Signs Of Oxidative Damage Research Articles

A blend of microalgae and cyanobacteria produced from industrial waste outputs for the enrichments of Artemia salina: Effects on growth performance, antioxidant status and anomalies rate of European seabass (Dicentrarchus labrax) larvae

The recent fast development of the microalgae-related biotechnologies has enabled the availability of sustainable and nutrients-rich raw materials to be used as substitution of conventional sources in aquafeed formulation. However the cost of energy of the photobioreactors used to produce these microorganisms still constrained their wider inclusion into aquafeed compounds. By exploiting industrial waste outputs, Nannochloropsis sp. and Spirulina sp. were produced and utilised to formulate two experimental enrichments (LM1 and LM2). During a 60 days trial, their efficacy have been tested as Artemia metanauplii enrichments in the diet of European seabass (Dicentrarchus labrax) larvae, in comparison to a commercial control. Larvae were fed with isonitrogenous and isolipidic dietary treatments. Each dietary treatment presented a specific profile for the long chain polyunsaturated fatty acids ARA, DHA and EPA. Ratio of DHA/EPA in enriched Artemia of 4:1 as in the case of LM1 and LM2 in the presence of 1.4% of ARA (as a % on total fatty acid) guaranteed equal results to the control which displayed a ratio of DHA/EPA of 2:1 with 2.2% of ARA. No significant effects of the dietary treatments were detected in final survival, growth performance and incidence of skeletal anomalies. Regarding oxidative status, larvae fed with LM2 enrichment presented lower catalase activity than control larvae with no signs of oxidative damage, suggesting a potential antioxidant effect of LM2. The present study contributes to expanding the existing literature on successful utilisation of microalgae and cyanobacteria, used to produce valuable nutrients, in a perspective of circular nutrients economy.

Twelve-hour normothermic liver perfusion in a rat model: characterization of the changes in the ex-situ bio-molecular phenotype and metabolism

The partial understanding of the biological events that occur during normothermic machine perfusion (NMP) and particularly during prolonged perfusion might hinder its deployment in clinical transplantation. The aim of our study was to implement a rat model of prolonged NMP to characterize the bio-molecular phenotype and metabolism of the perfused organs. Livers (n = 5/group) were procured and underwent 4 h (NMP4h) or 12 h (NMP12h) NMP, respectively, using a perfusion fluid supplemented with an acellular oxygen carrier. Organs that were not exposed to any procedure served as controls (Native). All perfused organs met clinically derived viability criteria at the end of NMP. Factors related to stress-response and survival were increased after prolonged perfusion. No signs of oxidative damage were detected in both NMP groups. Evaluation of metabolite profiles showed preserved mitochondrial function, activation of Cori cycle, induction of lipolysis, acetogenesis and ketogenesis in livers exposed to 12 h-NMP. Increased concentrations of metabolites involved in glycogen synthesis, glucuronidation, bile acid conjugation, and antioxidant response were likewise observed. In conclusion, our NMP12h model was able to sustain liver viability and function, thereby deeply changing cell homeostasis to maintain a newly developed equilibrium. Our findings provide valuable information for the implementation of optimized protocols for prolonged NMP.

Effects of Streptozotocin Induced Diabetes on One-Carbon Cycle and Sperm Function.

Diabetic men suffer an increased risk of infertility associated with signs of oxidative damage and decreased methylation in sperm pointing to a deficit of the one-carbon cycle (1CC). We aimed to investigate this deficit using mice models (type 1 and 2) of streptozotocin-induced diabetes. In this experimental study, 50 male mice, aged eight weeks, were divided randomly into four groups: sham, control, type 1 diabetes mellitus (DM1), and DM2. The DM1 group was fed a normal diet (ND) for eight weeks, followed by five consecutive days of intraperitoneal administration of Streptozotocin (STZ, 50 mg/kg body weight). The DM2 group was fed a high-fat diet (HFD) for eight weeks, followed by a single intraperitoneal injection of STZ (100 mg/kg). After twelve weeks, all the mice were euthanized, and study parameters assessed. In the sham group, citrate buffer as an STZ solvent was injected. Both types of diabetic animals had serious impairment of spermatogenesis backed by increased DNA damage (P=0.000) and decreased chromatin methylation (percent: P=0.019; intensity: P=0.001) and maturation (P=0.000). The 1CC was deeply disturbed with increased homocysteine (P=0.000) and decreased availability of carbon units [methionine (P=0.000), serine (P=0.088), folate (P=0.016), B12 (P=0.025)] to feed methylations. We have observed a distinct impairment of 1CC within the testes of individuals with diabetes. We speculate that this impairment may be linked to inadequate intracellular glucose and diminished carbon unit supply associated with diabetes. As a result, interventions focusing on enhancing glucose uptake into sperm cells and providing supplementary methyl donors have the potential to improve fertility issues in diabetic patients. However, additional clinical testing is required to validate these hypotheses.

Relation of MDA as Oxidative Stress Marker with Lipid Profile in a Diabetic Patient

Type-2 diabetes mellitus (T2DM) is a disease accompanied by induced oxidative stress (OS) conditions. A reduction in antioxidant activity characterizes the OS conditions. Antioxidants protect cell components from the harmful effects of reactive oxygen species (ROS). The oxidation of the lipid components by ROS has the potential to generate malondialdehyde (MDA). The assessment of MDA (which is a byproduct of lipid peroxidation) may serve as a sign of oxidative damage. This can shed light on the impact of ROS on lipids. This study aims to elucidate the correlation between MDA oxidative stress biomarkers and lipids in individuals diagnosed with type-2 diabetes mellitus. The study comprises two case groups of 30 diabetic patients, 30 obese patients, and 30 healthy patients as the control group. The levels of MDA in the plasma specimens are measured. The serum glucose, serum lipid, and glycated haemoglobin (HbA1c) are evaluated for these groups. The results among patients with and without T2DM are analyzed with regard to age and BMI. The concentration of the MDA is [17.08 ± 1.989 (nmol/ml)] for diabetic patients, [16.08 ± 2.049 (nmol/ml)] for obese patients, and [12.12 ± 1.508 (nmol/ml)] for control patients. A statistically significant difference of p <0.0001 is observed in the elevated levels of MDA among T2DM patients. As compared to healthy control participants, there is no significant difference between T2DM and obese patients. It is concluded that the MDA can be utilized for observing the oxidative stress related to T2DM. The data indicate that utilising MDA could help predict the oxidative environment.

Perfluorooctanoic acid (PFOA) caused oxidative stress and metabolic disorders in lettuce (Lactuca sativa) root

Eliminating the critical knowledge gaps of perfluorooctanoic acid (PFOA) effects in planta is the imperative target to accomplish accurate and meaningful exposure-risk assessment in the environment. Here, we investigated the effect of environmentally relevant concentrations of PFOA on the oxidative stress and metabolic regulation in lettuce (Lactuca sativa) root. Under the exposure to 5 and 50 μg/L PFOA for 10 days, 137.5 and 1275.0 ng PFOA/g dry weight were accumulated to roots, respectively. H2O2, the dominant reactive oxygen species, was slightly over-generated by 4.7%–9.5%. No signs of oxidative damage, such as lipid peroxidation, cell membrane integrity and soluble protein content, were observed. To deal with PFOA stress, the activities of ascorbate peroxidase and peroxidase and the contents of glutathione were dose-dependently up-regulated. Partial least-squares discriminant analysis revealed metabolite profiles were significantly altered by PFOA, involving the primary metabolism (e.g., sucrose, glucose, fructose-6-phosphate, methionine, γ-aminobutyric acid), and the biosynthesis of (poly)phenol (e.g., shikimate, naringenin) and alkaloid (e.g., geranyl diphosphate, dopamine). Our findings showed that environmentally relevant concentrations of PFOA significantly perturbed metabolisms in plant roots albeit no remarkable cell damage was induced.

Effects of the essential metals copper and zinc in two freshwater detritivores species: Biochemical approach

The input of metals into freshwater ecosystems from natural and anthropogenic sources impairs water quality and can lead to biological alterations in organisms and plants, compromising the structure and the function of these ecosystems. Biochemical biomarkers may provide early detection of exposure to contaminants and indicate potential effects at higher levels of biological organisation. The effects of 48h exposures to copper and zinc on Atyaephyra desmarestii and Echinogammarus meridionalis were evaluated with a battery of biomarkers of oxidative stress and the determination of ingestion rates. The results showed different responses of biomarkers between species and each metal. Copper inhibited the enzymatic defence system of both species without signs of oxidative damage. Zinc induced the defence system in E. meriodionalis with no evidence of oxidative damage. However, in A. desmarestii exposed to zinc was observed oxidative damage. In addition, only zinc had significantly reduced the ingestion rate and just for E. meridionalis. The value of the integrated biomarkers response increased with concentration of both metals, which indicates that might be a valuable tool to interpretation of data as a whole, as different parameters have different weight according to type of exposure.

The effects of an overnight holding of whole blood at room temperature on haemoglobin modification and in vitro markers of red blood cell aging.

Some effects of the red blood cell (RBC) storage lesion are well documented whereas others are not. Whether a period of room temperature hold (RTH) during RBC production enhances the RBC storage lesion has remained controversial. In this study, we compared whole blood (WB)-derived RBCs produced after 24-h RTH with rapidly cooled (RC) RBCs and tested them for classical metabolic markers and signs of oxidative damage. SAGM-RBCs were prepared from mixed and split pairs (n=12) of WB units. RBCs prepared after a 24-h period of RTH on day+1 after collection (RTH-RBCs) were compared with RC-RBCs. All RBCs were stored at 4°C for 42days with assay of in vitro variables on days+1, +15, +22, +29 and +42. The study examined standard quality parameters, glutathione, catalase and superoxide dismutase (SOD) activities, and indicative markers of oxidative cell damage including post-translational haemoglobin modification, malondialdehyde (MDA), and phosphatidylserine expression. RTH-RBCs exhibited decreased levels of potassium (1·98±0·26 vs. 5·23±0·65mmol/l) and of 2,3-diphosphoglycerate (2,3-DPG) on day+1 compared with RC-RBCs. Haemolysis rate on day+42 was higher in RTH-RBCs than in RC-RBCs (0·52±0·13 vs. 0·37±0·12%). The phosphatidylserine expression amounted to 0·25±0·20% in RTH-RBCs and 0·07±0·12% in RC-RBCs. Haemoglobin modification was not different between both RBC groups. RTH-RBCs showed slightly higher MDA concentration on days +29 and +42. RC-RBCs and RTH-RBCs show only small differences of classical in vitro parameters and no relevant differences in antioxidative metabolism and oxidative haemoglobin modification. These findings do not explain the loss observed in in vivo survival studies with RBCs.

Investigation on the Origin of Sperm DNA Fragmentation: Role of Apoptosis, Immaturity and Oxidative Stress.

Sperm DNA fragmentation (sDF) represents a threat to male fertility, human reproduction and the health of the offspring. The causes of sDF are still unclear, even if apoptosis, oxidative assault and defects in chromatin maturation are hypothesized. Using multicolor flow cytometry and sperm sorting, we challenged the three hypothesized mechanisms by simultaneously evaluating sDF and signs of oxidative damage (8-hydroxy, 2'-deoxyguanosine [8-OHdG] and malondialdehyde [MDA]), apoptosis (caspase activity and cleaved poly[ADP-ribose] polymerase [cPARP]) and sperm immaturity (creatine phosphokinase [CK] and excess of residual histones). Active caspases and c-PARP were concomitant with sDF in a high percentage of spermatozoa (82.6% ± 9.1% and 53.5% ± 16.4%, respectively). Excess of residual histones was significantly higher in DNA-fragmented sperm versus sperm without DNA fragmentation (74.8% ± 17.5% and 37.3% ± 16.6%, respectively, p < 0.005), and largely concomitant with active caspases. Conversely, oxidative damage was scarcely concomitant with sDF in the total sperm population, at variance with live sperm, where 8-OHdG and MDA were clearly associated to sDF. In addition, most live cells with active caspase also showed 8-OHdG, suggesting activation of apoptotic pathways in oxidative-injured live cells. This is the first investigation on the origin of sDF directly evaluating the simultaneous presence of the signs of the hypothesized mechanisms with DNA breaks at the single cell level. The results indicate that the main pathway leading to sperm DNA breaks is a process of apoptosis, likely triggered by an impairment of chromatin maturation in the testis and by oxidative stress during the transit in the male genital tract. These findings are highly relevant for clinical studies on the effects of drugs on sDF and oxidative stress in infertile men and for the development of new therapeutic strategies.

A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits

Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498–499InsTC mutation which causes the substitution of the last 9 amino acids and an elongation of extra 16 amino acids at the C-terminus of L-ferritin peptide. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. In order to analyze the impact of the mutation in vivo, we generated mouse models for the some pathogenic human FTL gene in FVB and C57BL/6J strains.Transgenic mice in the FVB background showed high accumulation of the mutated ferritin in brain where it correlated with increased iron deposition with age, as scored by magnetic resonance imaging. Notably, the accumulation of iron–ferritin bodies was accompanied by signs of oxidative damage. In the C57BL/6 background, both the expression of the mutant ferritin and the iron levels were lower than in the FVB strain. Nevertheless, also these mice showed oxidative alterations in the brain. Furthermore, post-natal hippocampal neurons obtained from these mice experienced a marked increased cell death in response to chronic iron overload and/or acute oxidative stress, in comparison to wild-type neurons. Ultrastructural analyses revealed an accumulation of lipofuscin granules associated with iron deposits, particularly enriched in the cerebellum and striatum of our transgenic mice. Finally, experimental subjects were tested throughout development and aging at 2-, 8- and 18-months for behavioral phenotype. Rotarod test revealed a progressive impaired motor coordination building up with age, FTL mutant old mice showing a shorter latency to fall from the apparatus, according to higher accumulation of iron aggregates in the striatum. Our data show that our 498–499InsTC mouse models recapitulate early pathological and clinical traits of the human neuroferritinopathy, thus providing a valuable model for the study of the disease. Finally, we propose a mechanistic model of lipofuscine formation that can account for the etiopathogenesis of human neuroferritinopathy.

Short- and long-term physiological responses of grapevine leaves to UV-B radiation

The present study aimed at evaluating the short- and long-term effects of UV-B radiation on leaves of grapevine Vitis vinifera (cv. Tempranillo). Grapevine fruit-bearing cuttings were exposed to two doses of supplemental biologically effective UV-B radiation (UV-BBE) under glasshouse-controlled conditions: 5.98 and 9.66kJm−2d−1. The treatments were applied either for 20d (from mid-veraison to ripeness) or 75d (from fruit set to ripeness). A 0kJm−2d−1 UV-B treatment was included as control. The main effects of UV-B were observed after the short-term exposure (20d) to 9.66kJm−2d−1. Significant decreases in net photosynthesis, stomatal conductance, sub-stomatal CO2 concentration, the actual photosystem II (PSII) efficiency, total soluble proteins and de-epoxidation state of the VAZ cycle were observed, whereas the activities of several antioxidant enzymes increased significantly. UV-B did not markedly affect dark respiration, photorespiration, the maximum potential PSII efficiency (Fv/Fm), non-photochemical quenching (NPQ), as well as the intrinsic PSII efficiency. However, after 75d of exposure to 5.98and 9.66kJm−2d−1 UV-B most photosynthetic and biochemical variables were unaffected and there were no sign of oxidative damage in leaves. The results suggest a high long-term acclimation capacity of grapevine to high UV-B levels, associated with a high accumulation of UV-B absorbing compounds in leaves, whereas plants seemed to be tolerant to moderate doses of UV-B.

Antioxidative defense and oxidative stress in ringed seals (Pusa hispida) from differently polluted areas

High contaminant levels detected in Baltic seals have been associated with various health effects. In this study several parameters related to antioxidative defense and oxidative stress (concentrations of reduced and oxidised glutathione, lipid hydroperoxide and vitamin E, activities of glutathione reductase, peroxidase and S-transferase, glucose-6-phosphate dehydrogenase, catalase, and superoxidedismutase) were measured in the livers of ringed seals from the Baltic Sea and from a less contaminated reference area, Svalbard, Norway. Seals were caught during two different time periods 1996–1997 and 2002–2007, which represent different levels of contamination. No signs of oxidative damage were found in the Baltic seals. However, glutathione metabolism was enhanced in the ringed seals from the Baltic Sea compared to the seals from Svalbard. The adaptation to dive where repetitive ischemia/reperfusion occurs naturally may contribute to the resistance of oxidative stress and to the capacity to increase enzymatic antioxidant defense in phocid seals. This could explain the similarities in oxidative stress levels despite the differences in antioxidant responses between the ringed seals from the Baltic Sea and Svalbard.

Reagents that block neuronal death from Huntington’s disease also curb oxidative stress

Patients with Huntington's disease suffer severe neuronal loss and signs of oxidative damage in the brain. Previously we found that primary neurons from embryonic cortex of mice bearing the Huntington's disease mutation (140 glutamines inserted into exon 1 of huntingtin) showed higher levels of reactive oxygen species before cell death. Here, we treated mutant neurons with known neuroprotective agents and determined the effects on neuronal survival and levels of reactive oxygen species. Primary neurons were exposed to the neurotrophin, brain derived neurotrophic factor, the antioxidant N-acetyl-cysteine or a specific inhibitor of glycogen synthase kinase 3-β, SB216763. Each reagent increased the survival of the mutant neurons compared with untreated mutant neurons and also reduced the levels of reactive oxygen species to levels of wild-type neurons. These results suggest that reducing the levels of reactive oxygen species may be necessary to protect neurons with the Huntington's disease mutation from cell death.

Identification of damaged proteins in human serum using modified Ehrlich’s reagent to target protein-bound pyrroles

Protein-bound pyrroles are a sign of oxidative damage. Here we report a specific method for detecting pyrrole-containing proteins using biotin-labeled Ehrlich’s reagent (ER-B). After treatment of either human serum or isolated human serum proteins with various oxidizing agents, damaged, biotin-labeled components could be detected by blotting. Combining the use of ER-B with proteomic techniques allowed human serum proteins susceptible to oxidative damage to be detected and then identified by LC/MS/MS. Identification of such proteins in different human conditions such as obesity, diabetes, and cardiovascular disease should lead to the discovery of new biomarkers and the development of specific assays to monitor health status.

Differential response of antioxidant systems in leaves and roots of barley subjected to anoxia and post-anoxia

Mitochondria and chloroplasts are the primary sources of reactive oxygen species in photosynthetic tissues. Mitochondria play a dual role in oxidative stress, being both ROS producers and integrators of the cell antioxidant defense systems. Anoxia followed by re-exposure to air may create conditions of elevated ROS generation in plants. The reactions of barley leaves and root antioxidant systems after anoxia were investigated. Alternative oxidase and low-mass antioxidants showed different patterns of change in leaves and roots in response to changing oxygen availability. Mitochondria from leaves showed a reduced AOX capacity and AOX protein level during post-anoxia, while the AOX capacity in root mitochondria increased. In leaf tissue, ascorbate and glutathione were immediately oxidized after restoration of aerobiosis due to the enhanced ROS production, whereas in roots ascorbate and glutathione became even more reduced. The capacity of antioxidant systems was not exceeded in either leaf or root tissue after anoxia; no signs of oxidative damage were observed and the respiratory activity of mitochondria was retained. We suggest that the leaf and root cell antioxidant systems react differentially to changes in oxygen concentration. In leaves, low-mass antioxidants play the major role in ROS detoxification, while in roots, increased AOX capacity supports the antioxidant systems, possibly by preventing ROS formation.

Protein carbonyl levels in serum and gingival crevicular fluid in patients with chronic periodontitis

Objective Evidence reveals the role of reactive oxygen species (ROS) in many pathologies including periodontitis. Protein carbonylation is the most widely used biomarker for oxidative damage to proteins, and reflects cellular damage induced by ROS. In this study protein carbonyl (PC) levels in serum and gingival crevicular fluid (GCF) in patients with chronic periodontitis (CP) was evaluated. Materials and methods Thirty-three patients with CP and 24 healthy controls were included in the study. Following the clinical measurements and samplings, total protein levels in serum and GCF were determined by Bradford method, and serum and GCF PC levels were measured by modified Levine method. Results PC levels in serum and GCF were significantly higher in the CP group compared to the control group ( p < 0.05). In all subjects, serum and GCF PC levels showed statistically significant positive correlations with all clinical parameters ( p < 0.05). Conclusions The results suggest that both systemic and local/periodontal protein carbonylation increase in CP compared to health and that elevated levels of PCs may be a sign of oxidative damage in periodontitis and correlate well with the periodontal status.

Oxidative stress and antioxidant defence in a healthy nonagenarian population

Results on oxidative markers during ageing are not consistent throughout the scientific literature; however, successful ageing may depend on better ability to cope with oxidative stress. A previous study of ours showed that successful ageing could actually be related to enhanced response to oxidatively modified proteins. In this study, a healthy nonagenarian population (OVER-90) was examined for various blood oxidative biomarkers and compared with a healthy population of blood donors (age range, 23–66 years). Blood glutathione, both total (tGSH) and oxidised (GSSG), and total plasmatic antioxidant status were maintained in the OVER-90 at a level similar to the control population. Sulphydryl (sulfhydryl) groups and glutathione peroxidase (GPx) were instead decreased. The results are discussed in a possible unifying view: the OVER-90 population could possess a globally preserved antioxidant ability, though some signs of oxidative damage are present and some structures could be 'sacrificed' in order to keep the redox equilibrium.

Effects of North Sea oil and alkylphenols on biomarker responses in juvenile Atlantic cod ( Gadus morhua)

A consequence of oil drilling at sea is the release of produced water contaminated with e.g. polycyclic aromatic hydrocarbons (PAH) and alkylphenols. In the present study, juvenile Atlantic cod were exposed to North Sea oil, nonylphenol and a combination of the North Sea oil and an alkylphenol mixture in a flow-through system. A suite of hepatic biomarkers were analysed. Exposure to North Sea oil resulted in strong induction of CYP1A protein levels and EROD activities. Exposure to nonylphenol, on the other hand, resulted in decreased CYP1A levels and EROD activities. Thus, nonylphenol appears to down-regulate CYP1A expression in Atlantic cod. Combined exposure to North Sea oil with an alkylphenol mixture resulted in lower EROD induction, compared to that in fish exposed to North Sea oil alone. This difference was not statistically significant, but still we believe that the alkylphenols have inhibited CYP1A activities in the fish which may have compromised CYP1A mediated metabolism of other xenobiotics, including PAH. CYP3A protein levels were lower, compared to controls, in fish exposed to nonylphenol and the combination of North Sea oil and alkylphenol mixture. In contrast, the oil alone had no effect on CYP3A protein content. North Sea oil exposure, alone or in combination with alkylphenols, caused oxidative stress observed as elevated levels of GSSG content and GR and CAT activities. Interestingly, exposure to nonylphenol resulted in a marked depletion of total glutathione levels. This apparent depletion may be a consequence of increased conjugation of glutathione to nonylphenol followed by excretion. An increase in conjugation enzyme GST activity was observed in the nonylphenol exposed group, although the difference was not significant. No sign of oxidative damage, measured as lipid peroxidation, was observed in any of the exposures experiments. This study suggests that North Sea oil may lead to oxidative stress and altered CYP1A and CYP3A expression. Alkylphenols, present in produced water, resulted in decreased CYP1A and CYP3A protein expression in Atlantic cod.

Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency

We have created a mouse model with an isolated cytochrome c oxidase (COX) deficiency by disrupting the COX10 gene in skeletal muscle. Missense mutations in COX10 have been previously associated with mitochondrial disorders. Cox10p is a protoheme:heme-O-farnesyl transferase required for the synthesis of heme a, the prosthetic group of the catalytic center of COX. COX10 conditional knockout mice were generated by crossing a LoxP-tagged COX10 mouse with a transgenic mouse expressing cre recombinase under the myosin light chain 1f promoter. The COX10 knockout mice were healthy until approximately 3 months of age when they started developing a slowly progressive myopathy. Surprisingly, even though COX activity in COX10 KO muscles was <5% of control muscle at 2.5 months, these muscles were still able to contract at 80-100% of control maximal forces and showed only a 10% increase in fatigability, and no signs of oxidative damage or apoptosis were detected. However, the myopathy worsened with time, particularly in female animals. This COX10 KO mouse allowed us to correlate the muscle function with residual COX activity, an estimate that can help predict the progression pattern of human mitochondrial myopathies.

Modulation of Oxidative Stress by Alcohol

It is well established that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are involved in causing acute and chronic alcohol toxicity. Biochemical signs of oxidative damage can be detected in experimental animals exposed to ethanol as well as in alcoholic patients. Ethanol-induced oxidative stress is the consequence of the combined effect of an increased production of ROS by the mitochondria and the alcohol-inducible cytochrome P-4502E1 (CYP2E1) and the impairment of antioxidant defenses. Furthermore, by promoting the activation of Kuppfer cells, ethanol causes the release of cytokines, ROS, and RNS. The mechanisms by which oxidative damage contribute to alcohol toxicity include direct hepatocellular damage, induction of apoptosis, and the stimulation of collagen deposition by hepatic stellate cells. In addition, lipid peroxidation products and, particularly acetaldehyde-malondialdehyde adducts, along with immune reactions triggered by oxidative stress, might also contribute to perpetuate hepatic inflammation. The implication of oxidative stress in alcohol liver damage gives a rationale to the clinical application of therapies aimed to prevent or reduce ethanol-induced oxidative damage by antioxidant compounds.

Mitochondrial damage in aging and apoptosis.

Mitochondria are essential to cellular aging, and free radical production by mitochondria is increased with aging. The rate of oxidant production by mitochondria correlates inversely with maximal life span of species. In many species, females live longer than males. We report that mitochondrial oxidant production by females is significantly lower than that of males. However, mitochondria from ovariectomized females have a similar oxidant production as those of males. Thus, gender difference in life span can be explained, at least in part, by different oxidant generation by mitochondria. Administration of antioxidants, such as vitamins C and E, or a Ginkgo biloba extract, protects against age-associated oxidative damage to mitochondrial DNA, oxidation of glutathione, and other signs of oxidative damage to mitochondria.