International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Aberrant Free Radical Biology Is a Unifying Theme in the Etiology and Pathogenesis of Major Human Diseases

by Frederick E. Domann

Int. J. Mol. Sci. 2013, 14(4), 8491-8495; https://doi.org/10.3390/ijms14048491 - 17 Apr 2013

Cited by 14 | Viewed by 7737

Abstract

The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature—the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS). Advances in our understanding of the effects [...] Read more.

The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature—the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS). Advances in our understanding of the effects of free radicals in biology and medicine have been, and continue to be, actively translated into clinically tractable diagnostic and therapeutic applications. This issue is dedicated to recent advances, both basic discoveries and clinical applications, in the field of free radicals in biology and medicine. As more is understood about the proximal biological targets of aberrantly produced or removed reactive species, their sensors, and effectors of compensatory response, a great deal more will be learned about the commonalities in mechanisms underlying seemingly disparate disease states. Together with this deeper understanding, opportunities will arise to devise rational therapeutic interventions to decrease the incidence and severity of these diseases and positively impact the human healthspan. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Research

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Oxidative Stress in Complex Regional Pain Syndrome (CRPS): No Systemically Elevated Levels of Malondialdehyde, F2-Isoprostanes and 8OHdG in a Selected Sample of Patients

by Sigrid G. L. Fischer, Roberto S. G. M. Perez, Jan Nouta, Wouter W. A. Zuurmond and Peter G. Scheffer

Int. J. Mol. Sci. 2013, 14(4), 7784-7794; https://doi.org/10.3390/ijms14047784 - 10 Apr 2013

Cited by 19 | Viewed by 6858

Abstract

Exaggerated inflammation and oxidative stress are involved in the pathogenesis of Complex Regional Pain Syndrome (CRPS). However, studies assessing markers for oxidative stress in CRPS patients are limited. In this study, markers for lipid peroxidation (malondialdehyde and F2-isoprostanes) and DNA damage (8-hydroxy-2-deoxyguanosine) were [...] Read more.

Exaggerated inflammation and oxidative stress are involved in the pathogenesis of Complex Regional Pain Syndrome (CRPS). However, studies assessing markers for oxidative stress in CRPS patients are limited. In this study, markers for lipid peroxidation (malondialdehyde and F2-isoprostanes) and DNA damage (8-hydroxy-2-deoxyguanosine) were measured in nine patients (mean age 50.1 ± 17.1 years) with short term CRPS-1 (median 3 months) and nine age and sex matched healthy volunteers (mean age 49.3 ± 16.8 years) to assess and compare the level of oxidative stress. No differences were found in plasma between CRPS patients and healthy volunteers for malondialdehyde (5.2 ± 0.9 µmol/L vs. 5.4 ± 0.5 µmol/L) F2-isoprostanes (83.9 ± 18.7 pg/mL vs. 80.5 ± 12.3 pg/mL) and 8-hydroxy-2-deoxyguanosine (92.6 ± 25.5 pmol/L vs. 86.9 ± 19.0 pmol/L). Likewise, in urine, no differences were observed between CRPS patients and healthy volunteers for F2-isoprostanes (117 ng/mmol, IQR 54.5–124.3 vs. 85 ng/mmol, IQR 55.5–110) and 8-hydroxy-2-deoxyguanosine (1.4 ± 0.7 nmol/mmol vs. 1.4 ± 0.5 nmol/mmol). Our data show no elevation of systemic markers of oxidative stress in CRPS patients compared to matched healthy volunteers. Future research should focus on local sampling methods of oxidative stress with adequate patient selection based on CRPS phenotype and lifestyle. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Brain Activity of Thioctic Acid Enantiomers: In Vitro and in Vivo Studies in an Animal Model of Cerebrovascular Injury

by Daniele Tomassoni, Francesco Amenta, Consuelo Amantini, Valerio Farfariello, Lorenzo Di Cesare Mannelli, Innocent E. Nwankwo, Carlotta Marini and Seyed Khosrow Tayebati

Int. J. Mol. Sci. 2013, 14(3), 4580-4595; https://doi.org/10.3390/ijms14034580 - 26 Feb 2013

Cited by 26 | Viewed by 8021

Abstract

Oxidative stress is an imbalance between the production of free radicals and antioxidant defense mechanisms, potentially leading to tissue damage. Oxidative stress has a key role in the development of cerebrovascular and/or neurodegenerative diseases. This phenomenon is mainly mediated by an enhanced superoxide [...] Read more.

Oxidative stress is an imbalance between the production of free radicals and antioxidant defense mechanisms, potentially leading to tissue damage. Oxidative stress has a key role in the development of cerebrovascular and/or neurodegenerative diseases. This phenomenon is mainly mediated by an enhanced superoxide production by the vascular endothelium with its consequent dysfunction. Thioctic, also known as alpha-lipoic acid (1,2-dithiolane-3-pentanoic acid), is a naturally occurring antioxidant that neutralizes free radicals in the fatty and watery regions of cells. Both the reduced and oxidized forms of the compound possess antioxidant ability. Thioctic acid has two optical isomers designated as (+)- and (−)-thioctic acid. Naturally occurring thioctic acid is the (+)-thioctic acid form, but the synthetic compound largely used in the market for stability reasons is a mixture of (+)- and (−)-thioctic acid. The present study was designed to compare the antioxidant activity of the two enantiomers versus the racemic form of thioctic acid on hydrogen peroxide-induced apoptosis in a rat pheochromocytoma PC12 cell line. Cell viability was evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and free oxygen radical species (ROS) production was assessed by flow cytometry. Antioxidant activity of the two enantiomers and the racemic form of thioctic acid was also evaluated in spontaneously hypertensive rats (SHR) used as an in vivo model of increased oxidative stress. A 3-h exposure of PC12 cells to hydrogen peroxide (H₂O₂) significantly decreased cell viability and increased levels of intracellular ROS production. Pre-treatment with racemic thioctic acid or (+)-enantiomer significantly inhibited H₂O₂-induced decrease in cell viability from the concentration of 50 μmol/L and 20 μmol/L, respectively. Racemic thioctic acid and (+)-salt decreased levels of intracellular ROS, which were unaffected by (−)-thioctic acid. In the brain of SHR, the occurrence of astrogliosis and neuronal damage, with a decreased expression of neurofilament 200 kDa were observed. Treatment of SHR for 30 days with (+)-thioctic acid reduced the size of astrocytes and increased the neurofilament immunoreaction. The above findings could contribute to clarify the role played by thioctic acid in central nervous system injury related to oxidative stress. The more pronounced effect of (+)-thioctic acid observed in this study may have practical therapeutic implications worthy of being investigated in further preclinical and clinical studies. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Low Oxygen Tension Maintains Multipotency, Whereas Normoxia Increases Differentiation of Mouse Bone Marrow Stromal Cells

by Ina Berniakovich and Marco Giorgio

Int. J. Mol. Sci. 2013, 14(1), 2119-2134; https://doi.org/10.3390/ijms14012119 - 22 Jan 2013

Cited by 63 | Viewed by 8793

Abstract

Optimization of mesenchymal stem cells (MSC) culture conditions is of great importance for their more successful application in regenerative medicine. O₂ regulates various aspects of cellular biology and, in vivo, MSC are exposed to different O₂ concentrations spanning from very [...] Read more.

Optimization of mesenchymal stem cells (MSC) culture conditions is of great importance for their more successful application in regenerative medicine. O₂ regulates various aspects of cellular biology and, in vivo, MSC are exposed to different O₂ concentrations spanning from very low tension in the bone marrow niche, to higher amounts in wounds. In our present work, we isolated mouse bone marrow stromal cells (BMSC) and showed that they contained a population meeting requirements for MSC definition. In order to establish the effect of low O₂ on cellular properties, we examined BSMC cultured under hypoxic (3% O₂) conditions. Our results demonstrate that 3% O₂ augmented proliferation of BMSC, as well as the formation of colonies in the colony-forming unit assay (CFU-A), the percentage of quiescent cells, and the expression of stemness markers Rex-1 and Oct-4, thereby suggesting an increase in the stemness of culture when exposed to hypoxia. In contrast, intrinsic differentiation processes were inhibited by 3% O₂. Overall yield of differentiation was dependent on the adjustment of O₂ tension to the specific stage of BMSC culture. Thus, we established a strategy for efficient BMSC in vitro differentiation using an initial phase of cell propagation at 3% O₂, followed by differentiation stage at 21% O₂. We also demonstrated that 3% O₂ affected BMSC differentiation in p53 and reactive oxygen species (ROS) independent pathways. Our findings can significantly contribute to the obtaining of high-quality MSC for effective cell therapy. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Nitric Oxide Synthesis Is Increased in Cybrid Cells with m.3243A>G Mutation

by Juliana Gamba, Luana T. Gamba, Gabriela S. Rodrigues, Beatriz H. Kiyomoto, Carlos T. Moraes and Celia H. Tengan

Int. J. Mol. Sci. 2013, 14(1), 394-410; https://doi.org/10.3390/ijms14010394 - 24 Dec 2012

Cited by 13 | Viewed by 6437

Abstract

Nitric oxide (NO) is a free radical and a signaling molecule in several pathways, produced by nitric oxide synthase (NOS) from the conversion of L-arginine to citrulline. Supplementation of L-arginine has been used to treat MELAS (mitochondrial encephalopathy with lactic acidosis and stroke [...] Read more.

Nitric oxide (NO) is a free radical and a signaling molecule in several pathways, produced by nitric oxide synthase (NOS) from the conversion of L-arginine to citrulline. Supplementation of L-arginine has been used to treat MELAS (mitochondrial encephalopathy with lactic acidosis and stroke like syndrome), a mitochondrial disease caused by the m.3243A>G mutation. Low levels of serum arginine and endothelium dysfunction have been reported in MELAS and this treatment may increase NO in endothelial cells and promote vasodilation, decreasing cerebral ischemia and strokes. Although clinical benefits have been reported, little is known about NO synthesis in MELAS. In this study we found that osteosarcoma derived cybrid cells with high levels of m.3243A>G had increased nitrite, an NO metabolite, and increased intracellular NO, demonstrated by an NO fluorescent probe (DAF-FM). Muscle vessels from patients with the same mutation had increased staining in NADPH diaphorase, suggestive of increased NOS. These results indicate increased production of NO in cells harboring the m.3243A>G, however no nitrated protein was detected by Western blotting. Further studies are necessary to clarify the exact mechanisms of L-arginine effect to determine the appropriate clinical use of this drug therapy. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Role of Carnitine Acetyl Transferase in Regulation of Nitric Oxide Signaling in Pulmonary Arterial Endothelial Cells

by Shruti Sharma, Xutong Sun, Saurabh Agarwal, Ruslan Rafikov, Sridevi Dasarathy, Sanjiv Kumar and Stephen M. Black

Int. J. Mol. Sci. 2013, 14(1), 255-272; https://doi.org/10.3390/ijms14010255 - 21 Dec 2012

Cited by 14 | Viewed by 7412

Abstract

Congenital heart defects with increased pulmonary blood flow (PBF) result in pulmonary endothelial dysfunction that is dependent, at least in part, on decreases in nitric oxide (NO) signaling. Utilizing a lamb model with left-to-right shunting of blood and increased PBF that mimics the [...] Read more.

Congenital heart defects with increased pulmonary blood flow (PBF) result in pulmonary endothelial dysfunction that is dependent, at least in part, on decreases in nitric oxide (NO) signaling. Utilizing a lamb model with left-to-right shunting of blood and increased PBF that mimics the human disease, we have recently shown that a disruption in carnitine homeostasis, due to a decreased carnitine acetyl transferase (CrAT) activity, correlates with decreased bioavailable NO. Thus, we undertook this study to test the hypothesis that the CrAT enzyme plays a major role in regulating NO signaling through its effect on mitochondrial function. We utilized the siRNA gene knockdown approach to mimic the effect of decreased CrAT activity in pulmonary arterial endothelial cells (PAEC). Our data indicate that silencing the CrAT gene disrupted cellular carnitine homeostasis, reduced the expression of mitochondrial superoxide dismutase-and resulted in an increase in oxidative stress within the mitochondrion. CrAT gene silencing also disrupted mitochondrial bioenergetics resulting in reduced ATP generation and decreased NO signaling secondary to a reduction in eNOS/Hsp90 interactions. Thus, this study links the disruption of carnitine homeostasis to the loss of NO signaling observed in children with CHD. Preserving carnitine homeostasis may have important clinical implications that warrant further investigation. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Increased Insulin Sensitivity and Distorted Mitochondrial Adaptations during Muscle Unloading

by Zhengtang Qi, Yuan Zhang, Wei Guo, Liu Ji and Shuzhe Ding

Int. J. Mol. Sci. 2012, 13(12), 16971-16985; https://doi.org/10.3390/ijms131216971 - 11 Dec 2012

Cited by 13 | Viewed by 6891

Abstract

We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal [...] Read more.

We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal muscle, HU decreased expression of pyruvate dehydrogenase kinase 4 (PDK4) and its protein level in mitochondria. HU decreased mtDNA content and mitochondrial biogenesis biomarkers. Dynamin-related protein (Drp1) in mitochondria and Mfn2 mRNA level were decreased significantly by HU. Our findings provide more extensive insight into mitochondrial adaptations to muscle disuse, involving the shift of fuel utilization towards glucose, the decreased mitochondrial biogenesis and the distorted mitochondrial dynamics. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Impact of Cyanidin-3-Glucoside on Glycated LDL-Induced NADPH Oxidase Activation, Mitochondrial Dysfunction and Cell Viability in Cultured Vascular Endothelial Cells

by Xueping Xie, Ruozhi Zhao and Garry X. Shen

Int. J. Mol. Sci. 2012, 13(12), 15867-15880; https://doi.org/10.3390/ijms131215867 - 27 Nov 2012

Cited by 31 | Viewed by 6392

Abstract

Elevated levels of glycated low density lipoprotein (glyLDL) are frequently detected in diabetic patients. Previous studies demonstrated that glyLDL increased the production of reactive oxygen species (ROS), activated NADPH oxidase (NOX) and suppressed mitochondrial electron transport chain (mETC) enzyme activities in vascular endothelial [...] Read more.

Elevated levels of glycated low density lipoprotein (glyLDL) are frequently detected in diabetic patients. Previous studies demonstrated that glyLDL increased the production of reactive oxygen species (ROS), activated NADPH oxidase (NOX) and suppressed mitochondrial electron transport chain (mETC) enzyme activities in vascular endothelial cells (EC). The present study examined the effects of cyanidin-3-glucoside (C3G), a type of anthocyanin abundant in dark-skinned berries, on glyLDL-induced ROS production, NOX activation and mETC enzyme activity in porcine aortic EC (PAEC). Co-treatment of C3G prevented glyLDL-induced upregulation of NOX4 and intracellular superoxide production in EC. C3G normalized glyLDL-induced inhibition on the enzyme activities of mETC Complex I and III, as well as the abundances of NADH dehydrogenase 1 in Complex I and cytochrome b in Complex III in EC. Blocking antibody for the receptor of advanced glycation end products (RAGE) prevented glyLDL-induced changes in NOX and mETC enzymes. Combination of C3G and RAGE antibody did not significantly enhance glyLDL-induced inhibition of NOX or mETC enzymes. C3G reduced glyLDL-induced RAGE expression with the presence of RAGE antibody. C3G prevented prolonged incubation with the glyLDL-induced decrease in cell viability and the imbalance between key regulators for cell viability (cleaved caspase 3 and B cell Lyphoma-2) in EC. The findings suggest that RAGE plays an important role in glyLDL-induced oxidative stress in vascular EC. C3G may prevent glyLDL-induced NOX activation, the impairment of mETC enzymes and cell viability in cultured vascular EC. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Protection against Ischemia-Induced Oxidative Stress Conferred by Vagal Stimulation in the Rat Heart: Involvement of the AMPK-PKC Pathway

by Shan-Shan Kong, Jin-Jun Liu, Xiao-Jiang Yu, Yi Lu and Wei-Jin Zang

Int. J. Mol. Sci. 2012, 13(11), 14311-14325; https://doi.org/10.3390/ijms131114311 - 5 Nov 2012

Cited by 51 | Viewed by 8286

Abstract

Reactive oxygen species (ROS) production is an important mechanism in myocardial ischemia and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of major sources of ROS in the heart. Previous studies showed that vagus nerve stimulation (VNS) is beneficial in treating ischemic heart [...] Read more.

Reactive oxygen species (ROS) production is an important mechanism in myocardial ischemia and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is one of major sources of ROS in the heart. Previous studies showed that vagus nerve stimulation (VNS) is beneficial in treating ischemic heart diseases. However, the effect of VNS on ROS production remains elusive. In this study, we investigated the role of VNS onischemia-induced ROS production. Our results demonstrated that VNS alleviated the myocardial injury, attenuated the cardiac dysfunction, reserved the antioxidant enzyme activity and inhibited the formation of ROS as evidenced by the decreased NADPH oxidase (Nox) activity and superoxide fluorescence intensity as well as the expression of p67phox, Rac1 and nitrotyrosine. Furthermore, VNS resulted in the phosphorylation and activation of adenosine monophosphate activated protein kinase (AMPK), which in turn led to an inactivation of Nox by protein kinase C (PKC); however, the phenomena were repressed by the administration of a muscarinic antagonist atropine. Taken together, these data indicate that VNS decreases ROS via AMPK-PKC-Nox pathway; this may have potential importance for the treatment of ischemic heart diseases. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Superoxide Dismutase as a Novel Macromolecular Nitric Oxide Carrier: Preparation and Characterization

by Ssu-Han Chen, Shih-Jiuan Chiu and Teh-Min Hu

Int. J. Mol. Sci. 2012, 13(11), 13985-14001; https://doi.org/10.3390/ijms131113985 - 29 Oct 2012

Cited by 2 | Viewed by 6507

Abstract

Nitric oxide (NO) is an important molecule that exerts multiple functions in biological systems. Because of the short-lived nature of NO, S-nitrosothiols (RSNOs) are believed to act as stable NO carriers. Recently, sulfhydryl (SH) containing macromolecules have been shown to be promising [...] Read more.

Nitric oxide (NO) is an important molecule that exerts multiple functions in biological systems. Because of the short-lived nature of NO, S-nitrosothiols (RSNOs) are believed to act as stable NO carriers. Recently, sulfhydryl (SH) containing macromolecules have been shown to be promising NO carriers. In the present study, we aimed to synthesize and characterize a potential NO carrier based on bovine Cu,Zn-superoxide dismutase (bSOD). To prepare S-nitrosated bSOD, the protein was incubated with S-nitrosoglutathione (GSNO) under varied experimental conditions. The results show that significant S-nitrosation of bSOD occurred only at high temperature (50 °C) for prolonged incubation time (>2 h). S-nitrosation efficiency increased with reaction time and reached a plateau at ~4 h. The maximum amount of NO loaded was determined to be about 0.6 mol SNO/mol protein (~30% loading efficiency). The enzymatic activity of bSOD, however, decreased with reaction time. Our data further indicate that NO functionality can only be measured in the presence of extremely high concentrations of Hg²⁺ or when the protein was denatured by guanidine. Moreover, mildly acidic pH was shown to favor S-nitrosation of bSOD. A model based on unfolding and refolding of bSOD during preparation was proposed to possibly explain our observation. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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High Mitochondrial DNA Copy Number and Bioenergetic Function Are Associated with Tumor Invasion of Esophageal Squamous Cell Carcinoma Cell Lines

by Chen-Sung Lin, Hui-Ting Lee, Shu-Yu Lee, Yao-An Shen, Liang-Shun Wang, Yann-Jang Chen and Yau-Huei Wei

Int. J. Mol. Sci. 2012, 13(9), 11228-11246; https://doi.org/10.3390/ijms130911228 - 10 Sep 2012

Cited by 53 | Viewed by 8603

Abstract

We previously reported a gradual increase of relative mitochondrial DNA (mtDNA) copy number during the progression of esophageal squamous cell carcinoma (ESCC). Because mitochondria are the intracellular organelles responsible for ATP production, we investigated the associations among mtDNA copy number, mitochondrial bioenergetic function, [...] Read more.

We previously reported a gradual increase of relative mitochondrial DNA (mtDNA) copy number during the progression of esophageal squamous cell carcinoma (ESCC). Because mitochondria are the intracellular organelles responsible for ATP production, we investigated the associations among mtDNA copy number, mitochondrial bioenergetic function, tumor invasion and the expression levels of epithelial mesenchymal transition (EMT) markers in a series of seven ESCC cell lines, including 48T, 81T, 146T, TE1, TE2, TE6 and TE9. Among them, TE1 had the highest relative mtDNA copy number of 240.7%. The mRNA of mtDNA-encoded ND1 gene (2.80), succinate-supported oxygen consumption rate (11.21 nmol/min/10⁶ cells), ATP content (10.7 fmol/cell), and the protein level of mitochondrial transcription factor A (TFAM) were the highest and the lactate concentration in the culture medium (3.34 mM) was the lowest in TE1. These findings indicate that TE1 exhibited the highest bioenergetic function of mitochondria. Furthermore, TE1 showed the highest trans-well migration activity of 223.0 cells/field, the highest vimentin but the lowest E-cadherin protein expression levels, which suggest that TE1 had the highest invasion capability. We then conducted a knockdown study using pLKO.1-based lentiviral particles to infect TE1 cells to suppress the expression of TFAM. Molecular analyses of the parental TE1, control TE1-NT and TFAM knockdown TE1-sh-TFAM(97) cells were performed. Interestingly, as compared to the control TE1-NT, TE1-sh-TFAM(97) exhibited lower levels of the relative mtDNA copy number (p = 0.001), mRNA of mtDNA-encoded ND1 gene (p = 0.050), succinate-supported oxygen consumption rate (p = 0.065), and ATP content (p = 0.007), but had a higher lactate concentration in the culture medium (p = 0.010) and higher protein level of lactate dehydrogenase. A decline in mitochondrial bioenergetic function was observed in TE1-sh-TFAM(97). Significantly, compared to the control TE1-NT, TE1-sh-TFAM(97) had a lower trans-well migration activity (p < 0.001), a higher E-cadherin level but a lower vimentin protein level, which indicates a decrease of invasiveness. Taken together, we suggest that high relative mtDNA copy number and bioenergetic function of mitochondria may confer an advantage for tumor invasion of ESCC. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Mitochondrial Adaptations to Oxidative Stress Confer Resistance to Apoptosis in Lymphoma Cells

by Sarah T. Wilkinson, Margaret E. Tome and Margaret M. Briehl

Int. J. Mol. Sci. 2012, 13(8), 10212-10228; https://doi.org/10.3390/ijms130810212 - 16 Aug 2012

Cited by 7 | Viewed by 6401

Abstract

Acquired resistance to drugs commonly used for lymphoma treatment poses a significant barrier to improving lymphoma patient survival. Previous work with a lymphoma tissue culture model indicates that selection for resistance to oxidative stress confers resistance to chemotherapy-induced apoptosis. This suggests that adaptation [...] Read more.

Acquired resistance to drugs commonly used for lymphoma treatment poses a significant barrier to improving lymphoma patient survival. Previous work with a lymphoma tissue culture model indicates that selection for resistance to oxidative stress confers resistance to chemotherapy-induced apoptosis. This suggests that adaptation to chronic oxidative stress can contribute to chemoresistance seen in lymphoma patients. Oxidative stress-resistant WEHI7.2 cell variants in a lymphoma tissue culture model exhibit a range of apoptosis sensitivities. We exploited this phenotype to test for mitochondrial changes affecting sensitivity to apoptosis in cells made resistant to oxidative stress. We identified impaired release of cytochrome c, and the intermembrane proteins adenylate kinase 2 and Smac/DIABLO, indicating inhibition of the pathway leading to permeabilization of the outer mitochondrial membrane. Blunting of a glucocorticoid-induced signal and intrinsic mitochondrial resistance to cytochrome c release contributed to both points of resistance. The level of Bcl-2 family members or a difference in Bim induction were not contributing factors. The extent of cardiolipin oxidation following dexamethasone treatment, however, did correlate with apoptosis resistance. The differences found in the variants were all proportionate to the degree of resistance to glucocorticoid treatment. We conclude that tolerance to oxidative stress leads to mitochondrial changes that confer resistance to apoptosis. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Metal-Sulfate Induced Generation of ROS in Human Brain Cells: Detection Using an Isomeric Mixture of 5- and 6-Carboxy-2′,7′-Dichlorofluorescein Diacetate (Carboxy-DCFDA) as a Cell Permeant Tracer

by Aileen I. Pogue, Brandon M. Jones, Surjyadipta Bhattacharjee, Maire E. Percy, Yuhai Zhao and Walter J. Lukiw

Int. J. Mol. Sci. 2012, 13(8), 9615-9626; https://doi.org/10.3390/ijms13089615 - 2 Aug 2012

Cited by 41 | Viewed by 11475

Abstract

Evolution of reactive oxygen species (ROS), generated during the patho-physiological stress of nervous tissue, has been implicated in the etiology of several progressive human neurological disorders including Alzheimer’s disease (AD) and amylotrophic lateral sclerosis (ALS). In this brief communication we used mixed isomers [...] Read more.

Evolution of reactive oxygen species (ROS), generated during the patho-physiological stress of nervous tissue, has been implicated in the etiology of several progressive human neurological disorders including Alzheimer’s disease (AD) and amylotrophic lateral sclerosis (ALS). In this brief communication we used mixed isomers of 5-(and-6)-carboxy-2′,7′-dichlorofluorescein diacetate (carboxy-DCFDA; C₂₅H₁₄C_l2O₉; MW 529.3), a novel fluorescent indicator, to assess ROS generation within human neuronal-glial (HNG) cells in primary co-culture. We introduced pathological stress using the sulfates of 12 environmentally-, industrially- and agriculturally-relevant divalent and trivalent metals including Al, Cd, Cu, Fe, Hg, Ga, Mg, Mn, Ni, Pb, Sn and Zn. In this experimental test system, of all the metal sulfates analyzed, aluminum sulfate showed by far the greatest ability to induce intracellular ROS. These studies indicate the utility of using isomeric mixtures of carboxy-H₂DCFDA diacetates as novel and highly sensitive, long-lasting, cell-permeant, fluorescein-based tracers for quantifying ROS generation in intact, metabolizing human brain cells, and in analyzing the potential epigenetic contribution of different metal sulfates to ROS-generation and ROS-mediated neurological dysfunction. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Leukocyte Mitochondrial DNA Alteration in Systemic Lupus Erythematosus and Its Relevance to the Susceptibility to Lupus Nephritis

by Hui-Ting Lee, Chen-Sung Lin, Wei-Sheng Chen, Hsien-Tzung Liao, Chang-Youh Tsai and Yau-Huei Wei

Int. J. Mol. Sci. 2012, 13(7), 8853-8868; https://doi.org/10.3390/ijms13078853 - 16 Jul 2012

Cited by 41 | Viewed by 7783

Abstract

The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA [...] Read more.

The role of mitochondrial DNA (mtDNA) alterations in the pathophysiology of systemic lupus erythematosus (SLE) remains unclear. We investigated sequence variations in the D310 region and copy number change of mtDNA in 85 SLE patients and 45 normal subjects. Leukocyte DNA and RNA were extracted from leukocytes of the peripheral venous blood. The D310 sequence variations and copy number of mtDNA, and mRNA expression levels of mtDNA-encoded genes in leukocytes were determined by quantitative real-time polymerase chain reaction (Q-PCR) and PCR-based direct sequencing, respectively. We found that leukocyte mtDNA in SLE patients exhibited higher frequency of D310 heteroplasmy (69.4% vs. 48.9%, p = 0.022) and more D310 variants (2.2 vs. 1.7, p = 0.014) than those found in controls. Among normal controls and patients with low, medium or high SLE disease activity index (SLEDAI), an ever-increasing frequency of D310 heteroplasmy was observed (p = 0.021). Leukocyte mtDNA copy number tended to be low in patients of high SLEDAI group (p = 0.068), especially in those harboring mtDNA with D310 heteroplasmy (p = 0.020). Moreover, the mtDNA copy number was positively correlated with the mRNA level of mtDNA-encoded ND1 (NADH dehydrogenase subunit 1) (p = 0.041) and ATPase 6 (ATP synthase subunit 6) (p = 0.030) genes. Patients with more D310 variants were more susceptible to lupus nephritis (p = 0.035). Taken together, our findings suggest that decrease in the mtDNA copy number and increase in D310 heteroplasmy of mtDNA are related to the development and progression of SLE, and that the patients harboring more D310 variants of mtDNA are more susceptible to lupus nephritis. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Lipid Oxidation Inhibitory Effects and Phenolic Composition of Aqueous Extracts from Medicinal Plants of Colombian Amazonia

by Leandro J. Lizcano, María Viloria-Bernal, Francisca Vicente, Luis Angel Berrueta, Blanca Gallo, Magdalena Martínez-Cañamero, Maria Begoña Ruiz-Larrea and José Ignacio Ruiz-Sanz

Int. J. Mol. Sci. 2012, 13(5), 5454-5467; https://doi.org/10.3390/ijms13055454 - 4 May 2012

Cited by 33 | Viewed by 8322

Abstract

Diverse plants of ethnobotanic interest in Amazonia are commonly used in traditional medicine. We determined the antioxidant potential against lipid peroxidation, the antimicrobial activity, and the polyphenol composition of several Amazonian plants (Brownea rosademonte, Piper glandulosissimum, Piper krukoffii, Piper [...] Read more.

Diverse plants of ethnobotanic interest in Amazonia are commonly used in traditional medicine. We determined the antioxidant potential against lipid peroxidation, the antimicrobial activity, and the polyphenol composition of several Amazonian plants (Brownea rosademonte, Piper glandulosissimum, Piper krukoffii, Piper putumayoense, Solanum grandiflorum, and Vismia baccifera). Extracts from the plant leaf, bark, and stem were prepared as aqueous infusions, as used in folk medicine, and added to rat liver microsomes exposed to iron. The polyphenolic composition was detected by reverse-phase HPLC coupled to diode-array detector and MS/MS analysis. The antimicrobial activity was tested by the spot-on-a-lawn method against several indicator microorganisms. All the extracts inhibited lipid oxidation, except the P. glandulosissimum stem. The plant extracts exhibiting high antioxidant potential (V. baccifera and B. rosademonte) contained high levels of flavanols (particularly, catechin and epicatechin). By contrast, S. grandiflorum leaf, which exhibited very low antioxidant activity, was rich in hydroxycinnamic acids. None of the extracts showed antimicrobial activity. This study demonstrates for the first time the presence of bioactive polyphenolic compounds in several Amazonian plants, and highlights the importance of flavanols as major phenolic contributors to antioxidant activity. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Oxidative Stress as an Underlying Contributor in the Development of Chronic Complications in Diabetes Mellitus

by Suziy De M. Bandeira, Lucas José S. Da Fonseca, Glaucevane Da S. Guedes, Luíza A. Rabelo, Marília O. F. Goulart and Sandra Mary L. Vasconcelos

Int. J. Mol. Sci. 2013, 14(2), 3265-3284; https://doi.org/10.3390/ijms14023265 - 5 Feb 2013

Cited by 152 | Viewed by 16205

Abstract

The high prevalence of diabetes mellitus and its increasing incidence worldwide, coupled with several complications observed in its carriers, have become a public health issue of great relevance. Chronic hyperglycemia is the main feature of such a disease, being considered the responsible for [...] Read more.

The high prevalence of diabetes mellitus and its increasing incidence worldwide, coupled with several complications observed in its carriers, have become a public health issue of great relevance. Chronic hyperglycemia is the main feature of such a disease, being considered the responsible for the establishment of micro and macrovascular complications observed in diabetes. Several efforts have been directed in order to better comprehend the pathophysiological mechanisms involved in the course of this endocrine disease. Recently, numerous authors have suggested that excess generation of highly reactive oxygen and nitrogen species is a key component in the development of complications invoked by hyperglycemia. Overproduction and/or insufficient removal of these reactive species result in vascular dysfunction, damage to cellular proteins, membrane lipids and nucleic acids, leading different research groups to search for biomarkers which would be capable of a proper and accurate measurement of the oxidative stress (OS) in diabetic patients, especially in the presence of chronic complications. In the face of this scenario, the present review briefly addresses the role of hyperglycemia in OS, considering basic mechanisms and their effects in diabetes mellitus, describes some of the more commonly used biomarkers of oxidative/nitrosative damage and includes selected examples of studies which evaluated OS biomarkers in patients with diabetes, pointing to the relevance of such biological components in general oxidative stress status of diabetes mellitus carriers. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Role of Oxidative Stress in Refractory Epilepsy: Evidence in Patients and Experimental Models

by Noemi Cardenas-Rodriguez, Bernardino Huerta-Gertrudis, Liliana Rivera-Espinosa, Hortencia Montesinos-Correa, Cindy Bandala, Liliana Carmona-Aparicio and Elvia Coballase-Urrutia

Int. J. Mol. Sci. 2013, 14(1), 1455-1476; https://doi.org/10.3390/ijms14011455 - 14 Jan 2013

Cited by 115 | Viewed by 10417

Abstract

Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological [...] Read more.

Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological disorder with refractoriness to drug therapy at about 30%. Currently, experimental evidence supports the involvement of oxidative stress in seizures, in the process of their generation, and in the mechanisms associated with refractoriness to drug therapy. Hence, the aim of this review is to present information in order to facilitate the handling of this evidence and determine the therapeutic impact of the biochemical status for this pathology. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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An Involvement of Oxidative Stress in Endoplasmic Reticulum Stress and Its Associated Diseases

by Bidur Bhandary, Anu Marahatta, Hyung-Ryong Kim and Han-Jung Chae

Int. J. Mol. Sci. 2013, 14(1), 434-456; https://doi.org/10.3390/ijms14010434 - 24 Dec 2012

Cited by 318 | Viewed by 21854

Abstract

The endoplasmic reticulum (ER) is the major site of calcium storage and protein folding. It has a unique oxidizing-folding environment due to the predominant disulfide bond formation during the process of protein folding. Alterations in the oxidative environment of the ER and also [...] Read more.

The endoplasmic reticulum (ER) is the major site of calcium storage and protein folding. It has a unique oxidizing-folding environment due to the predominant disulfide bond formation during the process of protein folding. Alterations in the oxidative environment of the ER and also intra-ER Ca²⁺ cause the production of ER stress-induced reactive oxygen species (ROS). Protein disulfide isomerases, endoplasmic reticulum oxidoreductin-1, reduced glutathione and mitochondrial electron transport chain proteins also play crucial roles in ER stress-induced production of ROS. In this article, we discuss ER stress-associated ROS and related diseases, and the current understanding of the signaling transduction involved in ER stress. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Nitric Oxide in Skeletal Muscle: Role on Mitochondrial Biogenesis and Function

by Celia Harumi Tengan, Gabriela Silva Rodrigues and Rosely Oliveira Godinho

Int. J. Mol. Sci. 2012, 13(12), 17160-17184; https://doi.org/10.3390/ijms131217160 - 14 Dec 2012

Cited by 88 | Viewed by 18320

Abstract

Nitric oxide (NO) has been implicated in several cellular processes as a signaling molecule and also as a source of reactive nitrogen species (RNS). NO is produced by three isoenzymes called nitric oxide synthases (NOS), all present in skeletal muscle. While neuronal NOS [...] Read more.

Nitric oxide (NO) has been implicated in several cellular processes as a signaling molecule and also as a source of reactive nitrogen species (RNS). NO is produced by three isoenzymes called nitric oxide synthases (NOS), all present in skeletal muscle. While neuronal NOS (nNOS) and endothelial NOS (eNOS) are isoforms constitutively expressed, inducible NOS (iNOS) is mainly expressed during inflammatory responses. Recent studies have demonstrated that NO is also involved in the mitochondrial biogenesis pathway, having PGC-1α as the main signaling molecule. Increased NO synthesis has been demonstrated in the sarcolemma of skeletal muscle fiber and NO can also reversibly inhibit cytochrome c oxidase (Complex IV of the respiratory chain). Investigation on cultured skeletal myotubes treated with NO donors, NO precursors or NOS inhibitors have also showed a bimodal effect of NO that depends on the concentration used. The present review will discuss the new insights on NO roles on mitochondrial biogenesis and function in skeletal muscle. We will also focus on potential therapeutic strategies based on NO precursors or analogs to treat patients with myopathies and mitochondrial deficiency. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Oxidative Stress in Malaria

by Sandro Percário, Danilo R. Moreira, Bruno A. Q. Gomes, Michelli E. S. Ferreira, Ana Carolina M. Gonçalves, Paula S. O. C. Laurindo, Thyago C. Vilhena, Maria F. Dolabela and Michael D. Green

Int. J. Mol. Sci. 2012, 13(12), 16346-16372; https://doi.org/10.3390/ijms131216346 - 3 Dec 2012

Cited by 237 | Viewed by 12066

Abstract

Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this [...] Read more.

Malaria is a significant public health problem in more than 100 countries and causes an estimated 200 million new infections every year. Despite the significant effort to eradicate this dangerous disease, lack of complete knowledge of its physiopathology compromises the success in this enterprise. In this paper we review oxidative stress mechanisms involved in the disease and discuss the potential benefits of antioxidant supplementation as an adjuvant antimalarial strategy. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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An Advanced Electron Spin Resonance (ESR) Spin-Trapping and LC/(ESR)/MS Technique for the Study of Lipid Peroxidation

by Yi Xu, Yan Gu and Steven Y. Qian

Int. J. Mol. Sci. 2012, 13(11), 14648-14666; https://doi.org/10.3390/ijms131114648 - 12 Nov 2012

Cited by 22 | Viewed by 8304

Abstract

There are two types of nutritionally important polyunsaturated fatty acids (PUFAs), namely ω-6s and ω-3s. PUFAs and their metabolites generated from lipid peroxidation via cyclooxygenase (COX) and lipoxygenase (LOX) are believed to be involved in a variety of physiological and pathological processes in [...] Read more.

There are two types of nutritionally important polyunsaturated fatty acids (PUFAs), namely ω-6s and ω-3s. PUFAs and their metabolites generated from lipid peroxidation via cyclooxygenase (COX) and lipoxygenase (LOX) are believed to be involved in a variety of physiological and pathological processes in the human body. Both COX- and LOX-catalyzed PUFA peroxidation are complex events that generate a series of radicals, which may then bind proteins, target DNA/RNA, and lead to a number of biological changes. However, due to the lack of an appropriate method, it was not possible until recently to identify the short-lived PUFA-derived radicals in COX-/LOX-catalyzed peroxidation. Failure to characterize free radicals during peroxidation has greatly restricted our knowledge about COX/LOX biology in human health. Here we review the development and refinement of combined ESR spin trapping and LC/ESR/MS to characterize PUFA-derived radicals formed from in vitro (cell-free) peroxidation. We also present the most recent approach for studying peroxidation in cells which allows us to directly assess the potential bioactivity of PUFA-derived free radicals. This advanced technique has resulted in a major breakthrough in radical structural characterization, as well as assessment of free radical-associated cell growth response, thereby greatly improving our knowledge of PUFAs, COX-/LOX-catalyzed lipid peroxidation, and their related biological consequences. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Adaptive Response, Evidence of Cross-Resistance and Its Potential Clinical Use

by Irina Milisav, Borut Poljsak and Dušan Šuput

Int. J. Mol. Sci. 2012, 13(9), 10771-10806; https://doi.org/10.3390/ijms130910771 - 29 Aug 2012

Cited by 69 | Viewed by 11478

Abstract

Organisms and their cells are constantly exposed to environmental fluctuations. Among them are stressors, which can induce macromolecular damage that exceeds a set threshold, independent of the underlying cause. Stress responses are mechanisms used by organisms to adapt to and overcome stress stimuli. [...] Read more.

Organisms and their cells are constantly exposed to environmental fluctuations. Among them are stressors, which can induce macromolecular damage that exceeds a set threshold, independent of the underlying cause. Stress responses are mechanisms used by organisms to adapt to and overcome stress stimuli. Different stressors or different intensities of stress trigger different cellular responses, namely induce cell repair mechanisms, induce cell responses that result in temporary adaptation to some stressors, induce autophagy or trigger cell death. Studies have reported life-prolonging effects of a wide variety of so-called stressors, such as oxidants, heat shock, some phytochemicals, ischemia, exercise and dietary energy restriction, hypergravity, etc. These stress responses, which result in enhanced defense and repair and even cross-resistance against multiple stressors, may have clinical use and will be discussed, while the emphasis will be on the effects/cross-effects of oxidants. Full article

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Cell Signaling through Protein Kinase C Oxidation and Activation

by Daniela Cosentino-Gomes, Nathália Rocco-Machado and José Roberto Meyer-Fernandes

Int. J. Mol. Sci. 2012, 13(9), 10697-10721; https://doi.org/10.3390/ijms130910697 - 24 Aug 2012

Cited by 199 | Viewed by 20585

Abstract

Due to the growing importance of cellular signaling mediated by reactive oxygen species (ROS), proteins that are reversibly modulated by these reactant molecules are of high interest. In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction [...] Read more.

Due to the growing importance of cellular signaling mediated by reactive oxygen species (ROS), proteins that are reversibly modulated by these reactant molecules are of high interest. In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox-sensitive cysteine residues. Protein kinase C (PKC) is involved in a variety of cellular signaling pathways. These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification. A large number of scientific studies have highlighted the importance of ROS as a second messenger in numerous cellular processes, including cell proliferation, gene expression, adhesion, differentiation, senescence, and apoptosis. In this context, the goal of this review is to discuss the mechanisms by which PKCs are modulated by ROS and how these processes are involved in the cellular response. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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Recent Advances in Intracellular and In Vivo ROS Sensing: Focus on Nanoparticle and Nanotube Applications

by Larissa M. Uusitalo and Nadine Hempel

Int. J. Mol. Sci. 2012, 13(9), 10660-10679; https://doi.org/10.3390/ijms130910660 - 24 Aug 2012

Cited by 51 | Viewed by 10049

Abstract

Reactive oxygen species (ROS) are increasingly being implicated in the regulation of cellular signaling cascades. Intracellular ROS fluxes are associated with cellular function ranging from proliferation to cell death. Moreover, the importance of subtle, spatio-temporal shifts in ROS during localized cellular signaling events [...] Read more.

Reactive oxygen species (ROS) are increasingly being implicated in the regulation of cellular signaling cascades. Intracellular ROS fluxes are associated with cellular function ranging from proliferation to cell death. Moreover, the importance of subtle, spatio-temporal shifts in ROS during localized cellular signaling events is being realized. Understanding the biochemical nature of the ROS involved will enhance our knowledge of redox-signaling. An ideal intracellular sensor should therefore resolve real-time, localized ROS changes, be highly sensitive to physiologically relevant shifts in ROS and provide specificity towards a particular molecule. For in vivo applications issues such as bioavailability of the probe, tissue penetrance of the signal and signal-to-noise ratio also need to be considered. In the past researchers have heavily relied on the use of ROS-sensitive fluorescent probes and, more recently, genetically engineered ROS sensors. However, there is a great need to improve on current methods to address the above issues. Recently, the field of molecular sensing and imaging has begun to take advantage of the unique physico-chemical properties of nanoparticles and nanotubes. Here we discuss the recent advances in the use of these nanostructures as alternative platforms for ROS sensing, with particular emphasis on intracellular and in vivo ROS detection and quantification. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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The Role of Free Radicals in the Aging Brain and Parkinson’s Disease: Convergence and Parallelism

by Hemant Kumar, Hyung-Woo Lim, Sandeep Vasant More, Byung-Wook Kim, Sushruta Koppula, In Su Kim and Dong-Kug Choi

Int. J. Mol. Sci. 2012, 13(8), 10478-10504; https://doi.org/10.3390/ijms130810478 - 21 Aug 2012

Cited by 181 | Viewed by 18548

Abstract

Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons [...] Read more.

Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5–10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD. Full article

(This article belongs to the Special Issue Advances in Free Radicals in Biology and Medicine)

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