Oxidative Medicine and Cellular Longevity http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. High Mobility Group B Proteins, Their Partners, and Other Redox Sensors in Ovarian and Prostate Cancer Mon, 23 Nov 2015 13:49:02 +0000 http://www.hindawi.com/journals/omcl/2016/5845061/ Cancer cells try to avoid the overproduction of reactive oxygen species by metabolic rearrangements. These cells also develop specific strategies to increase ROS resistance and to express the enzymatic activities necessary for ROS detoxification. Oxidative stress produces DNA damage and also induces responses, which could help the cell to restore the initial equilibrium. But if this is not possible, oxidative stress finally activates signals that will lead to cell death. High mobility group B (HMGB) proteins have been previously related to the onset and progressions of cancers of different origins. The protein HMGB1 behaves as a redox sensor and its structural changes, which are conditioned by the oxidative environment, are associated with different functions of the protein. This review describes recent advances in the role of human HMGB proteins and other proteins interacting with them, in cancerous processes related to oxidative stress, with special reference to ovarian and prostate cancer. Their participation in the molecular mechanisms of resistance to cisplatin, a drug commonly used in chemotherapy, is also revised. Aida Barreiro-Alonso, Mónica Lamas-Maceiras, Esther Rodríguez-Belmonte, Ángel Vizoso-Vázquez, María Quindós, and M. Esperanza Cerdán Copyright © 2016 Aida Barreiro-Alonso et al. All rights reserved. The Tumorigenic Roles of the Cellular REDOX Regulatory Systems Mon, 23 Nov 2015 07:20:25 +0000 http://www.hindawi.com/journals/omcl/2016/8413032/ The cellular REDOX regulatory systems play a central role in maintaining REDOX homeostasis that is crucial for cell integrity, survival, and proliferation. To date, a substantial amount of data has demonstrated that cancer cells typically undergo increasing oxidative stress as the tumor develops, upregulating these important antioxidant systems in order to survive, proliferate, and metastasize under these extreme oxidative stress conditions. Since a large number of chemotherapeutic agents currently used in the clinic rely on the induction of ROS overload or change of ROS quality to kill the tumor, the cancer cell REDOX adaptation represents a significant obstacle to conventional chemotherapy. In this review we will first examine the different factors that contribute to the enhanced oxidative stress generally observed within the tumor microenvironment. We will then make a comprehensive assessment of the current literature regarding the main antioxidant proteins and systems that have been shown to be positively associated with tumor progression and chemoresistance. Finally we will make an analysis of commonly used chemotherapeutic drugs that induce ROS. The current knowledge of cancer cell REDOX adaptation raises the issue of developing novel and more effective therapies for these tumors that are usually resistant to conventional ROS inducing chemotherapy. Stéphanie Anaís Castaldo, Joana Raquel Freitas, Nadine Vasconcelos Conchinha, and Patrícia Alexandra Madureira Copyright © 2016 Stéphanie Anaís Castaldo et al. All rights reserved. Protective Effect of D-Limonene against Oxidative Stress-Induced Cell Damage in Human Lens Epithelial Cells via the p38 Pathway Mon, 23 Nov 2015 06:49:04 +0000 http://www.hindawi.com/journals/omcl/2016/5962832/ Oxidative stress, as mediated by ROS, is a significant factor in initiating the development of age-associated cataracts; D-limonene is a common natural terpene with powerful antioxidative properties which occurs naturally in a wide variety of living organisms. It has been shown to have antioxidant effect; we found that D-limonene can effectively prevent the oxidative damage caused by H2O2 and propose that the main mechanism underlying the inhibitory effects of D-limonene is the inhibition of HLECs apoptosis. In the present study, we used confocal-fluorescence microscopy, flow cytometry analysis, Hoechst staining, H2DCFDA staining, transmission electron microscopy, and immunoblot analysis; the results revealed that slightly higher concentrations of D-limonene (125–1800 μM) reduced the H2O2-induced ROS generation and inhibited the H2O2-induced caspase-3 and caspase-9 activation and decreased the Bcl-2/Bax ratio. Furthermore, it inhibited H2O2-induced p38 MAPK phosphorylation. Thus, we conclude that D-limonene could effectively protect HLECs from H2O2-induced oxidative stress and that its antioxidative effect is significant, thereby increasing the cell survival rate. Jie Bai, Yi Zheng, Gang Wang, and Ping Liu Copyright © 2016 Jie Bai et al. All rights reserved. Dietary Restriction and Nutrient Balance in Aging Mon, 23 Nov 2015 06:36:27 +0000 http://www.hindawi.com/journals/omcl/2016/4010357/ Dietary regimens that favour reduced calorie intake delay aging and age-associated diseases. New evidences revealed that nutritional balance of dietary components without food restriction increases lifespan. Particular nutrients as several nitrogen sources, proteins, amino acid, and ammonium are implicated in life and healthspan regulation in different model organisms from yeast to mammals. Aging and dietary restriction interact through partially overlapping mechanisms in the activation of the conserved nutrient-signalling pathways, mainly the insulin/insulin-like growth factor (IIS) and the Target Of Rapamycin (TOR). The specific nutrients of dietary regimens, their balance, and how they interact with different genes and pathways are currently being uncovered. Taking into account that dietary regimes can largely influence overall human health and changes in risk factors such as cholesterol level and blood pressure, these new findings are of great importance to fully comprehend the interplay between diet and humans health. Júlia Santos, Fernanda Leitão-Correia, Maria João Sousa, and Cecília Leão Copyright © 2016 Júlia Santos et al. All rights reserved. Fisetin Modulates Antioxidant Enzymes and Inflammatory Factors to Inhibit Aflatoxin-B1 Induced Hepatocellular Carcinoma in Rats Sun, 22 Nov 2015 14:27:02 +0000 http://www.hindawi.com/journals/omcl/2016/1972793/ Fisetin, a known antioxidant, has been found to be cytotoxic against certain cell lines. However, the mechanism by which it inhibits tumor growth in vivo remains unexplored. Recently, we have demonstrated that Aflatoxin-B1 (AFB1) induced hepatocarcinogenesis is associated with activation of oxidative stress-inflammatory pathway in rat liver. The present paper describes the effect of in vivo treatment with 20 mg/kg b.w. Fisetin on antioxidant enzymes vis-a-vis oxidative stress level and on the profile of certain proinflammatory cytokines in the hepatocellular carcinoma (HCC) induced by two doses of 1 mg/kg b.w. AFB1 i.p. in rats. The reduced levels of most of the antioxidant enzymes, coinciding with the enhanced level of reactive oxygen species in the HCC liver, were observed to regain their normal profiles due to Fisetin treatment. Also, Fisetin treatment could normalize the enhanced expression of TNFα and IL1α, the two proinflammatory cytokines, reported to be involved in HCC pathogenesis. These observations were consistent with the regression of neoplastic lesion and declined GST-pi (placental type glutathione-S-transferase) level, a HCC marker, in the liver of the Fisetin treated HCC rats. The findings suggest that Fisetin attenuates oxidative stress-inflammatory pathway of AFB1 induced hepatocarcinogenesis. Brajesh Kumar Maurya and Surendra Kumar Trigun Copyright © 2016 Brajesh Kumar Maurya and Surendra Kumar Trigun. All rights reserved. Fibroblast Growth Factor-9 Activates c-Kit Progenitor Cells and Enhances Angiogenesis in the Infarcted Diabetic Heart Sun, 22 Nov 2015 14:20:03 +0000 http://www.hindawi.com/journals/omcl/2016/5810908/ We hypothesized that fibroblast growth factor-9 (FGF-9) would enhance angiogenesis via activating c-kit positive stem cells in the infarcted nondiabetic and diabetic heart. In brief, animals were divided into three groups: Sham, MI, and MI+FGF-9. Two weeks following MI or sham surgery, our data suggest that treatment with FGF-9 significantly diminished vascular apoptosis compared to the MI group in both C57BL/6 and db/db mice (). Additionally, the number of c-kit+ve/SM α-actin+ve cells and c-kit+ve/CD31+ve cells were greatly enhanced in the MI+FGF-9 groups relative to the MI suggesting FGF-9 enhances c-Kit cell activation and their differentiation into vascular smooth muscle cells and endothelial cells, respectively (). Histology shows that the total number of vessels were quantified for all groups and our data suggest that the FGF-9 treated groups had significantly more vessels than their MI counterparts (). Finally, echocardiographic data suggests a significant improvement in left ventricular output, as indicated by fractional shortening and ejection fraction in both nondiabetic and diabetic animals treated with FGF-9 (). Overall, our data suggests FGF-9 has the potential to attenuate vascular cell apoptosis, activate c-Kit progenitor cells, and enhance angiogenesis and neovascularization in C57BL/6 and db/db mice leading to improved cardiac function. Dinender Singla and Jing Wang Copyright © 2016 Dinender Singla and Jing Wang. All rights reserved. Reviews on Mechanisms of In Vitro Antioxidant Activity of Polysaccharides Sun, 22 Nov 2015 14:11:19 +0000 http://www.hindawi.com/journals/omcl/2016/5692852/ It is widely acknowledged that the excessive reactive oxygen species (ROS) or reactive nitrogen species (RNS) induced oxidative stress will cause significant damage to cell structure and biomolecular function, directly or indirectly leading to a number of diseases. The overproduction of ROS/RNS will be balanced by nonenzymatic antioxidants and antioxidant enzymes. Polysaccharide or glycoconjugates derived from natural products are of considerable interest from the viewpoint of potent in vivo and in vitro antioxidant activities recently. Particularly, with regard to the in vitro antioxidant systems, polysaccharides are considered as effective free radical scavenger, reducing agent, and ferrous chelator in most of the reports. However, the underlying mechanisms of these antioxidant actions have not been illustrated systematically and sometimes controversial results appeared among various literatures. To address this issue, we summarized the latest discoveries and advancements in the study of antioxidative polysaccharides and gave a detailed description of the possible mechanisms. Junqiao Wang, Shuzhen Hu, Shaoping Nie, Qiang Yu, and Mingyong Xie Copyright © 2016 Junqiao Wang et al. All rights reserved. Dexmedetomidine Pretreatment Attenuates Kidney Injury and Oxidative Stress during Orthotopic Autologous Liver Transplantation in Rats Sun, 22 Nov 2015 14:09:53 +0000 http://www.hindawi.com/journals/omcl/2016/4675817/ This paper aims to explore whether pretreatment with dexmedetomidine (Dex) has antioxidative and renal protective effects during orthotopic autologous liver transplantation (OALT) and its impact on nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Sprague-Dawley rats were randomized into groups that include sham-operated (group S), model (group M), low dose Dex (group D1), high dose Dex (group D2), atipamezole (a nonspecific α2 receptor blocker) + high dose Dex (group B1), ARC239 (a specific receptor blocker) + high dose Dex (group B2), and BRL-44408 (a specific receptor blocker) + high dose Dex (group B3). Then histopathologic examination of the kidneys and measurement of renal function, the renal Nrf2 protein expression, and oxidants and antioxidants were performed 8 hours after OALT. We found that pretreatment with Dex activated Nrf2 in glomerular cells and upregulated antioxidants but reduced oxidants (all , group D2 versus group M). Atipamezole and BRL-44408, but not ARC239, reversed these protective effects. In conclusion, pretreatment with Dex activates Nrf2 through receptor, increases the antioxidant levels, and attenuates renal injury during OALT. Xiaofang Yu, Xinjin Chi, Shan Wu, Yi Jin, Hui Yao, Yiheng Wang, Zhengyuan Xia, and Jun Cai Copyright © 2016 Xiaofang Yu et al. All rights reserved. Histone Deacetylase Inhibitors Increase p27Kip1 by Affecting Its Ubiquitin-Dependent Degradation through Skp2 Downregulation Sun, 22 Nov 2015 14:04:41 +0000 http://www.hindawi.com/journals/omcl/2016/2481865/ Histone deacetylase inhibitors (HDACIs) represent an intriguing class of pharmacologically active compounds. Currently, some HDACIs are FDA approved for cancer therapy and many others are in clinical trials, showing important clinical activities at well tolerated doses. HDACIs also interfere with the aging process and are involved in the control of inflammation and oxidative stress. In vitro, HDACIs induce different cellular responses including growth arrest, differentiation, and apoptosis. Here, we evaluated the effects of HDACIs on p27Kip1, a key cyclin-dependent kinase inhibitor (CKI). We observed that HDACI-dependent antiproliferative activity is associated with p27Kip1 accumulation due to a reduced protein degradation. p27Kip1 removal requires a preliminary ubiquitination step due to the Skp2-SCF E3 ligase complex. We demonstrated that HDACIs increase p27Kip1 stability through downregulation of Skp2 protein levels. Skp2 decline is only partially due to a reduced Skp2 gene expression. Conversely, the protein decrease is more profound and enduring compared to the changes of Skp2 transcript. This argues for HDACIs effects on Skp2 protein posttranslational modifications and/or on its removal. In summary, we demonstrate that HDACIs increase p27Kip1 by hampering its nuclear ubiquitination/degradation. The findings might be of relevance in the phenotypic effects of these compounds, including their anticancer and aging-modulating activities. Adriana Borriello, Silvio Naviglio, Debora Bencivenga, Ilaria Caldarelli, Annunziata Tramontano, Maria Carmela Speranza, Emanuela Stampone, Luigi Sapio, Aide Negri, Adriana Oliva, Antonio Agostino Sinisi, Annamaria Spina, and Fulvio Della Ragione Copyright © 2016 Adriana Borriello et al. All rights reserved. The Relevance of Nrf2 Pathway and Autophagy in Pancreatic Cancer Cells upon Stimulation of Reactive Oxygen Species Sun, 22 Nov 2015 13:30:12 +0000 http://www.hindawi.com/journals/omcl/2016/3897250/ Nrf2 (NF-E2-related factor 2) pathway and autophagy both can respond to oxidative stress to promote cancer cells to survive in the tumor microenvironment. We, therefore, explored the relevance between Nrf2 pathway and autophagy in pancreatic cancer cells upon stimulation of reactive oxygen species (ROS). Pancreatic cancer cells were cultured under controlled ROS stressing condition or basal condition. Different inhibitors were used to prevent autophagy at particular stages. Nrf2 siRNA was used to inhibit Nrf2 pathway activation. Ad-mRFP-GFP-LC3 infection was used to monitor autophagic flux. The result shows that a small amount of exogenous hydrogen peroxide (H2O2) can significantly improve the level of intracellular ROS. Moreover, our findings indicate that ROS promotes the activation of both Nrf2 pathway and autophagy in pancreatic cancer cells. Moreover, our data demonstrate that suppression of autophagic activity at particular stages results in an increased promotion of Nrf2 pathway activation upon ROS stimulation. Furthermore, we found that silencing of Nrf2 promotes autophagy upon ROS stimulation. In addition, Nrf2 interference effectively promotes autophagic flux upon ROS stimulation. In summary, our findings suggest that Nrf2 pathway and autophagy have a negative interaction with each other upon ROS stimulation. Lun Zhang, Jiahui Li, Jiguang Ma, Xin Chen, Ke Chen, Zhengdong Jiang, Liang Zong, Shuo Yu, Xuqi Li, Qinhong Xu, Jianjun Lei, Wanxing Duan, Wei Li, Tao Shan, Qingyong Ma, and Xin Shen Copyright © 2016 Lun Zhang et al. All rights reserved. Relation between Endothelial Nitric Oxide Synthase Genotypes and Oxidative Stress Markers in Larynx Cancer Sun, 22 Nov 2015 13:27:07 +0000 http://www.hindawi.com/journals/omcl/2016/4985063/ Nitric oxide synthase (eNOS/NOS3) is responsible for the endothelial synthesis of nitric oxide (NO•). G894T polymorphism leads to the amino acid substitution from Glu298Asp that causes lower NOS3 activity and basal NO• production in NOS3 894T (298Asp) allele carriers compared with the GG homozygotes. NO• acts as an antioxidant protecting against Fenton’s reaction which generates highly reactive hydroxyl radicals. Allelic variation of NOS3 may influence an individual’s risk of laryngeal cancer (LC). In the current study we have examined the possible relationship between NOS3 G894T genotypes and various systemic oxidative damage markers such as protein carbonyl, advanced oxidation protein products, Cu, Zn-superoxide dismutase, thiol group fractions, and lipid hydroperoxides in LC patients. Genotyping was carried out by PCR-RFLP. In LC patients with TT genotype, Cu, Zn-superoxide dismutase activities and nonprotein thiol levels were significantly higher than the controls. In patients with GT and GG genotype, high levels of lipid hydroperoxides showed statistical significance when compared to controls. Our results indicate a potential relationship among G894T polymorphism of NOS3, and impaired redox homeostasis. Further studies are required to determine the role of NOS3 gene polymorphism and impaired plasma redox homeostasis. K. Yanar, U. Çakatay, S. Aydın, A. Verim, P. Atukeren, N. E. Özkan, K. Karatoprak, T. Cebe, S. Turan, E. Ozkök, G. Korkmaz, C. Cacına, O. Küçükhüseyin, and İ. Yaylım Copyright © 2016 K. Yanar et al. All rights reserved. Juglanthraquinone C Induces Intracellular ROS Increase and Apoptosis by Activating the Akt/Foxo Signal Pathway in HCC Cells Sun, 22 Nov 2015 13:20:41 +0000 http://www.hindawi.com/journals/omcl/2016/4941623/ Juglanthraquinone C (JC), a naturally occurring anthraquinone extracted from Juglans mandshurica, could induce apoptosis of cancer cells. This study aims to investigate the detailed cytotoxicity mechanism of JC in HepG2 and BEL-7402 cells. The Affymetrix HG-U133 Plus 2.0 arrays were first used to analyze the mRNA expression exposed to JC or DMSO in HepG2 cells. Consistent with the previous results, the data indicated that JC could induce apoptosis and hyperactivated Akt. The Western blot analysis further revealed that Akt, a well-known survival protein, was strongly activated in HepG2 and BEL-7402 cells. Furthermore, an obvious inhibitory effect on JC-induced apoptosis was observed when the Akt levels were decreased, while the overexpression of constitutively active mutant Akt greatly accelerated JC-induced apoptosis. The subsequent results suggested that JC treatment suppressed nuclear localization and increased phosphorylated levels of Foxo3a, and the overexpression of Foxo3a abrogated JC-induced apoptosis. Most importantly, the inactivation of Foxo3a induced by JC further led to an increase of intracellular ROS levels by suppressing ROS scavenging enzymes, and the antioxidant N-acetyl-L-cysteine and catalase successfully decreased JC-induced apoptosis. Collectively, this study demonstrated that JC induced the apoptosis of hepatocellular carcinoma (HCC) cells by activating Akt/Foxo signaling pathway and increasing intracellular ROS levels. Ya-Qin Hou, Yao Yao, Yong-Li Bao, Zhen-Bo Song, Cheng Yang, Xiu-Li Gao, Wen-Jing Zhang, Lu-Guo Sun, Chun-Lei Yu, Yan-Xin Huang, Guan-Nan Wang, and Yu-Xin Li Copyright © 2016 Ya-Qin Hou et al. All rights reserved. Redox Modulating NRF2: A Potential Mediator of Cancer Stem Cell Resistance Sun, 22 Nov 2015 13:20:07 +0000 http://www.hindawi.com/journals/omcl/2016/2428153/ Tumors contain a distinct small subpopulation of cells that possess stem cell-like characteristics. These cells have been called cancer stem cells (CSCs) and are thought to be responsible for anticancer drug resistance and tumor relapse after therapy. Emerging evidence indicates that CSCs share many properties, such as self-renewal and quiescence, with normal stem cells. In particular, CSCs and normal stem cells retain low levels of reactive oxygen species (ROS), which can contribute to stem cell maintenance and resistance to stressful tumor environments. Current literatures demonstrate that the activation of ataxia telangiectasia mutated (ATM) and forkhead box O3 (FoxO3) is associated with the maintenance of low ROS levels in normal stem cells such as hematopoietic stem cells. However, the importance of ROS signaling in CSC biology remains poorly understood. Recent studies demonstrate that nuclear factor-erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidant defense system, is involved in the maintenance of quiescence, survival, and stress resistance of CSCs. Here, we review the recent findings on the roles of NRF2 in maintenance of the redox state and multidrug resistance in CSCs, focusing on how NRF2-mediated ROS modulation influences the growth and resistance of CSCs. In-geun Ryoo, Sang-hwan Lee, and Mi-Kyoung Kwak Copyright © 2016 In-geun Ryoo et al. All rights reserved. Antioxidant Intake and Antitumor Therapy: Toward Nutritional Recommendations for Optimal Results Sun, 22 Nov 2015 13:13:25 +0000 http://www.hindawi.com/journals/omcl/2016/6719534/ The role of the induction of oxidative stress as the mechanism of action of many antitumor drugs is acquiring an increasing interest. In such cases, the antitumor therapy success may be conditioned by the antioxidants present in our own body, which can be synthesized de novo (endogenous) or incorporated through the diet and nutritional supplements (exogenous). In this paper, we have reviewed different aspects of antioxidants, including their classification, natural sources, importance in diet, consumption of nutritional supplements, and the impact of antioxidants on health. Moreover, we have focused especially on the study of the interaction between antioxidants and antitumor therapy, considering both radiotherapy and chemotherapy. In this regard, we found that the convenience of administration of antioxidants during cancer treatment still remains a very controversial issue. In general terms, antioxidants could promote or suppress the effectiveness of antitumor treatment and even protect healthy tissues against damage induced by oxidative stress. The effects may depend on many factors discussed in the paper. These factors should be taken into consideration in order to achieve precise nutritional recommendations for patients. The evidence at the moment suggests that the supplementation or restriction of exogenous antioxidants during cancer treatment, as appropriate, could contribute to improving its efficiency. Nuria Mut-Salud, Pablo Juan Álvarez, Jose Manuel Garrido, Esther Carrasco, Antonia Aránega, and Fernando Rodríguez-Serrano Copyright © 2016 Nuria Mut-Salud et al. All rights reserved. Equine Metabolic Syndrome Affects Viability, Senescence, and Stress Factors of Equine Adipose-Derived Mesenchymal Stromal Stem Cells: New Insight into EqASCs Isolated from EMS Horses in the Context of Their Aging Sun, 22 Nov 2015 12:56:18 +0000 http://www.hindawi.com/journals/omcl/2016/4710326/ Currently, equine metabolic syndrome (EMS), an endocrine disease linked to insulin resistance, affects an increasing number of horses. However, little is known about the effect of EMS on mesenchymal stem cells that reside in adipose tissue (ASC). Thus it is crucial to evaluate the viability and growth kinetics of these cells, particularly in terms of their application in regenerative medicine. In this study, we investigated the proliferative capacity, morphological features, and accumulation of oxidative stress factors in mesenchymal stem cells isolated from healthy animals () and horses suffering from EMS (). displayed senescent phenotype associated with β-galactosidase accumulation, enlarged cell bodies and nuclei, increased apoptosis, and reduced heterochromatin architecture. Moreover, we observed increased amounts of nitric oxide (NO) and reactive oxygen species (ROS) in these cells, accompanied by reduced superoxide dismutase (SOD) activity. We also found in an elevated number of impaired mitochondria, characterized by membrane raptures, disarrayed cristae, and vacuole formation. Our results suggest that the toxic compounds, accumulating in the mitochondria under oxidative stress, lead to alternations in their morphology and may be partially responsible for the senescent phenotype and decreased proliferation potential of . Krzysztof Marycz, Katarzyna Kornicka, Katarzyna Basinska, and Aleksandra Czyrek Copyright © 2016 Krzysztof Marycz et al. All rights reserved. The Effect of Lycopene Preexposure on UV-B-Irradiated Human Keratinocytes Tue, 17 Nov 2015 07:22:55 +0000 http://www.hindawi.com/journals/omcl/2016/8214631/ Lycopene has been reported as the antioxidant most quickly depleted in skin upon UV irradiation, and thus it might play a protective role. Our goal was to investigate the effects of preexposure to lycopene on UV-B-irradiated skin cells. Cells were exposed for 24 h to 10 M lycopene, and subsequently irradiated and left to recover for another 24 h period. Thereafter, several parameters were analyzed by FCM and RT-PCR: genotoxicity/clastogenicity by assessing the cell cycle distribution; apoptosis by performing the Annexin-V assay and analyzing gene expression of apoptosis biomarkers; and oxidative stress by ROS quantification. Lycopene did not significantly affect the profile of apoptotic, necrotic and viable cells in nonirradiated cells neither showed cytostatic effects. However, irradiated cells previously treated with lycopene showed an increase in both dead and viable subpopulations compared to nonexposed irradiated cells. In irradiated cells, lycopene preexposure resulted in overexpression of BAX gene compared to nonexposed irradiated cells. This was accompanied by a cell cycle delay at S-phase transition and consequent decrease of cells in G0/G1 phase. Thus, lycopene seems to play a corrective role in irradiated cells depending on the level of photodamage. Thus, our findings may have implications for the management of skin cancer. Andreia Ascenso, Tiago Pedrosa, Sónia Pinho, Francisco Pinho, José Miguel P. Ferreira de Oliveira, Helena Cabral Marques, Helena Oliveira, Sandra Simões, and Conceição Santos Copyright © 2016 Andreia Ascenso et al. All rights reserved. Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases Mon, 16 Nov 2015 14:16:15 +0000 http://www.hindawi.com/journals/omcl/2016/6859523/ Reactive oxygen species (ROS) play a crucial role in the inflammatory response and cytokine outbreak, such as during virus infections, diabetes, cancer, cardiovascular diseases, and neurodegenerative diseases. Therefore, antioxidant is an important medicine to ROS-related diseases. For example, ascorbic acid (vitamin C, VC) was suggested as the candidate antioxidant to treat multiple diseases. However, long-term use of high-dose VC causes many side effects. In this review, we compare and analyze all kinds of mitochondrion-permeable antioxidants, including edaravone, idebenone, α-Lipoic acid, carotenoids, vitamin E, and coenzyme Q10, and mitochondria-targeted antioxidants MitoQ and SkQ and propose astaxanthin (a special carotenoid) to be the best antioxidant for ROS-burst-mediated acute diseases, like avian influenza infection and ischemia-reperfusion. Nevertheless, astaxanthins are so unstable that most of them are inactivated after oral administration. Therefore, astaxanthin injection is suggested hypothetically. The drawbacks of the antioxidants are also reviewed, which limit the use of antioxidants as coadjuvants in the treatment of ROS-associated disorders. Zhong-Wei Zhang, Xiao-Chao Xu, Ting Liu, and Shu Yuan Copyright © 2016 Zhong-Wei Zhang et al. All rights reserved. Lipoxin A4 Attenuates Cell Invasion by Inhibiting ROS/ERK/MMP Pathway in Pancreatic Cancer Mon, 16 Nov 2015 11:08:18 +0000 http://www.hindawi.com/journals/omcl/2016/6815727/ Lipoxin A4 (LXA4), an endogenous arachidonic acid metabolite, was previously considered an anti-inflammatory lipid mediator. But it also has the potential to inhibit cancer progression. To explore the therapeutic effect of LXA4 in pancreatic cancer, we used Panc-1 cells to investigate the mechanism by which LXA4 can attenuate pancreatic cancer cell invasion. Our data showed that LXA4 significantly inhibited both cell invasion and the expression of matrix metalloproteinase- (MMP-) 9 and MMP-2. Further experiments implied that LXA4 decreased the levels of intracellular reactive oxygen species (ROS) and the activity of the extracellular signal regulated kinases (ERK) pathway to achieve similar outcome to ROS scavenger N-acetyl-L-cysteine (NAC). However, a decreased level of intracellular ROS was not observed in cells treated with the specific ERK pathway inhibitor FR180204. The blocking of either intracellular ROS or ERK pathway caused the downregulation of MMP-9 and MMP-2 expression. Furthermore, tests revealed that LXA4 inhibited MMP-9 and MMP-2 at the mRNA, protein, and functional levels. Finally, LXA4 dramatically limited the invasion of CoCl2-mimic hypoxic cells and abrogated intracellular ROS levels, ERK activity, and MMPs expression. These results suggest that LXA4 attenuates cell invasion in pancreatic cancer by suppressing the ROS/ERK/MMPs pathway, which may be beneficial for preventing the invasion of pancreatic cancer. Liang Zong, Jiahui Li, Xin Chen, Ke Chen, Wei Li, Xuqi Li, Lun Zhang, Wanxing Duan, Jianjun Lei, Qinhong Xu, Tao Shan, Qingyong Ma, and Hao Sun Copyright © 2016 Liang Zong et al. All rights reserved. Nr2e1 Deficiency Augments Palmitate-Induced Oxidative Stress in Beta Cells Mon, 16 Nov 2015 09:18:24 +0000 http://www.hindawi.com/journals/omcl/2016/9648769/ Nuclear receptor subfamily 2 group E member 1 (Nr2e1) has been regarded as an essential regulator of the growth of neural stem cells. However, its function elsewhere is unknown. In the present study, we generated Nr2e1 knockdown MIN6 cells and studied whether Nr2e1 knockdown affected basal beta cell functions such as proliferation, cell death, and insulin secretion. We showed that knockdown of Nr2e1 in MIN6 cells resulted in increased sensitivity to lipotoxicity, decreased proliferation, a partial G0/G1 cell-cycle arrest, and higher rates of apoptosis. Moreover, Nr2e1 deficiency exaggerates palmitate-induced impairment in insulin secretion. At the molecular level, Nr2e1 deficiency augments palmitate-induced oxidative stress. Nr2e1 deficiency also resulted in decreases in antioxidant enzymes and expression level of Nrf2. Together, this study indicated a potential protective effect of Nr2e1 on beta cells, which may serve as a target for the development of novel therapies for diabetes. Xiaoli Shi, Haohua Deng, Zhe Dai, Yancheng Xu, Xiaokan Xiong, Pei Ma, and Jing Cheng Copyright © 2016 Xiaoli Shi et al. All rights reserved. The Cellular Response to Oxidatively Induced DNA Damage and Polymorphism of Some DNA Repair Genes Associated with Clinicopathological Features of Bladder Cancer Mon, 16 Nov 2015 08:14:09 +0000 http://www.hindawi.com/journals/omcl/2016/5710403/ Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H2O2-treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H2O2-induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03–1.81), . The frequency of the XPD 312Asn allele was significantly higher in T ≥ 2 high grade than in T ≥ 2 low grade tumors ; the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle-invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression. Nataliya V. Savina, Nataliya V. Nikitchenko, Tatyana D. Kuzhir, Alexander I. Rolevich, Sergei A. Krasny, and Roza I. Goncharova Copyright © 2016 Nataliya V. Savina et al. All rights reserved. Acetaldehyde Induces Cytotoxicity of SH-SY5Y Cells via Inhibition of Akt Activation and Induction of Oxidative Stress Mon, 16 Nov 2015 07:36:07 +0000 http://www.hindawi.com/journals/omcl/2016/4512309/ Excessive alcohol consumption can lead to brain tissue damage and cognitive dysfunction. It has been shown that heavy drinking is associated with an earlier onset of neurodegenerative diseases such as Alzheimer’s disease. Acetaldehyde, the most toxic metabolite of ethanol, is speculated to mediate the brain tissue damage and cognitive dysfunction induced by the chronic excessive consumption of alcohol. However, the exact mechanisms by which acetaldehyde induces neurotoxicity are not totally understood. In this study, we investigated the cytotoxic effects of acetaldehyde in SH-SY5Y cells and found that acetaldehyde induced apoptosis of SH-SY5Y cells by downregulating the expression of antiapoptotic Bcl-2 and Bcl-xL and upregulating the expression of proapoptotic Bax. Acetaldehyde treatment led to a significant decrease in the levels of activated Akt and cyclic AMP-responsive element binding protein (CREB). In addition, acetaldehyde induced the activation of p38 mitogen-activated protein kinase (MAPK) while inhibiting the activation of extracellular signal-regulated kinases (ERKs, p44/p42MAPK). Meanwhile, acetaldehyde treatment caused an increase in the production of reactive oxygen species and elevated the oxidative stress in SH-SY5Y cells. Therefore, acetaldehyde induces cytotoxicity of SH-SY5Y cells via promotion of apoptotic signaling, inhibition of cell survival pathway, and induction of oxidative stress. Tingting Yan, Yan Zhao, and Xia Zhang Copyright © 2016 Tingting Yan et al. All rights reserved. Polyphenols as Modulator of Oxidative Stress in Cancer Disease: New Therapeutic Strategies Mon, 16 Nov 2015 07:11:16 +0000 http://www.hindawi.com/journals/omcl/2016/6475624/ Cancer onset and progression have been linked to oxidative stress by increasing DNA mutations or inducing DNA damage, genome instability, and cell proliferation and therefore antioxidant agents could interfere with carcinogenesis. It is well known that conventional radio-/chemotherapies influence tumour outcome through ROS modulation. Since these antitumour treatments have important side effects, the challenge is to develop new anticancer therapeutic strategies more effective and less toxic for patients. To this purpose, many natural polyphenols have emerged as very promising anticancer bioactive compounds. Beside their well-known antioxidant activities, several polyphenols target epigenetic processes involved in cancer development through the modulation of oxidative stress. An alternative strategy to the cytotoxic treatment is an approach leading to cytostasis through the induction of therapy-induced senescence. Many anticancer polyphenols cause cellular growth arrest through the induction of a ROS-dependent premature senescence and are considered promising antitumour therapeutic tools. Furthermore, one of the most innovative and interesting topics is the evaluation of efficacy of prooxidant therapies on cancer stem cells (CSCs). Several ROS inducers-polyphenols can impact CSCs metabolisms and self-renewal related pathways. Natural polyphenol roles, mainly in chemoprevention and cancer therapies, are described and discussed in the light of the current literature data. Anna Maria Mileo and Stefania Miccadei Copyright © 2016 Anna Maria Mileo and Stefania Miccadei. All rights reserved. Efficiency of Base Excision Repair of Oxidative DNA Damage and Its Impact on the Risk of Colorectal Cancer in the Polish Population Mon, 16 Nov 2015 07:06:53 +0000 http://www.hindawi.com/journals/omcl/2016/3125989/ DNA oxidative lesions are widely considered as a potential risk factor for colorectal cancer development. The aim of this work was to determine the role of the efficiency of base excision repair, both in lymphocytes and in epithelial tissue, in patients with CRC and healthy subjects. SNPs were identified within genes responsible for steps following glycosylase action in BER, and patients and healthy subjects were genotyped. A radioisotopic BER assay was used for assessing repair efficiency and TaqMan for genotyping. Decreased BER activity was observed in lymphocyte extract from CRC patients and in cancer tissue extract, compared to healthy subjects. In addition, polymorphisms of EXO1, LIG3, and PolB may modulate the risk of colorectal cancer by decreasing (PolB) or increasing (LIG3 and EXO1) the chance of malignant transformation. J. Kabzinski, B. Mucha, M. Cuchra, L. Markiewicz, K. Przybylowska, A. Dziki, L. Dziki, and I. Majsterek Copyright © 2016 J. Kabzinski et al. All rights reserved. Longxuetongluo Capsule Improves Erythrocyte Function against Lipid Peroxidation and Abnormal Hemorheological Parameters in High Fat Diet-Induced ApoE−/− Mice Mon, 16 Nov 2015 07:00:47 +0000 http://www.hindawi.com/journals/omcl/2016/2603219/ Chinese dragon’s blood, the red resin of Dracaena cochinchinensis, one of the renowned traditional medicines, has been used to facilitate blood circulation and disperse blood stasis for thousands of years. Phenolic compounds are considered to be responsible for its main biological activities. In this study, total phenolic compounds of Chinese dragon’s blood were made into capsule (Longxuetongluo Capsule, LTC) and their effects on the abnormal hemorheological properties were examined by high fat diet (HFD) induced ApoE−/− mice. Compared to the model group, LTC recovered the abnormal hemorheological parameters in HFD-induced ApoE−/− mice by reducing whole blood viscosity (WBV) at high rate and improving erythrocyte function. In conclusion, LTC could ameliorate erythrocyte deformability and osmotic fragility through the reduction of lipid peroxidation on plasma and erythrocyte membranes in HFD-induced ApoE−/− mice, which supported the traditional uses of Chinese dragon’s blood as an effective agent for improving blood microcirculation in hypercholesterolemia. Jiao Zheng, Binglin Liu, Qixing Lun, Weijuan Yao, Yunfang Zhao, Wei Xiao, Wenzhe Huang, Yonghua Wang, Jun Li, and Pengfei Tu Copyright © 2016 Jiao Zheng et al. All rights reserved. Bioavailability Study of an Innovative Orobuccal Formulation of Glutathione Mon, 16 Nov 2015 06:39:04 +0000 http://www.hindawi.com/journals/omcl/2016/3286365/ Alteration of the ubiquitous thiol tripeptide glutathione (GSH) is involved in oxidative stress, which plays a role in ageing; consequently, GSH is closely related to this process characterized by progressive decline in the efficiency of physiological function and increased susceptibility to disease. When circulating GSH decreases, oral administration might be considered a therapeutic benefit. Unfortunately, due to the hydrolysis of the tripeptide by intestinal -glutamyltransferase, dietary glutathione is not a major determinant for its increase. Aim of this work was to evaluate improvement of GSH systemic availability testing, in vitro and in vivo, an optimized orobuccal fast-slow release formulation tablet containing pure stabilized GSH. In vitro evaluation of the penetration capability of the innovative GSH-release formulation showed that GSH was well absorbed by the reconstructed oral epithelium and its absorption has features of time-dependence. In addition, in vivo results, obtained from 15 healthy volunteers, were in favor of GSH level improvement in blood showing fast (after 30 and 60 minutes) absorption through oral mucosa. In conclusion, the intake of GSH formulated through optimized orobuccal fast-slow release tablets gave positive results in raising GSH blood concentration. Daniela Buonocore, Matteo Grosini, Silvana Giardina, Angela Michelotti, Mariaelena Carrabetta, Antonio Seneci, Manuela Verri, Maurizia Dossena, and Fulvio Marzatico Copyright © 2016 Daniela Buonocore et al. All rights reserved. Nrf2/ARE Pathway Involved in Oxidative Stress Induced by Paraquat in Human Neural Progenitor Cells Sun, 15 Nov 2015 13:47:56 +0000 http://www.hindawi.com/journals/omcl/2016/8923860/ Compelling evidences have shown that diverse environmental insults arising during early life can either directly lead to a reduction in the number of dopaminergic neurons or cause an increased susceptibility to neurons degeneration with subsequent environmental insults or with aging alone. Oxidative stress is considered the main effect of neurotoxins exposure. In this study, we investigated the oxidative stress effect of Paraquat (PQ) on immortalized human embryonic neural progenitor cells by treating them with various concentrations of PQ. We show that PQ can decrease the activity of SOD and CAT but increase MDA and LDH level. Furthermore, the activities of Cyc and caspase-9 were found increased significantly at 10 μM of PQ treatment. The cytoplasmic Nrf2 protein expressions were upregulated at 10 μM but fell back at 100 μM. The nuclear Nrf2 protein expressions were upregulated as well as the downstream mRNA expressions of HO-1 and NQO1 in a dose-dependent manner. In addition, the proteins expression of PKC and CKII was also increased significantly even at 1 μM. The results suggested that Nrf2/ARE pathway is involved in mild to moderate PQ-induced oxidative stress which is evident from dampened Nrf2 activity and low expression of antioxidant genes in PQ induced oxidative damage. Tingting Dou, Mengling Yan, Xinjin Wang, Wen Lu, Lina Zhao, Dan Lou, Chunhua Wu, Xiuli Chang, and Zhijun Zhou Copyright © 2016 Tingting Dou et al. All rights reserved. Redox Stimulation of Human THP-1 Monocytes in Response to Cold Physical Plasma Sun, 15 Nov 2015 13:45:18 +0000 http://www.hindawi.com/journals/omcl/2016/5910695/ In plasma medicine, cold physical plasma delivers a delicate mixture of reactive components to cells and tissues. Recent studies suggested a beneficial role of cold plasma in wound healing. Yet, the biological processes related to the redox modulation via plasma are not fully understood. We here used the monocytic cell line THP-1 as a model to test their response to cold plasma in vitro. Intriguingly, short term plasma treatment stimulated cell growth. Longer exposure only modestly compromised cell viability but apparently supported the growth of cells that were enlarged in size and that showed enhanced metabolic activity. A significantly increased mitochondrial content in plasma treated cells supported this notion. On THP-1 cell proteome level, we identified an increase of protein translation with key regulatory proteins being involved in redox regulation (hypoxia inducible factor 2α), differentiation (retinoic acid signaling and interferon inducible factors), and cell growth (Yin Yang 1). Regulation of inflammation is a key element in many chronic diseases, and we found a significantly increased expression of the anti-inflammatory heme oxygenase 1 (HMOX1) and of the neutrophil attractant chemokine interleukin-8 (IL-8). Together, these results foster the view that cold physical plasma modulates the redox balance and inflammatory processes in wound related cells. Sander Bekeschus, Anke Schmidt, Lydia Bethge, Kai Masur, Thomas von Woedtke, Sybille Hasse, and Kristian Wende Copyright © 2016 Sander Bekeschus et al. All rights reserved. Modulation of RhoA GTPase Activity Sensitizes Human Cervix Carcinoma Cells to γ-Radiation by Attenuating DNA Repair Pathways Sun, 15 Nov 2015 13:38:51 +0000 http://www.hindawi.com/journals/omcl/2016/6012642/ Radiotherapy with γ-radiation is widely used in cancer treatment to induce DNA damage reducing cell proliferation and to kill tumor cells. Although RhoA GTPase overexpression/hyperactivation is observed in many malignancies, the effect of RhoA activity modulation on cancer radiosensitivity has not been previously investigated. Here, we generated stable HeLa cell clones expressing either the dominant negative RhoA-N19 or the constitutively active RhoA-V14 and compared the responses of these cell lines with those of parental HeLa cells, after treatment with low doses of γ-radiation. HeLa-RhoA-N19 and HeLa-RhoA-V14 clones displayed reduced proliferation and survival compared to parental cells after radiation and became arrested at cell cycle stages correlated with increased cellular senescence and apoptosis. Also, Chk1/Chk2 and histone H2A phosphorylation data, as well as comet assays, suggest that the levels of DNA damage and DNA repair activation and efficiency in HeLa cell lines are correlated with active RhoA. In agreement with these results, RhoA inhibition by C3 toxin expression drastically affected homologous recombination (HR) and nonhomologous end joining (NHEJ). These data suggest that modulation of RhoA GTPase activity impairs DNA damage repair, increasing HeLa cell radiosensitivity. Juliana H. Osaki, Gisele Espinha, Yuli T. Magalhaes, and Fabio L. Forti Copyright © 2016 Juliana H. Osaki et al. All rights reserved. HDAC6 Regulates the Chaperone-Mediated Autophagy to Prevent Oxidative Damage in Injured Neurons after Experimental Spinal Cord Injury Sun, 15 Nov 2015 13:13:41 +0000 http://www.hindawi.com/journals/omcl/2016/7263736/ Hypoxia-ischemia- (HI-) induced oxidative stress plays a role in secondary pathocellular processes of acute spinal cord injury (SCI) due to HI from many kinds of mechanical trauma. Increasing evidence suggests that the histone deacetylase-6 (HDAC6) plays an important role in cell homeostasis in both physiological and abnormal, stressful, pathological conditions. This paper found that inhibition of HDAC6 accelerated reactive oxygen species (ROS) generation and cell apoptosis in response to the HI. Deficiency of HDAC6 hindered the chaperone-mediated autophagy (CMA) activity to resistance of HI-induced oxidative stress. Furthermore, this study provided the experimental evidence for the potential role of HDAC6 in the regulation of CMA by affecting HSP90 acetylation. Therefore, HDAC6 plays an important role in the function of CMA pathway under the HI stress induced by SCI and it may be a potential therapeutic target in acute SCI model. Min Su, Huaqing Guan, Fan Zhang, Yarong Gao, Xiaomei Teng, and Weixin Yang Copyright © 2016 Min Su et al. All rights reserved. Oxidative Stress and Mitochondrial Activation as the Main Mechanisms Underlying Graphene Toxicity against Human Cancer Cells Sun, 15 Nov 2015 12:54:39 +0000 http://www.hindawi.com/journals/omcl/2016/5851035/ Due to the development of nanotechnology graphene and graphene-based nanomaterials have attracted the most attention owing to their unique physical, chemical, and mechanical properties. Graphene can be applied in many fields among which biomedical applications especially diagnostics, cancer therapy, and drug delivery have been arousing a lot of interest. Therefore it is essential to understand better the graphene-cell interactions, especially toxicity and underlying mechanisms for proper use and development. This review presents the recent knowledge concerning graphene cytotoxicity and influence on different cancer cell lines. Anna Jarosz, Marta Skoda, Ilona Dudek, and Dariusz Szukiewicz Copyright © 2016 Anna Jarosz et al. All rights reserved.