Oxidative Medicine and Cellular Longevity http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Redox Signaling and the Cardiovascular and Skeletal Muscle System Wed, 07 Oct 2015 07:15:30 +0000 http://www.hindawi.com/journals/omcl/2015/849095/ Aldrin V. Gomes, Namakkal S. Rajasekaran, and Xinchun Pi Copyright © 2015 Aldrin V. Gomes et al. All rights reserved. Oxidative Stress in Dilated Cardiomyopathy Caused by MYBPC3 Mutation Mon, 05 Oct 2015 09:27:04 +0000 http://www.hindawi.com/journals/omcl/2015/424751/ Cardiomyopathies can result from mutations in genes encoding sarcomere proteins including MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). However, whether oxidative stress is augmented due to contractile dysfunction and cardiomyocyte damage in MYBPC3-mutated cardiomyopathies has not been elucidated. To determine whether oxidative stress markers were elevated in MYBPC3-mutated cardiomyopathies, a previously characterized 3-month-old mouse model of dilated cardiomyopathy (DCM) expressing a homozygous MYBPC3 mutation (cMyBP-) was used, compared to wild-type (WT) mice. Echocardiography confirmed decreased percentage of fractional shortening in DCM versus WT hearts. Histopathological analysis indicated a significant increase in myocardial disarray and fibrosis while the second harmonic generation imaging revealed disorganized sarcomeric structure and myocyte damage in DCM hearts when compared to WT hearts. Intriguingly, DCM mouse heart homogenates had decreased glutathione (GSH/GSSG) ratio and increased protein carbonyl and lipid malondialdehyde content compared to WT heart homogenates, consistent with elevated oxidative stress. Importantly, a similar result was observed in human cardiomyopathy heart homogenate samples. These results were further supported by reduced signals for mitochondrial semiquinone radicals and Fe-S clusters in DCM mouse hearts measured using electron paramagnetic resonance spectroscopy. In conclusion, we demonstrate elevated oxidative stress in MYPBC3-mutated DCM mice, which may exacerbate the development of heart failure. Thomas L. Lynch IV, Mayandi Sivaguru, Murugesan Velayutham, Arturo J. Cardounel, Michelle Michels, David Barefield, Suresh Govindan, Cristobal dos Remedios, Jolanda van der Velden, and Sakthivel Sadayappan Copyright © 2015 Thomas L. Lynch IV et al. All rights reserved. Oxidative Stress State Is Associated with Left Ventricular Mechanics Changes, Measured by Speckle Tracking in Essential Hypertensive Patients Sun, 04 Oct 2015 06:45:53 +0000 http://www.hindawi.com/journals/omcl/2015/502107/ The oxidative stress state is characterized by an increase in oxygen reactive species that overwhelms the antioxidant defense; we do not know if these pathological changes are correlated with alterations in left ventricular mechanics. The aim was correlating the oxidative stress state with the left ventricular global longitudinal strain (GLS) and the left ventricular end diastolic pressure (LVEDP). Twenty-five patients with essential hypertension and 25 controls paired by age and gender were studied. All of the participants were subjected to echocardiography and biochemical determination of oxidative stress markers. The hypertensive patients, compared with control subjects, had significantly () higher levels of oxidized proteins ( versus  nmol/mg), lower levels of extracellular superoxide dismutase (EC-SOD) activity ( versus  U/mg), higher LVEDP ( versus  mm Hg), and lower GLS (−12% versus −16%). Both groups had preserved ejection fraction and the results showed a positive correlation of oxidized proteins with GLS (, ) and LVEDP (, ); we also found a negative correlation of EC-SOD activity with GLS (, ) and LVEDP (, ). Luis Antonio Moreno-Ruíz, David Ibarra-Quevedo, Erika Rodríguez-Martínez, Perla D. Maldonado, Benito Sarabia-Ortega, José Gustavo Hernández-Martínez, Beda Espinosa-Caleti, Beatriz Mendoza-Pérez, and Selva Rivas-Arancibia Copyright © 2015 Luis Antonio Moreno-Ruíz et al. All rights reserved. Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress Tue, 29 Sep 2015 08:10:22 +0000 http://www.hindawi.com/journals/omcl/2015/795602/ Chemotherapy-induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. Understanding molecular mechanisms of chemotherapy-induced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen. Although no reliable and effective preventive treatment has become available, numerous evidence demonstrates that chemotherapy-induced cardiotoxicity involves the generation of reactive oxygen species (ROS). This review provides an overview of the roles of oxidative stress in chemotherapy-induced cardiotoxicity using doxorubicin, which is one of the most effective chemotherapeutic agents against a wide range of cancers, as an example. Current understanding in the molecular mechanisms of ROS-mediated cardiotoxicity will be explored and discussed, with emphasis on cardiomyocyte apoptosis leading to cardiomyopathy. The review will conclude with perspectives on model development needed to facilitate further progress and understanding on chemotherapy-induced cardiotoxicity. Paweorn Angsutararux, Sudjit Luanpitpong, and Surapol Issaragrisil Copyright © 2015 Paweorn Angsutararux et al. All rights reserved. The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease Mon, 28 Sep 2015 08:38:44 +0000 http://www.hindawi.com/journals/omcl/2015/676893/ Ischemic heart disease is the leading cause of death worldwide. Oxygen-sensing proteins are critical components of the physiological response to hypoxia and reperfusion injury, but the role of oxygen and oxygen-mediated effects is complex in that they can be cardioprotective or deleterious to the cardiac tissue. Over 200 oxygen-sensing proteins mediate the effects of oxygen tension and use oxygen as a substrate for posttranslational modification of other proteins. Hydroxylases are an essential component of these oxygen-sensing proteins. While a major role of hydroxylases is regulating the transcription factor HIF, we investigate the increasing scope of hydroxylase substrates. This review discusses the importance of oxygen-mediated effects in the heart as well as how the field of oxygen-sensing proteins is expanding, providing a more complete picture into how these enzymes play a multifaceted role in cardiac function and disease. We also review how oxygen-sensing proteins and hydroxylase function could prove to be invaluable in drug design and therapeutic targets for heart disease. W. H. Davin Townley-Tilson, Xinchun Pi, and Liang Xie Copyright © 2015 W. H. Davin Townley-Tilson et al. All rights reserved. Allopurinol Protects against Ischemia/Reperfusion-Induced Injury in Rat Urinary Bladders Sun, 27 Sep 2015 07:23:09 +0000 http://www.hindawi.com/journals/omcl/2015/906787/ Bladder ischemia-reperfusion (I/R) injury results in the generation of reactive oxygen species (ROS) and markedly elevates the risk of lower urinary tract symptoms (LUTS). Allopurinol is an inhibitor of xanthine oxidase (XO) and thus can serve as an antioxidant that reduces oxidative stress. Here, a rat model was used to assess the ability of allopurinol treatment to ameliorate the deleterious effects of urinary bladder I/R injury. I/R injury reduced the in vitro contractile responses of longitudinal bladder strips, elevated XO activity in the plasma and bladder tissue, increased the bladder levels of tumor necrosis factor-α (TNF-α), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase, reduced the bladder levels of extracellular regulated kinase (ERK), and decreased and increased the bladder levels of Bcl-2 and Bax, respectively. I/R injury also elevated lipid peroxidation in the bladder. Allopurinol treatment in the I/R injury was generated significantly ameliorating all I/R-induced changes. Moreover, an in situ fluorohistological approach also showed that allopurinol reduces the generation of intracellular superoxides enlarged by I/R injury. Together, the beneficial effects of allopurinol reducing ROS production may be mediated by normalizing the activity of the ERK, JNK, and Bax/Bcl-2 pathways and by controlling TNF-α expression. Ju-Hyun Shin, Kwang Sik Chun, Yong-Gil Na, Ki-Hak Song, Seung Il Kim, Jae-Sung Lim, and Gun-Hwa Kim Copyright © 2015 Ju-Hyun Shin et al. All rights reserved. Comment on “New Antioxidant Drugs for Neonatal Brain Injury” Mon, 21 Sep 2015 07:34:13 +0000 http://www.hindawi.com/journals/omcl/2015/384372/ Lajos Lakatos and György Balla Copyright © 2015 Lajos Lakatos and György Balla. All rights reserved. NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species Sun, 20 Sep 2015 09:23:49 +0000 http://www.hindawi.com/journals/omcl/2015/536962/ Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs worldwide. NSAIDs are used for a variety of conditions including pain, rheumatoid arthritis, and musculoskeletal disorders. The beneficial effects of NSAIDs in reducing or relieving pain are well established, and other benefits such as reducing inflammation and anticancer effects are also documented. The undesirable side effects of NSAIDs include ulcers, internal bleeding, kidney failure, and increased risk of heart attack and stroke. Some of these side effects may be due to the oxidative stress induced by NSAIDs in different tissues. NSAIDs have been shown to induce reactive oxygen species (ROS) in different cell types including cardiac and cardiovascular related cells. Increases in ROS result in increased levels of oxidized proteins which alters key intracellular signaling pathways. One of these key pathways is apoptosis which causes cell death when significantly activated. This review discusses the relationship between NSAIDs and cardiovascular diseases (CVD) and the role of NSAID-induced ROS in CVD. Rajeshwary Ghosh, Azra Alajbegovic, and Aldrin V. Gomes Copyright © 2015 Rajeshwary Ghosh et al. All rights reserved. Effect of Selenium Supplementation on Redox Status of the Aortic Wall in Young Spontaneously Hypertensive Rats Sun, 20 Sep 2015 09:10:15 +0000 http://www.hindawi.com/journals/omcl/2015/609053/ Selenium (Se) is an exogenous antioxidant that performs its function via the expression of selenoproteins. The aim of this study was to explore the effect of varying Se intake on the redox status of the aortic wall in young spontaneously hypertensive rats (SHR). Sixteen male Wistar Kyoto (WKY) rats and nineteen male SHR, 16-week-old, were tested after being given diets with different Se content for eight weeks. They were divided into 4 groups: control groups of WKY NSe and SHR NSe on an adequate Se diet and groups of WKY HSe and SHR HSe that received Se supplementation. The Se nutritional status was assessed by measuring whole blood glutathione peroxidase-1 (GPx-1) activity. Serum concentration of lipid hydroperoxides and serum level of antibodies against advanced glycation end products (anti-AGEs abs) were determined. Expression of GPx-1 and endothelial nitric oxide synthase (eNOS) were examined in aortic wall. Se supplementation significantly increased GPx-1 activity of whole blood and in the aortas of WKY and SHR. Decreased lipid peroxidation level, eNOS-3 expression in the aortic wall, and serum level of anti-AGEs abs were found in SHR HSe compared with SHR NSe. In conclusion, Se supplementation improved the redox status of the aortic wall in young SHR. Boryana Ruseva, Milena Atanasova, Reni Tsvetkova, Tatyana Betova, Margarita Mollova, Margarita Alexandrova, Pavlina Laleva, and Aneliya Dimitrova Copyright © 2015 Boryana Ruseva et al. All rights reserved. Physical Activity, Aerobic Capacity, and Total Antioxidant Capacity in Healthy Men and in Men with Coronary Heart Disease Mon, 14 Sep 2015 11:12:00 +0000 http://www.hindawi.com/journals/omcl/2015/197307/ Objective. The purpose of the study was to assess total antioxidant capacity (TAC) of blood serum in relation with habitual leisure time physical activity (LTPA) and aerobic capacity in a group of 90 men with coronary heart disease (CHD) aged 34.8–77.0 years and in 90 age-matched peers without CHD. Methods. Two spectrophotometric methods were applied to assess TAC: Ferric Reducing Ability of Serum (TAC-FRAS) and 2.2-diphenyl-1-picryl-hydrazyl (TAC-DPPH) tests. Aerobic capacity was expressed as physical working capacity at 85% of the maximal heart rate (). Results. CHD patients had higher values of TACFRAS ( versus  mmol FeCl2·L−1; ) but there were no group differences for TAC-DPPH and for uric acid (UA). Negative correlation was found between LTPA (also when calculated per kg of body mass) and TAC-DPPH in CHD patients. In CHD patients, TAC-FRAS and UA were lower in subjects with higher aerobic capacity expressed as . Those associations were not found in healthy men. Conclusions. We conclude that TAC of blood serum is moderately adversely related to LTPA and aerobic capacity in patients with CHD. UA, as the main determinant of serum TAC, may be partially responsible for those associations. Anna Gawron-Skarbek, Jacek Chrzczanowicz, Joanna Kostka, Dariusz Nowak, Wojciech Drygas, Anna Jegier, and Tomasz Kostka Copyright © 2015 Anna Gawron-Skarbek et al. All rights reserved. Serum Ferritin Is Associated with Metabolic Syndrome and Red Meat Consumption Mon, 14 Sep 2015 07:34:16 +0000 http://www.hindawi.com/journals/omcl/2015/769739/ Background and Aims. Hyperferritinemia has been related with a wide spectrum of pathologies, including diabetes, cardiovascular disease, neurodegenerative disorders, and metabolic syndrome. The aim of this study was to investigate the association between hyperferritinemia and iron consumption. Methods and Results. Serum ferritin concentration was evaluated in 66 presumed healthy men, along with other clinical and biochemical markers of chronic diseases. A three-day food questionnaire was applied for nutrition information. Hyperferritinemia was a condition found in 13.4% of the volunteers analyzed. Significant correlations were found between serum ferritin concentration and metabolic syndrome parameters (HDL cholesterol, triglycerides, and fasting glucose) as well as an increase of the serum ferritin mean value with the number of risk factors of metabolic syndrome. Also, oxidative stress markers (carbonyl groups, AOPP, and glycated hemoglobin), hepatic damage markers (GGT, SGOT), and parameters related to insulin resistance (HOMA, blood insulin, and blood glucose) correlate significantly with serum ferritin. Volunteers had an excessive iron intake, principally by bread consumption. Analyses of food intake showed that red meat consumption correlates significantly with serum ferritin. Conclusion. Red meat consumption, metabolic syndrome, and chronic disease markers are associated with hyperferritinemia in a population of Chilean men. Avila Felipe, Echeverría Guadalupe, Pérez Druso, Martinez Carlos, Strobel Pablo, Castillo Oscar, Villaroel Luis, Mezzano Diego, Rozowski Jaime, Urquiaga Inés, and Leighton Federico Copyright © 2015 Avila Felipe et al. All rights reserved. Myostatin Activates the Ubiquitin-Proteasome and Autophagy-Lysosome Systems Contributing to Muscle Wasting in Chronic Kidney Disease Sun, 13 Sep 2015 13:26:58 +0000 http://www.hindawi.com/journals/omcl/2015/684965/ Our evidence demonstrated that CKD upregulated the expression of myostatin, TNF-α, and p-IkBa and downregulated the phosphorylation of PI3K, Akt, and FoxO3a, which were also associated with protein degradation and muscle atrophy. The autophagosome formation and protein expression of autophagy-related genes were increased in muscle of CKD rats. The mRNA level and protein expression of MAFbx and MuRF-1 were also upregulated in CKD rats, as well as proteasome activity of 26S. Moreover, activation of myostatin elicited by TNF-α induces C2C12 myotube atrophy via upregulating the expression of autophagy-related genes, including MAFbx and MuRF1 and proteasome subunits. Inactivation of FoxO3a triggered by PI3K inhibitor LY294002 prevented the myostatin-induced increase of expression of MuRF1, MAFbx, and LC3-II protein in C2C12 myotubes. The findings were further consolidated by using siRNA interference and overexpression of myostatin. Additionally, expression of myostatin was activated by TNF-α via a NF-κB dependent pathway in C2C12 myotubes, while inhibition of NF-κB activity suppressed myostatin and improved myotube atrophy. Collectively, myostatin mediated CKD-induced muscle catabolism via coordinate activation of the autophagy and the ubiquitin-proteasome systems. Dong-Tao Wang, Ya-Jun Yang, Ren-Hua Huang, Zhi-Hua Zhang, and Xin Lin Copyright © 2015 Dong-Tao Wang et al. All rights reserved. Physical Training Regulates Mitochondrial Parameters and Neuroinflammatory Mechanisms in an Experimental Model of Parkinson’s Disease Thu, 10 Sep 2015 13:51:32 +0000 http://www.hindawi.com/journals/omcl/2015/261809/ This study aimed to evaluate the effects of two different protocols for physical exercise (strength and aerobic training) on mitochondrial and inflammatory parameters in the 6-OHDA experimental model of Parkinson’s disease. Six experimental groups were used ( per group): untrained + vehicle (Sham), strength training + vehicle (STR), treadmill training + vehicle (TTR), untrained + 6-OHDA (U + 6-OHDA), strength training + 6-OHDA (STR + 6-OHDA), and treadmill training + 6-OHDA (TTR + 6-OHDA). The mice were subjected to strength or treadmill training for 8 weeks. PD was induced via striatal injection of 6-OHDA 24 h after the last exercise session. Mice were euthanized by cervical dislocation and the striatum and hippocampus were homogenized to determine levels of tyrosine hydroxylase (TH), nuclear factor kappa B (NF-κB) p65, and sirtuin 1 (Sirt1) by western blot; tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-17, interferon-γ (IFN-γ), and transforming growth factor β1 (TGF-β1) levels by ELISA; NO content; and complex I (CI) activity. STR + 6-OHDA mice had higher TH levels and CI activity and lower NF-κB p65 and IFN-γ levels in the striatum compared to U + 6-OHDA mice, while TTR + 6-OHDA mice had higher Sirt1 levels and CI activity in both the striatum and the hippocampus, compared to U + 6-OHDA mice. Strength training increased CI activity and TH and Sirt1 levels and reduced NO, NF-κB p65, TNF-α, IFN-γ, IL-1β, and TGF-β1 levels in 6-OHDA mice, while treadmill exercise increased CI activity and NO, TH, and Sirt1 levels and reduced NF-κB p65, TNF-α, IFN-γ, and IL-1β levels. Our results demonstrated that both treadmill training and strength training promote neuroprotection, possibly by stimulating Sirt1 activity, which may in turn regulate both mitochondrial function and neuroinflammation via deacetylation of NF-κB p65. Changes in nitric oxide levels may also be a mechanism by which 6-OHDA-induced inflammation is controlled. Talita Tuon, Priscila S. Souza, Marcela F. Santos, Fernanda T. Pereira, Giulia S. Pedroso, Thais F. Luciano, Claudio T. De Souza, Rafael C. Dutra, Paulo C. L. Silveira, and Ricardo A. Pinho Copyright © 2015 Talita Tuon et al. All rights reserved. Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage Thu, 10 Sep 2015 10:04:05 +0000 http://www.hindawi.com/journals/omcl/2015/764375/ We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits -caused oxidative damage. Our modeling revealed that sustained exposure to can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical’s toxicity dose dependence based on the dose-response of early genotoxic events. Maria A. Spassova, David J. Miller, and Alexander S. Nikolov Copyright © 2015 Maria A. Spassova et al. All rights reserved. Anti-Aging Potential of Phytoextract Loaded-Pharmaceutical Creams for Human Skin Cell Longetivity Thu, 10 Sep 2015 09:45:12 +0000 http://www.hindawi.com/journals/omcl/2015/709628/ The exposure to ultraviolet radiations (UVR) is the key source of skin sunburn; it may produce harmful entities, reactive oxygen species (ROS), leading to aging. The skin can be treated and protected from the injurious effects of ROS by using various pharmaceutical formulations, such as cream. Cream can be loaded with antioxidants to quench ROS leading to photo-protective effects. Moreover, modern medicines depend on ethnobotanicals for protection or treatment of human diseases. This review article summarizes various in vivo antioxidant studies on herbal creams loaded with phyto-extracts. These formulations may serve as cosmeceuticals to protect skin against injurious effects of UVR. The botanicals studied for dermatologic use in cream form include Acacia nilotica, Benincasa hispida, Calendula officinalis, Camellia sinensis, Camellia sinensis, Nelumbo nucifera, Capparis decidua, Castanea sativa, Coffea arabica, Crocus sativus, Emblica officinalis Gaertn, Foeniculum vulgare, Hippophae rhamnoides, Lithospermum erythrorhizon, Malus domestica, Matricaria chamomilla L., Moringa oleifera, Morus alba, Ocimum basilicum, Oryza sativa, Polygonum minus, Punica granatum, Silybum marianum, Tagetes erecta Linn., Terminalia chebula, Trigonella foenum-graecum, and Vitis vinifera. The observed anti-aging effects of cream formulations could be an outcome of a coordinating action of multiple constituents. Of numerous botanicals, the phenolic acids and flavonoids appear effective against UVR-induced damage; however the evidence-based studies for their anti-aging effects are still needed. Saima Jadoon, Sabiha Karim, Muhammad Hassham Hassan Bin Asad, Muhammad Rouf Akram, Abida Kalsoom Khan, Arif Malik, Chunye Chen, and Ghulam Murtaza Copyright © 2015 Saima Jadoon et al. All rights reserved. Total Glucosides of Danggui Buxue Tang Attenuate BLM-Induced Pulmonary Fibrosis via Regulating Oxidative Stress by Inhibiting NOX4 Tue, 11 Aug 2015 08:18:03 +0000 http://www.hindawi.com/journals/omcl/2015/645814/ Pulmonary fibrosis (PF) is a serious chronic lung disease with unknown pathogenesis. Researches have confirmed that oxidative stress which is regulated by NADPH oxidase-4 (NOX4), a main source of reactive oxygen species (ROS), is an important molecular mechanism underlying PF. Previous studies showed that total glucosides of Danggui Buxue Tang (DBTG), an extract from a classical traditional Chinese herbal formula, Danggui Buxue Tang (DBT), attenuated bleomycin-induced PF in rats. However, the mechanisms of DBTG are still not clear. We hypothesize that DBTG attenuates PF through regulating the level of oxidative stress by inhibiting NOX4. And we found that fibrosis indexes hydroxyproline (HYP) and type I collagen (Col-I) were lower in DBTG groups compared with the model group. In addition, the expression of transforming growth factor-β1 (TGF-β1) and expression of alpha smooth muscle actin (α-SMA) were also much more decreased than the model group. For oxidative stress indicators, DBTG blunted the decrease of superoxide dismutase (SOD) activity, total antioxidant capacity (T-AOC), and the increase in malondialdehyde (MDA), 8-iso-prostaglandin in lung homogenates. Treatment with DBTG restrained the expression of NOX4 compared to the model group. Present study confirms that DBTG inhibits BLM-induced PF by modulating the level of oxidative stress via suppressing NOX4. Ping Zhao, Wen-Cheng Zhou, De-Lin Li, Xiao-Ting Mo, Liang Xu, Liu-Cheng Li, Wen-Hui Cui, and Jian Gao Copyright © 2015 Ping Zhao et al. All rights reserved. Antihyperglycemic Potential of Grewia asiatica Fruit Extract against Streptozotocin-Induced Hyperglycemia in Rats: Anti-Inflammatory and Antioxidant Mechanisms Wed, 05 Aug 2015 15:43:59 +0000 http://www.hindawi.com/journals/omcl/2015/549743/ Diabetes mellitus is regarded as a serious chronic disease that carries a high risk for considerable complications. In folk medicine, the edible Grewia asiatica fruit is used in a number of pathological conditions. This study aimed to investigate the possible curative effect of G. asiatica fruit ethanolic extract against streptozotocin- (STZ-) induced hyperglycemia in rats. Furthermore, mechanism of antihyperglycemic action is investigated. Hyperglycemic rats are either treated with 100 or 200 mg/kg/day G. asiatica fruits extract. Serum glucose, liver glycogen, malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin- (IL-) 1β, and tumor necrosis factor- (TNF-) α are measured. G. asiatica fruits extract reduces blood glucose and pancreatic MDA levels. It increases liver glycogen and pancreatic GSH contents and SOD enzyme activity. Furthermore, Grewia asiatica fruits extract decreases serum IL-1β and TNF-α. The treatment also protects against STZ-induced pathological changes in the pancreas. The results of this study indicated that G. asiatica fruit extract exerts antihyperglycemic activity against STZ-induced hyperglycemia. The improvement in the pancreatic β-cells and antioxidant and anti-inflammatory effects of G. asiatica fruit extract may explain the antihyperglycemic effect. Hala A. H. Khattab, Nagla A. El-Shitany, Inas Z. A. Abdallah, Fatimah M. Yousef, and Huda M. Alkreathy Copyright © 2015 Hala A. H. Khattab et al. All rights reserved. Polyphenols as Modulators of Aquaporin Family in Health and Disease Tue, 04 Aug 2015 10:42:15 +0000 http://www.hindawi.com/journals/omcl/2015/196914/ Polyphenols are bioactive molecules widely distributed in fruits, vegetables, cereals, and beverages. Polyphenols in food sources are extensively studied for their role in the maintenance of human health and in the protection against development of chronic/degenerative diseases. Polyphenols act mainly as antioxidant molecules, protecting cell constituents against oxidative damage. The enormous number of polyphenolic compounds leads to huge different mechanisms of action not fully understood. Recently, some evidence is emerging about the role of polyphenols, such as curcumin, pinocembrin, resveratrol, and quercetin, in modulating the activity of some aquaporin (AQP) isoforms. AQPs are integral, small hydrophobic water channel proteins, extensively expressed in many organs and tissues, whose major function is to facilitate the transport of water or glycerol over cell plasma membranes. Here we summarize AQP physiological functions and report emerging evidence on the implication of these proteins in a number of pathophysiological processes. In particular, this review offers an overview about the role of AQPs in brain, eye, skin diseases, and metabolic syndrome, focusing on the ability of polyphenols to modulate AQP expression. This original analysis can contribute to elucidating some peculiar effects exerted by polyphenols and can lead to the development of an innovative potential preventive/therapeutic strategy. Diana Fiorentini, Laura Zambonin, Francesco Vieceli Dalla Sega, and Silvana Hrelia Copyright © 2015 Diana Fiorentini et al. All rights reserved. Redox Status and Aging Link in Neurodegenerative Diseases 2015 Sun, 02 Aug 2015 16:09:46 +0000 http://www.hindawi.com/journals/omcl/2015/494316/ Verónica Pérez de la Cruz, Sathyasaikumar V. Korrapati, and José Pedraza Chaverrí Copyright © 2015 Verónica Pérez de la Cruz et al. All rights reserved. Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice Sun, 02 Aug 2015 13:36:04 +0000 http://www.hindawi.com/journals/omcl/2015/238914/ Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2−/−) using nestin-Cre-loxp system. B-Sod2−/− showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2−/−, without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice. Naotaka Izuo, Hidetoshi Nojiri, Satoshi Uchiyama, Yoshihiro Noda, Satoru Kawakami, Shuji Kojima, Toru Sasaki, Takuji Shirasawa, and Takahiko Shimizu Copyright © 2015 Naotaka Izuo et al. All rights reserved. Polydatin Alleviates Small Intestine Injury during Hemorrhagic Shock as a SIRT1 Activator Sun, 02 Aug 2015 13:26:52 +0000 http://www.hindawi.com/journals/omcl/2015/965961/ Objective. To evaluate the role of SIRT1 in small intestine damage following severe hemorrhagic shock and to investigate whether polydatin (PD) can activate SIRT1 in shock treatment. Research Design and Methods. The severe hemorrhagic shock model was reproduced in Sprague Dawley rats. Main Outcome Measures. Two hours after drug administration, half of the rats were assessed for survival time evaluation and the remainder were used for small intestinal tissue sample collection. Results. Bleeding and swelling appeared in the small intestine with epithelial apoptosis and gut barrier disturbance during hemorrhagic shock. SIRT1 activity and PGC-1α protein expression of the small intestine were decreased, which led to an increase in acetylated SOD2 and decreases in the expression and activity of SOD2, resulting in severe oxidative stress. The decreased SIRT1 activity and expression were partially restored in the PD administration group, which showed reduced intestine injury and longer survival time. Notably, the effect of PD was abolished after the addition of Ex527, a selective inhibitor of SIRT1. Conclusions. The results collectively suggest a role for the SIRT1-PGC-1α-SOD2 axis in small intestine injury following severe hemorrhagic shock and that PD is an effective SIRT1 activator for the shock treatment. Zhenhua Zeng, Zhongqing Chen, Siqi Xu, Rui Song, Hong Yang, and Ke-seng Zhao Copyright © 2015 Zhenhua Zeng et al. All rights reserved. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi’s Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics Sun, 02 Aug 2015 12:49:46 +0000 http://www.hindawi.com/journals/omcl/2015/498401/ Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these diseases lack effective disease modifying therapy. Following a brief commemoration of Professor Albert Szent-Györgyi, a Nobel Prize laureate who pioneered in the field of cellular respiration, antioxidant processes, and the roles of free radicals in health and disease, the present paper overviews the current knowledge on the involvement of mitochondrial dysfunction in central nervous system diseases associated with neurodegeneration including Parkinson’s and Huntington’s disease as well as mitochondrial encephalopathies. The review puts special focus on the involvement and the potential therapeutic relevance of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), a nuclear-encoded master regulator of mitochondrial biogenesis and antioxidant responses in these disorders, the transcriptional activation of which may hold novel therapeutic value as a more system-based approach aiming to restore mitochondrial functions in neurodegenerative processes. Levente Szalárdy, Dénes Zádori, Péter Klivényi, József Toldi, and László Vécsei Copyright © 2015 Levente Szalárdy et al. All rights reserved. Dietary Tocotrienol/γ-Cyclodextrin Complex Increases Mitochondrial Membrane Potential and ATP Concentrations in the Brains of Aged Mice Sun, 02 Aug 2015 12:46:22 +0000 http://www.hindawi.com/journals/omcl/2015/789710/ Brain aging is accompanied by a decrease in mitochondrial function. In vitro studies suggest that tocotrienols, including γ- and δ-tocotrienol (T3), may exhibit neuroprotective properties. However, little is known about the effect of dietary T3 on mitochondrial function in vivo. In this study, we monitored the effect of a dietary T3/γ-cyclodextrin complex (T3CD) on mitochondrial membrane potential and ATP levels in the brain of 21-month-old mice. Mice were fed either a control diet or a diet enriched with T3CD providing 100 mg T3 per kg diet for 6 months. Dietary T3CD significantly increased mitochondrial membrane potential and ATP levels compared to those of controls. The increase in MMP and ATP due to dietary T3CD was accompanied by an increase in the protein levels of the mitochondrial transcription factor A (TFAM). Furthermore, dietary T3CD slightly increased the mRNA levels of superoxide dismutase, γ-glutamyl cysteinyl synthetase, and heme oxygenase 1 in the brain. Overall, the present data suggest that T3CD increases TFAM, mitochondrial membrane potential, and ATP synthesis in the brains of aged mice. Anke Schloesser, Tuba Esatbeyoglu, Stefanie Piegholdt, Janina Dose, Naoko Ikuta, Hinako Okamoto, Yoshiyuki Ishida, Keiji Terao, Seiichi Matsugo, and Gerald Rimbach Copyright © 2015 Anke Schloesser et al. All rights reserved. The Role of Oxidative Damage in the Pathogenesis and Progression of Alzheimer’s Disease and Vascular Dementia Sun, 02 Aug 2015 12:38:32 +0000 http://www.hindawi.com/journals/omcl/2015/504678/ Oxidative stress (OS) has been demonstrated to be involved in the pathogenesis of the two major types of dementia: Alzheimer’s disease (AD) and vascular dementia (VaD). Evidence of OS and OS-related damage in AD is largely reported in the literature. Moreover, OS is not only linked to VaD, but also to all its risk factors. Several researches have been conducted in order to investigate whether antioxidant therapy exerts a role in the prevention and treatment of AD and VaD. Another research field is that pertaining to the heat shock proteins (Hsps), that has provided promising findings. However, the role of OS antioxidant defence system and more generally stress responses is very complex. Hence, research on this topic should be improved in order to reach further knowledge and discover new therapeutic strategies to face a disorder with such a high burden which is dementia. Maria Luca, Antonina Luca, and Carmela Calandra Copyright © 2015 Maria Luca et al. All rights reserved. Epicatechin Reduces Striatal MPP+-Induced Damage in Rats through Slight Increases in SOD-Cu,Zn Activity Sun, 02 Aug 2015 11:51:30 +0000 http://www.hindawi.com/journals/omcl/2015/276039/ Parkinson’s disease is a neurodegenerative disorder characterized by movement alterations caused by reduced dopaminergic neurotransmission in the nigrostriatal pathway, presumably by oxidative stress (OS). MPP+ intrastriatal injection leads to the overproduction of free radicals (FR). The increasing formation of FR produces OS, a decline in dopamine (DA) content, and behavioral disorders. Epicatechin (EC) has shown the ability to be FR scavenger, an antioxidant enzyme inductor, a redox state modulator, and transition metal chelator. Acute administration of 100 mg/kg of EC significantly prevented () the circling MPP+-induced behavior (10 μg/8 μL). Likewise, EC significantly () reduced the formation of fluorescent lipid products caused by MPP+. MPP+ injection produced () increased enzymatic activity of the constitutive nitric oxide synthase (cNOS). This effect was blocked with acute EC pretreatment. Cu/Zn-dependent superoxide dismutase (Cu/Zn-SOD) activity was significantly () reduced as a consequence of MPP+ damage. EC produced a slight increase (≈20%) in Cu/Zn-SOD activity in the control group. Such effects persisted in animals injured with MPP+. The results show that EC is effective against MPP+-induced biochemical and behavioral damage, which is possible by an increase in Cu/Zn-SOD activity. M. Rubio-Osornio, E. Gorostieta-Salas, S. Montes, F. Pérez-Severiano, C. Rubio, C. Gómez, C. Ríos, and J. Guevara Copyright © 2015 M. Rubio-Osornio et al. All rights reserved. Mitochondrial Respiratory Chain Inhibitors Involved in ROS Production Induced by Acute High Concentrations of Iodide and the Effects of SOD as a Protective Factor Wed, 29 Jul 2015 08:49:02 +0000 http://www.hindawi.com/journals/omcl/2015/217670/ A major source of reactive oxygen species (ROS) generation is the mitochondria. By using flow cytometry of the mitochondrial fluorescent probe, MitoSOX Red, western blot of mitochondrial ROS scavenger Peroxiredoxin (Prx) 3 and fluorescence immunostaining, ELISA of cleaved caspases 3 and 9, and TUNEL staining, we demonstrated that exposure to 100 μM KI for 2 hours significantly increased mitochondrial superoxide production and Prx 3 protein expression with increased expressions of cleaved caspases 3 and 9. Besides, we indicated that superoxide dismutase (SOD) at 1000 unit/mL attenuated the increase in mitochondrial superoxide production, Prx 3 protein expression, and lactate dehydrogenase (LDH) release and improved the relative cell viability at 100 μM KI exposure. However, SOD inhibitor diethyldithiocarbamic acid (DETC) (2 mM), Rotenone (0.5 μM), a mitochondrial complex I inhibitor, and Antimycin A (10 μM), a complex III inhibitor, caused an increase in mitochondrial superoxide production, Prx 3 protein expression, and LDH release and decreased the relative cell viability. We conclude that the inhibitors of mitochondrial respiratory chain complex I or III may be involved in oxidative stress caused by elevated concentrations of iodide, and SOD demonstrates its protective effect on the Fischer rat thyroid cell line (FRTL) cells. Lingyan Wang, Qi Duan, Tingting Wang, Mohamed Ahmed, Na Zhang, Yongmei Li, Lanying Li, and Xiaomei Yao Copyright © 2015 Lingyan Wang et al. All rights reserved. Reactive Oxygen Species in Stem Cells Wed, 29 Jul 2015 08:34:09 +0000 http://www.hindawi.com/journals/omcl/2015/159080/ Tullia Maraldi, Cristina Angeloni, Elisa Giannoni, and Christian Sell Copyright © 2015 Tullia Maraldi et al. All rights reserved. LPS Induces Occludin Dysregulation in Cerebral Microvascular Endothelial Cells via MAPK Signaling and Augmenting MMP-2 Levels Tue, 28 Jul 2015 11:53:43 +0000 http://www.hindawi.com/journals/omcl/2015/120641/ Disrupted blood-brain barrier (BBB) integrity contributes to cerebral edema during central nervous system infection. The current study explored the mechanism of lipopolysaccharide- (LPS-) induced dysregulation of tight junction (TJ) proteins. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to LPS, SB203580 (p38MAPK inhibitor), or SP600125 (JNK inhibitor), and cell vitality was determined by MTT assay. The proteins expressions of p38MAPK, JNK, and TJs (occludin and zonula occludens- (ZO-) 1) were determined by western blot. The mRNA levels of TJ components and MMP-2 were measured with quantitative real-time polymerase chain reaction (qRT-PCR), and MMP-2 protein levels were determined by enzyme-linked immunosorbent assay (ELISA). LPS, SB203580, and SP600125 under respective concentrations of 10, 7.69, or 0.22 µg/mL had no effects on cell vitality. Treatment with LPS decreased mRNA and protein levels of occludin and ZO-1 and enhanced p38MAPK and JNK phosphorylation and MMP-2 expression. These effects were attenuated by pretreatment with SB203580 or SP600125, but not in ZO-1 expression. Both doxycycline hyclate (a total MMP inhibitor) and SB-3CT (a specific MMP-2 inhibitor) partially attenuated the LPS-induced downregulation of occludin. These data suggest that MMP-2 overexpression and p38MAPK/JNK pathways are involved in the LPS-mediated alterations of occludin in hCMEC/D3; however, ZO-1 levels are not influenced by p38MAPK/JNK. Lan-hui Qin, Wen Huang, Xue-an Mo, Yan-lan Chen, and Xiang-hong Wu Copyright © 2015 Lan-hui Qin et al. All rights reserved. Effects of Ezetimibe/Simvastatin and Rosuvastatin on Oxidative Stress in Diabetic Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Tue, 28 Jul 2015 11:25:01 +0000 http://www.hindawi.com/journals/omcl/2015/756294/ Objective. To evaluate the effects of ezetimibe/simvastatin (EZE/SIMV) and rosuvastatin (ROSUV) on oxidative stress (OS) markers in patients with diabetic polyneuropathy (DPN). Methods. We performed a randomized, double-blind, placebo-controlled phase III clinical trial in adult patients with Type 2 Diabetes Mellitus (T2DM) and DPN, as evaluated by composite scores and nerve conduction studies (NCS). Seventy-four subjects with T2DM were allocated 1 : 1 : 1 to placebo, EZE/SIMV 10/20 mg, or ROSUV 20 mg for 16 weeks. All patients were assessed before and after treatment: primary outcomes were lipid peroxidation (LPO), and nitric oxide (NO) surrogate levels in plasma; secondary outcomes included NCS, neuropathic symptom scores, and metabolic parameters. Data were expressed as mean ± SD or SEM, frequencies, and percentages; we used nonparametric analysis. Results. LPO levels were reduced in both statin arms after 16 weeks of treatment ( versus baseline), without changes in the placebo group. NO levels were not significantly affected by statin treatment, although a trend towards significance concerning increased NO levels was noted in both statin arms. No significant changes were observed for the NCS or composite scores. Discussion. EZE/SIMV and ROSUV are superior to placebo in reducing LPO in subjects with T2DM suffering from polyneuropathy. This trial is registered with NCT02129231. Geannyne Villegas-Rivera, Luis Miguel Román-Pintos, Ernesto Germán Cardona-Muñoz, Oscar Arias-Carvajal, Adolfo Daniel Rodríguez-Carrizalez, Rogelio Troyo-Sanromán, Fermín Paul Pacheco-Moisés, Aldo Moreno-Ulloa, and Alejandra Guillermina Miranda-Díaz Copyright © 2015 Geannyne Villegas-Rivera et al. All rights reserved. Upregulation of Multidrug Resistance-Associated Protein 1 by Allyl Isothiocyanate in Human Bronchial Epithelial Cell: Involvement of c-Jun N-Terminal Kinase Signaling Pathway Mon, 27 Jul 2015 12:12:44 +0000 http://www.hindawi.com/journals/omcl/2015/903782/ Multidrug resistance-associated protein 1 (MRP1) plays a protective role in the etiology and progression of chronic obstructive pulmonary disease (COPD) which results from oxidative stress and inflammation of lung injury. The lower functional MRP1 activity is related to COPD development. Our previous study showed that Allyl isothiocyanate (AITC) induced the expression and activity of MRP1 in a dose-dependent manner. However, which signaling pathway contributes to the upregulation of MRP1 by AITC is unclear. In this study, signaling pathway specific inhibitors were used to examine the mechanism of AITC. We found that JNK inhibitor SP600125 treatment decreased MRP1 mRNA expression in 16HBE14o- cells. But the ERK inhibitor U0126 or PI3K/Akt inhibitor LY294002 produced no obvious effect. The AITC-induced increase of MRP1 mRNA expression was abolished by cotreatment of SP600125, while it was not obviously affected by U0126 or LY294002. Furthermore, AITC acivates the JNK signaling pathway in 16HBE14o- cells. Finally, we found that JNK pathway mediated the upregulation of AITC-induced expression and function of MRP1. Taken together, our results indicated that AITC increased the expression and the activity of MRP1 via a JNK-dependent pathway. ERK and PI3K signaling pathway were not involved in the expression of MRP1 mRNA. Shujun Wang, Shanshan Wang, Chenyin Wang, Yajun Chen, Jie Li, Xueqi Wang, Dianlei Wang, Zegeng Li, Zhaoliang Peng, and Ling Fan Copyright © 2015 Shujun Wang et al. All rights reserved.