Stress,Aging, and Brain Oxidative Damage

Stress may contribute to aging acceleration and age-related degenerative diseases. Stress and adaptation to stress require numerous homeostatic adjustments including hormones, neurotransmitters, oxidants, and other mediators. The stress-induced hormones, neurotransmitters, and oxidants all have beneficial, but also harmful effects if out of balance. Therefore, the homeostasis of stress and adaptation should be governed by the hormone balance, neurotransmitter balance, and oxidant balance, as well as the interactions among these substances. The imbalance and the over-interaction of these balances may ultimately cause increased oxidant generation and oxidative damage to biomolecules. This increased oxidative damage may add to the oxidant burden associated with normal aerobic metabolism, which in itself, generates oxidants, causes accumulation of oxidative damage in mitochondria, and contributes to normal aging. Therefore, the stress-associated increase of oxidative damage may, in part, contribute to stress-associated aging acceleration and age-related neurodegenerative diseases.     

Protective Effects of Selenium on Cyclophosphamide-Induced Oxidative Stress and Kidney Injury

Cyclophosphamide (CP) is a common anticancer drug, but its use in cancer treatment is limited due to its severe toxicities induced mainly by oxidative stress in normal cells. Reactive oxygen species (ROS) lead to multiple organ injuries, including the kidneys. Selenium (Se) is a nutritionally essential trace element with antioxidant properties. In the present study, the possible protective effect of Se on CP-induced acute nephrotoxicity was investigated. Forty-two Sprague-Dawley rats were equally divided into six groups of seven rats in each. The control group received saline, and other groups were injected with CP (150 mg/kg), Se (0.5 or 1 mg/kg), or CP + Se intraperitoneally. Total antioxidant capacity (TAC), total oxidant state (TOS), oxidative stress index (OSI), creatinine, and cystatin C (Cys C) levels were measured in the sera. In addition, kidney tissues were examined histologically. In the CP alone treated rats, creatinine, Cys C, TOS, and OSI levels increased, while TAC level decreased. CP-induced histological damages were decreased by co-treatment of Se and biochemical results supported the microscopic observations. In conclusion, our study points to the therapeutic potential of Se and indicates a significant role of ROS in CP-induced kidney toxicity.     

Amelioration of Cd-Induced Oxidative Stress,MT Gene Expression,and Immune Damage by Vitamin C in Grass Carp Kidney Cells

Biological Trace Element Research - Cadmium (Cd) is the most common heavy metal and is easily detected in aquatic environments on a global scale. Vitamin C was a widely used vitamin in aquaculture....     

The Tacrolimus Metabolism Rate Influences Renal Function after Kidney Transplantation

The effective calcineurin inhibitor (CNI) tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, as a potent CNI it has nephrotoxic potential leading to impaired renal function in some cases. Therefore, it is of high clinical impact to identify factors which can predict who is endangered to develop CNI toxicity. We hypothesized that the Tac metabolism rate expressed as the blood concentration normalized by the dose (C/D ratio) is such a simple predictor. Therefore, we analyzed the impact of the C/D ratio on kidney function after RTx. Renal function was analyzed 1, 2, 3, 6, 12 and 24 months after RTx in 248 patients with an immunosuppressive regimen including basiliximab, tacrolimus, mycophenolate mofetil and prednisolone. According to keep the approach simple, patients were split into three C/D groups: fast, intermediate and slow metabolizers. Notably, compared with slow metabolizers fast metabolizers of Tac showed significantly lower estimated glomerular filtration rate (eGFR) values at all the time points analyzed. Moreover, fast metabolizers underwent more indication renal biopsies (p = 0.006) which revealed a higher incidence of CNI nephrotoxicity (p = 0.015) and BK nephropathy (p = 0.024) in this group. We herein identified the C/D ratio as an easy calculable risk factor for the development of CNI nephrotoxicity and BK nephropathy after RTx. We propose that the simple C/D ratio should be taken into account early in patient’s risk management strategies.     

Protective Effects of Selenium,Zinc, or Their Combination on Cadmium-Induced Oxidative Stress in Rat Kidney

The present study was conducted to investigate whether the combined treatment with Se and Zn offers more beneficial effects than that provided by either of them alone in reversing Cd-induced oxidative stress in the kidney of rat. For this purpose, 30 adult male Wistar albino rats, equally divided into control and four treated groups, received either 200 ppm Cd (as CdCl₂), 200 ppm Cd + 500 ppm Zn (as ZnCl₂), 200 ppm Cd + 0.1 ppm Se (as Na₂SeO₃), or 200 ppm Cd + 500 ppm Zn + 0.1 ppm Se in their drinking water for 35 days. The results showed that Cd treatment decreased significantly the catalase (CAT) and glutathione peroxidase (GSH-Px) activities, whereas the superoxide dismutase (SOD) activity and the renal levels of lipid peroxidation (as malondialdehyde, MDA) were increased compared to control rats. The treatment of Cd-exposed rats with Se alone had no significant effect on the Cd-induced increase in the MDA concentrations but increased significantly the CAT activities and reversed Cd-induced increase in SOD activity. It also partially prevented Cd-induced decrease in GSH-Px activity. The treatment of Cd-exposed animals with Zn alone increased significantly the CAT activity and partially protected against Cd-induced increase in the MDA concentrations, whereas it had no significant effect on the Cd-induced increase in SOD activity and decrease in GSH-Px activity. The combined treatment of Cd-exposed animals with Se and Zn was more effective than that with either of them alone in reversing Cd-induced decrease in CAT and GSH-Px activities and Cd-induced increase in MDA concentrations. Results demonstrated beneficial effects of combined Se and Zn treatment in Cd-induced oxidative stress in kidney and suggest that Se and Zn can have a synergistic role against Cd toxicity. I. Messaoudi and J. El Heni have equally contributed to this work.     

Effects of Shock Waves on Oxidative Stress, Antioxidant Enzyme and Element Levels in Kidney of Rats

The aim of this study was to investigate the effect of extracorporeal shock wave lithotripsy (ESWL) on kidney oxidative stress and trace element levels of adult rats. Twelve male Wistar albino rats were divided equally into two groups. First group was used as control. The right-side kidneys of animals in second group were treated with 2,000 18-kV shock waves under anesthesia. Localization of the right kidney was achieved following contrast medium injection through a tail vein under flouroscopy control. The animals were sacrificed 72?h after the ESWL treatment, and the kidneys were taken. Malondialdehyde level was higher in the ESWL group than in the control. Reduced glutathione levels, superoxide dismutase, and glutathione peroxidase activities were lower in the ESWL group than those of the control. Fe, Cu, Pb, Mn, Cd, and Ni levels were lower in the ESWL group than in the control, although Mg level was higher in the ESWL group than in the control. In conclusion, the result of the present study indicated that ESWL treatment produced oxidative stress in the kidney and caused impairments on the antioxidant and trace element levels in the kidneys of rats.     

Tissue Typing,Antilymphocyte Globulin,and Prophylactic Graft Irradiation in Cadaver Kidney Transplantation

In a series of 27 recipients of cadaver kidney grafts, 26 were at the time of writing alive, 3 to 25 months after transplantation, and 25 patients were alive with functioning first grafts. The one-year patient survival in 18 patients was 94% and the one-year graft survival was 89%. There was no beneficial correlation between tissue matching and the frequency of major early rejection episodes or graft function 12 or more months after transplantation. Antilymphocyte globulin administration was associated with a lower incidence of early rejection episodes, but this was not statistically significant. A combination of prophylactic graft irradiation and antilymphocyte globulin administration for at least the first two weeks was associated with a significantly reduced frequency of major early rejection episodes and appreciably better graft function at 12 months. This effect could not be ascribed to better tissue matching.     

Mitochondrial DNA Mutation-Elicited Oxidative Stress, Oxidative Damage, and Altered Gene Expression in Cultured Cells of Patients with MERRF Syndrome

Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. It has been documented that 80–90% of the patients with MERRF syndrome are caused by the A8344G mutation in the tRNA^Lys gene of mitochondrial DNA (mtDNA). We and other investigators have reported that the mtDNA mutation results in not only inefficient generation of adenosine triphosphate but also increased production of reactive oxygen species (ROS) in cultured cells harboring A8344G mutation of mtDNA. In addition, we found an imbalance in the gene expression of antioxidant enzymes in the skin fibroblasts of MERRF patients. The mRNA, protein, and enzyme activity levels of manganese-superoxide dismutase were increased, but those of Cu,Zn-SOD, catalase, and glutathione peroxidase did not show significant changes. Recently, we showed that the excess ROS could damage voltage-dependent anion channel, prohibitin, Lon protease, and aconitase in the MERRF cells. Moreover, there was a dramatic increase in the gene expression and activity of matrix metalloproteinase 1, which may contribute to the cytoskeleton remodeling involved in the weakness and atrophy of muscle commonly seen in MERRF patients. Taken together, we suggest that mtDNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression are involved in the pathogenesis and progression of MERRF syndrome.     

Lack of Association between Interleukin-10 Gene Polymorphisms and Graft Rejection Risk in Kidney Transplantation Recipients: A Meta-Analysis

Background

Interleukin-10 (IL-10) is an important immunomodulatory cytokine. Several studies focused the association between IL-10 promoter gene polymorphisms and graft rejection risk in kidney transplantation recipients. However, the results of these studies remain inconclusive. The aim of this study was to conduct a meta-analysis to further assess the associations.

Methods

The PubMed, Embase, and Ovid Medline databases were searched. Two independent authors extracted data, and the effects were estimated from an odds ratio (OR) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses identified sources of heterogeneity.

Results

A total of 16 studies including 595 rejection patients and 1239 stable graft patients were included in order to study the IL-10 -1082 (rs1800896 G/A), -819 (rs1800871 C/T), -592 (rs1800872 C/A) and IL-10 (-1082,-819,-592) polymorphisms. The -1082 G/A polymorphism was not associated with an increased graft rejection risk (OR = 1.03; 95%CI, 0.85–1.25, P = 0.74 for GA+AA vs. GG model). Moreover, all of the -819 C/T (OR = 1.06, 95%CI, 0.79–1.42, P = 0.70 for TA+TT vs. CC model), -592 C/A (OR = 1.10, 95% CI, 0.85–1.42, P = 0.47 for AC+AA vs. CC model) and IL-10 (-1082,-819,-592) polymorphisms (OR = 1.00, 95%CI, 0.79–1.27, P = 0.98 for I+L vs. H model) did not increase the graft rejection risk. In addition, we also performed subgroup analysis by ethnic group (mainly in Europeans or Asians) and rejection type (acute or chronic). There was also lack of evidence of a significant association between the IL-10 gene polymorphism and graft rejection risk. The present meta-analysis indicated that the IL-10 gene polymorphism was not associated with graft rejection risk in kidney transplantation recipients.

Conclusion

This meta-analysis found evidence that the IL-10 polymorphism does not increase the risk of graft rejection in kidney transplantation recipients. Further chronic rejection and other ethnic population studies are needed to confirm our results.     

The Role of Oxidative Stress in Nervous System Aging

While oxidative stress is implicated in aging, the impact of oxidative stress on aging in the peripheral nervous system is not well understood. To determine a potential mechanism for age-related deficits in the peripheral nervous system, we examined both functional and morphological changes and utilized microarray technology to compare normal aging in wild-type mice to effects in copper/zinc superoxide dismutase-deficient (Sod1^−/−) mice, a mouse model of increased oxidative stress. Sod1^−/− mice exhibit a peripheral neuropathy phenotype with normal sensory nerve function and deficits in motor nerve function. Our data indicate that a decrease in the synthesis of cholesterol, which is vital to myelin formation, correlates with the structural deficits in axons, myelin, and the cell body of motor neurons in the Sod1^+/+ mice at 30 months and the Sod1^−/− mice at 20 months compared with mice at 2 months. Collectively, we have demonstrated that the functional and morphological changes within the peripheral nervous system in our model of increased oxidative stress are manifested earlier and resemble the deficits observed during normal aging.     

Gene Expression and Pathway Analysis of Effects of the CMAH Deactivation on Mouse Lung,Kidney and Heart

BackgroundN-glycolylneuraminic acid (Neu5Gc) is generated by hydroxylation of CMP-Neu5Ac to CMP-Neu5Gc, catalyzed by CMP-Neu5Ac hydroxylase (CMAH). However, humans lack this common mammalian cell surface molecule, Neu5Gc, due to inactivation of the CMAH gene during evolution. CMAH is one of several human-specific genes whose function has been lost by disruption or deletion of the coding frame. It has been suggested that CMAH inactivation has resulted in biochemical or physiological characteristics that have resulted in human-specific diseases.Conclusions/SignificanceMice bearing a human-like deletion of the Cmah gene serve as an important model for the study of abnormal pathogenesis and/or metabolism caused by the evolutionary loss of Neu5Gc synthesis in humans.     

Oxidative Stress and Inflammation in Brain Aging: Nutritional Considerations

Aging can be defined as the condition where stressors are not counteracted by protective functions, leading to a dysregulation in development. These changes can be translated into decrements in neuronal functioning accompanied by behavioral declines, such as decreases in motor and cognitive performance, in both humans and animals. When coupled with genetic alterations, the ultimate expression of these changes is seen in diseases such as Alzheimer disease (AD). This association will be discussed in the last section of this chapter. In this review we will describe motor and cognitive deficits in behavior due to aging, and show how these deficits are related to increased vulnerability to oxidative stress, inflammation or signaling. Importantly, using muscarinic receptors as examples, we will also try to show that the sensitivity to these insults may be differentially expressed among neurotransmitter receptor subtypes.     

Toxic Effects of Maternal Zearalenone Exposure on Intestinal Oxidative Stress,Barrier Function,Immunological and Morphological Changes in Rats

The present study was conducted to investigate the effects of maternal zearalenone (ZEN) exposure on the intestine of pregnant Sprague-Dawley (SD) rats and its offspring. Ninety-six pregnant SD rats were randomly divided into four groups and were fed with diets containing ZEN at concentrations of 0.3 mg/kg, 48.5 mg/kg, 97.6 mg/kg or 146.0 mg/kg from gestation days (GD) 1 to 7. All rats were fed with mycotoxin-free diet until their offspring were weaned at three weeks of age. The small intestinal fragments from pregnant rats at GD8, weaned dams and pups were collected and studied for toxic effects of ZEN on antioxidant status, immune response, expression of junction proteins, and morphology. The results showed that ZEN induced oxidative stress, affected the villous structure and reduced the expression of junction proteins claudin-4, occludin and connexin43 (Cx43) in a dose-dependent manner in pregnant rats. Different effects on the expression of cytokines were also observed both in mRNA and protein levels in these pregnant groups. Ingestion of high levels of ZEN caused irreversible damage in weaned dams, such as oxidative stress, decreased villi hight and low expression of junction proteins and cytokines. Decreased expression of jejunal interleukin-8 (IL-8) and increased expression of gastrointestinal glutathione peroxidase (GPx2) mRNA were detected in weaned offspring, indicating long-term damage caused by maternal ZEN. We also found that the Nrf2 expression both in mRNA and protein levels were up-regulated in the ZEN-treated groups of pregnant dams and the high-dose of ZEN group of weaned dams. The data indicate that modulation of Nrf2-mediated pathway is one of mechanism via which ZEN affects gut wall antioxidant and inflammatory responses.     

Iron Increases Diabetes-Induced Kidney Injury and Oxidative Stress in Rats

Diabetic nephropathy is both a common and a severe complication of diabetes mellitus. Iron is an essential trace element. However, excess iron is toxic, playing a role in the pathogenesis of diabetic nephropathy. The present study aimed to determine the extent of the interaction between iron and type 2 diabetes in the kidney. Male rats were randomly assigned into four groups: control, iron (300-mg/kg iron dextran), diabetes (a single dose of intraperitoneal streptozotocin), and iron + diabetes group. Iron supplementation resulted in a higher liver iron content, and diabetic rats showed higher serum glucose compared with control rats, which confirmed the model as iron overload and diabetic. It was found that iron + diabetes group showed a greater degree of kidney pathological changes, a remarkable reduction in body weight, and a significant increase in relative kidney weight and iron accumulation in rat kidneys compared with iron or diabetes group. Moreover, malondialdehyde values in the kidney were higher in iron + diabetes group than in iron or diabetes group, sulfhydryl concentration and glutathione peroxidase activity were decreased by the diabetes and iron + diabetes groups, and protein oxidation and nitration levels were higher in the kidney of iron + diabetes group as compared to iron or diabetes group. However, iron supplementation did not elevate the glucose level of a diabetic further. These results suggested that iron increased the diabetic renal injury probably through increased oxidative/nitrative stress and reduced antioxidant capacity instead of promoting a rise in blood sugar levels; iron might be a potential cofactor of diabetic nephropathy, and strict control of iron would be important under diabetic state.     

Detraining Differentially Preserved Beneficial Effects of Exercise on Hypertension: Effects on Blood Pressure,Cardiac Function,Brain Inflammatory Cytokines and Oxidative Stress

Aims

This study sought to investigate the effects of physical detraining on blood pressure (BP) and cardiac morphology and function in hypertension, and on pro- and anti-inflammatory cytokines (PICs and AIC) and oxidative stress within the brain of hypertensive rats.

Methods and Results

Hypertension was induced in male Sprague-Dawley rats by delivering AngiotensinII for 42 days using implanted osmotic minipumps. Rats were randomized into sedentary, trained, and detrained groups. Trained rats underwent moderate-intensity exercise (ExT) for 42 days, whereas, detrained groups underwent 28 days of exercise followed by 14 days of detraining. BP and cardiac function were evaluated by radio-telemetry and echocardiography, respectively. At the end, the paraventricular nucleus (PVN) was analyzed by Real-time RT-PCR and Western blot. ExT in AngII-infused rats caused delayed progression of hypertension, reduced cardiac hypertrophy, and improved diastolic function. These results were associated with significantly reduced PICs, increased AIC (interleukin (IL)-10), and attenuated oxidative stress in the PVN. Detraining did not abolish the exercise-induced attenuation in MAP in hypertensive rats; however, detraining failed to completely preserve exercise-mediated improvement in cardiac hypertrophy and function. Additionally, detraining did not reverse exercise-induced improvement in PICs in the PVN of hypertensive rats; however, the improvements in IL-10 were abolished.

Conclusion

These results indicate that although 2 weeks of detraining is not long enough to completely abolish the beneficial effects of regular exercise, continuing cessation of exercise may lead to detrimental effects.