Oxidative Medicine and Cellular Longevity http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . 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. Reactive Oxygen Species Are Required for Human Mesenchymal Stem Cells to Initiate Proliferation after the Quiescence Exit Mon, 27 Jul 2015 08:06:14 +0000 http://www.hindawi.com/journals/omcl/2015/502105/ The present study focuses on the involvement of reactive oxygen species (ROS) in the process of mesenchymal stem cells “waking up” and entering the cell cycle after the quiescence. Using human endometrial mesenchymal stem cells (eMSCs), we showed that intracellular basal ROS level is positively correlated with the proliferative status of the cell cultures. Our experiments with the eMSCs synchronized in the G0 phase of the cell cycle revealed a transient increase in the ROS level upon the quiescence exit after stimulation of the cell proliferation. This increase was registered before the eMSC entry to the S-phase of the cell cycle, and elimination of this increase by antioxidants (N-acetyl-L-cysteine, Tempol, and Resveratrol) blocked G1–S-phase transition. Similarly, a cell cycle arrest which resulted from the antioxidant treatment was observed in the experiments with synchronized human mesenchymal stem cells derived from the adipose tissue. Thus, we showed that physiologically relevant level of ROS is required for the initiation of human mesenchymal stem cell proliferation and that low levels of ROS due to the antioxidant treatment can block the stem cell self-renewal. O. G. Lyublinskaya, Ya. G. Borisov, N. A. Pugovkina, I. S. Smirnova, Ju. V. Obidina, Ju. S. Ivanova, V. V. Zenin, A. N. Shatrova, A. V. Borodkina, N. D. Aksenov, V. I. Zemelko, E. B. Burova, M. V. Puzanov, and N. N. Nikolsky Copyright © 2015 O. G. Lyublinskaya et al. All rights reserved. Controlling Redox Status for Stem Cell Survival, Expansion, and Differentiation Mon, 27 Jul 2015 08:03:24 +0000 http://www.hindawi.com/journals/omcl/2015/105135/ Reactive oxygen species (ROS) have long been considered as pathological agents inducing apoptosis under adverse culture conditions. However, recent findings have challenged this dogma and physiological levels of ROS are now considered as secondary messengers, mediating numerous cellular functions in stem cells. Stem cells represent important tools for tissue engineering, drug screening, and disease modeling. However, the safe use of stem cells for clinical applications still requires culture improvements to obtain functional cells. With the examples of mesenchymal stem cells (MSCs) and pluripotent stem cells (PSCs), this review investigates the roles of ROS in the maintenance of self-renewal, proliferation, and differentiation of stem cells. In addition, this work highlights that the tight control of stem cell microenvironment, including cell organization, and metabolic and mechanical environments, may be an effective approach to regulate endogenous ROS generation. Taken together, this paper indicates the need for better quantification of ROS towards the accurate control of stem cell fate. Sébastien Sart, Liqing Song, and Yan Li Copyright © 2015 Sébastien Sart et al. All rights reserved. Redox Regulation in Cancer Stem Cells Sun, 26 Jul 2015 11:57:08 +0000 http://www.hindawi.com/journals/omcl/2015/750798/ Reactive oxygen species (ROS) and ROS-dependent (redox regulation) signaling pathways and transcriptional activities are thought to be critical in stem cell self-renewal and differentiation during growth and organogenesis. Aberrant ROS burst and dysregulation of those ROS-dependent cellular processes are strongly associated with human diseases including many cancers. ROS levels are elevated in cancer cells partially due to their higher metabolism rate. In the past 15 years, the concept of cancer stem cells (CSCs) has been gaining ground as the subpopulation of cancer cells with stem cell-like properties and characteristics have been identified in various cancers. CSCs possess low levels of ROS and are responsible for cancer recurrence after chemotherapy or radiotherapy. Unfortunately, how CSCs control ROS production and scavenging and how ROS-dependent signaling pathways contribute to CSCs function remain poorly understood. This review focuses on the role of redox balance, especially in ROS-dependent cellular processes in cancer stem cells (CSCs). We updated recent advances in our understanding of ROS generation and elimination in CSCs and their effects on CSC self-renewal and differentiation through modulating signaling pathways and transcriptional activities. The review concludes that targeting CSCs by manipulating ROS metabolism/dependent pathways may be an effective approach for improving cancer treatment. Shijie Ding, Chunbao Li, Ninghui Cheng, Xiaojiang Cui, Xinglian Xu, and Guanghong Zhou Copyright © 2015 Shijie Ding et al. All rights reserved. Nuclear Nox4 Role in Stemness Power of Human Amniotic Fluid Stem Cells Sun, 26 Jul 2015 08:34:07 +0000 http://www.hindawi.com/journals/omcl/2015/101304/ Human amniotic fluid stem cells (AFSC) are an attractive source for cell therapy due to their multilineage differentiation potential and accessibility advantages. However the clinical application of human stem cells largely depends on their capacity to expand in vitro, since there is an extensive donor-to-donor heterogeneity. Reactive oxygen species (ROS) and cellular oxidative stress are involved in many physiological and pathophysiological processes of stem cells, including pluripotency, proliferation, differentiation, and stress resistance. The mode of action of ROS is also dependent on the localization of their target molecules. Thus, the modifications induced by ROS can be separated depending on the cellular compartments they affect. NAD(P)H oxidase family, particularly Nox4, has been known to produce ROS in the nucleus. In the present study we show that Nox4 nuclear expression (nNox4) depends on the donor and it correlates with the expression of transcription factors involved in stemness regulation, such as Oct4, SSEA-4, and Sox2. Moreover nNox4 is linked with the nuclear localization of redox sensitive transcription factors, as Nrf2 and NF-κB, and with the differentiation potential. Taken together, these results suggest that nNox4 regulation may have important effects in stem cell capability through modulation of transcription factors and DNA damage. Tullia Maraldi, Marianna Guida, Manuela Zavatti, Elisa Resca, Laura Bertoni, Giovanni B. La Sala, and Anto De Pol Copyright © 2015 Tullia Maraldi et al. All rights reserved. GC-Rich Extracellular DNA Induces Oxidative Stress, Double-Strand DNA Breaks, and DNA Damage Response in Human Adipose-Derived Mesenchymal Stem Cells Sun, 26 Jul 2015 08:23:04 +0000 http://www.hindawi.com/journals/omcl/2015/782123/ Background. Cell free DNA (cfDNA) circulates throughout the bloodstream of both healthy people and patients with various diseases. CfDNA is substantially enriched in its GC-content as compared with human genomic DNA. Principal Findings. Exposure of haMSCs to GC-DNA induces short-term oxidative stress (determined with H2DCFH-DA) and results in both single- and double-strand DNA breaks (comet assay and γH2AX, foci). As a result in the cells significantly increases the expression of repair genes (BRCA1 (RT-PCR), PCNA (FACS)) and antiapoptotic genes (BCL2 (RT-PCR and FACS), BCL2A1, BCL2L1, BIRC3, and BIRC2 (RT-PCR)). Under the action of GC-DNA the potential of mitochondria was increased. Here we show that GC-rich extracellular DNA stimulates adipocyte differentiation of human adipose-derived mesenchymal stem cells (haMSCs). Exposure to GC-DNA leads to an increase in the level of RNAPPARG2 and LPL (RT-PCR), in the level of fatty acid binding protein FABP4 (FACS analysis) and in the level of fat (Oil Red O). Conclusions. GC-rich fragments in the pool of cfDNA can potentially induce oxidative stress and DNA damage response and affect the direction of mesenchymal stem cells differentiation in human adipose—derived mesenchymal stem cells. Such a response may be one of the causes of obesity or osteoporosis. Svetlana Kostyuk, Tatiana Smirnova, Larisa Kameneva, Lev Porokhovnik, Anatolij Speranskij, Elizaveta Ershova, Sergey Stukalov, Vera Izevskaya, and Natalia Veiko Copyright © 2015 Svetlana Kostyuk et al. All rights reserved. Increased Oxidative Stress as a Selective Anticancer Therapy Sun, 26 Jul 2015 08:22:22 +0000 http://www.hindawi.com/journals/omcl/2015/294303/ Reactive oxygen species (ROS) are closely related to tumorgenesis. Under hypoxic environment, increased levels of ROS induce the expression of hypoxia inducible factors (HIFs) in cancer stem cells (CSCs), resulting in the promotion of the upregulation of CSC markers, and the reduction of intracellular ROS level, thus facilitating CSCs survival and proliferation. Although the ROS level is regulated by powerful antioxidant defense mechanisms in cancer cells, it is observed to remain higher than that in normal cells. Cancer cells may be more sensitive than normal cells to the accumulation of ROS; consequently, it is supposed that increased oxidative stress by exogenous ROS generation therapy has an effect on selectively killing cancer cells without affecting normal cells. This paper reviews the mechanisms of redox regulation in CSCs and the pivotal role of ROS in anticancer treatment. Jiahui Liu and Zhichong Wang Copyright © 2015 Jiahui Liu and Zhichong Wang. All rights reserved. Reactive Oxygen Species in Mesenchymal Stem Cell Aging: Implication to Lung Diseases Sun, 26 Jul 2015 08:13:08 +0000 http://www.hindawi.com/journals/omcl/2015/486263/ MSCs have become an emerging cell source with their immune modulation, high proliferation rate, and differentiation potential; indeed, they have been challenged in clinical trials. Recently, it has shown that ROS play a dual role as both deleterious and beneficial species depending on their concentration in MSCs. Various environmental stresses-induced excessive production of ROS triggers cellular senescence and abnormal differentiation on MSCs. Moreover, MSCs have been suggested to participate in the treatment of ALI/ARDS and COPD as a major cause of high morbidity and mortality. Therapeutic mechanisms of MSCs in the treatment of ARDS/COPD were focused on cell engraftment and paracrine action. However, ROS-mediated therapeutic mechanisms of MSCs still remain largely unknown. Here, we review the key factors associated with cell cycle and chromatin remodeling to accelerate or delay the MSC aging process. In addition, the enhanced ROS production and its associated pathophysiological pathways will be discussed along with the MSC senescence process. Furthermore, the present review highlights how the excessive amount of ROS-mediated oxidative stress might interfere with homeostasis of lungs and residual lung cells in the pathogenesis of ALI/ARDS and COPD. Se-Ran Yang, Jeong-Ran Park, and Kyung-Sun Kang Copyright © 2015 Se-Ran Yang et al. All rights reserved. Isoflavones Reduce Copper with Minimal Impact on Iron In Vitro Sun, 26 Jul 2015 06:37:10 +0000 http://www.hindawi.com/journals/omcl/2015/437381/ Isoflavones are commonly consumed in many Asian countries and have potentially positive effects on human being. Only a few and rather controversial data on their interactions with copper and iron are available to date. 13 structurally related isoflavones were tested in the competitive manner for their Cu/Fe-chelating/reducing properties. Notwithstanding the 5-hydroxy-4-keto chelation site was associated with ferric, ferrous, and cupric chelation, the chelation potential of isoflavones was low and no cuprous chelation was observed. None of isoflavones was able to substantially reduce ferric ions, but the vast majority reduced cupric ions. The most important feature for cupric reduction was the presence of an unsubstituted 4′-hydroxyl; contrarily the presence of a free 5-hydroxyl decreased or abolished the reduction due to chelation of cupric ions. The results from this study may enable additional experiments which might clarify the effects of isoflavones on human being and/or mechanisms of copper absorption. Jana Karlíčková, Kateřina Macáková, Michal Říha, Liliane Maria Teixeira Pinheiro, Tomáš Filipský, Veronika Horňasová, Radomír Hrdina, and Přemysl Mladěnka Copyright © 2015 Jana Karlíčková et al. All rights reserved. Oxidative Stress-Mediated Reperfusion Injury 2014 Wed, 22 Jul 2015 12:16:48 +0000 http://www.hindawi.com/journals/omcl/2015/689416/ Zhengyuan Xia, Yanfang Chen, Qian Fan, Mengzhou Xue, and Ke-xuan Liu Copyright © 2015 Zhengyuan Xia et al. All rights reserved. Protective Effects of Kaempferol against Myocardial Ischemia/Reperfusion Injury in Isolated Rat Heart via Antioxidant Activity and Inhibition of Glycogen Synthase Kinase-3 Wed, 22 Jul 2015 06:55:45 +0000 http://www.hindawi.com/journals/omcl/2015/481405/ Objective. This study aimed to evaluate the protective effect of kaempferol against myocardial ischemia/reperfusion (I/R) injury in rats. Method. Left ventricular developed pressure (LVDP) and its maximum up/down rate () were recorded as myocardial function. Infarct size was detected with 2,3,5-triphenyltetrazolium chloride staining. Cardiomyocyte apoptosis was determined using terminal deoxynucleotidyl nick-end labeling (TUNEL). The levels of creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione/glutathione disulfide (GSH/GSSG) ratio, and tumor necrosis factor-alpha (TNF-α) were determined using enzyme linked immunosorbent assay (ELISA). Moreover, total glycogen synthase kinase-3β (GSK-3β), phospho-GSK-3β (P-GSK-3β), precaspase-3, cleaved caspase-3, and cytoplasm cytochrome C were assayed using Western blot analysis. Results. Pretreatment with kaempferol significantly improved the recovery of LVDP and , as well as increased the levels of SOD and P-GSK-3β and GSH/GSSG ratio. However, the pretreatment reduced myocardial infarct size and TUNEL-positive cell rate, as well as decreased the levels of cleaved caspase-3, cytoplasm cytochrome C, CK, LDH, MDA, and TNF-α. Conclusion. These results suggested that kaempferol provides cardioprotection via antioxidant activity and inhibition of GSK-3β activity in rats with I/R. Mingjie Zhou, Huanhuan Ren, Jichun Han, Wenjuan Wang, Qiusheng Zheng, and Dong Wang Copyright © 2015 Mingjie Zhou et al. All rights reserved. Daily Oxygen/O3 Treatment Reduces Muscular Fatigue and Improves Cardiac Performance in Rats Subjected to Prolonged High Intensity Physical Exercise Tue, 21 Jul 2015 12:32:42 +0000 http://www.hindawi.com/journals/omcl/2015/190640/ Rats receiving daily intraperitoneal administration of O2 and running on a treadmill covered an average distance of 482.8 ± 21.8 m/week as calculated during 5-week observation. This distance was increased in rats receiving daily intraperitoneal administration of an oxygen/O3 mixture at a dose of 100; 150; and 300 μg/kg with the maximum increase being +34.5% at 300 μg/kg and still present after stopping the administration of oxygen/O3. Oxygen/O3 decreased the mean arterial blood pressure (−13%), the heart rate (−6%), the gastrocnemius and cardiac hypertrophy, and fibrosis and reduced by 49% the left ventricular mass and relative wall thickness measurements. Systolic and diastolic functions were improved in exercised oxygen/O3 rats compared to O2 rats. Oxygen/O3 treatment led to higher MPI index starting from the dose of 150 μg/kg () and more effective (+14%) at a dose of 300 μg/kg oxygen/O3. Oxygen/O3 dose-dependently increased the expression of the antioxidant enzymes Mn-SOD and GPx1 and of eNOS compared to the exercised O2 rats. The same doses resulted in decrease of LDH levels, CPK, TnI, and nitrotyrosine concentration in the heart and gastrocnemius tissues, arguing a beneficial effect of the ozone molecule against the fatigue induced by a prolonged high intensity exercise. C. Di Filippo, M. C. Trotta, R. Maisto, D. Siniscalco, M. Luongo, L. Mascolo, R. Alfano, M. Accardo, C. Rossi, F. Ferraraccio, and M. D’Amico Copyright © 2015 C. Di Filippo et al. All rights reserved. Dietary Polyphenols and Their Effects on Cell Biochemistry and Pathophysiology 2014 Tue, 21 Jul 2015 11:34:22 +0000 http://www.hindawi.com/journals/omcl/2015/782424/ Cristina Angeloni, Tullia Maraldi, Dragan Milenkovic, and David Vauzour Copyright © 2015 Cristina Angeloni et al. All rights reserved. Plant Natural Products Calycosin and Gallic Acid Synergistically Attenuate Neutrophil Infiltration and Subsequent Injury in Isoproterenol-Induced Myocardial Infarction: A Possible Role for Leukotriene B4 12-Hydroxydehydrogenase? Tue, 21 Jul 2015 09:19:48 +0000 http://www.hindawi.com/journals/omcl/2015/434052/ Leukotriene B4 12-hydroxydehydrogenase (LTB4DH) catalyzes the oxidation of proinflammatory LTB4 into less bioactive 12-oxo-LTB4. We recently discovered that LTB4DH was induced by two different natural products in combination. We previously isolated gallic acid from Radix Paeoniae through a bioactivity-guided fractionation procedure. The purpose of this study is to test the hypothesis that LTB4DH inducers may suppress neutrophil-mediated inflammation in myocardial infarction. We first isolated the active compound(s) from another plant, Radix Astragali, by the similar strategy. By evaluating LTB4DH induction, we identified calycosin and formononetin from Radix Astragali by HPLC-ESI-MS technique. We confirmed that gallic acid and commercial calycosin or formononetin could synergistically induce LTB4DH expression in HepG2 cells and human neutrophils. Moreover, calycosin and gallic acid attenuated the effects of LTB4 on the survival and chemotaxis of neutrophil cell culture. We further demonstrated that calycosin and gallic acid synergistically suppressed neutrophil infiltration and protected cardiac integrity in the isoproterenol-induced mice model of myocardial infarction. Calycosin and gallic acid dramatically suppressed isoproterenol-induced increase in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level. Collectively, our results suggest that LTB4DH inducers (i.e., calycosin and gallic acid) may be a novel combined therapy for the treatment of neutrophil-mediated myocardial injury. Yuanyuan Cheng, Jia Zhao, Hung Fat Tse, X. Chris Le, and Jianhui Rong Copyright © 2015 Yuanyuan Cheng et al. All rights reserved. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β-Cell Dysfunction Tue, 14 Jul 2015 12:35:23 +0000 http://www.hindawi.com/journals/omcl/2015/181643/ The prevalence of diabetes mellitus (DM) is increasing worldwide, a consequence of the alarming rise in obesity and metabolic syndrome (MetS). Oxidative stress and inflammation are key physiological and pathological events linking obesity, insulin resistance, and the progression of type 2 DM (T2DM). Unresolved inflammation alongside a “glucolipotoxic” environment of the pancreatic islets, in insulin resistant pathologies, enhances the infiltration of immune cells which through secretory activity cause dysfunction of insulin-secreting β-cells and ultimately cell death. Recent molecular investigations have revealed that mechanisms responsible for insulin resistance associated with T2DM are detected in conditions such as obesity and MetS, including impaired insulin receptor (IR) signalling in insulin responsive tissues, oxidative stress, and endoplasmic reticulum (ER) stress. The aim of the present review is to describe the evidence linking oxidative stress and inflammation with impairment of insulin secretion and action, which result in the progression of T2DM and other conditions associated with metabolic dysregulation. Kevin Noel Keane, Vinicius Fernandes Cruzat, Rodrigo Carlessi, Paulo Ivo Homem de Bittencourt Jr., and Philip Newsholme Copyright © 2015 Kevin Noel Keane et al. All rights reserved. Brewers’ Rice: A By-Product from Rice Processing Provides Natural Hepatorenal Protection in Azoxymethane-Induced Oxidative Stress in Rats Tue, 14 Jul 2015 11:02:18 +0000 http://www.hindawi.com/journals/omcl/2015/539798/ Brewers’ rice, which is known locally as temukut, is a mixture of broken rice, rice bran, and rice germ. Our present study was designed to identify the effect of brewers’ rice on the attenuation of liver and kidney damage induced by azoxymethane (AOM). Alanine transaminase (ALT), alkaline phosphatase (ALP), aspartate transaminase (AST), creatinine, and urea were evaluated to understand potential hepatoprotective effects and the ability of brewers’ rice to attenuate kidney pathology induced by AOM treatment. Liver and kidney tissues were evaluated by hematoxylin and eosin (H&E) staining. Overall analyses revealed that brewers’ rice improved the levels of serum markers in a manner associated with better histopathological outcomes, which indicated that brewers’ rice could enhance recovery from hepatocyte and kidney damage. Taken together, these results suggest that brewers’ rice could be used in future applications to combat liver and kidney disease. Bee Ling Tan, Mohd Esa Norhaizan, Ithnin Hairuszah, Hamzah Hazilawati, and Karim Roselina Copyright © 2015 Bee Ling Tan et al. All rights reserved.