IGF-1 Levels Increase during an Immune but Not an Oxidative Challenge in an Avian Model, the Japanese Quail.

Nitrosative stress in patients with asthma−chronic obstructive pulmonary disease overlap

Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice

Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy

This article reviews the role of free radicals in causing oxidative stress during exercise. High intensity exercise induces oxidative stress and although there is no evidence that this affects sporting performance in the short term, it may have longer term health consequences. The mechanisms of exercise-induced oxidative stress are not well understood. Mitochondria are sometimes considered to be the main source of free radicals, but in vitro studies suggest they may play a more minor role than was first thought. There is a growing acceptance of the importance of haem proteins in inducing oxidative stress. The release of metmyoglobin from damaged muscle is known to cause renal failure in exercise rhabdomyolysis. Furthermore, levels of methaemoglobin increase during high intensity exercise, while levels of antioxidants, such as reduced glutathione, decrease. We suggest that the free-radical-mediated damage caused by the interaction of metmyoglobin and methaemoglobin with peroxides may be an important source of oxidative stress during exercise.

Oxidative stress is caused by an imbalance between reactive oxygen species (ROS) generation and the capacity of antioxidant ROS scavenging systems and plays an essential role in the pathogenesis of many diseases. It is connected with cell damage, such as lipid peroxidation of membranes. One important source of oxidative stress is UV radiation, which can come from the natural environment or artificial sources like welding. While sources of artificial UV radiation emit specific wavelengths depending on the application, occupational exposure to natural UV radiation has a continuous spectrum from 290 nm to 400 nm. Oxidative stress can be measured by synchrotron radiation-based Fourier Transform Infrared (SR-FTIR) microspectroscopy. Oxidative effect of UV can be studied on human postoperative tissue. Here we show an in vitro study of the effect of UV C on the oxidative stress in human eye postoperative tissue.

This article reviews the role of free radicals in causing oxidative stress during exercise. High intensity exercise induces oxidative stress and although there is no evidence that this affects sporting performance in the short term, it may have longer term health consequences. The mechanisms of exercise-induced oxidative stress are not well understood. Mitochondria are sometimes considered to be the main source of free radicals, but in vitro studies suggest they may play a more minor role than was first thought. There is a growing acceptance of the importance of haem proteins in inducing oxidative stress. The release of metmyoglobin from damaged muscle is known to cause renal failure in exercise rhabdomyolysis. Furthermore, levels of methaemoglobin increase during high intensity exercise, while levels of antioxidants, such as reduced glutathione, decrease. We suggest that the free-radical-mediated damage caused by the interaction of metmyoglobin and methaemoglobin with peroxides may be an important source of oxidative stress during exercise.

Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress

Subarachnoid hemorrhage is one of the most common events related to hypertensive crisis. The cerebral vasospasm is the complication of subarachnoid hemorrhage that causes more frequently death. Experimental evidences describe a direct relationship between hemolysed blood and vasospasm. Understand the molecular basis of vasospasm could help to reduce the mortality in patients with cerebrovascular damage. To clarify this aim, carotid and basilary arteries of rats were mounted on pressure myography and perfused at 100 mmHg. The vessels were placed in intracerebral fluid and entire (eb) or hemolysed blood (hb) was added. Our results showed that the eb did not modify the diameter of the vessel. Meanwhile, hb caused a clear vasoconstriction (max vasoconstriction: 10±1 vs 430±15, p<0.01). Previous studies have hypothesized that oxidative stress could be involved in the cerebral vasospasm. So, the vessels were incubated with Tyron, an antioxidant agent. Our data demonstrated that the administration of Tyron reduced the vasoconstriction induced by hb (max vasoconstriction: 205±7 vs 410±12, p<0.01) without influencing the effect of eb, suggesting an involvement of oxidative stress in the vascular response. Moreover, using lucigenin assay we found an increase in oxidative stress directly in the vessel treated with hb. One of the most important source of oxidative stress is the NADPH oxidase which needs Rac-1 to be activated. Our results demonstrated that the hb, and not the eb, was able to activate Rac-1 in the vessel, evaluated by Rac-1/PAK complex. To clearly define the role of Rac-1 in the vasoconstriction induced by hb, the vessels were transfected with an adenoviral vector containing Rac-1 dominant negative or an empty adenoviral vector. In this experimental condition, the vascular response induced by the hb was significantly blunted as compared to vessels treated with the empty adenovirus (max vasoconstriction: 180±7 vs 390±17, p<0.01). Our results demonstrate that the vasoconstriction induced by the hb is induced by Rac-1-mediated oxidative stress. Thus, Rac-1 could represent the target of novel therapeutic strategies to reduce the cerebral vasospasm and so the mortality in patients with subarachnoid hemorrhage.

Oxidative stress plays an important role in the ageing of the retina and in the pathogenesis of retinal diseases such as age‐related macular degeneration (ARMD). Hydrogen peroxide is a reactive oxygen species generated by the photo‐excited lipofuscin that accumulates during ageing in the retinal pigment epithelium (RPE), and the age‐related accumulation of lipofuscin is associated with ARMD. Iron also accumulates with age in the RPE that may contribute to ARMD as an important source of oxidative stress. The aim of this work was to investigate the effects of L‐Citrulline (CIT), a naturally occurring amino acid with known antioxidant properties, on oxidative stressed cultured RPE cells. Human RPE (ARPE‐19) cells were exposed to hydrogen peroxide (H2O2) or iron/ascorbate (I/A) for 4 h, either in the presence of CIT or after 24 h of pretreatment. Here, we show that supplementation with CIT protects ARPE‐19 cells against H2O2 and I/A. CIT improves cell metabolic activity, decreases ROS production, limits lipid peroxidation, reduces cell death and attenuates IL‐8 secretion. Our study evidences that CIT is able to protect human RPE cells from oxidative damage and suggests potential protective effect for the treatment of retinal diseases associated with oxidative stress.

A major goal of the 2006 NIEHS Strategic Plan encompasses the institute’s desire to “recruit and train the next generation of environmental health scientists.” To begin to achieve that goal, the NIEHS has unveiled a new annual grants program called the Outstanding New Environmental Scientist (ONES) Award. The five-year grants are designed to identify, encourage, inspire, and support outstanding investigators early in their careers, who have not yet received their first R01 grant. The first ONES grants, totaling $3.6 million, were awarded in September 2006 to eight promising young scientists chosen from more than 70 applicants through a rigorous application, review, and interview process. The program is the brainchild of NIEHS director David Schwartz, who has been concerned for some time about the loss of promising young scientific talent from the field for lack of support. “As a faculty member at Duke,” he says, “I found that the individuals who were particularly vulnerable in terms of their career development were those at that transitional stage between mentored and independent research, and that many very bright, creative people simply were not supported in ways that enhanced their career development.” Schwartz says the awards are also intended to help attract innovative young investigators to the NIEHS and the environmental health sciences, as well as to support the institutions that are helping new scientists develop their careers. The program’s long-term impact on the field, in terms of both the science and the scientists, could be significant. “These individuals represent very promising early career trajectories that are likely to have a substantial effect on environmental health sciences, and hopefully will evolve into the leaders in the field in the future,” says Schwartz. To ease that tricky early-career transition, ONES grantees are encouraged to establish and meet annually with an advisory committee comprising senior experts in their disciplines. According to Pat Mastin, chief of the NIEHS Cellular, Organ, and Systems Pathobiology Branch, who helped coordinate the initial ONES process, the grants represent a hybrid between mentored career development awards and independent R01 grants. “We think the young investigators should continue to be mentored,” Mastin says. “So we encouraged them to identify not a specific mentor, but an advisory committee, to give not only scientific advice but also career path advice.” The grantees recognize and appreciate the value of this hybrid approach to mentoring. “It gives us access to people we wouldn’t normally be interacting with,” says ONES grantee Thomas Begley, an assistant professor in the Department of Biomedical Sciences at the University at Albany State University of New York. “Having a mechanism to ensure that will promote good science on my end, and also will help me network with others in the field.” Grantee Patricia Opresko, an assistant professor in the Department of Environmental and Occupational Health at the University of Pittsburgh, agrees. “The grant has funds that will allow the four investigators on my advisory committee to come to Pittsburgh and meet with me once a year to focus on my project and offer their ideas, insight, input, and criticisms,” she says. “It adds an additional layer of mentoring that is really critical for a young investigator’s development.”

Oxidative damage is thought to be a major causal factor for replicative senescence and human aging (Harman, 1994). Leakage of superoxide from the mitochondrial respiratory chain is an important source of oxidative stress (Raha & Robinson, 2000). Targeting antioxidants to mitochondria is an efficient way to attenuate oxidative damage in mitochondria due to the production of reactive oxygen species (ROS) in isolated mitochondria (Kelso et al., 2001; Echtay et al., 2002) and in mitochondria within cells (Kelso et al., 2001; Hwang et al., 2001). Therefore, by determining the effect of these antioxidants it should be possible to establish whether oxidative damage has a role in telomere shortening. It has been shown that selective targeting of a potent antioxidant to mitochondria is achieved by attaching the redox active moiety of ubiquinol to the decyltriphenylphosphonium (DPPT) cation, resulting in the mitochondria-specific antioxidant mitoQ [10-(6′-ubiquinonyl) decyltriphenylphosphonium bromide] (Kelso et al., 2001). Ubiquinol acts as an antioxidant by donating a hydrogen atom from one of its hydroxyl groups to a lipid peroxyl radical, which decreases lipid peroxidation within the mitochondrial inner membrane (Ingold et al., 1993). MitoQ reduces oxidative damage and decreases ROS-induced apoptosis in short-term experiments (Kelso et al., 2001; Echtay et al., 2002). As mitoQ is predominantly located within mitochondria in cells due to its accumulation by the mitochondrial membrane potential, its effects in cells are thought to be largely due to the prevention of mitochondrial oxidative damage (Kelso et al., 2001) and there is also evidence that mitoQ decreases the release of ROS from mitochondria (Hwang et al., 2001). The possibility of such effects being due to non-specific interactions with mitochondria within cells can be discounted by the use of control compounds such as DPPT, which are also accumulated within mitochondria driven by the membrane potential but which do not act as antioxidants. Therefore, the blocking of a process by mitoQ but not by DPPT indicates a role for ROS production in the process and is consistent with the increased ROS production being primarily mitochondrial. Telomeres act as 'mitotic clocks' in human fibroblasts because they shorten with each round of replication due to both the inability of DNA polymerases to replicate the very ends of chromosomes (Olovnikow, 1973) and the specific accumulation of stress-induced DNA damage (von Zglinicki, 2002). Eventually, telomere dysfunction triggers replicative senescence (Bodnar et al., 1998). Although intense stress can cause a senescence-like arrest without involvement of telomeres (Chen et al., 2001; Gorbunova et al., 2002), one possibility is that ROS production accelerates replicative senescence via its contribution to telomere shortening under conditions of mild stress. Therefore, we wanted to find out whether mitoQ could prolong the replicative lifespan of human fibroblasts under mild stress conditions, and whether this would correlate with a reduction in the rate of telomere shortening. MitoQ in micromolar concentrations selectively blocks mitochondrial oxidative damage and prevents apoptosis induced by acute treatments with hydrogen peroxide (Kelso et al., 2001). When mitoQ was incubated with MRC-5 fibroblasts, concentrations above 50–100 nm were cytostatic in long-term culture, and even for concentrations of 10–20 nm an adaptation period of at least one week under normoxic conditions was necessary before beneficial effects on growth could be seen (data not shown). Such an adaptation period seems to be a characteristic effect of powerful antioxidants and may reflect the involvement of ROS in a multitude of cellular signal transduction chains (Forman et al., 2002). Neither DPPT nor mitoQ had a significant effect on the intracellular peroxide content under normoxic culture conditions as measured by 2′,7′-dichlorofluorescein fluorescence. However, mitoQ, but not DPPT, abolished nearly half of the rise in peroxides induced by hyperoxic culture in untreated cultures (Fig. 1a). Chronically increased oxidative stress exerted by culture under mild hyperoxia (40% oxygen partial pressure) shortens the replicative lifespan of MRC-5 fibroblasts down to few population doublings (von Zglinicki et al., 1995; von Zglinicki, 2002). This premature aging phenotype is indistinguishable from replicative senescence under standard culture conditions (von Zglinicki et al., 1995; Saretzki et al., 1998; Toussaint et al., 2000). Treatment of MRC-5 cells under these conditions with mitoQ significantly elongated the replicative lifespan by an average of 40% (ranging from 15 to 70%) in four independent experiments whereas the lifespan of DPPT-treated control cells remained unchanged (Fig. 1b). This is in agreement with effects of other potent antioxidants on the replicative lifespan of human cells, e.g. the spin trap α-phenyl-N-t-butyl nitrone (Chen et al., 1995; von Zglinicki et al., 2000), its derivative N-t-butyl hydroxylamine (Atamna et al., 2000) or an oxidation-resistant vitamin C derivative (Asp-2-O-phosphate (Furumoto et al., 1998). MitoQ decreases the cellular peroxide content and prolongs replicative lifespan of MRC-5 cells under hyperoxia. Cells (PD between 20 and 28) were left untreated (no) or were pretreated for one week with 10–20 nm (data pooled) of either mitoQ or DPPT and then subjected to 40% hyperoxia until cessation of proliferation (4–6 weeks). MitoQ or DPPT, respectively, were prepared as stock solutions in 100% alcohol and added to the medium every other day. (a) Cell peroxide content under normoxia (filled bars) and after one week of hyperoxia (open bars) was measured by 2′,7′-dichlorofluorescein using flow cytometry as described (Lorenz et al., 2001). Data are mean ± SEM from 3 to 5 independent experiments. (B) Replicative lifespan under hyperoxia (in population doublings, PD) was measured in nine (no treatment), three (DPPT) or four (MitoQ) independent experiments. Box plots indicate the median, upper and lower quartiles and percentiles. Asterisks indicate a significant difference (P < 0.05) between mitoQ and either DPPT or no treatment. To examine the involvement of telomeres, we measured telomere length at the start point of the treatment and at up to four different time points under hyperoxic culture by non-radioactive Southern blotting as described (Petersen et al., 1998; Serra et al., 2002). MitoQ treatment minimized telomere shortening under hyperoxia (Fig. 2a). Quantitative evaluation of data from four independent experiments (Fig. 2b) indicated that hyperoxia increased the rate of telomere shortening per population doubling (PD), similar to that seen in DPPT-treated and untreated control cells. This is in close agreement with earlier data (von Zglinicki, 2002). However, mitoQ treatment completely prevented this rise in telomere shortening rate due to hyperoxia and instead gave a negligible rate of telomere shortening. Again, this is in agreement with the reported protective effect of PBN (von Zglinicki et al., 2000), Asp-2-O-phosphate (Furumoto et al., 1998) or superoxide dismutase overexpression (Serra et al., 2002) on telomere maintenance. MitoQ counteracts telomere shortening under hyperoxia. Cells were grown under normoxia (NO) and, after one week pretreatment with either DPPT or mitoQ, under 40% hyperoxia (HO) and DNA was sampled at the times and PD as indicated. (A) Telomere Southern blot including λHindIII marker (M). Blots were scanned with a FUJI LAS-100 luminescence imager. Average telomere length was calculated using the AIDA software and is indicated by white lines. (B) Telomere shortening rates per PD (mean ± SEM) under normoxia (filled bar) and hyperoxia (open bars). Cells were untreated (no) or treated with either DPPT or mitoQ. Data were calculated by linear regression of triplicate measurements from three or four independent experiments. Telomere shortening rate in mitoQ-treated cells under hyperoxia is not significantly different from zero, but is significantly (P < 0.05, anova) smaller than in both untreated or DPPT-treated cells. Together, these data indicate that minimizing oxidative stress significantly slows down telomere shortening and prolongs replicative lifespan. Moreover, they suggest that it is accelerated telomere shortening in response to increased mitochondrial ROS production that induces premature senescence-like arrest under conditions of mild stress such as chronic hyperoxia. Intense, acute stress, which leads to an immediate arrest in the vast majority of cells, is of course telomere length-independent (Chen et al., 2001; Gorbunova et al., 2002). Such stress will damage DNA all over the genome and thus trigger arrest before replication and concomitant telomere shortening occurs. On the other hand, low levels of interstitial DNA damage are compatible with cell proliferation, but damage will contribute to telomere shortening because of the low telomere-specific efficiency of single-strand break repair (Petersen et al., 1998). Thus, telomeres appear to act as cellular sentinels for oxidative damage under near-physiological conditions by limiting cell proliferation if and when stress and thus greater mutational risks accumulate (von Zglinicki, 2002). This work was supported by MRC grant G0100140 57030 to T.v.Z.

ObjectiveTo investigate the effect and mechanism of Glucocorticoids (GCs) induced oxidative stress and apoptosis on necrosis of the femoral head in patients and rats.MethodsEight patients with steroid‐induced avascular necrosis of the femoral head (SINFH) and eight patients with developmental dysplasia of the hips (DDH) were enrolled in our study. In animal model, twenty male Sprague‐Dawley rats were randomly divided into two groups (SINFH group and NS group). The SINFH model group received the methylprednisolone (MPS) injection, while control group was injected with normal saline (NS). MRI was used to confirm SINFH rat model was established successfully. Then, the rats were sacrificed 4 weeks later and femoral head samples were harvested. Histopathological staining was preformed to evaluate osteonecrosis. TUNEL staining was performed with 8‐OHdG and DAPI immunofluorescence staining to evaluate oxidative injury and osteocyte apoptosis. Immunohistochemistry staining was used to detect Nox1, Nox2, and Nox4 protein expression.ResultsMRI showed signs of typical osteonecrosis of femoral head in SIHFH patients. Histopathological staining showed that the rate of empty lacunae in SINFH patients was significantly higher (56.88% ± 9.72% vs 19.92% ± 4.18%, T = −11.04, P < 0.001) than that in DDH patients. The immunofluorescence staining indicated that the TUNEL‐positive cell and 8‐OHdG‐positve cell in SINFH patients were significantly higher (49.32% ± 12.95% vs 8.00% ± 2.11%, T = −7.04, P = 0.002, 54.6% ± 23.8% vs 9.75% ± 3.31%, T = −4.17, P = 0.003) compared to the DDH patients. The immunohistochemistry staining showed that the protein expression of NOX1, NOX2 and NOX4 in SINFH patients were significantly increased (64.50% ± 7.57% vs 37.58% ± 9.23%, T = −3.88, P = 0.018, 90.84% ± 2.93% vs 49.56% ± 16.47%, T = −5.46, P = 0.001, 85.46% ± 9.3% vs 40.69% ± 6.77%, T = −8.03, P = 0.001) compared to the DDH patients. In animal model, MRI showed signs of edema of femoral head in MPS group, which represents SINFH rat model was established successfully. Histological evaluation showed the rate of empty lacunae in MPS group was significantly higher (25.85% ± 4.68% vs 9.35% ± 1.99%, T = −7.96, P < 0.001) than that in NS group. The immunofluorescence staining indicated that the TUNEL‐positive cell and 8‐OHdG‐positve cell (in MPS group were significantly increased (31.93% ± 1.01% vs 11.73% ± 1.16%, T = −32.26, P < 0.001, 47.59% ± 1.39% vs 22.07% ± 2.45%, T = −22.18, P < 0.001) compared to the NS group. The immunohistochemistry staining showed that the expression of NOX2 in MPS group was significantly increased (76.77% ± 8.34% vs 50.32% ± 10.84%, T = −4.74, P = 0.001) compare with NS group.ConclusionOur findings indicated that GC‐induced NOXs expression may be an important source of oxidative stress, which could lead to osteocyte apoptosis in the process of SINFH

Preferential use of less toxic detoxification pathways by long-lived species.

Oxidative stress is vital for pathophysiology of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Monoamine oxidase (MAO) is an important source of oxidative stress in the vascular system and liver. However, the effect of MAO inhibition on atherosclerosis and NAFLD has not been explored. In the present study, MAO A and B expressions were increased in atherosclerotic plaques in human and apolipoprotein E (ApoE)-deficient mice. Inhibition of MAO B (by deprenyl), but not MAO A (by clorgyline), reduced the atheroma area in the thoracic aorta and aortic sinus in ApoE-deficient mice fed the cholesterol-enriched diet for 15 weeks. MAO B inhibition attenuated oxidative stress, expression of adhesion molecules, production of inflammatory cytokines, and macrophage infiltration in atherosclerotic plaques and decreased plasma triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. MAO B inhibition had no therapeutic effect on restenosis in the femoral artery wire-induced injury model in C57BL/6 mice. In the NAFLD mouse model, MAO B inhibition reduced lipid droplet deposition in the liver and hepatic total cholesterol and triglyceride levels in C57BL/6 mice fed high-fat diets for 10 weeks. Key enzymes for triglyceride and cholesterol biosynthesis (fatty acid synthase and 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and inflammatory markers were inhibited, and cholesterol clearance was up-regulated (increased LDL receptor expression and reduced proprotein convertase subtilisin/kexin type 9, PCSK9, expression) by MAO B inhibition in the liver. These results were also demonstrated in the HepG2 liver cell model. Our data suggest that MAO B inhibition is a potential and novel treatment for atherosclerosis and NAFLD.

Reactive oxygen species (ROS) are generated during normal cell physiology; however increased ROS formations are highly detrimental in many cardiometabolic disorders, including atherosclerosis, hypertension, diabetes, obesity, neurodegenerative diseases, and aneurism [1–3]. Despite the numerous existing data the role of ROS and the associated redox mechanisms of the disease inception and progression remain elusive. A common feature of all cardiovascular disorders is the occurrence of oxidative stress, a condition characterized by an imbalance between ROS production and the ability of biological systems to detoxify the reactive intermediates [4]. Produced in excess, ROS react indiscriminately and cause irreversible damage of the majority of biological molecules, thereby altering cell functions [5]. Although extensive studies have focused on the redox control of vascular response to inflammatory and metabolic insults, the molecular mechanisms ROS generation and the way that this class of molecules contributes to vascular damage are not entirely clear. Therefore, uncovering the intimate molecular control mechanisms involved in regulation of the delicate balance of ROS formation and neutralization in the vascular wall cells is a prerequisite for the development of an effective antioxidative stress therapy. The topic of this special issue focuses on recent advances in experimental aspects of oxidative stress in cardiovascular disorders. In the current issue, H. Osorio et al. have addressed the role of sodium-glucose cotransporter (SGLT2) in the oxidative and nitrative stress processes taking place in the kidney of diabetic rats. The authors have shown that SGLT2 inhibition reverse streptozotocin-induced diabetes and redox disbalance in the kidney, suggesting the potential therapeutic role of SGLT2 inhibitors in diabetic nephropathy. The role of oxygen supplementation in systemic redox balance in rats has been investigated in the paper by F. Nagatomo et al. The authors demonstrated that exposure to oxygen concentrations higher than 40% leads to a prooxidant response able to produce morphological changes in red blood cells, whereas antioxidant response does not seem to be modified in the 24 h period of the study. J. Dudka et al. have evaluated the implication of hypothyreosis on the oxidative stress induced by doxorubicin. The authors also analyzed the effect of both hypothyreosis and the drug on cytochrome P450 NADPH-reductase and inducible nitric oxide synthase expression. The results of this study bring additional support that hipothyroid conditions may increase the cardiac oxidative stress caused by doxorubicin. In the paper by M. Al-Shebly and M. Mansour the authors have analyzed whether oxidative stress status is modified in hypertensive/diabetic women during labor. The findings of this study clearly demonstrate that different biomarkers of redox balance-altered in hypertensive/diabetic women during labor and suggest that this redox imbalance could increase the risk of fetal abnormalities. In the paper of S. Muhammad et al., the authors aimed at investigating the antioxidant effects of mineral elements supplementation using a rat model of hypertension. They showed that copper, manganese, and zinc supplementation reduces the blood pressure as compared with hypertensive control. In addition, a significant reduction in the plasma total cholesterol, triglyceride, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, malondialdehyde, and insulin level, as well as increases in the high density lipoprotein cholesterol, total antioxidant activities, and nitric oxide have been demonstrated in the supplemented groups relative to the hypertensive control. Together, the present report highlights that various minerals may play a role in preventing oxidative stress, dyslipidemia, and insulin resistance associated with hypertension. Interestingly, R. Wu et al. demonstrated the beneficial effects of chronic acetylsalicylic acid (ASA) treatment on cardiac hypertrophy and oxidative stress in cardiomyopathic hamsters. The authors concluded that ASA present a therapeutic potential to prevent cardiac dysfunction. The review of J. Madrigal-Matute et al. is focused on the thioredoxin (TRX) system, which is composed of several proteins such as TRX and Peroxiredoxin (PRDX). In addition to their main role as antioxidants, recent data highlights their function in several processes involved on the development of atherothrombosis. In fact, since TRX and PRDX are present in the atherosclerotic plaque and can be secreted under prooxidative conditions to the circulation, their role as diagnostic, prognostic, and therapeutic biomarkers of cardiovascular diseases (CVD) has been addressed. In conclusion, J. Madrigal-Matute et al. summarized several findings that demonstrate the major role of the TRX system in the maintenance of the redox status in CVD. Furthermore, the extracellular levels of PRDX/TRX seem to be related with a pro-oxidative scenario suggesting their potential role as biomarkers for oxidative related diseases. Nevertheless, their value as useful therapeutic tools is being tested and future studies are necessary to validate its prospective beneficial effects in CVD. Vascular NADPH oxidases (Nox) are a class of heterooligomeric enzymes, whose unique function is the generation of ROS in a highly regulated manner [6]; conversely, the specific role of each enzyme is yet to be discovered. Nox expression and activity are significantly upregulated in the vasculature of hypertensive subjects and are associated with the development of macro- and microvascular diseases [7]. Since the members of the Nox family are major triggers of oxidative stress they have a prominent role in the pathology of diabetes-induced vasculopathies [8, 9]; thus, Nox and their upstream regulators may become important therapeutic targets [10]. In the paper of J. Miguel-Carrasco et al., the authors investigated the effects of the profibrotic factor TGF-beta 1 in mediating Nox overactivity and oxidative stress in hypertensive rats. The results showed that pharmacological inhibition of TGF-beta 1 pathway greatly reduces the Nox activity, expression of the Nox2 and Nox4 isoforms, and nitrotyrosine levels in hypertensive rats compared to control animals. Collectively, the data of this study provides conclusive evidence on the involvement of this enzyme in the profibrotic actions of TGF-beta 1. The major cause for diastolic heart failure is cardiac aging, which is referred to a dramatic decline in cardiac pump function with advanced age and resulted in diastolic dysfunction. Current clinical treatment for patients with diastolic heart failure is disappointing. The cardioprotective effects of EGB761, a standard extract from the leaves of Ginkgo biloba, have been demonstrated already. The aim of the present study was to investigate the potential antiaging-associated cellular diastolic dysfunction effects of EGB761, exploring underlying molecular mechanisms. Cardiomyocyte aging model was established by treating with D-galactose. Treatment with EGB761 attenuated the intracellular formation of AGEs, delays the cellular senescence, and increase reuptake of Ca2+ stores in the sarcoplasmic reticulum. J. Liu et al. have suggested that EGB761 may protect against aging-associated diastolic dysfunction in cardiomyocytes. Furthermore, it was possible that EGB761 could upregulate SERCA2a function through improvement of the amount of Ser16 sites PLN phosphorylation. In conclusion, EGB761 significantly improved the diastolic function in cardiomyocytes, through the regulation of myocardial sarcoplasmic reticulum calcium transport regulatory. NF-E2-related factor 2 (Nrf2) represents a promising therapeutic target to prevent oxidative stress and oxidative damage in various pathologies, including cardiovascular diseases. In the study of E. Donovan et al., the beneficial effects of phytochemicals included in dietary supplements might be an effective strategy to protect the cells against the detrimental effects of oxidative stress. The authors have demonstrated the Protandim activates Nrf2, a condition that ultimately influenced the protection of human coronary artery endothelial cells against an oxidative challenge. In the paper by A. Ashour et al., the authors have addressed the potential use of metformin to prevent cardiotoxic effects of doxorubicin, a potent antitumor agent, in an experimental model of cardiomyopathy in rats. The adverse effects of doxorubicin include biochemical and morphological cardiac markers of injury, associated to decreasing antioxidant systems. Interestingly, the authors demonstrated that treatment with metformin prevents deleterious changes associated to doxorubicin mainly by modulation of redox balance. Collectively, the original articles published in this special issue stimulate the ongoing efforts to identify the basic molecular mechanisms regulating the oxidative stress that may be used to find ways to manage its occurrence and correct its adverse effects.