Oxidative Medicine and Cellular Longevity http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . 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. Quercetin Affects Hsp70/IRE1α Mediated Protection from Death Induced by Endoplasmic Reticulum Stress Thu, 02 Apr 2015 10:27:48 +0000 http://www.hindawi.com/journals/omcl/2015/645157/ Relative to their normal counterparts, tumor cells generally exhibit a greater “stress phenotype” and express heat shock proteins (Hsp) that represent candidate targets for anticancer therapy. Here we investigated the role of Hsp70 in survival induced by endoplasmic reticulum (ER) stressors in human leukemia U937 cells. Quercetin, a major dietary flavonoid, or specific silencing affected the expression level of Hsp70 and did not allow the upregulation of inositol-requiring kinase 1α (IRE1α), the prototype ER stress sensor regulating the unfolded protein response (UPR), that protects the cells against the stress of misfolded proteins in the ER. The reduction of Hsp70 prevented the upregulation of immunoglobulin heavy-chain binding protein (BiP), but not of CCAAT/enhancer-binding protein-homologous protein (CHOP), and induced apoptosis. Also specific silencing of IRE1α or inhibition of its endoribonuclease activity by 4μ8c hampered the upregulation of BiP, but not of CHOP, and induced apoptosis. These results suggest that drugs affecting the Hsp70-IRE1α axis, like quercetin, or affecting directly IRE1α may represent an effective adjuvant antileukemia therapy. Antonello Storniolo, Marisa Raciti, Alessandra Cucina, Mariano Bizzarri, and Livia Di Renzo Copyright © 2015 Antonello Storniolo et al. All rights reserved. Epigallocatechin-3-Gallate Enhances the Therapeutic Effects of Leptomycin B on Human Lung Cancer A549 Cells Wed, 01 Apr 2015 09:19:16 +0000 http://www.hindawi.com/journals/omcl/2015/217304/ Our previous studies have shown Leptomycin B (LMB) is a promising antilung cancer drug. Epigallocatechin-3-gallate (EGCG) has antitumor properties but a debatable clinical application. The objective of this study is to evaluate the combination therapeutic effect of LMB and EGCG and its molecular mechanisms in human lung cancer A549 cells. Increased cytotoxicity was observed in LMB+EGCG-treated cells compared to LMB-treated cells. Elevated ROS was maximized 2 h after treatment, and LMB+EGCG-treated cells had higher ROS levels compared to LMB. N-Acetyl-L-cysteine (NAC) studies confirmed the oxidative role of LMB and/or EGCG treatment. In comparison to the control, CYP3A4, SOD, GPX1, and p21 mRNA expression levels were increased 7.1-, 2.0-, 4.6-, and 13.1-fold in LMB-treated cells, respectively, while survivin was decreased 42.6-fold. Additionally, these increases of CYP3A4, SOD, and GPX1 were significantly reduced, while p21 was significantly increased in LMB+EGCG-treated cells compared to LMB-treated cells. The qRT-PCR results for p21 and survivin were further confirmed by Western blot. Our study first shows that LMB produces ROS and is possibly metabolized by CYP3A4, GPX1, and SOD in A549 cells, and combination treatment of LMB and EGCG augments LMB-induced cytotoxicity through enhanced ROS production and the modulation of drug metabolism and p21/survivin pathways. Meghan M. Cromie and Weimin Gao Copyright © 2015 Meghan M. Cromie and Weimin Gao. All rights reserved. Oxidative Stress in Myopia Wed, 01 Apr 2015 07:11:57 +0000 http://www.hindawi.com/journals/omcl/2015/750637/ Myopia affected approximately 1.6 billion people worldwide in 2000, and it is expected to increase to 2.5 billion by 2020. Although optical problems can be corrected by optics or surgical procedures, normal myopia and high myopia are still an unsolved medical problem. They frequently predispose people who have them to suffer from other eye pathologies: retinal detachment, glaucoma, macular hemorrhage, cataracts, and so on being one of the main causes of visual deterioration and blindness. Genetic and environmental factors have been associated with myopia. Nevertheless, lack of knowledge in the underlying physiopathological molecular mechanisms has not permitted an adequate diagnosis, prevention, or treatment to be found. Nowadays several pieces of evidence indicate that oxidative stress may help explain the altered regulatory pathways in myopia and the appearance of associated eye diseases. On the one hand, oxidative damage associated with hypoxia myopic can alter the neuromodulation that nitric oxide and dopamine have in eye growth. On the other hand, radical superoxide or peroxynitrite production damage retina, vitreous, lens, and so on contributing to the appearance of retinopathies, retinal detachment, cataracts and so on. The objective of this review is to suggest that oxidative stress is one of the key pieces that can help solve this complex eye problem. Bosch-Morell Francisco, Mérida Salvador, and Navea Amparo Copyright © 2015 Bosch-Morell Francisco et al. All rights reserved. Antioxidative Diet Supplementation Reverses High-Fat Diet-Induced Increases of Cardiovascular Risk Factors in Mice Wed, 01 Apr 2015 07:06:44 +0000 http://www.hindawi.com/journals/omcl/2015/467471/ Obesity is a worldwide epidemic that is characterized not only by excessive fat deposition but also by systemic microinflammation, high oxidative stress, and increased cardiovascular risk factors. While diets enriched in natural antioxidants showed beneficial effects on oxidative stress, blood pressure, and serum lipid composition, diet supplementation with synthetic antioxidants showed contradictive results. Thus, we tested in C57Bl/6 mice whether a daily dosage of an antioxidative mixture consisting of vitamin C, vitamin E, L-arginine, eicosapentaenoic acid, and docosahexaenoic acid (corabion) would affect cardiovascular risk factors associated with obesity. Obese mice showed increased serum triglyceride and glucose levels and hypertension after eight weeks of being fed a high-fat diet (HFD). Importantly, corabion ameliorated all of these symptoms significantly. Oxidative stress and early signs of systemic microinflammation already developed after two weeks of high-fat diet and were significantly reduced by daily doses of corabion. Of note, the beneficial effects of corabion could not be observed when applying its single antioxidative components suggesting that a combination of various nutrients is required to counteract HFD-induced cardiovascular risk factors. Thus, daily consumption of corabion may be beneficial for the management of obesity-related cardiovascular complications. Hilda Vargas-Robles, Amelia Rios, Monica Arellano-Mendoza, Bruno A. Escalante, and Michael Schnoor Copyright © 2015 Hilda Vargas-Robles et al. All rights reserved. Traumatic Brain Injury and NADPH Oxidase: A Deep Relationship Tue, 31 Mar 2015 12:41:35 +0000 http://www.hindawi.com/journals/omcl/2015/370312/ Traumatic brain injury (TBI) represents one of the major causes of mortality and disability in the world. TBI is characterized by primary damage resulting from the mechanical forces applied to the head as a direct result of the trauma and by the subsequent secondary injury due to a complex cascade of biochemical events that eventually lead to neuronal cell death. Oxidative stress plays a pivotal role in the genesis of the delayed harmful effects contributing to permanent damage. NADPH oxidases (Nox), ubiquitary membrane multisubunit enzymes whose unique function is the production of reactive oxygen species (ROS), have been shown to be a major source of ROS in the brain and to be involved in several neurological diseases. Emerging evidence demonstrates that Nox is upregulated after TBI, suggesting Nox critical role in the onset and development of this pathology. In this review, we summarize the current evidence about the role of Nox enzymes in the pathophysiology of TBI. Cristina Angeloni, Cecilia Prata, Francesco Vieceli Dalla Sega, Roberto Piperno, and Silvana Hrelia Copyright © 2015 Cristina Angeloni et al. All rights reserved. Renal Oxidative Stress Induced by Long-Term Hyperuricemia Alters Mitochondrial Function and Maintains Systemic Hypertension Tue, 31 Mar 2015 10:34:43 +0000 http://www.hindawi.com/journals/omcl/2015/535686/ We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. Magdalena Cristóbal-García, Fernando E. García-Arroyo, Edilia Tapia, Horacio Osorio, Abraham S. Arellano-Buendía, Magdalena Madero, Bernardo Rodríguez-Iturbe, José Pedraza-Chaverrí, Francisco Correa, Cecilia Zazueta, Richard J. Johnson, and Laura-Gabriela Sánchez Lozada Copyright © 2015 Magdalena Cristóbal-García et al. All rights reserved. The Mitochondrial Translocator Protein and Arrhythmogenesis in Ischemic Heart Disease Mon, 30 Mar 2015 13:26:48 +0000 http://www.hindawi.com/journals/omcl/2015/234104/ Mitochondrial dysfunction is a hallmark of multiple cardiovascular disorders, including ischemic heart disease. Although mitochondria are well recognized for their role in energy production and cell death, mechanisms by which they control excitation-contraction coupling, excitability, and arrhythmias are less clear. The translocator protein (TSPO) is an outer mitochondrial membrane protein that is expressed in multiple organ systems. The abundant expression of TSPO in macrophages has been leveraged to image the immune response of the heart to inflammatory processes. More recently, the recognition of TSPO as a regulator of energy-dissipating mitochondrial pathways has extended its utility from a diagnostic marker of inflammation to a therapeutic target influencing diverse pathophysiological processes. Here, we provide an overview of the emerging role of TSPO in ischemic heart disease. We highlight the importance of TSPO in the regenerative process of reactive oxygen species (ROS) induced ROS release through its effects on the inner membrane anion channel (IMAC) and the permeability transition pore (PTP). We discuss evidence implicating TSPO in arrhythmogenesis in the settings of acute ischemia-reperfusion injury and myocardial infarction. Lukas J. Motloch, Jun Hu, and Fadi G. Akar Copyright © 2015 Lukas J. Motloch et al. All rights reserved. Oxidative Stress Responses and NRF2 in Human Leukaemia Mon, 30 Mar 2015 12:03:17 +0000 http://www.hindawi.com/journals/omcl/2015/454659/ Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival. Amina Abdul-Aziz, David J. MacEwan, Kristian M. Bowles, and Stuart A. Rushworth Copyright © 2015 Amina Abdul-Aziz et al. All rights reserved. In Vitro Toxicity of Epigallocatechin Gallate in Rat Liver Mitochondria and Hepatocytes Mon, 30 Mar 2015 10:11:22 +0000 http://www.hindawi.com/journals/omcl/2015/476180/ Epigallocatechin-3-gallate (EGCG) is the main compound of green tea with well-described antioxidant, anti-inflammatory, and tumor-suppressing properties. However, EGCG at high doses was reported to cause liver injury. In this study, we evaluated the effect of EGCG on primary culture of rat hepatocytes and on rat liver mitochondria in permeabilized hepatocytes. The 24-hour incubation with EGCG in concentrations of 10 μmol/L and higher led to signs of cellular injury and to a decrease in hepatocyte functions. The effect of EGCG on the formation of reactive oxygen species (ROS) was biphasic. While low doses of EGCG decreased ROS production, the highest tested dose induced a significant increase in ROS formation. Furthermore, we observed a decline in mitochondrial membrane potential in cells exposed to EGCG when compared to control cells. In permeabilized hepatocytes, EGCG caused damage of the outer mitochondrial membrane and an uncoupling of oxidative phosphorylation. EGCG in concentrations lower than 10 μmol/L was recognized as safe for hepatocytes in vitro. Otto Kucera, Vojtech Mezera, Alena Moravcova, Rene Endlicher, Halka Lotkova, Zdenek Drahota, and Zuzana Cervinkova Copyright © 2015 Otto Kucera et al. All rights reserved. Analysis of Chemokines and Receptors Expression Profile in the Myelin Mutant Taiep Rat Wed, 25 Mar 2015 12:28:09 +0000 http://www.hindawi.com/journals/omcl/2015/397310/ Taiep rat has a failure in myelination and remyelination processes leading to a state of hypomyelination throughout its life. Chemokines, which are known to play a role in inflammation, are also involved in the remyelination process. We aimed to demonstrate that remyelination-stimulating factors are altered in the brainstem of 1- and 6-month-old taiep rats. We used a Rat RT2 Profiler PCR Array to assess mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors. We also evaluated protein levels of CCL2, CCR1, CCR2, CCL5, CCR5, CCR8, CXCL1, CXCR2, CXCR4, FGF2, and VEGFA by ELISA. Sprague-Dawley rats were used as a control. PCR Array procedure showed that proinflammatory cytokines were not upregulated in the taiep rat. In contrast, some mRNA levels of beta and alpha chemokines were upregulated in 1-month-old rats, but CXCR4 was downregulated at their 6 months of age. ELISA results showed that CXCL1, CCL2, CCR2, CCR5, CCR8, and CXCR4 protein levels were decreased in brainstem at the age of 6 months. These results suggest the presence of a chronic neuroinflammation process with deficiency of remyelination-stimulating factors (CXCL1, CXCR2, and CXCR4), which might account for the demyelination in the taiep rat. Guadalupe Soto-Rodriguez, Juan-Antonio Gonzalez-Barrios, Daniel Martinez-Fong, Victor-Manuel Blanco-Alvarez, Jose R. Eguibar, Araceli Ugarte, Francisco Martinez-Perez, Eduardo Brambila, Lourdes Millán-Perez Peña, Nidia-Gary Pazos-Salazar, Maricela Torres-Soto, Guadalupe Garcia-Robles, Constantino Tomas-Sanchez, and Bertha Alicia Leon-Chavez Copyright © 2015 Guadalupe Soto-Rodriguez et al. All rights reserved. Effects of Polyphenols from Grape Seeds on Renal Lithiasis Wed, 25 Mar 2015 08:48:33 +0000 http://www.hindawi.com/journals/omcl/2015/813737/ Nephrolithiasis is a complex disease that results from a combination of factors related to both urine composition and kidney morphoanatomy. Development of calcium oxalate monohydrate papillary calculi is linked to initial subepithelial calcification of renal papilla. Progressive tissue calcification depends on preexisting injury and involves reactive oxygen species. Many plant extracts that protect against oxidative stress manifest antilithiasic activity. Our study focused on determining the effects of polyphenols on a lithiasis rat model. Rats were pretreated with polyphenols and grape seed extracts, followed by posterior induction of hyperoxalosis via treatment with ethylene glycol plus NH4Cl. The concentrations of calcium and other elements in kidney were determined, along with histological examination of kidney and 24 h urine analysis. Significant differences were observed in the renal calcium content between the control plus ethylene glycol-treated group and the epicatechin plus ethylene glycol-treated, red grape seed extract plus ethylene glycol-treated, and white grape seed extract plus ethylene glycol-treated groups, with reductions of about 50%. The antioxidant activity of polyphenols extracted from red and white grape seeds may be critical in the prevention of calcium oxalate monohydrate papillary calculus formation, particularly if calculi are induced by lesions caused by cytotoxic compounds with oxidative capacity. Felix Grases, Rafel M. Prieto, Rafel A. Fernandez-Cabot, Antonia Costa-Bauzá, Fernando Tur, and Jose Juan Torres Copyright © 2015 Felix Grases et al. All rights reserved. Oxidant Antioxidants and Adaptive Responses to Exercise Tue, 24 Mar 2015 12:39:42 +0000 http://www.hindawi.com/journals/omcl/2015/290190/ Paola Venditti, Mari Carmen Gomez-Cabrera, Yong Zhang, and Zsolt Radak Copyright © 2015 Paola Venditti et al. All rights reserved. Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms Tue, 24 Mar 2015 10:00:06 +0000 http://www.hindawi.com/journals/omcl/2015/230182/ The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies. Elena Gammella, Stefania Recalcati, Ilona Rybinska, Paolo Buratti, and Gaetano Cairo Copyright © 2015 Elena Gammella et al. All rights reserved. Corrigendum to “Reduced Oxidative Stress Contributes to the Lipid Lowering Effects of Isoquercitrin in Free Fatty Acids Induced Hepatocytes” Mon, 23 Mar 2015 13:21:23 +0000 http://www.hindawi.com/journals/omcl/2015/383525/ Waseem Hassan, Gao Rongyin, Abdelkader Daoud, Lin Ding, Lulu Wang, Jun Liu, and Jing Shang Copyright © 2015 Waseem Hassan et al. All rights reserved. Oxidative Stress and Adipocyte Biology: Focus on the Role of AGEs Mon, 23 Mar 2015 08:24:04 +0000 http://www.hindawi.com/journals/omcl/2015/534873/ Diabetes is a major health problem that is usually associated with obesity, together with hyperglycemia and increased advanced glycation endproducts (AGEs) formation. Elevated AGEs elicit severe downstream consequences via their binding to receptors of AGEs (RAGE). This includes oxidative stress and oxidative modifications of biological compounds together with heightened inflammation. For example, albumin (major circulating protein) undergoes increased glycoxidation with diabetes and may represent an important biomarker for monitoring diabetic pathophysiology. Despite the central role of adipose tissue in many physiologic/pathologic processes, recognition of the effects of greater AGEs formation in this tissue is quite recent within the obesity/diabetes context. This review provides a brief background of AGEs formation and adipose tissue biology and thereafter discusses the impact of AGEs-adipocyte interactions in pathology progression. Novel data are included showing how AGEs (especially glycated albumin) may be involved in hyperglycemia-induced oxidative damage in adipocytes and its potential links to diabetes progression. Florence Boyer, Jennifer Baraka Vidot, Alexis Guerin Dubourg, Philippe Rondeau, M. Faadiel Essop, and Emmanuel Bourdon Copyright © 2015 Florence Boyer et al. All rights reserved. 3-(3-Pyridylmethylidene)-2-indolinone Reduces the Severity of Colonic Injury in a Murine Model of Experimental Colitis Sun, 22 Mar 2015 13:41:28 +0000 http://www.hindawi.com/journals/omcl/2015/959253/ Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerous in vivo studies indicate that Nrf2 plays a protective role in anti-inflammatory response. 3-(3-Pyridylmethylidene)-2-indolinone (PMID) is a synthesized derivative of 2-indolinone compounds. Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response. Kun-Ping Wang, Chao Zhang, Shou-Guo Zhang, En-Dong Liu, Lan Dong, Xiang-Zhen Kong, Peng Cao, Chun-Ping Hu, Ke Zhao, Yi-Qun Zhan, Xiao-Ming Dong, Chang-Hui Ge, Miao Yu, Hui Chen, Lin Wang, Xiao-Ming Yang, and Chang-Yan Li Copyright © 2015 Kun-Ping Wang et al. All rights reserved.