan P. Silva, Carlos R. Kaiser, Ernani A. Basso, and Iseli L. Nantes Copyright © 2015 Felipe S. Pessoto et al. All rights reserved. TSG (2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside) from the Chinese Herb Polygonum multiflorum Increases Life Span and Stress Resistance of Caenorhabditis elegans Tue, 05 May 2015 06:46:48 +0000 http://www.hindawi.com/journals/omcl/2015/124357/ 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) was isolated from Polygonum multiflorum, a plant which is traditionally used as an anti-ageing drug. We have analysed ageing-related effects of TSG in the model organism C. elegans in comparison to resveratrol. TSG exerted a high antioxidative capacity both in a cell-free assay and in the nematode. The antioxidative capacity was even higher compared to resveratrol. Presumably due to its antioxidative effects, treatment with TSG decreased the juglone-mediated induction of the antioxidative enzyme SOD-3; the induction of the GST-4 by juglone was diminished slightly. TSG increased the resistance of C. elegans against lethal thermal stress more prominently than resveratrol (50 μM TSG increased mean survival by 22.2%). The level of the ageing pigment lipofuscin was decreased after incubation with the compound. TSG prolongs the mean, median, and maximum adult life span of C. elegans by 23.5%, 29.4%, and 7.2%, respectively, comparable to the effects of resveratrol. TSG-mediated extension of life span was not abolished in a DAF-16 loss-of-function mutant strain showing that this ageing-related transcription factor is not involved in the effects of TSG. Our data show that TSG possesses a potent antioxidative capacity, enhances the stress resistance, and increases the life span of the nematode C. elegans. Christian Büchter, Liang Zhao, Susannah Havermann, Sebastian Honnen, Gerhard Fritz, Peter Proksch, and Wim Wätjen Copyright © 2015 Christian Büchter et al. All rights reserved. Arginase as a Critical Prooxidant Mediator in the Binomial Endothelial Dysfunction-Atherosclerosis Mon, 04 May 2015 12:46:18 +0000 http://www.hindawi.com/journals/omcl/2015/924860/ Arginase is a metalloenzyme which hydrolyzes L-arginine to L-ornithine and urea. Since its discovery, in the early 1900s, this enzyme has gained increasing attention, as literature reports have progressively pointed to its critical participation in regulating nitric oxide bioavailability. Indeed, accumulating evidence in the following years would picture arginase as a key player in vascular health. Recent studies have highlighted the arginase regulatory role in the progression of atherosclerosis, the latter an essentially prooxidant state. Apart from the fact that arginase has been proven to impair different metabolic pathways, and also as a consequence of this, the repercussions of the actions of such enzyme go further than first thought. In fact, such metalloenzyme exhibits direct implications in multiple cardiometabolic diseases, among which are hypertension, type 2 diabetes, and hypercholesterolemia. Considering the epidemiological repercussions of these clinical conditions, arginase is currently seen under the spotlights of the search for developing specific inhibitors, in order to mitigate its deleterious effects. That said, the present review focuses on the role of arginase in endothelial function and its participation in the establishment of atherosclerotic lesions, discussing the main regulatory mechanisms of the enzyme, also highlighting the potential development of pharmacological strategies in related cardiovascular diseases. Luiza A. Rabelo, Fernanda O. Ferreira, Valéria Nunes-Souza, Lucas José Sá da Fonseca, and Marília O. F. Goulart Copyright © 2015 Luiza A. Rabelo et al. All rights reserved. The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells Sun, 03 May 2015 09:38:40 +0000 http://www.hindawi.com/journals/omcl/2015/792342/ We previously found that Ratanasampil (RNSP), a traditional Tibetan medicine, improves the cognitive function of mild-to-moderate AD patients living at high altitude, as well as learning and memory in an AD mouse model (Tg2576); however, mechanism underlying the effects of RNSP is unknown. In the present study, we investigated the effects and molecular mechanisms of RNSP on oxidative stress-induced neuronal toxicity using human neuroblastoma SH-SY5Y cells. Pretreatment with RNSP significantly ameliorated the hydrogen peroxide- (H2O2-) induced cytotoxicity of SH-SY5Y cells in a dose-dependent manner (up to 60 μg/mL). Furthermore, RNSP significantly reduced the H2O2-induced upregulation of 8-oxo-2′-deoxyguanosine (8-oxo-dG, the oxidative DNA damage marker) but significantly reversed the expression of repressor element-1 silencing transcription factor (REST) from H2O2 associated (100 μM) downregulation. Moreover, RNSP significantly attenuated the H2O2-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in SH-SY5Y cells. These observations strongly suggest that RNSP may protect the oxidative stress-induced neuronal damage that occurs through the properties of various antioxidants and inhibit the activation of MAPKs. We thus provide the principle molecular mechanisms of the effects of RNSP and indicate its role in the prevention and clinical management of AD. Aiqin Zhu, Zhou Wu, Jie Meng, Patrick L. McGeer, Yi Zhu, Hiroshi Nakanishi, and Shizheng Wu Copyright © 2015 Aiqin Zhu et al. All rights reserved. Impact of Atmospheric Microparticles on the Development of Oxidative Stress in Healthy City/Industrial Seaport Residents Thu, 30 Apr 2015 17:21:08 +0000 http://www.hindawi.com/journals/omcl/2015/412173/ Atmospheric microsized particles producing reactive oxygen species can pose a serious health risk for city residents. We studied the responses of organisms to microparticles in 255 healthy volunteers living in areas with different levels of microparticle air pollution. We analyzed the distribution of microparticles in snow samples by size and content. ELISA and flow cytometry methods were employed to determine the parameters of the thiol-disulfide metabolism, peroxidation and antioxidant, genotoxicity, and energy state of the leukocytes. We found that, in the park areas, microparticles with a size of 800 μm or more were predominant (96%), while in the industrial areas, they tended to be less than 50 μm (93%), including size 200–300 nm (7%). In the industrial areas, we determined the oxidative modification of proteins (21% compared to the park areas, ) and DNA (12%, ), as well as changes in leukocytes’ energy potential (53%, ). An increase in total antioxidant activity (82%, ) and thiol-disulfide system response (thioredoxin increasing by 33%, ; glutathione, 30%, with stable reductases levels) maintains a balance of peroxidation-antioxidant processes, protecting cellular and subcellular structures from significant oxidative damage. Kirill Golokhvast, Tatyana Vitkina, Tatyana Gvozdenko, Victor Kolosov, Vera Yankova, Elena Kondratieva, Anna Gorkavaya, Anna Nazarenko, Vladimir Chaika, Tatyana Romanova, Alexander Karabtsov, Juliy Perelman, Pavel Kiku, and Aristidis Tsatsakis Copyright © 2015 Kirill Golokhvast et al. All rights reserved. Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage Wed, 29 Apr 2015 12:35:31 +0000 http://www.hindawi.com/journals/omcl/2015/240918/ Multiple sclerosis (MS) is the autoimmune disease of the central nervous system with complex pathogenesis, different clinical courses and recurrent neurological relapses and/or progression. Despite various scientific papers that focused on early stage of MS, our study targets selective group of late stage secondary progressive MS patients. The presented work is concerned with the reactivity of blood platelets in primary hemostasis in SP MS patients. 50 SP MS patients and 50 healthy volunteers (never diagnosed with MS or other chronic diseases) were examined to evaluate the biological activity of blood platelets (adhesion, aggregation), especially their response to the most important physiological agonists (thrombin, ADP, and collagen) and the effect of oxidative stress on platelet activity. We found that the blood platelets from SP MS patients were significantly more sensitive to all used agonists in comparison with control group. Moreover, the platelet hemostatic function was advanced in patients suffering from SP MS and positively correlated with increased production of in these cells, as well as with Expanded Disability Status Scale. We postulate that the increased oxidative stress in blood platelets in SP MS may be primarily responsible for the altered haemostatic properties of blood platelets. Agnieszka Morel, Michał Bijak, Elżbieta Miller, Joanna Rywaniak, Sergiusz Miller, and Joanna Saluk Copyright © 2015 Agnieszka Morel et al. All rights reserved. Antioxidant Mechanisms and ROS-Related MicroRNAs in Cancer Stem Cells Wed, 29 Apr 2015 09:22:59 +0000 http://www.hindawi.com/journals/omcl/2015/425708/ Increasing evidence indicates that most of the tumors are sustained by a distinct population of cancer stem cells (CSCs), which are responsible for growth, metastasis, invasion, and recurrence. CSCs are typically characterized by self-renewal, the key biological process allowing continuous tumor proliferation, as well as by differentiation potential, which leads to the formation of the bulk of the tumor mass. CSCs have several advantages over the differentiated cancer cell populations, including the resistance to radio- and chemotherapy, and their gene-expression programs have been shown to correlate with poor clinical outcome, further supporting the relevance of stemness properties in cancer. The observation that CSCs possess enhanced mechanisms of protection from reactive oxygen species (ROS) induced stress and a different metabolism from the differentiated part of the tumor has paved the way to develop drugs targeting CSC specific signaling. In this review, we describe the role of ROS and of ROS-related microRNAs in the establishment and maintenance of self-renewal and differentiation capacities of CSCs. Ilaria Dando, Marco Cordani, Elisa Dalla Pozza, Giulia Biondani, Massimo Donadelli, and Marta Palmieri Copyright © 2015 Ilaria Dando et al. All rights reserved. Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age Wed, 29 Apr 2015 09:02:02 +0000 http://www.hindawi.com/journals/omcl/2015/926067/ Oxidative stress is a major determinant of human aging and common hallmark of age-related diseases. A protective role against free radicals accumulation was shown for thioredoxin reductase TrxR1, a key antioxidant selenoprotein. The variability of encoding gene (TXNRD1) was previously found associated with physical status at old age and extreme survival in a Danish cohort. To further investigate the influence of the gene variability on age-related physiological decline, we analyzed 9 tagging SNPs in relation to markers of physical (Activity of Daily Living, Hand Grip, Chair stand, and Walking) and cognitive (Mini Mental State Examination) status, in a Southern-Italian cohort of 64–107 aged individuals. We replicated the association of TXNRD1 variability with physical performance, with three variants (rs4445711, rs1128446, and rs11111979) associated with physical functioning after 85 years of age . In addition, we found two SNPs borderline influencing longevity (rs4964728 and rs7310505) in our cohort, the last associated with health status and survival in Northern Europeans too. Overall, the evidences of association in a different population here reported extend the proposed role of TXNRD1 gene in modulating physical decline at extreme ages, further supporting the investigation of thioredoxin pathway in relation to the quality of human aging. Serena Dato, Francesco De Rango, Paolina Crocco, Giuseppe Passarino, and Giuseppina Rose Copyright © 2015 Serena Dato et al. All rights reserved. Mitochondria-Targeted Protective Compounds in Parkinson’s and Alzheimer’s Diseases Wed, 29 Apr 2015 06:50:25 +0000 http://www.hindawi.com/journals/omcl/2015/408927/ Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways; their most highlighted functions include cellular energy generation in the form of adenosine triphosphate (ATP), regulation of cellular calcium homeostasis, balance between ROS production and detoxification, mediation of apoptosis cell death, and synthesis and metabolism of various key molecules. Consistent evidence suggests that mitochondrial failure is associated with early events in the pathogenesis of ageing-related neurodegenerative disorders including Parkinson’s disease and Alzheimer’s disease. Mitochondria-targeted protective compounds that prevent or minimize mitochondrial dysfunction constitute potential therapeutic strategies in the prevention and treatment of these central nervous system diseases. This paper provides an overview of the involvement of mitochondrial dysfunction in Parkinson’s and Alzheimer’s diseases, with particular attention to in vitro and in vivo studies on promising endogenous and exogenous mitochondria-targeted protective compounds. Carlos Fernández-Moriano, Elena González-Burgos, and M. Pilar Gómez-Serranillos Copyright © 2015 Carlos Fernández-Moriano et al. All rights reserved. Enhanced Locomotor Activity Is Required to Exert Dietary Restriction-Dependent Increase of Stress Resistance in Drosophila Tue, 28 Apr 2015 11:40:33 +0000 http://www.hindawi.com/journals/omcl/2015/813801/ Dietary restriction (DR) is known to be one of the most effective interventions to increase stress resistance, yet the mechanisms remain elusive. One of the most obvious DR-induced changes in phenotype is an increase in locomotor activity. Although it is conceptually perceivable that nutritional scarcity should prompt enhanced foraging behavior to garner additional dietary resources, the significance of enhanced movement activity has not been associated with the DR-dependent increase of stress resistance. In this study, we confirmed that flies raised on DR exhibited enhanced locomotive activity and increased stress resistance. Excision of fly wings minimized the DR-induced increase in locomotive activity, which resulted in attenuation of the DR-dependent increase of stress resistance. The possibility that wing clipping counteracts the DR by coercing flies to have more intake was ruled out since it did not induce any weight gain. Rather it was found that elimination of reactive oxygen species (ROS) that is enhanced by DR-induced upregulation of expression of antioxidant genes was significantly reduced by wing clipping. Collectively, our data suggests that DR increased stress resistance by increasing the locomotor activity, which upregulated expression of protective genes including, but not limited to, ROS scavenger system. Saurav Ghimire and Man Su Kim Copyright © 2015 Saurav Ghimire and Man Su Kim. All rights reserved. miR-103 Regulates Oxidative Stress by Targeting the BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 in HUVECs Mon, 27 Apr 2015 14:18:48 +0000 http://www.hindawi.com/journals/omcl/2015/489647/ Oxidative stress plays a critical role in cardiovascular diseases. Salidroside, a glycoside from Rhodiola rosea, has been used as an antioxidative therapy for oxidative injury in cardiac diseases. However, the mechanism underlying its antioxidant effect needs to be elucidated. Treatment of HUVECs with H2O2 significantly decreased the expression of miR-103 in a dose- and time-dependent manner, whereas pretreatment with salidroside significantly inhibited this decrease. Subsequent analysis showed that overexpression of miR-103 abrogated cell activity and ROS production induced by H2O2. Bcl2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) was determined to be a novel miR-103 target in HUVECs. Interestingly, H2O2 treatment upregulated BNIP3 expression; in turn, this effect was inhibited by pretreatment with salidroside. Further studies confirmed that the knockdown of BNIP3 enhanced cell activity and suppressed the ROS production induced by H2O2. These results demonstrated for the first time that salidroside protects HUVECs in part by upregulating the expression of miR-103, which mediates BNIP3 downregulation and plays an important role in the cytoprotective actions. Mao-Chun Xu, Xiu-Fang Gao, Changwu Ruan, Zhi-Ru Ge, Ji-De Lu, Jian-Jun Zhang, Yu Zhang, Lu Wang, and Hai-Ming Shi Copyright © 2015 Mao-Chun Xu et al. All rights reserved. Effect of Myricetin, Pyrogallol, and Phloroglucinol on Yeast Resistance to Oxidative Stress Mon, 27 Apr 2015 08:56:08 +0000 http://www.hindawi.com/journals/omcl/2015/782504/ The health beneficial effects of dietary polyphenols have been attributed to their intrinsic antioxidant activity, which depends on the structure of the compound and number of hydroxyl groups. In this study, the protective effects of pyrogallol, phloroglucinol, and myricetin on the yeast Saccharomyces cerevisiae were investigated. Pyrogallol and myricetin, which have a pyrogallol structure in the B ring, increased H2O2 resistance associated with a reduction in intracellular oxidation and protein carbonylation, whereas phloroglucinol did not exert protective effects. The acquisition of oxidative stress resistance in cells pretreated with pyrogallol and myricetin was not associated with an induction of endogenous antioxidant defences as assessed by the analysis of superoxide dismutase and catalase activities. However, myricetin, which provided greater stress resistance, prevented H2O2-induced glutathione oxidation. Moreover, myricetin increased the chronological lifespan of yeast lacking the mitochondrial superoxide dismutase (Sod2p), which exhibited a premature aging phenotype and oxidative stress sensitivity. These findings show that the presence of hydroxyl groups in the ortho position of the B ring in pyrogallol and myricetin contributes to the antioxidant protection afforded by these compounds. In addition, myricetin may alleviate aging-induced oxidative stress, particularly when redox homeostasis is compromised due to downregulation of endogenous defences present in mitochondria. Vanda Mendes, Rita Vilaça, Victor de Freitas, Pedro Moradas Ferreira, Nuno Mateus, and Vítor Costa Copyright © 2015 Vanda Mendes et al. All rights reserved. Nonenzymatic Reactions above Phospholipid Surfaces of Biological Membranes: Reactivity of Phospholipids and Their Oxidation Derivatives Tue, 21 Apr 2015 13:29:45 +0000 http://www.hindawi.com/journals/omcl/2015/319505/ Phospholipids play multiple and essential roles in cells, as components of biological membranes. Although phospholipid bilayers provide the supporting matrix and surface for many enzymatic reactions, their inherent reactivity and possible catalytic role have not been highlighted. As other biomolecules, phospholipids are frequent targets of nonenzymatic modifications by reactive substances including oxidants and glycating agents which conduct to the formation of advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs). There are some theoretical studies about the mechanisms of reactions related to these processes on phosphatidylethanolamine surfaces, which hypothesize that cell membrane phospholipids surface environment could enhance some reactions through a catalyst effect. On the other hand, the phospholipid bilayers are susceptible to oxidative damage by oxidant agents as reactive oxygen species (ROS). Molecular dynamics simulations performed on phospholipid bilayers models, which include modified phospholipids by these reactions and subsequent reactions that conduct to formation of ALEs and AGEs, have revealed changes in the molecular interactions and biophysical properties of these bilayers as consequence of these reactions. Then, more studies are desirable which could correlate the biophysics of modified phospholipids with metabolism in processes such as aging and diseases such as diabetes, atherosclerosis, and Alzheimer’s disease. Christian Solís-Calero, Joaquín Ortega-Castro, Juan Frau, and Francisco Muñoz Copyright © 2015 Christian Solís-Calero et al. All rights reserved. Comparative Meta-Analysis of Transcriptomics Data during Cellular Senescence and In Vivo Tissue Ageing Tue, 21 Apr 2015 13:20:16 +0000 http://www.hindawi.com/journals/omcl/2015/732914/ Several studies have employed DNA microarrays to identify gene expression signatures that mark human ageing; yet the features underlying this complicated phenomenon remain elusive. We thus conducted a bioinformatics meta-analysis on transcriptomics data from human cell- and biopsy-based microarrays experiments studying cellular senescence or in vivo tissue ageing, respectively. We report that coregulated genes in the postmitotic muscle and nervous tissues are classified into pathways involved in cancer, focal adhesion, actin cytoskeleton, MAPK signalling, and metabolism regulation. Genes that are differentially regulated during cellular senescence refer to pathways involved in neurodegeneration, focal adhesion, actin cytoskeleton, proteasome, cell cycle, DNA replication, and oxidative phosphorylation. Finally, we revealed genes and pathways (referring to cancer, Huntington’s disease, MAPK signalling, focal adhesion, actin cytoskeleton, oxidative phosphorylation, and metabolic signalling) that are coregulated during cellular senescence and in vivo tissue ageing. The molecular commonalities between cellular senescence and tissue ageing are also highlighted by the fact that pathways that were overrepresented exclusively in the biopsy- or cell-based datasets are modules either of the same reference pathway (e.g., metabolism) or of closely interrelated pathways (e.g., thyroid cancer and melanoma). Our reported meta-analysis has revealed novel age-related genes, setting thus the basis for more detailed future functional studies. Konstantinos Voutetakis, Aristotelis Chatziioannou, Efstathios S. Gonos, and Ioannis P. Trougakos Copyright © 2015 Konstantinos Voutetakis et al. All rights reserved. Alzheimer’s Pathogenesis and Its Link to the Mitochondrion Mon, 20 Apr 2015 11:34:13 +0000 http://www.hindawi.com/journals/omcl/2015/803942/ Alzheimer’s disease (AD) is the most common form of dementia in the elderly. This neurodegenerative disorder is clinically characterized by impairment of cognitive functions and changes in behaviour and personality. The pathogenesis of AD is still unclear. Recent evidence supports some role of mitochondria dysfunction and oxidative stress in the development of the neurodegenerative process. In this review, we discuss the role of mitochondrial dysfunction in AD, focusing on the mechanisms that lead to mitochondrial impairment, oxidative stress, and neurodegeneration, a “vicious circle” that ends in dementia. C. Simoncini, D. Orsucci, E. Caldarazzo Ienco, G. Siciliano, U. Bonuccelli, and M. Mancuso Copyright © 2015 C. Simoncini et al. All rights reserved. Oxidative Stress during the Progression of β-Amyloid Pathology in the Neocortex of the Tg2576 Mouse Model of Alzheimer’s Disease Mon, 20 Apr 2015 07:04:22 +0000 http://www.hindawi.com/journals/omcl/2015/967203/ Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive neurodegeneration. Pathogenetic mechanisms, triggered by β-amyloid (Aβ) accumulation, include oxidative stress, derived from energy homeostasis deregulation and involving mitochondria and peroxisomes. We here addressed the oxidative stress status and the elicited cellular response at the onset and during the progression of Aβ pathology, studying the neocortex of Tg2576 model of AD. Age-dependent changes of oxidative damage markers, antioxidant enzymes, and related transcription factors were analysed in relation to the distribution of Aβ peptide and oligomers, by a combined molecular/morphological approach. Nucleic acid oxidative damage, accompanied by defective antioxidant defences, and decreased PGC1α expression are already detected in 3-month-old Tg2576 neurons. Conversely, PPARα is increased in these cells, with its cytoplasmic localization suggesting nongenomic, anti-inflammatory actions. At 6 months, when intracellular Aβ accumulates, PMP70 is downregulated, indicating impairment of fatty acids peroxisomal translocation and their consequent harmful accumulation. In 9-month-old Tg2576 neocortex, Aβ oligomers and acrolein deposition correlate with GFAP, GPX1, and PMP70 increases, supporting a compensatory response, involving astroglial peroxisomes. At severe pathological stages, when senile plaques disrupt cortical cytoarchitecture, antioxidant capacity is gradually lost. Overall, our data suggest early therapeutic intervention in AD, also targeting peroxisomes. Sara Porcellotti, Francesca Fanelli, Anna Fracassi, Sara Sepe, Francesco Cecconi, Cinzia Bernardi, AnnaMaria Cimini, Maria Paola Cerù, and Sandra Moreno Copyright © 2015 Sara Porcellotti et al. All rights reserved. Role of the Lipoperoxidation Product 4-Hydroxynonenal in the Pathogenesis of Severe Malaria Anemia and Malaria Immunodepression Sun, 19 Apr 2015 16:58:31 +0000 http://www.hindawi.com/journals/omcl/2015/638416/ Oxidative stress plays an important role in the pathogenesis of falciparum malaria, a disease still claiming close to 1 million deaths and 200 million new cases per year. Most frequent complications are severe anemia, cerebral malaria, and immunodepression, the latter being constantly present in all forms of malaria. Complications are associated with oxidative stress and lipoperoxidation. Its final product 4-hydroxynonenal (4-HNE), a stable yet very reactive and diffusible molecule, forms covalent conjugates with proteins, DNA, and phospholipids and modulates important cell functions at very low concentrations. Since oxidative stress plays important roles in the pathogenesis of severe malaria, it appears important to explore the role of 4-HNE in two important malaria complications such as malaria anemia and malaria immunodepression where oxidative stress is considered to be involved. In this review we will summarize data about 4-HNE chemistry, its biologically relevant chemical properties, and its role as regulator of physiologic processes and as pathogenic factor. We will review studies documenting the role of 4-HNE in severe malaria with emphasis on malaria anemia and immunodepression. Data from other diseases qualify 4-HNE both as oxidative stress marker and as pathomechanistically important molecule. Further studies are needed to establish 4-HNE as accepted pathogenic factor in severe malaria. Evelin Schwarzer, Paolo Arese, and Oleksii A. Skorokhod Copyright © 2015 Evelin Schwarzer et al. All rights reserved. Effects of Docosahexaenoic Supplementation and In Vitro Vitamin C on the Oxidative and Inflammatory Neutrophil Response to Activation Sun, 19 Apr 2015 11:42:20 +0000 http://www.hindawi.com/journals/omcl/2015/187849/ We studied the effects of diet supplementation with docosahexaenoic (DHA) and in vitro vitamin C (VitC) at physiological concentrations on oxidative and inflammatory neutrophil response to phorbol myristate acetate (PMA). Fifteen male footballers ingested a beverage enriched with DHA or a placebo for 8 weeks in a randomized double-blind study. Neutrophils were isolated from blood samples collected in basal conditions at the end of nutritional intervention. Neutrophils were cultured for 2 hours at 37°C in (a) control media, (b) media with PMA, and (c) media with PMA + VitC. PMA induces neutrophil degranulation with increased extracellular myeloperoxidase and catalase activities, nitric oxide production, expression of the inflammatory genes cyclooxygenase-2, nuclear factor κβ, interleukin 8 and tumor necrosis factor α, and interleukin 6 production. DHA diet supplementation boosts the exit of CAT from neutrophils but moderates the degranulation of myeloperoxidase granules induced by PMA. VitC facilitates azurophilic degranulation of neutrophils and increases gene expression of myeloperoxidase induced by PMA. VitC and DHA diet supplementation prevent PMA effects on inflammatory gene expression, although together they do not produce additional effects. DHA diet supplementation enhances antioxidant defences and anti-inflammatory neutrophil response to in vitro PMA activation. VitC facilitates neutrophil degranulation but prevents an inflammatory response to PMA. Xavier Capó, Miquel Martorell, Antoni Sureda, Josep Antoni Tur, and Antoni Pons Copyright © 2015 Xavier Capó et al. All rights reserved. Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2 Wed, 15 Apr 2015 11:32:53 +0000 http://www.hindawi.com/journals/omcl/2015/379538/ Macrophage survival is believed to be a contributing factor in the development of early atherosclerotic lesions. Dysregulated apoptosis of macrophages is involved in the inflammatory process of atherogenesis. Apigenin is a flavonoid that possesses various clinically relevant properties such as anti-inflammatory, antiplatelet, and antitumor activities. Here we showed that apigenin attenuated atherogenesis in apo mice in an in vivo test. In vitro experiments suggested that apigenin induced apoptosis of oxidized low density lipoprotein- (OxLDL-) loaded murine peritoneal macrophages (MPMs). Proteomic analysis showed that apigenin reduced the expression of plasminogen activator inhibitor 2 (PAI-2). PAI-2 has antiapoptotic effects in OxLDL-loaded MPMs. Enhancing PAI-2 expression significantly reduced the proapoptosis effects of apigenin. Molecular docking assay with AutoDock software predicted that residue Ser473 of Akt1 is a potential binding site for apigenin. Lentiviral-mediated overexpression of Akt1 wild type weakened the proapoptosis effect of apigenin in OxLDL-loaded MPMs. Collectively, apigenin executes its anti-atherogenic effects through inducing OxLDL-loaded MPMs apoptosis. The proapoptotic effects of apigenin were at least partly attributed to downregulation of PAI-2 through suppressing phosphorylation of AKT at Ser473. Ping Zeng, Bin Liu, Qun Wang, Qin Fan, Jian-Xin Diao, Jing Tang, Xiu-Qiong Fu, and Xue-Gang Sun Copyright © 2015 Ping Zeng et al. All rights reserved. Increased Clearance of Reactive Aldehydes and Damaged Proteins in Hypertension-Induced Compensated Cardiac Hypertrophy: Impact of Exercise Training Tue, 14 Apr 2015 11:13:11 +0000 http://www.hindawi.com/journals/omcl/2015/464195/ Background. We previously reported that exercise training (ET) facilitates the clearance of damaged proteins in heart failure. Here, we characterized the impact of ET on cardiac protein quality control during compensated ventricular hypertrophy in spontaneously hypertensive rats (SHR). Methods and Results. SHR were randomly assigned into sedentary and swimming-trained groups. Sedentary SHR displayed cardiac hypertrophy with preserved ventricular function compared to normotensive rats, characterizing a compensated cardiac hypertrophy. Hypertensive rats presented signs of cardiac oxidative stress, depicted by increased lipid peroxidation. However, these changes were not followed by accumulation of lipid peroxidation-generated reactive aldehydes and damaged proteins. This scenario was explained, at least in part, by the increased catalytic activity of both aldehyde dehydrogenase 2 (ALDH2) and proteasome. Of interest, ET exacerbated cardiac hypertrophy, improved ventricular function, induced resting bradycardia, and decreased blood pressure in SHR. These changes were accompanied by reduced cardiac oxidative stress and a consequent decrease in ALDH2 and proteasome activities, without affecting small chaperones levels and apoptosis in SHR. Conclusion. Increased cardiac ALDH2 and proteasomal activities counteract the deleterious effect of excessive oxidative stress in hypertension-induced compensated cardiac hypertrophy in rats. ET has a positive effect in reducing cardiac oxidative stress without affecting protein quality control. Juliane Cruz Campos, Tiago Fernandes, Luiz Roberto Grassmann Bechara, Nathalie Alves da Paixão, Patricia Chakur Brum, Edilamar Menezes de Oliveira, and Julio Cesar Batista Ferreira Copyright © 2015 Juliane Cruz Campos et al. All rights reserved. Regulation of System by Pharmacological Manipulation of Cellular Thiols Thu, 09 Apr 2015 07:25:14 +0000 http://www.hindawi.com/journals/omcl/2015/269371/ The cystine/glutamate exchanger (system ) mediates the transport of cystine into the cell in exchange for glutamate. By releasing glutamate, system can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and may protect cells against oxidative stress. We tested two different compounds that deplete primary cortical cultures containing both neurons and astrocytes of intracellular GSH, L-buthionine-sulfoximine (L-BSO), and diethyl maleate (DEM). Both compounds caused significant concentration and time dependent decreases in intracellular GSH levels. However; DEM caused an increase in radiolabeled cystine uptake through system , while unexpectedly BSO caused a decrease in uptake. The compounds caused similar low levels of neurotoxicity, while only BSO caused an increase in oxidative stress. The mechanism of GSH depletion by these two compounds is different, DEM directly conjugates to GSH, while BSO inhibits γ-glutamylcysteine synthetase, a key enzyme in GSH synthesis. As would be expected from these mechanisms of action, DEM caused a decrease in intracellular cysteine, while BSO increased cysteine levels. The results suggest that negative feedback by intracellular cysteine is an important regulator of system in this culture system. Rebecca Albano, Nicholas J. Raddatz, Julie Hjelmhaug, David A. Baker, and Doug Lobner Copyright © 2015 Rebecca Albano et al. All rights reserved. Protective Role of Nuclear Factor E2-Related Factor 2 against Acute Oxidative Stress-Induced Pancreatic β-Cell Damage Wed, 08 Apr 2015 11:19:20 +0000 http://www.hindawi.com/journals/omcl/2015/639191/ Oxidative stress is implicated in the pathogenesis of pancreatic β-cell dysfunction that occurs in both type 1 and type 2 diabetes. Nuclear factor E2-related factor 2 (NRF2) is a master regulator in the cellular adaptive response to oxidative stress. The present study found that MIN6 β-cells with stable knockdown of Nrf2 (Nrf2-KD) and islets isolated from Nrf2-knockout mice expressed substantially reduced levels of antioxidant enzymes in response to a variety of stressors. In scramble MIN6 cells or wild-type islets, acute exposure to oxidative stressors, including hydrogen peroxide (H2O2) and S-nitroso-N-acetylpenicillamine, resulted in cell damage as determined by decrease in cell viability, reduced ATP content, morphology changes of islets, and/or alterations of apoptotic biomarkers in a concentration- and/or time-dependent manner. In contrast, silencing of Nrf2 sensitized MIN6 cells or islets to the damage. In addition, pretreatment of MIN6 β-cells with NRF2 activators, including CDDO-Im, dimethyl fumarate (DMF), and tert-butylhydroquinone (tBHQ), protected the cells from high levels of H2O2-induced cell damage. Given that reactive oxygen species (ROS) are involved in regulating glucose-stimulated insulin secretion (GSIS) and persistent activation of NRF2 blunts glucose-triggered ROS signaling and GSIS, the present study highlights the distinct roles that NRF2 may play in pancreatic β-cell dysfunction that occurs in different stages of diabetes. Jingqi Fu, Hongzhi Zheng, Huihui Wang, Bei Yang, Rui Zhao, Chunwei Lu, Zhiyuan Liu, Yongyong Hou, Yuanyuan Xu, Qiang Zhang, Weidong Qu, and Jingbo Pi Copyright © 2015 Jingqi Fu et al. All rights reserved. The Protective Effect of Lipoic Acid on Selected Cardiovascular Diseases Caused by Age-Related Oxidative Stress Wed, 08 Apr 2015 08:46:16 +0000 http://www.hindawi.com/journals/omcl/2015/313021/ Oxidative stress is considered to be the primary cause of many cardiovascular diseases, including endothelial dysfunction in atherosclerosis and ischemic heart disease, hypertension, and heart failure. Oxidative stress increases during the aging process, resulting in either increased reactive oxygen species (ROS) production or decreased antioxidant defense. The increase in the incidence of cardiovascular disease is directly related to age. Aging is also associated with oxidative stress, which in turn leads to accelerated cellular senescence and organ dysfunction. Antioxidants may help lower the incidence of some pathologies of cardiovascular diseases and have antiaging properties. Lipoic acid (LA) is a natural antioxidant which is believed to have a beneficial effect on oxidative stress parameters in relation to diseases of the cardiovascular system. Beata Skibska and Anna Goraca Copyright © 2015 Beata Skibska and Anna Goraca. All rights reserved. Inhibition of Adenylyl Cyclase Type 5 Increases Longevity and Healthful Aging through Oxidative Stress Protection Tue, 07 Apr 2015 14:04:05 +0000 http://www.hindawi.com/journals/omcl/2015/250310/ Mice with disruption of adenylyl cyclase type 5 (AC5 knockout, KO) live a third longer than littermates. The mechanism, in part, involves the MEK/ERK pathway, which in turn is related to protection against oxidative stress. The AC5 KO model also protects against diabetes, obesity, and the cardiomyopathy induced by aging, diabetes, and cardiac stress and also demonstrates improved exercise capacity. All of these salutary features are also mediated, in part, by oxidative stress protection. For example, chronic beta adrenergic receptor stimulation induced cardiomyopathy was rescued by AC5 KO. Conversely, in AC5 transgenic (Tg) mice, where AC5 is overexpressed in the heart, the cardiomyopathy was exacerbated and was rescued by enhancing oxidative stress resistance. Thus, the AC5 KO model, which resists oxidative stress, is uniquely designed for clinical translation, since it not only increases longevity and exercise, but also protects against diabetes, obesity, and cardiomyopathy. Importantly, inhibition of AC5’s action to prolong longevity and enhance healthful aging, as well as its mechanism through resistance to oxidative stress, is unique among all of the nine AC isoforms. Stephen F. Vatner, Ronald E. Pachon, and Dorothy E. Vatner Copyright © 2015 Stephen F. Vatner et al. All rights reserved. Sleep Deprivation and Oxidative Stress in Animal Models: A Systematic Review Mon, 06 Apr 2015 11:29:11 +0000 http://www.hindawi.com/journals/omcl/2015/234952/ Because the function and mechanisms of sleep are partially clear, here we applied a meta-analysis to address the issue whether sleep function includes antioxidative properties in mice and rats. Given the expansion of the knowledge in the sleep field, it is indeed ambitious to describe all mammals, or other animals, in which sleep shows an antioxidant function. However, in this paper we reviewed the current understanding from basic studies in two species to drive the hypothesis that sleep is a dynamic-resting state with antioxidative properties. We performed a systematic review of articles cited in Medline, Scopus, and Web of Science until March 2015 using the following search terms: Sleep or sleep deprivation and oxidative stress, lipid peroxidation, glutathione, nitric oxide, catalase or superoxide dismutase. We found a total of 266 studies. After inclusion and exclusion criteria, 44 articles were included, which are presented and discussed in this study. The complex relationship between sleep duration and oxidative stress is discussed. Further studies should consider molecular and genetic approaches to determine whether disrupted sleep promotes oxidative stress. Gabriel Villafuerte, Adán Miguel-Puga, Eric Murillo Rodríguez, Sergio Machado, Elias Manjarrez, and Oscar Arias-Carrión Copyright © 2015 Gabriel Villafuerte et al. All rights reserved. Age-Related Responses in Circulating Markers of Redox Status in Healthy Adolescents and Adults during the Course of a Training Macrocycle Mon, 06 Apr 2015 07:13:41 +0000 http://www.hindawi.com/journals/omcl/2015/283921/ Redox status changes during an annual training cycle in young and adult track and field athletes and possible differences between the two age groups were assessed. Forty-six individuals (24 children and 22 adults) were assigned to four groups: trained adolescents, (TAD, ), untrained adolescents (UAD, ), trained adults (TA, ), and untrained adults (UA, ). Aerobic capacity and redox status related variables [total antioxidant capacity (TAC), glutathione (GSH), catalase activity, TBARS, protein carbonyls (PC), uric acid, and bilirubin] were assessed at rest and in response to a time-trial bout before training, at mid- and posttraining. TAC, catalase activity, TBARS, PC, uric acid, and bilirubin increased and GSH declined in all groups in response to acute exercise independent of training status and age. Training improved aerobic capacity, TAC, and GSH at rest and in response to exercise. Age affected basal and exercise-induced responses since adults demonstrated a greater TAC and GSH levels at rest and a greater rise of TBARS, protein carbonyls, and TAC and decline of GSH in response to exercise. Catalase activity, uric acid, and bilirubin responses were comparable among groups. These results suggest that acute exercise, age, and training modulate the antioxidant reserves of the body. Athanasios Zalavras, Ioannis G. Fatouros, Chariklia K. Deli, Dimitris Draganidis, Anastasios A. Theodorou, Dimitrios Soulas, Yiannis Koutsioras, Yiannis Koutedakis, and Athanasios Z. Jamurtas Copyright © 2015 Athanasios Zalavras et al. All rights reserved. Smooth Muscle Specific Overexpression of p22phox Potentiates Carotid Artery Wall Thickening in Response to Injury Sun, 05 Apr 2015 10:03:04 +0000 http://www.hindawi.com/journals/omcl/2015/305686/ We hypothesized that transgenic mice overexpressing the subunit of the NADPH oxidase selectively in smooth muscle () would exhibit an exacerbated response to transluminal carotid injury compared to wild-type mice. To examine the role of reactive oxygen species (ROS) as a mediator of vascular injury, the injury response was quantified by measuring wall thickness (WT) and cross-sectional wall area (CSWA) of the injured and noninjured arteries in both and wild-type animals at days 3, 7, and 14 after injury. Akt, p38 MAPK, and Src activation were evaluated at the same time points using Western blotting. WT and CSWA following injury were significantly greater in mice at both 7 and 14 days after injury while noninjured contralateral carotids were similar between groups. Apocynin treatment attenuated the injury response in both groups and rendered the response similar between mice and wild-type mice. Following injury, carotid arteries from mice demonstrated elevated activation of Akt at day 3, while p38 MAPK and Src activation was elevated at day 7 compared to wild-type mice. Both increased activation and temporal regulation of these signaling pathways may contribute to enhanced vascular growth in response to injury in this transgenic model of elevated vascular ROS. Michael R. Manogue, Justin R. Bennett, Drury S. Holland, Chung-Sik Choi, Douglas A. Drake, Mark S. Taylor, and David S. Weber Copyright © 2015 Michael R. Manogue et al. All rights reserved. The Pleiotropic Effect of Physical Exercise on Mitochondrial Dynamics in Aging Skeletal Muscle Sun, 05 Apr 2015 08:08:28 +0000 http://www.hindawi.com/journals/omcl/2015/917085/ Decline in human muscle mass and strength (sarcopenia) is one of the principal hallmarks of the aging process. Regular physical exercise and training programs are certain powerful stimuli to attenuate the physiological skeletal muscle alterations occurring during aging and contribute to promote health and well-being. Although the series of events that led to these muscle adaptations are poorly understood, the mechanisms that regulate these processes involve the “quality” of skeletal muscle mitochondria. Aerobic/endurance exercise helps to maintain and improve cardiovascular fitness and respiratory function, whereas strength/resistance-exercise programs increase muscle strength, power development, and function. Due to the different effect of both exercises in improving mitochondrial content and quality, in terms of biogenesis, dynamics, turnover, and genotype, combined physical activity programs should be individually prescribed to maximize the antiaging effects of exercise. Elena Barbieri, Deborah Agostini, Emanuela Polidori, Lucia Potenza, Michele Guescini, Francesco Lucertini, Giosuè Annibalini, Laura Stocchi, Mauro De Santi, and Vilberto Stocchi Copyright © 2015 Elena Barbieri et al. All rights reserved.