Possible mechanism of pesticide toxicity-related oxidative stress leading to airway narrowing

Abstract

The study was conducted to assess the magnitude of oxidative stress and lung function abnormalities in 34 male pesticide sprayers on exposure to pesticides in mango plantations. Biochemical studies on blood antioxidant enzymes revealed an unchanged glutathione level and increased level of malondialdehyde (P < 0.001), which indicates that pesticide sprayers may have suffered from oxidative stress. Decreased acetyl-cholinesterase levels (P < 0.001) in sprayers compared to the controls suggest inhibition of cholinesterase activity. The present study shows that pesticide toxicity might lead to oxidative stress and airway narrowing resulting in decreased peak expiratory flow rate.     

The role of oxidative stress in an equine model of human asthma

Equine recurrent airway obstruction (RAO) is a naturally occurring respiratory disease in horses with many similarities to human asthma and, as a result, has been used as an animal model of this disease. Oxidative stress has been demonstrated to occur in a range of respiratory diseases in human beings including asthma. Quantitatively, horses have a greater non-enzymatic antioxidant capacity in the pulmonary epithelial lining fluid compared to human beings due to high ascorbic acid concentrations, which reflects their ability to synthesise ascorbic acid. Consequently, a greater oxidative load is likely to be required to induce oxidative stress in horses compared to human beings. Induction of acute neutrophilic airway inflammation in RAO horses by exposure to organic dust does not result in marked pulmonary oxidative stress. However, with a more prolonged inflammatory response, the antioxidant capacity is depleted and oxidative stress occurs. Despite the clear evidence of oxidative stress in RAO, there is currently limited data linking oxidative stress with a causal role in the development of the pathophysiological features of RAO, namely airway obstruction, airway hyper-responsiveness, airway inflammation and mucus accumulation. However, pathways do exist whereby oxidants could potentially augment the production of important mediators in RAO. Further work is required to ascertain the benefits of antioxidant supplementation in RAO and to determine the role of oxidative stress in the pathogenesis of the disease. Given the similarities with human asthma, results from RAO horses could enhance the understanding of the role of oxidative stress in human asthma.     

Critical role of exposure time to endogenous oxidative stress in hepatocyte apoptosis

Abstract

We have previously shown that inhibition of catalase and glutathione peroxidase activities in rat primary hepatocytes by 3-amino-1,2,4-triazole (ATZ) and mercaptosuccinic acid (MS) results in sustained oxidative stress, followed by apoptosis. To examine the effects of duration of oxidative stress, ATZ and MS were removed from culture medium at 3, 6 and 9 h after treatment with both inhibitors. Oxidative stress was induced for periods of time by ATZ and MS exposures in primary hepatocytes. Treatment with ATZ and MS reduced catalase (CAT) and glutathione peroxidase (GPx) activities, and decreased CAT and GPx activities recovered to normal values upon withdrawal. Although oxidative stress of up to 6 h duration did not cause cell death, sustained oxidative stress (over 9 h) induced apoptosis. The increase in the glutathione disulfide/reduced glutathione ratio under oxidative stress up to 6 h was transient and reversible, while that due to sustained oxidative stress was irreversible. These results suggest that irreversible redox shifts resulting from sustained oxidative stress play a critical role in the induction of hepatocyte apoptosis in this experimental system.     

The acute phase protein haptoglobin and its relation to oxidative status in piglets undergoing weaning-induced stress

Abstract

Haptoglobin (Hp) prevents the hemoglobin driven generation of hydroxyl radicals and lipid peroxides. Hp can reduce the neutrophil respiratory burst and is an antioxidative molecule in its own right. We aimed to evaluate Hp concentrations, oxidative stress and antioxidative capacity in blood during weaning and to characterise potential relationships between these parameters. Two batches of 10 piglets each (2 trials) weaned at the age of 27–30 days were fed a starter feed mix ad libitum. Blood samples were taken 1 week before weaning and at weekly intervals thereafter. Oxidative stress was monitored via the D-ROM^® system, antioxidative capacity was measured with the TEAC assay and Hp concentrations were measured by ELISA. Neutrophil phagocytic activity and oxidative burst were examined via flow-cytometry. Body weights were recorded weekly. Hp concentrations were increased in both trials post-weaning (P < 0.01); oxidative stress and oxidative burst were elevated in trial I (P < 0.005). In trial I, Hp and ROM values returned to baseline levels at 6 weeks post-weaning. The piglets in trial II showed respiratory symptoms and maintained elevated Hp concentrations. ROM values and Hp were related (r = 0.58; P < 0.01). Hp and body weight gain were inversely related post-weaning.     

Neuroprotective effects of PrxI over‐expression in an in vitro human Alzheimer's disease model

Peroxiredoxins are ubiquitous proteins that recently attracted major interests in view of the strict correlation observed in several cell lines and/or tissues between different levels of their expression and the increased capacity of cells to survive in different pathophysiological conditions. They are recently considered as the most important enzymes regulating the concentration of hydroperoxides inside the cells. Most of neurodisorders such as Parkinson, Huntington, Alzheimer's diseases, and ischemic injury are characterized by conditions of oxidative stress inside cells. In these pathophysiological conditions, a strict correlation between cell survival and Prx expression has been found. In CNS all the Prx isoforms are present though with different expression pattern depending on cell phenotype. Interestingly, neurons treated with amyloid beta peptide (Aβ), showed an overexpression of PrxI. In this study, the neuroprotective effect of PrxI after Aβ exposure and the underlying mechanisms by which PrxI expression counteracts cell death was investigated in a well established human AD in vitro model. Taking advantage on cells transfected by a construct where human PrxI is fused with a Green fluorescent protein (GFP) at the C‐terminus, we report some events at the basis of cell survival after Aβ injury, suggesting possible new signal cascades dealing with the antiapoptotic effect of PrxI. The results obtained indicated a protective role for PrxI in counteracting Aβ injury by increasing cell viability, preserving neurites, and decreasing cell death. J. Cell. Biochem. 114: 708–715, 2013. © 2012 Wiley Periodicals, Inc.     

Triptolide attenuate the oxidative stress induced by LPS/D-GalN in mice

Triptolide, a diterpene triepoxide, is one of the major components of most functional extracts of Tripterygium wilfordii Hook f, which is known to have various biological effects, including immunosuppressive, anti-inflammatory and anti-tumor functions. We studied the inhibitory effect of triptolide on endotoxemia (ETM)-induced oxidative stress, which was induced in C57BL/6 mice by lipopolysaccharide (LPS) and D-galactosamine (D-GalN). Pretreatment with triptolide decreased the reactive oxygen species (ROS) levels, mortality rate and liver injury after LPS/D-GalN injection. We utilized comprehensive proteomics to identify alterations in liver protein expression during pretreatment with triptolide or N-acetylcysteine (NAC) after LPS/D-GalN injection, 44 proteins were found to be related to oxidative stress, mitochondria, metabolism and signal transduction, and 23 proteins of them seemed to be significantly up- or down-regulated. Furthermore, both triptolide and NAC inhibited activation of c-jun NH2-terminal kinases (JNK) and mitogen-activated protein kinase p38 (p38), phosphorylation of inhibitor of nuclear factor-kappa B (IκB) and activation of nuclear factor-κB (NF-κB). These results demonstrated that triptolide inhibited the activation of JNK and p38 by decreasing ROS levels, which in turn inhibited the hepatic injury. In addition, we set and validated the phosphorylation model of extracellular signal-regulated kinase (ERK) and proposed that triptolide probably induced ERK phosphorylation through inhibiting its dephosphorylation rates. These results showed that triptolide can effectively reduce the oxidative stress and partially rescue the damage in the liver induced by LPS/D-GalN.     

Cerebrotendinous xanthomatosis: case report with evidence of oxidative stress

Abstract

Cerebrotendinous xanthomatosis is an autosomal recessive disorder of bile acid synthesis, characterized by mutation in the mitochondrial enzyme 27-hydroxylase that leads to an accumulation of cholestanol and cholesterol. Characterized clinically by premature bilateral cataracts, slowly progressive neurological deterioration with dementia, cerebellar and brainstem signs, peripheral neuropathy, and seizures, the disease presents pathologically with lipid granulomata with foamy histiocytes and cholesterol clefts. Replacement therapy with chenodeoxycholic acid slows progression of the disease but does not reverse neurological deficits. Here, we present the case of a 49-year-old woman diagnosed at autopsy with cerebrotendinous xanthomatosis, on the basis of bilateral Achilles tendon granulomas, and typical foamy histiocytic infiltration of the brain, most severe in the dentate nucleus, and a typical clinical presentation. To investigate the pathological manifestations of this disease further, we performed immunohistochemistry for N^?-(carboxymethyl)-lysine, an indicator of oxidative damage, and found strong labeling of cytoplasmic material within histiocytes. In summary, this case of undiagnosed cerebrotendinous xanthomatosis during life emphasizes the need for a greater awareness of the disease, and early diagnosis and treatment. Further, the involvement of oxidative stress in cerebrotendinous xanthomatosis indicates that combined therapy with chenodeoxycholic acid and antioxidants may improve clinical outcome.     

Atherothrombosis and oxidative stress: the connection and correlation in diabetes

Abstract

Background: Hyperglycaemia-induced depletion of reduced glutathione (GSH) causes erythrocyte oxidative stress (EOS), which leads to vascular events including exacerbation of thrombotic events evidenced by changes in D-dimer level. It would, therefore, appear that there is a complex link between GSH and D-dimer, which are part of an emerging array of biomarkers associated with diabetes. The objective of this study was to investigate evidence of correlation between levels of plasma D-dimer and erythrocyte GSH in diabetes disease progression.

Subjects and methods: A cohort of 69 subjects were selected based on medical history plus clinical findings and equally divided into control, prediabetes and diabetes groups, matched for age and sex. Plasma D-dimer and erythrocyte reduced glutathione (GSH) were determined and separated into quartiles as a means of indicating disease severity. Statistical analysis was by Pearson's correlation coefficient.

Results: Of the three groups, only the diabetes group showed any correlation between GSH and D-dimer. Of importance is that for increasing GSH, the second quartile range of GSH (xbar ± SD = 45 ± 22 mg/100ml) showed a statistically significant negative correlation for ranked D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = ?0.88; P < 0.02). The fourth quartile GSH range (xbar ± SD = 79 ± 40 mg/100 ml) showed a statistically significant positive correlation with D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = 0.91; P < 0.02). Thus, within the diabetes group only, the increasing level of oxidative stress as measured by GSH first indicates a reduction in D-dimer followed by a rise in D-dimer, which led to the proposal of a two-part process of atherosclerosis that reconciles previous contradictory findings.

Conclusions: This study provides not only evidence of a correlation between oxidative stress level and fibrinolysis in diabetes, but also an explanation of why previous studies have found both hypo- or hyperfibrinolysis associated with diabetes.     

Effect of mesenchymal stem cells on inhibiting airway remodeling and airway inflammation in chronic asthma

Previous studies proved that bone marrow‐derived mesenchymal stem cells (BMSCs) could improve a variety of immune‐mediated disease by its immunomodulatory properties. In this study, we investigated the effect on airway remodeling and airway inflammation by administrating BMSCs in chronic asthmatic mice. Forty‐eight female BALB/c mice were randomly distributed into PBS group, BMSCs treatment group, BMSCs control group, and asthmatic group. The levels of cytokine and immunoglobulin in serum and bronchoalveolar lavage fluid were detected by enzyme‐linked immunosorbent assay. The number of CD4⁺CD25⁺regulatory T cells and morphometric analysis was determined by flow cytometry, hematoxylin‐eosin, immunofluorescence staining, periodic‐acid Schiff, and masson staining, respectively. We found that airway remodeling and airway inflammation were evident in asthmatic mice. Moreover, low level of IL‐12 and high levels of IL‐13, IL‐4, OVA‐specific IgG1, IgE, and IgG2a and the fewer number of CD4⁺CD25⁺regulatory T cells were present in asthmatic group. However, transplantation of BMSCs significantly decreased airway inflammation and airway remodeling and level of IL‐4, OVA‐specific IgE, and OVA‐specific IgG1, but elevated level of IL‐12 and the number of CD4 + CD25 + regulatory T cells in asthma (P < 0.05). However, BMSCs did not contribute to lung regeneration and had no significant effect on levels of IL‐10, IFN‐Y, and IL‐13. In our study, BMSCs engraftment prohibited airway inflammation and airway remodeling in chronic asthmatic group. The beneficial effect of BMSCs might involved the modulation imbalance cytokine toward a new balance Th1–Th2 profiles and up‐regulation of protective CD4 + CD25 + regulatory T cells in asthma, but not contribution to lung regeneration. J. Cell. Biochem. 114: 1595–1605, 2013. © 2013 Wiley Periodicals, Inc.     

Colonic healing after portal ischemia and reperfusion: an experimental study with oxidative stress biomarkers

Abstract

This experimental study aimed to evaluate colon healing after portal ischemia followed by reperfusion. Seventy male Wistar rats randomly distributed in four groups were used: Group 1, colonic anastomosis (n = 20); Group 2, portal ischemia-reperfusion (n = 20); Group 3, colonic anastomosis and portal ischemia-reperfusion (n = 20); and Group 4, control (n = 10). In the postoperative period, these rats were re-allocated into subgroups and lipid peroxidation and protein oxidation plasma levels were evaluated on days 1 and 5 by thiobarbituric acid reactive substances (TBARS) and slot-blotting assays, respectively. A segment of the right colon was also removed for collagen analysis. Both malondialdehyde (MDA) and protein carbonyl levels (oxidative markers of lipids and proteins) presented a significant increase after reperfusion in Group 3 on days 1 (P < 0.002) and 5 (P < 0.0001). In this same group, an extensive inflammatory process showing decreased fibroplasia was observed, with deficiency in collagen deposition on both sides of the anastomosis edges. Taken together, these results indicate that portal congestion followed by reperfusion induces an oxidative stress, which impaired the mechanism of colon anastomotic healing.     

A role for acute-phase serum amyloid A and high-density lipoprotein in oxidative stress,endothelial dysfunction and atherosclerosis

Abstract

The acute-phase protein serum amyloid A (SAA) is a clinically useful marker of inflammation and associates strongly with increased risk of cardiovascular events. Chronically elevated SAA concentrations may contribute to physiological processes that lead to atherosclerosis, including endothelial dysfunction, an early and predictive event in the development of cardiovascular disease. Accumulating data suggest that SAA can be a direct mediator in the development and progression of atherogenesis and atherothrombosis. SAA may affect key events underlying acute coronary syndromes, including cholesterol transport, contribute to endothelial dysfunction, promote thrombosis, and enhance leukocyte trafficking and activation. This review summarizes the evidence supporting a role for SAA as a potential regulator of inflammation and endothelial dysfunction, which underlie the adverse outcomes that complicate coronary artery disease. The findings suggest that novel therapeutic strategies to reduce SAA levels and/or oppose the actions of SAA may have beneficial effects in patients with coronary artery disease.     

Vitamin E inhibits hepatic oxidative stress,toxicity and hyperproliferation in rats treated with the renal carcinogen ferric nitrilotriacetate

Abstract

Ferric nitrilotriacetate (Fe-NTA) is a potent renal and hepatic tumor promoter, which acts through a mechanism involving oxidative stress. Fe-NTA when injected intraperitoneally into rats induces hepatic ornithine decarboxylase activity as well as hepatic DNA synthesis. Vitamin E is a well-known, lipid-soluble and chain-breaking antioxidant which protects cell membranes from peroxidative damage. In this study, we investigated the protective effect of vitamin E, a major fat-soluble antioxidant, against Fe-NTA-mediated hepatic oxidative stress, toxicity and hyperproliferation in Wistar rats. Animals were treated with two different doses of vitamin E for 1 week prior to Fe-NTA treatment. Vitamin E at a higher dose of 2.0 mg/animal/day showed significant reduction in Fe-NTA-induced hepatic ornithine decarboxylase activity, DNA synthesis, microsomal lipid peroxidation and hydrogen peroxide generation. Fe-NTA treatment alone caused depletion of glutathione, glutathione metabolizing and antioxidant enzymes in rat liver, whereas pretreatment of animals with vitamin E reversed these changes in a dose-dependent manner. Taken together, our results suggest that vitamin E may afford substantial protection against the damage caused by Fe-NTA exposure and can serve as a potent preventive agent to suppress oxidant-induced tissue injury.     

Regulatory roles of thioredoxin in oxidative stress-induced cellular responses

Abstract

Thioredoxin (TRX) is a small ubiquitous and multifunctional protein having a redox-active dithiol/disulfide within the conserved active site sequence –Cys–Gly–Pro–Cys–. TRX is induced by a variety of oxidative stimuli, including UV irradiation, inflammatory cytokines and chemical carcinogens, and has been shown to play crucial roles in the regulation of cellular responses such as gene expression, cell proliferation and apoptosis. Overexpression of TRX protects cells from cytotoxicity elicited by oxidative stress in both in vitro and in vivo models. The regulatory mechanism of TRX expression and activity is also being elucidated. Recently, TRX binding protein-2 (TBP-2)/vitamin D3 up-regulated protein 1 (VDUP1) was identified as a negative regulator of TRX. The analysis of TRX promoter region has revealed putative regulatory elements responsible for oxidative stress. Thus, the modulation of TRX functions may be a new therapeutic strategy for the treatment of oxidative stress-mediated diseases.     

Time course and attenuation of ischaemia-reperfusion induced oxidative injury by propofol in human renal transplantation

Abstract

Ischaemia-reperfusion injury resulting from interruption and restoration of blood flow might be related to free radical mediated oxidative stress and inflammation, and subsequently to post-surgery related complications. We studied the impact of renal transplantation on oxidative stress and inflammation by measuring F₂-isoprostanes and prostaglandin F_2α, respectively, during transplantation and post-surgery. Additionally, due to earlier observations, two dissimilar anaesthetic agents (thiopentone and propofol) were compared to determine their antioxidative capacity rather than their anaesthetic properties. Blood samples were collected before, post-intubation, immediately, 30, 60,120, 240 min, and 12 and 24 h after reperfusion. Oxidative stress and inflammatory response were detected by measuring 8-iso-PGF_2α (a major F₂-isoprostane and a biomarker of oxidative stress) and 15-keto-dihydro-PGF_2α (a major metabolite of PGF_2α and a biomarker of COX-mediated inflammatory response), respectively. Reperfusion of the transplanted graft significantly increased plasma levels of 8-iso-PGF_2α. PGF_2α metabolite levels, although elevated, did not reach statistical significance. In addition, significantly lower levels of 8-iso-PGF_2a were observed in the propofol group compared to the thiopentone group. Together, these findings underline an augmented oxidative stress activity following an inflammatory response after human renal transplantation. Furthermore, propofol a well-known anaesthetic, counteracted oxidative stress by lowering the formation of a major F₂-isoprostane.     

The ERalpha/ERbeta ratio determines oxidative stress in breast cancer cell lines in response to 17Beta-estradiol

The effects of 17beta‐estradiol (E2) are mediated through activation of estrogen receptors (ER): ERalpha and ERbeta. It is known that ERalpha/ERbeta ratio is higher in breast tumors than in normal tissue. Since antioxidant enzymes and uncoupling proteins (UCPs) are reactive oxygen species (ROS) production and mitochondrial biogenesis regulators, our aim was to study the E2‐effect on oxidative stress, antioxidant enzyme expression, and UCPs in breast cancer cell lines with different ERalpha/ERbeta ratios. The lower ERalpha/ERbeta ratio T47D cell line showed low ROS production and high UCP5 levels. However, the higher ERalpha/ERbeta ratio MCF‐7 cell line showed an up‐regulation of antioxidant enzymes and UCPs, yet exhibited high oxidative stress. As a result, a decrease in antioxidant enzyme activities and UCP2 protein levels, coupled with an increase in oxidative damage was found. On the whole, these results show different E2‐effects on oxidative stress regulation, modulating UCPs, and antioxidant enzymes, which were ERalpha/ERbeta ratio dependent in breast cancer cell lines. J. Cell. Biochem. 113: 3178–3185, 2012. © 2012 Wiley Periodicals, Inc.     

The various impacts of the hepatitis C virus core protein upon hepatic oxidative stress after common bile duct ligation and partial hepatectomy

Abstract

Introduction: Although it is uncertain how the hepatitis C virus (HCV) core protein influences hepatic oxidative stress after partial hepatectomy and common bile duct ligation (CBDL) this may be crucial for the prognosis of patients with HCV infection who have undergone hepatic resection, or who have complications due to a biliary tract obstruction.

Materials and methods: A group of double transgenic mice (DTM) that express both the tetracycline transactivator (tTA) and the HCV core, with conditional, acute expression of the HCV core in the context of the mature liver were subjected to 43% partial hepatectomy and CBDL. The levels of thioredoxin-1, thiobarbituric acid reactive substances (TBARS), and 4-hydroxynonenal (4-HNE) were evaluated in liver samples taken 3 days after the operations.

Results: The DTM had significantly higher TBARS levels than mice that were transgenic for only tTA (i.e. single transgenic mice; STM) and non-transgenic mice (NTM) after a sham laparotomy, CBDL and partial hepatectomy. Of the DTM, the TBARS levels were higher in female mice than in males after a sham laparotomy (P = 0.02) and CBDL (P = 0.0001). 4-HNE staining data were compatible with these results. Furthermore, male DTM exhibited higher levels of thioredoxin-1 than female DTM after sham laparotomy (P = 0.012) and CBDL (P = 0.008).

Conclusions: The HCV core increases hepatic oxidative stress in vivo and female DTM are more vulnerable to the oxidative stress caused by acute core expression with, or without, CBDL. The fact that the female DTM had lower thioredoxin-1 levels may account for this observation.