Moderate Levels Of Oxidative Stress Research Articles

Biomarkers of oxidative stress in urine and plasma of operators at six Singapore printing centers and their association with several metrics of printer-emitted nanoparticle exposures

Inhalation of nanoparticles emitted from toner-based printing equipment (TPE), such as laser printers and photocopiers, also known as PEPs, has been associated with systemic inflammation, hypertension, cardiovascular disease, respiratory disorders, and genotoxicity. Global serum metabolomics analysis in 19 healthy TPE operators found 52 dysregulated biomolecules involved in upregulation of inflammation, immune, and antioxidant responses and downregulation of cellular energetics and cell proliferation. Here, we build on the metabolomics study by investigating the association of a panel of nine urinary OS biomarkers reflecting DNA/RNA damage (8OHdG, 8OHG, and 5OHMeU), protein/amino acid oxidation (o-tyrosine, 3-chlorotyrosine, and 3-nitrotyrosine), and lipid oxidation (8-isoprostane, 4-hydroxy nonenal, and malondialdehyde [MDA]), as well as plasma total MDA and total protein carbonyl (TPC), with several nanoparticle exposure metrics in the same 19 healthy TPE operators. Plasma total MDA, urinary 5OHMeU, 3-chlorotyrosine, and 3-nitrotyrosine were positively, whereas o-tyrosine inversely and statistically significantly associated with PEPs exposure in multivariate models, after adjusting for age and urinary creatinine. Urinary 8OHdG, 8OHG, 5OHMeU, and total MDA in urine and plasma had group mean values higher than expected in healthy controls without PEPs exposure and comparable to those of workers experiencing low to moderate levels of oxidative stress (OS). The highest exposure group had OS biomarker values, most notably 8OHdG, 8OHG, and total MDA, that compared to workers exposed to welding fumes and titanium dioxide. Particle number concentration was the most sensitive and robust exposure metric. A combination of nanoparticle number concentration and OS potential of fresh aerosols is recommended for larger scale future studies.

MiR-195 regulates mitochondrial function by targeting mitofusin-2 in breast cancer cells

ABSTRACTMitochondrial dynamics is a highly dysregulated process in cancer. Apoptosis and mitochondrial fission are two concurrent events wherein increased mitochondrial fragmentation serves as a hallmark of apoptosis. We have shown earlier that miR-195 exerts pro-apoptotic effects in breast cancer cells. Herein, we have demonstrated miR-195 as a modulator of mitochondrial dynamics and function. Imaging experiments upon miR-195 treatment have shown that mitochondria undergo extensive fission. We validated mitofusin2 as a potential target of miR-195. This may provide a molecular explanation for the respiratory defects induced by miR-195 over-expression in breast cancer cells. Active, but not total, mitochondrial mass, was reduced with increasing levels of miR-195. We have further shown that miR-195 enhances mitochondrial SOD-2 expression but does not affect PINK1 levels in breast cancer cells. Collectively, we have revealed that miR-195 is a modulator of mitochondrial dynamics by targeting MFN2 thereby impairing mitochondrial function. Concomitantly, it enhances the scavenger of reactive oxygen species (SOD-2) to maintain moderate levels of oxidative stress. Our findings suggest a therapeutic potential of miR-195 in both ER-positive as well as ER-negative breast cancer cells.

Piceatannol Mediated Modulation of Oxidative Stress and Regeneration in the Liver of Endotoxemic Mice.

Liver plays a pivotal role in host defense mechanisms related to endotoxemia. However, liver dysfunction often occurs in early sepsis. This study investigated the hepatoprotective potential of natural stilbenoid piceatannol (PIC) in lipopolysaccharide (LPS)-induced endotoxemic mice. Swiss Albino mice were divided into four groups: Control (C), LPS administrated (LPS), PIC administrated (PIC), and LPS administrated/PIC preadministrated (LPS+PIC) animals. PIC was administrated intraperitoneally (i.p.) at the dose of 4 mg/kg/day during 7 days. Endotoxemia was induced with a single i.p. administration of LPS at the dose of 4 mg/kg. Superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LP) levels, light microscopic pathology, and genotoxicity were investigated. Proliferating cell nuclear antigen and SQSTM1/p62 immunofluorescence were measured. PIC preadministration restored SOD activity, reduced LP and genotoxicity. However, moderate level of oxidative stress (OS) had been progressed in PIC preadministrated animals depending upon prolonged autophagic response and selective degradation of CAT. Positive OS stimulated liver regeneration by upregulating oval cells' and downregulating hepatocytes' proliferation and resulted in the maintanence of hepatic tissue integrity in PIC preadministrated animals. These results suggested that PIC may be a useful hepatoprotective agent in LPS-induced endotoxemia as a modulator of OS and genotoxicity, as an inducer of autophagy, and as a promoter of liver regeneration.

The Organization of Mitochondrial Supercomplexes is Modulated by Oxidative Stress In Vivo in Mouse Models of Mitochondrial Encephalopathy.

We examine the effect of oxidative stress on the stability of mitochondrial respiratory complexes and their association into supercomplexes (SCs) in the neuron-specific Rieske iron sulfur protein (RISP) and COX10 knockout (KO) mice. Previously we reported that these two models display different grades of oxidative stress in distinct brain regions. Using blue native gel electrophoresis, we observed a redistribution of the architecture of SCs in KO mice. Brain regions with moderate levels of oxidative stress (cingulate cortex of both COX10 and RISP KO and hippocampus of the RISP KO) showed a significant increase in the levels of high molecular weight (HMW) SCs. High levels of oxidative stress in the piriform cortex of the RISP KO negatively impacted the stability of CI, CIII and SCs. Treatment of the RISP KO with the mitochondrial targeted antioxidant mitoTEMPO preserved the stability of respiratory complexes and formation of SCs in the piriform cortex and increased the levels of glutathione peroxidase. These results suggest that mild to moderate levels of oxidative stress can modulate SCs into a more favorable architecture of HMW SCs to cope with rising levels of free radicals and cover the energetic needs.

Involvement of oxidative stress associated with glutathione depletion and p38 mitogen-activated protein kinase activation in arsenic disulfide-induced differentiation in HL-60 cells

Arsenic disulfide (As2S2) has been traditionally used to treat certain types of leukemia. However, a detailed mechanism of action of As2S2 is not sufficiently documented. The effects of As2S2 on HL-60 cells were therefore investigated by focusing on proliferation, differentiation, generation of reactive oxygen species (ROS), intracellular glutathione (GSH) depletion and activation of p38 mitogen-activated protein kinase (MAPK). As2S2 at 0.5–8 μM induced cell differentiation based on an increment in CD11b expression, nitroblue tetrazolium (NBT)-positive cells and cell size change. A transient increase in ROS level along with intracellular GSH level was also observed. p38 MAPK activation gradually increased after ROS generation and was sustained during cell differentiation. Decreased CD11b expression was accompanied by p38 MAPK activation, and a p38 MAPK inhibitor restored CD11b expression. The results suggest that moderate levels of oxidative stress induced by As2S2 correlate with HL-60 cell differentiation. Suppression of p38 MAPK can augment the efficacy of As2S2 to induce HL-60 cell differentiation.

Schistosoma mansoni infection causes oxidative stress and alters receptor for advanced glycation endproduct (RAGE) and tau levels in multiple organs in mice

Schistosomiasis is a parasitic disease caused by trematode worms from the Schistosoma genus and is characterized by high rates of morbidity. The main organs affected in this pathology, such as liver, kidneys and spleen, are shifted to a pro-oxidant state in the course of the infection. Here, we compared oxidative stress parameters of liver, kidney and spleen with other organs affected by schistosomiasis – heart, brain cortex and lungs. The results demonstrated that mice infected with Schistosoma mansoni had altered non-enzymatic antioxidant status in lungs and brain, increased carbonyl levels in lungs, and a moderate level of oxidative stress in heart. A severe redox imbalance in liver and kidneys and decreased non-enzymatic antioxidant capacity in spleen were also observed. Superoxide dismutase and catalase activities were differently modulated in liver, kidney and heart, and we found that differences in Superoxide dismutase 2 and catalase protein content may be responsible for these differences. Lungs had decreased receptor for advanced glycation endproduct expression and the brain cortex presented altered tau expression and phosphorylation levels, suggesting important molecular changes in these tissues, as homeostasis of these proteins is widely associated with the normal function of their respective organs. We believe that these results demonstrate for the first time that changes in the redox profile and expression of tissue-specific proteins of organs such as heart, lungs and brain are observed in early stages of S. mansoni infection.

Implications of maternal systemic oxidative stress in normal pregnancy and in pregnancy complicated by preeclampsia

Objectives: To evaluate the intensity of oxidative stress in normal pregnancy and in pregnancy complicated by preeclampsia. To investigate a possible correlation between the intensity of oxidative stress, severity of preeclampsia and the fetal status at birth. Materials and methods: A retrospective transversal study was performed in three groups of 80 patients each: Group I—preeclampsia; Group II—normal pregnancy; Group III—control (non-pregnant patients). Degradation products of reactive oxygen species (lipid peroxides and protein carbonyls) and some antioxidants (hydrogen donor capacity and ceruloplasmin) were determined in the serum of patients. The data obtained were processed by descriptive and comparative statistical methods. Results: A moderate level of oxidative stress was found in normal pregnancy. We found statistically significant differences between the control group and the normal pregnancy group (p < 0.000). In preeclampsia, oxidative stress increases. Statistically significant differences were found in the evaluated parameters between the normal pregnancy group and the preeclampsia group (p < 0.000). There were no correlations between the intensity of oxidative stress, severity of preeclampsia and the fetal status at birth in the group with preeclampsia. Conclusion: Oxidative stress in preeclampsia is the result of the increase in reactive oxygen species and of the decrease in antioxidants.

Oxidative stress therapy for solid tumors – A proposal

Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation - as with 2-deoxyglucose administration or a hypoglycemic insulin clamp - and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials.

Mechanisms of Noise-Induced Hair Cell Death

Mechanisms of Noise-Induced Hair Cell Death

Short-term exposure of multicellular tumor spheroids of a human glioma cell line to the glycolytic inhibitor 2-deoxy-D-glucose is more toxic than continuous exposure

The glycolytic inhibitor 2-deoxy-D-glucose (2-DG) has been used as a therapeutic agent and as an adjuvant in cancer therapy with either weekly fractions of the treatment or daily administration. While the weekly fraction has often been found to be nontoxic and effective, other treatment regimes are tolerated to a relatively lesser extent. It was therefore, considered worthwhile to investigate the efficacy of short- and long-term exposure of tumor cells to 2-DG under the controlled conditions. Seven-day-old MTS were exposed to 2-DG (5 mM, equimolar to glucose concentration in media) for different time intervals (30 min to 24 h) trypsinized and plated for clonogenicity. Alternatively, spheroids were grown either continuously in the presence of 2-DG or were treated with 2-DG for 2 h (short-term exposure) and grown in 2-DG-free media for 21 days and assessed for spheroid growth, cell viability, apoptosis, cytogenetic damage, mitochondrial status, and oxidative stress. Exposure of spheroids to 2-DG for 2-4 h induced 30% cell death (SF 0.70) while, a 24-h exposure resulted in only a marginal decrease in clonogenicity (SF 0.95). Furthermore, the spheroids disintegrated completely by 28 days in the case of 2-h exposure to 2-DG, while spheroids grown continuously in the presence of 2-DG repopulated. The cytotoxicity following short-term exposure of MTS to 2-DG was primarily due to the induction of apoptosis revealed by morphological features as well as flow cytometric analysis of the DNA content. Interestingly however, cytogenetic damage (micronuclei induction) was observed in spheroids that were continuously exposed to 2-DG. Short-term exposure to 2-DG resulted in a significant increase in ROS levels and a reduction in the levels of unoxidized cardiolipin as measured by NAO suggesting the involvement of mitochondria leakiness leading to oxidative stress which, could be responsible for apoptotic cell death observed under these conditions. However, continuous exposure to 2-DG resulted in a moderate level of oxidative stress leading to the genomic instability. Preliminary studies also show that spheroids exposed continuously to 2-DG result in the development of resistance to certain chemotherapeutic drugs which could be correlated with elevated levels of mdr1. The present results suggest that a persistent down-regulation of glycolysis (as seen here with continuous exposure to 2-DG) could activate prosurvival responses besides inducing moderate levels of oxidative stress resulting in the development of resistance against therapeutic agents.

Comparative evaluation of oxidative and antioxidative capacity during high-flux hemodialysis using two different membranes

In patients with end-stage renal disease (ESRD) cardiovascular morbidity and mortality are increased. Apart from traditional and uremia-specific factors oxidative stress has been implicated as a main risk factor. This study investigated the influence of two different high-flux hemodialysis membranes on parameters of oxidative stress during a dialysis session. 14 stable ESRD patients were enrolled in the study and randomly assigned to high-flux hemodialysis using either a polyamide membrane (Polyflux 14; PA group) or a new polysulfone membrane (Diacap Polysulfone HI PS 15; PS group). All patients received 6 treatments with the same membrane. During the 5th treatment parameters of dialysis efficiency, biocompatibility (cell counts, complement C3a, thrombin-antithrombin complex) and oxidative stress (lipid peroxides, total antioxidative capacity) were measured. Parameters of dialysis efficiency and biocompatibility were similar in both treatment groups. At the beginning of the dialysis session both groups showed a low to moderate level of oxidative stress and a reduced total antioxidative capacity as compared to healthy controls. Both parameters deteriorated significantly during the extracorporeal procedure with a similar magnitude in both membrane groups. No correlation between oxidative or antioxidative capacity and parameters of biocompatibility or dialysis efficiency could be found. Dialysis with synthetic high-flux membranes induces a temporary deterioration of oxidative stress parameters in ESRD patients despite good dialysis efficiency and biocompatibility.

Response of antioxidant defences to oxidative stress induced by prolonged exercise: antioxidant enzyme gene expression in lymphocytes

The response of lymphocyte and plasma antioxidant defences to a prolonged exercise as a cycling stage in a professional race was analysed. Antioxidant enzyme activities and gene expression, carbonyl derivative and MDA levels were determined in lymphocytes. Plasma levels of vitamin E, carotenes, protein carbonyl derivatives and the test d-Roms were measured. Significant increases in plasmatic carbonyls and in the test d-Roms were observed after the cycling stage. No significant differences were found in the lymphocyte MDA and carbonyl derivative levels. A significant increase was found in plasma vitamin E concentration after the cycling stage; however, the lymphocyte vitamin E concentration did not change. Significant increases were observed in lymphocyte total superoxide dismutase (SOD) activity and in the levels of CuZn-SOD and Mn-SOD isoenzymes. The moderate levels of oxidative stress in the lymphocyte induced a cellular adaptation to exercise enough to counteract the negative effects of oxidative stress.

Activation of ERK or inhibition of JNK ameliorates H2O2 cytotoxicity in mouse renal proximal tubule cells

Our previous studies suggest that the balance between the activation of extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal/stress-activated protein kinase (JNK) might determine cell fate following oxidant injury in vivo. The mouse proximal tubule cell line (TKPTS) was used to study hydrogen peroxide (H(2)O(2))-induced death and survival. The role of ERK and JNK in this process was studied by using adenoviruses that contain either a constitutively active mitogen-activated protein kinase kinase 1 (MEK1) or a dominant-negative JNK. Acridine orange plus ethidium bromide staining was applied to distinguish between viable, apoptotic, and necrotic cells following H(2)O(2) treatment. We analyzed cell cycle events by fluorescence-activated cell sorter (FACS) analysis and the phosphorylation status of ERK and JNK by Western blotting. TKPTS cells survived a moderate level of oxidative stress (0.5 mM/L H(2)O(2)) via temporary growth arrest, while high dose of H(2)O(2) (1 mM/L) caused extensive necrosis. Survival was associated with activation of both ERK and JNK, while death was associated with JNK activation only. Prior adenovirus-mediated up-regulation of ERK or inhibition of JNK function increased the survival (8- or 7-fold, respectively) of TKPTS cells after 1 mmol/L H(2)O(2) treatment. Interestingly, ERK activation and, thus, survival was associated with growth arrest not proliferation. We demonstrate that oxidant injury-induced necrosis could be ameliorated by either up-regulation of endogenous ERK or by inhibition of JNK-related pathways. These results directly demonstrate that the intracellular balance between prosurvival and prodeath mitogen-activated protein kinases (MAPKs) determine proximal tubule cell survival from oxidant injury and reveal possible mediators of survival.

Oxidative stress in HIV-1-infected injection drug users.

Low serum antioxidant levels observed in many HIV-infected populations could be largely due to an increase in oxidative stress (defined as a disturbance in the equilibrium status of prooxidant/antioxidant systems of intact cells). In HIV infection, oxidative stress may be caused by both overproduction of reactive oxygen intermediates (ROIs) and a simultaneous deficiency of antioxidant defenses. Furthermore, injection drug use has been associated with increased levels of oxidative stress in animal models. Currently, there is widespread use of self-prescribed antioxidant supplementation among the HIV-infected population and a prevailing belief that high-dose supplementation is beneficial, or at the very least, not harmful. Data from our studies show that HIV-positive injection drug users (IDUs) who are on antiretroviral combination therapies including a protease inhibitor have significantly higher mean serum levels of several antioxidants, independent of dietary and supplemental intake, compared with both HIV-negative IDUs and HIV-positive IDUs not taking protease inhibitors. This suggests that oxidative stress may be reduced in patients taking protease inhibitors. Preliminary data suggest that the future of antioxidant supplementation therapy, if any, will be one in which different doses of supplements are recommended for HIV-infected patients on the various antiretroviral treatment regimens. More research is needed to determine the interactions among injection drug use, oxidative stress, antiretroviral therapy, and the use of antioxidant supplements in HIV infection. Until more is known, caution should be exercised when using or recommending high-dose antioxidant supplementation in HIV-infected individuals, particularly in those on protease inhibitors, since moderate levels of oxidative stress are involved in a number of useful physiologic processes.

Oxidative Stress in HIV-1-Infected Injection Drug Users

Low serum antioxidant levels observed in many HIV-infected populations could be largely due to an increase in oxidative stress (defined as a disturbance in the equilibrium status of prooxidant/antioxidant systems of intact cells). In HIV infection, oxidative stress may be caused by both overproduction of reactive oxygen intermediates (ROIs) and a simultaneous deficiency of antioxidant defenses. Furthermore, injection drug use has been associated with increased levels of oxidative stress in animal models. Currently, there is widespread use of self-prescribed antioxidant supplementation among the HIV-infected population and a prevailing belief that high-dose supplementation is beneficial, or at the very least, not harmful. Data from our studies show that HIV-positive injection drug users (IDUs) who are on antiretroviral combination therapies including a protease inhibitor have significantly higher mean serum levels of several antioxidants, independent of dietary and supplemental intake, compared with both HIV-negative IDUs and HIV-positive IDUs not taking protease inhibitors. This suggests that oxidative stress may be reduced in patients taking protease inhibitors. Preliminary data suggest that the future of antioxidant supplementation therapy, if any, will be one in which different doses of supplements are recommended for HIV-infected patients on the various antiretroviral treatment regimens. More research is needed to determine the interactions among injection drug use, oxidative stress, antiretroviral therapy, and the use of antioxidant supplements in HIV infection. Until more is known, caution should be exercised when using or recommending high-dose antioxidant supplementation in HIV-infected individuals, particularly in those on protease inhibitors, since moderate levels of oxidative stress are involved in a number of useful physiologic processes.