Free Radical-mediated Oxidative Damage Research Articles

Near-infrared-IIb emitting single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown after traumatic brain injury

The blood-brain barrier breakdown, as a prominent feature after traumatic brain injury, always triggers a cascade of biochemical events like inflammatory response and free radical-mediated oxidative damage, leading to neurological dysfunction. The dynamic monitoring the status of blood-brain barrier will provide potent guidance for adopting appropriate clinical intervention. Here, we engineer a near-infrared-IIb Ag2Te quantum dot-based Mn single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown of mice after traumatic brain injury. The dynamic change of blood-brain barrier, including the transient cerebral hypoperfusion and cerebrovascular damage, could be resolved with high spatiotemporal resolution (150 ms and ~ 9.6 µm). Notably, the isolated single Mn atoms on the surface of Ag2Te exhibited excellent catalytic activity for scavenging reactive oxygen species to alleviate neuroinflammation in brains. The timely injection of Mn single-atom catalyst guided by imaging significantly promoted the reconstruction of blood-brain barrier and recovery of neurological function after traumatic brain injury.

Protective effect of quercetin in combination with caloric restriction against oxidative stress-induced cell death of Saccharomyces cerevisiae cells.

Impairment of antioxidant enzymes activities has been well reported in several human diseases. Effective anti-ageing strategies involving antioxidant supplementation and/or caloric restriction (CR) are receiving a great attention to mitigate free radical-mediated oxidative damage in several disease conditions to improve active longevity. Therefore, in this work, we have evaluated the protective effect of quercetin under non restriction (NR) and CR conditions on the sensitivity of Saccharomyces cerevisiae mutant strains (sod1∆, sod2∆, cta1∆, ctt1∆, tsa1∆ and glr1∆) deficient in antioxidant defence systems (superoxide dismutase, catalase, thioredoxin peroxidase and glutathione reductase) against H2 O2 -induced oxidative stress. Our results demonstrate that quercetin in combination with CR has strongly reduced the H2 O2 -mediated stress in the yeast mutant cells compared to NR conditions. Furthermore, we show that quercetin in combination with CR enhanced the percentage viability of yeast cells during chronological ageing. Our research findings suggest that antioxidant supplementation in combination with CR might have potent beneficial effects than individual therapies against free radical-mediated oxidative stress. SIGNIFICANCE AND IMPACT OF THE STUDY: Oxidative stress results from an imbalance between free radicals and antioxidant defense systems in our body. Supplementation with exogenous antioxidants is necessary to neutralize the free radical mediated damage. Polyphenols are a group of naturally occurring plant compounds with strong free radical-scavenging activity and exhibits potent anti-aging property by mitigating oxidative stress. On the other hand, caloric restriction (CR) has been reported to be a popular leading anti-aging approach to ameliorate age-associate macromolecular damages in various chronic human diseases. Evaluation of protective effects of antioxidant supplementation in combination with CR against free radical mediated oxidative stress is pivotal for the development of novel anti-aging strategies to improve active longevity.

Prevalence and distribution of G6PD deficiency: implication for the use of primaquine in malaria treatment in Ethiopia

BackgroundG6PD enzyme deficiency is a common enzymatic X-linked disorder. Deficiency of the G6PD enzyme can cause free radical-mediated oxidative damage to red blood cells, leading to premature haemolysis. Treatment of Plasmodium vivax malaria with primaquine poses a potential risk of mild to severe acute haemolytic anaemia in G6PD deficient people. In this study, the prevalence and distribution of G6PD mutations were investigated across broad areas of Ethiopia, and tested the association between G6PD genotype and phenotype with the goal to provide additional information relevant to the use of primaquine in malaria treatment.MethodsThis study examined G6PD mutations in exons 3–11 for 344 febrile patient samples collected from seven sites across Ethiopia. In addition, the G6PD enzyme level of 400 febrile patient samples from Southwestern Ethiopia was determined by the CareStart™ biosensor. The association between G6PD phenotype and genotype was examined by Fisher exact test on a subset of 184 samples.ResultsMutations were observed at three positions of the G6PD gene. The most common G6PD mutation across all sites was A376G, which was detected in 21 of 344 (6.1%) febrile patients. Thirteen of them were homozygous and eight were heterozygous for this mutation. The G267+119C/T mutation was found in 4 (1.2%) individuals in South Ethiopia, but absent in other sites. The G1116A mutation was also found in 4 (1.2%) individuals from East and South Ethiopia. For the 400 samples in the south, 17 (4.25%) were shown to be G6PD-deficient. G6PD enzyme level was not significantly different by age or gender. Among a subset of 202 febrile patients who were diagnosed with malaria, 11 (5.45%) were G6PD-deficient. These 11 infected samples were diagnosed with Plasmodium vivax by microscopy. Parasitaemia was not significantly different between the G6PD-deficient and G6PD-normal infections.ConclusionsThe prevalence of G6PD deficiency is modest among febrile patients in Ethiopia. G6PD deficiency testing is thus recommended before administrating primaquine for radical cure of P. vivax infected patients. The present study did not indicate a significant association between G6PD gene mutations and enzyme levels.

Disrupted iron metabolism in peritoneal fluid may induce oxidative stress in the peritoneal cavity of women with endometriosis.

Data on the possible role of peritoneal fluid free radical-mediated oxidative damage in the pathogenesis of endometriosis still remains inconsistent. The aim of the study was to determine iron metabolism markers and their influence on oxidative stress arameters in the peritoneal fluid of women with endometriosis. 110 women with endometriosis and 119 patients with benign ovarian cysts were included in the study. All visible peritoneal fluid was aspirated during laparoscopy from the anterior and posterior cul-de-sacs. under direct vision to avoid blood contamination. Haemoglobin, iron, total oxidative status, and total antioxidant status were measured using standard colourimetric kits. Haemoglobin, iron levels, as well as total oxidative status values were significantly higher, whereas total antioxidant status values were significantly lower in the peritoneal fluid of patients with endometriosis, in comparison to the reference groups. No differences were observed in peritoneal fluid concentrations of all parameters measured in relation to the phase of the menstrual cycle. Peritoneal fluid of women with endometriosis is characterized by disrupted iron metabolism. This is most likely related to an increased number of erythrocytes in the peritoneal cavity of endometriotic women, which leads to a higher concentration of haemoglobin in this environment. Impaired iron homeostasis may have a significant influence on the pathophysiology of peritoneal endometriosis by the direct impact of haemoglobin derivatives and/or formation of the pro-inflammatory and pro-oxidative environment. Peritoneal cavity oxidative stress occurs predominantly in women in advanced stages of the disease.

Early involvement of lysosome dysfunction in the degeneration of cerebral cortical neurons caused by the lipid peroxidation product 4-hydroxynonenal.

Free radical-mediated oxidative damage to proteins, lipids, and DNA occurs in neurons during acute brain injuries and in neurodegenerative disorders. Membrane lipid peroxidation contributes to neuronal dysfunction and death, in part by disrupting neuronal ion homeostasis and cellular bioenergetics. Emerging findings suggest that 4-hydroxynonenal (HNE), an aldehyde produced during lipid peroxidation, impairs the function of various proteins involved in neuronal homeostasis. Here we tested the hypothesis that HNE impairs the cellular system that removes damaged proteins and organelles, the autophagy-lysosome pathway in rat primary cortical neurons. We found that HNE, at a concentration that causes apoptosis over a 48-72h period, increases protein levels of LC3 II and p62 and within 1 and 4h of exposure, respectively; LC3 II and p62 immunoreactive puncta were observed in the cytoplasm of HNE-treated neurons at 6h. The extent of up-regulation of p62 and LC3 II in response to HNE was not affected by co-treatment with the lysosome inhibitor bafilomycin A1, suggesting that the effects of HNE on autophagy were secondary to lysosome inhibition. Indeed, we found that neurons exposed to HNE exhibit elevated pH levels, and decreased protein substrate hydrolysis and cathepsin B activity. Neurons exposed to HNE also exhibited the accumulation of K63-linked polyubiquitinated proteins, which are substrates targeted for lysosomal degradation. Moreover, we found that the levels of LAMP2a and constitutively active heat-shock protein 70, and numbers of LAMP2a-positive lysosomes, are decreased in neurons exposed to HNE. Our findings demonstrate that the lipid peroxidation product HNE causes early impairment of lysosomes which may contribute to the accumulation of damaged and dysfunctional proteins and organelles and consequent neuronal death. Because impaired lysosome function is increasingly recognized as an early event in the neuronal death that occurs in neurodegenerative disorders, our findings suggest a role for HNE in such lysosomal dysfunction.

Protein vicinal thiol oxidations in the healthy brain: not so radical links between physiological oxidative stress and neural cell activities.

Reversible oxidations of protein thiols have emerged as alternatives to free radical-mediated oxidative damage with which to consider the impacts of oxidative stress on cellular activities but the scope and pathways of such oxidations in tissues, including the brain, have yet to be fully defined. We report here a characterization of reversible oxidations of glutathione and protein thiols in extracts from rat brains, from two sources, which had been (1) frozen quickly after euthanasia to preserve in vivo redox states and (2) subjected to alkylation upon tissue disruption to trap reduced thiols. Brains were defined, relatively, as Reduced and Moderately Oxidized based on measured ratios of reduced (GSH) to oxidized (GSSG) glutathione. Levels of protein disulfides formed by the cross-linking of closely-spaced (vicinal) protein thiols, but not protein S-glutathionylation, were higher in extracts from the Moderately Oxidized brains compared to the Reduced brains. Moreover, the oxidized vicinal thiol proteome contains proteins that impact cellular energetics, signaling, neurotransmission, and cytoskeletal dynamics among others. These findings argue that kinetically-competent pathways for reversible, two-electron oxidations, of protein vicinal thiols can be activated in healthy brains in response to physiological oxidative stresses. We propose that such oxidations may link oxidative stress to adaptive, but also potentially deleterious, changes in neural cell activities in otherwise healthy brains.

The influence of storage age on iron status, oxidative stress and antioxidant protection in paediatric packed cell units.

Receipt of blood transfusions is associated with the major consequences of prematurity such as bronchopulmonary dysplasia. Transfusion-mediated (iron-induced) oxidative damage, coupled with the limited ability of the premature baby to deal with enhanced iron and oxidative load may contribute to this. Adverse effects of transfusion may be related to duration of storage. This study examined the influence of storage on iron and oxidative status in paediatric packed red blood cell units. Paediatric packed red blood cell units were sampled 3 days post-donation, then at 7 days and weekly until day 35. The extracellular medium was separated and the following measured: total iron concentration, total iron binding capacity, non-transferrin-bound iron, haemoglobin, total and reduced ascorbate, glutathione and malondialdehyde. Measurable total and non-transferrin bound iron were present in the extracellular fluid of paediatric packs on day 3. Both parameters rose almost linearly to maximal values at 35 days. Haemoglobin and malondialdehyde levels rose gradually from day 3 to day 21, then more steeply to day 35. Ascorbate existed mainly in the oxidised form and fell rapidly towards the end of storage. Intracellular GSH fell throughout the period of storage. Strong correlations existed between biomarkers of oxidative damage and iron parameters. These data suggest that iron released following the initial preparation of packed red blood cell units may derive from free radical-mediated oxidative damage to the red blood cells and haemoglobin, rather than from extracellular haemoglobin. Iron continues to be released during storage as antioxidant protection declines. A cycle of free radical-mediated damage may initiate and then further exacerbate iron release during storage which, in turn, may mediate further free radical-mediated cellular damage. The potential consequences to recipients of older stored blood may be significant.

Carnosic acid protects biomolecules from free radical-mediated oxidative damage in vitro

The protective effects of carnosic acid (CA), a naturally occurring catechol-type poly-phenolic diterpene, against free radical-induced oxidative damage to lipids, proteins, and DNA were evaluated in this study. The oxidation of human serum albumin and rat liver homogenate were induced by Cu2+/H2O2. Fe2+/VitC and 2,2′-azobis(2,4-dimethylvaleronitrile) were used to initiate linoleic acid (LA) peroxidation. Oxidative damage of DNA was carried out using 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH). The results showed that CA significantly inhibited the oxidative damages to proteins, LA and DNA caused by various types of free radicals. Moreover, in the Fe2+/VitC induced-LA peroxidation reaction system, the addition of CA also inhibited the cytotoxic effects of oxidized linoleic acid on RAW 264.7 cells. These results suggest that it might be possible to use CA to prevent or treat the oxidative stress-related disorders and diseases.

Protective effects of Chrysanthemi Flos extract against streptozotocin-induced oxidative damage in diabetic mice

The present study was aimed to evaluate the protective role of Chrysanthemi Flos extract (CFE) against free radical-mediated oxidative damage in liver and kidney of streptozotocin (STZ) - induced diabetic mice. Chrysanthemi Flos was extracted with methanol. Male ICR mice (n = 24) were divided into four groups. Diabetes was induced by STZ injection (ip) at a dose of 100 mg/kg. Animals of treated groups were given CFE and gliclazide (1000 and 50 mg kg −1 body weight) for 30 days. The results revealed that oral administration of CFE and gliclazide inhibited the increase in lipid peroxidation, aspartate transaminase (AST), alanin transaminase (ALT) and alkaline phosphatase (ALP) activities caused by STZ. Besides, a significant amelioration in antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) was observed. On the other hand, non enzymic antioxidant such as reduced glutathione (GSH) and ascorbic acid level was significantly increased while α-tocopherol level was decreased. Furthermore, CFE caused significant restoration in DNA fragmentation induced by STZ. These findings suggest that CFE has protective effects against STZ induced oxidative damage in liver and kidney of diabetic mice.

Synergy between sulforaphane and selenium in the up-regulation of thioredoxin reductase and protection against hydrogen peroxide-induced cell death in human hepatocytes

Dietary isothiocyanates and selenium are chemopreventive agents and potent inducers of antioxidant enzymes. It has been previously shown that sulforaphane and selenium have a synergistic effect on the upregulation of thioredoxin reductase-1 (TrxR-1) in human hepatoma HepG2 cells. In this paper, further evidence is presented to show that sulforaphane and selenium synergistically induce TrxR-1 expression in immortalised human hepatocytes. Sulforaphane was found to be more toxic toward hepatocytes than HepG2 cells with IC50=25.1 and 56.4μM, respectively. Sulforaphane can protect against hydrogen peroxide-induced cell death and this protection was enhanced by co-treatment with selenium. Using siRNA to knock down TrxR-1 or Nrf2, sulforaphane (5μM)-protected cell viability was reduced from 73% to 46% and 34%, respectively, suggesting that TrxR-1 is an important enzyme in protection against hydrogen peroxide-induced cell death. Sulforaphane-induced TrxR-1 expression was positively associated with significant levels of Nrf2 translocation into the nucleus, but co-treatment with selenium showed no significant increase in Nrf2 translocation. Moreover, MAPK (ERK, JNK and p38) and PI3K/Akt signalling pathways were found to play no significant role in sulforaphane-induced Nrf2 translocation into the nucleus. However, blocking ERK and JNK signalling pathways decreased sulforaphane-induced TrxR-1 mRNA by about 20%; whereas blocking p38 and PI3K/AKT increased TrxR-1 transcription. In summary, a combination of sulforaphane and selenium resulted in a synergistic upregulation of TrxR-1 that contributed to the enhanced protection against free radical-mediated oxidative damage in human hepatocytes.

Protective Role of l-Arginine Against Free-Radical Mediated Oxidative Damage in Patients with Unstable Angina.

Unstable angina is a critical condition of heart resulting from narrowing of vessels supplying blood to heart. Ischemia of the myocardium leads to oxidative stress and severe tissue damage. The objective of the present study was to determine the effect of l-arginine administration on the oxidant-antioxidant homeostasis which otherwise gets imbalanced in patients with cardiovascular diseases. The results obtained, show improvement in the oxidant-antioxidant levels of the subjects upon incorporation of l-arginine. Our findings suggest that supplementation of l-arginine along with regular anti-anginal therapy may be beneficial to the patients of unstable angina.

Lipid Peroxidation Generates Body Odor Component trans-2-Nonenal Covalently Bound to Protein in Vivo

trans-2-Nonenal is an unsaturated aldehyde with an unpleasant greasy and grassy odor endogenously generated during the peroxidation of polyunsaturated fatty acids. 2-Nonenal covalently modified human serum albumin through a reaction in which the aldehyde preferentially reacted with the lysine residues. Modified proteins were immunogenic, and a specific monoclonal antibody (mAb) 27Q4 that cross-reacted with the protein covalently modified with 2-nonenal was raised from mouse. To verify the presence of the protein-bound 2-nonenal in vivo, the mAb 27Q4 against the 2-nonenal-modified keyhole limpet hemocyanin was raised. It was found that a novel 2-nonenal-lysine adduct, cis- and trans-N(epsilon)-3-[(hept-1-enyl)-4-hexylpyridinium]lysine (HHP-lysine), constitutes an epitope of the antibody. The immunoreactive materials with mAb 27Q4 were detected in the kidney of rats exposed to ferric nitrilotriacetate, an iron chelate that induces free radical-mediated oxidative tissue damage. Using high performance liquid chromatography with on-line electrospray ionization tandem mass spectrometry, we also established a highly sensitive method for detection of the cis- and trans-HHP-lysine and confirmed that the 2-nonenal-lysine adducts were indeed formed during the lipid peroxidation-mediated modification of protein in vitro and in vivo. Furthermore, we examined the involvement of the scavenger receptor lectin-like oxidized low density lipoprotein receptor-1 in the recognition of 2-nonenal-modified proteins and established that the receptor recognized the HHP-lysine adducts as a ligand.

Oxidative Stress After Thrombolysis-Induced Reperfusion in Human Stroke

Animal models of transient ischemia suggest that oxygen-derived free radicals produced on reperfusion of ischemic brain could constitute the main cause of reperfusion injury. We aimed to determine the presence and role of lipid peroxidation and protein oxidation-related molecules after tissue plasminogen activator-induced recanalization in human stroke. A total of 160 patients with strokes involving the middle cerebral artery and treated with tissue plasminogen activator and 60 healthy controls were included. Blood samples, transcranial Doppler recordings, and National Institutes of Health Stroke Scale scores were obtained at baseline (pretreatment), 1 hour and 2 hours after tissue plasminogen activator bolus, and 12 hours and 24 hours after stroke onset. The main lipid peroxidation end-product malondialdehyde, advanced oxidation protein products, and plasma concentrations of myeloperoxidase were assessed. At baseline, all oxidative stress biomarkers were higher than in control subjects (P<0.01 for all comparisons). Malondialdehyde remained high compared with controls during the study period, whereas myeloperoxidase concentrations were significantly raised at baseline, 1 hour after tissue plasminogen activator administration, and 12 hours after stroke onset. Malondialdehyde concentrations correlated with stroke severity and were associated with outcome and with hemorrhagic complications. Regarding recanalization, among those patients with middle cerebral artery recanalization by the end of tissue plasminogen activator infusion (44%) or anytime thereafter, no peaking of any of the studied molecules could be identified. Our study showed that systemic oxidative damage to lipids and proteins had already occurred at baseline in stroke. In contrast to animal studies, a relationship between free radical-mediated oxidative damage to lipids or proteins and reperfusion injury after arterial recanalization could not be established.

Rosiglitazone, peroxisome proliferator receptor-gamma agonist, ameliorates gentamicin-induced nephrotoxicity in rats

Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe gram-negative infections. Reactive oxygen spaces (ROS) are important mediators of gentamicin-induced nephrotoxicity. Peroxisome proliferator-activated receptors (PPARs) have different activities including antioxidant properties. This study was performed to investigate the protective role of PPAR-γ agonist against GEN-induced nephrotoxicity. Male Wistar Albino rats were randomly divided into the following four groups, each of which consisted of six animals: (1) control; (2) intraperitoneally injected with GEN for 14 consecutive days (100 mg/kg/day); (3) treatment with rosiglitazone (RSG) via nasogastric gavage (10 mg/kg/daily for 14 days); (4) treatment with GEN + RSG combination for 14 day. Rats were decapitated on the 15th day and kidneys were removed. Urine was collected for every 24 h for the determination of daily urine volume. Urea, creatinine, Na(+) and K(+) levels were measured in blood. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels along with glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities were determined in the renal tissue. Changes in body weight were recorded. GEN treatment was found to cause nephrotoxicity as evidenced by elevation of serum urea and creatinine levels. Renal impairment was also assessed by the renal histology. The significant decrease in GSH and increases in MDA and NO levels as well as a decrease in GSH-Px, CAT, and SOD activities indicated that GEN-induced renal damage was mediated through oxidative reactions. On the other hand, RSG administration protected kidney tissue against GEN-induced and free radical-mediated oxidative renal damage in rats.

Superoxide-mediated Formation of Tyrosine Hydroperoxides and Methionine Sulfoxide in Peptides through Radical Addition and Intramolecular Oxygen Transfer

The chemistry underlying superoxide toxicity is not fully understood. A potential mechanism for superoxide-mediated injury involves addition to tyrosyl radicals, to give peptide or protein hydroperoxides. The rate constant for the reaction of tyrosyl radicals with superoxide is higher than for dimerization, but the efficiency of superoxide addition to peptides depends on the position of the Tyr residue. We have examined the requirements for superoxide addition and structurally characterized the products for a range of tyrosyl peptides exposed to a peroxidase/O(2)(.) system. These included enkephalins as examples of the numerous proteins and physiological peptides with N-terminal tyrosines. The importance of amino groups in promoting hydroperoxide formation and effect of methionine residues on the reaction were investigated. When tyrosine was N-terminal, the major products were hydroperoxides that had undergone cyclization through conjugate addition of the terminal amine. With non-N-terminal tyrosine, electron transfer from O(2)(.) to the peptide radical prevailed. Peptides containing methionine revealed a novel and efficient intramolecular oxygen transfer mechanism from an initial tyrosine hydroperoxide to give a dioxygenated derivative with one oxygen on the tyrosine and the other forming methionine sulfoxide. Exogenous amines promoted hydroperoxide formation on tyrosyl peptides lacking a terminal amine, without forming an adduct. These findings, plus the high hydroperoxide yields with N-terminal tyrosine, can be explained by a mechanism in which hydrogen bonding of O(2)(.) to the amine increases is oxidizing potential and alters its reactivity. If this amine effect occurred more generally, it could increase the biological reactivity of O(2)(.) and have major implications.

The reaction of cell-free oxyhemoglobin with nitrite under physiologically relevant conditions: Implications for nitrite-based therapies

Nitric oxide (NO ) participates in the regulation of a wide array of biological processes and its deficit contributes to the severity of many diseases. Recently, a role of NO deficiency that occurs as a result of intravascular hemolysis and increases in levels of cell-free hemoglobin in the pathway of chronic anemic pathologies has been suggested. Experimental evidence for deoxyhemoglobin-catalyzed reduction of nitrite to NO leads to the possibility of nitrite infusion-based therapies to correct NO deficits. However, the presence of plasma hemoglobin also raises the possibility of deleterious free radical-mediated oxidative damage from the reaction between nitrite and oxyhemoglobin in the vasculature. We show that the conditions required for the reaction between nitrite and oxyhemoglobin to exhibit free radical-mediated autocatalytic kinetics are highly unlikely to occur in the plasma compartment, even during extensive hemolysis and with pharmacological nitrite doses. Although the presence of haptoglobin enhances the rate of the reaction between nitrite and oxyhemoglobin, common plasma antioxidants—ascorbate and urate, as well as catalase—prevent autocatalysis. Our findings suggest that pharmacological doses of nitrite are unlikely to cause free radical or ferrylhemoglobin formation in plasma originating from the reaction of nitrite with cell-free oxyhemoglobin in vivo.

Age-Related Correlation Between Antioxidant Enzymes and DNA Damage With Smoking and Body Mass Index

To understand whether oxidants contribute to the initiation and/or promulgation toward aging, the present study has been undertaken on 220 healthy male volunteers aged 20-80 years selected from the defined electoral area (suburbs of Tirupati, Andhra Pradesh, India) to evaluate the concentrations of free radicals (superoxide anion, hydrogen peroxide), lymphocyte antioxidant enzymes (glutathione S-transferase, superoxide dismutase, catalase), and DNA damage in relation to obesity and smoking (lifestyles). A two fold increase of lymphocyte free radical generation (DNA damage) was observed in older age groups with a reduced antioxidant potential, forming a link between cigarette smoking and oxidative stress represented by an antioxidant imbalance. Body mass index had a positive relationship with oxidative stress, but antioxidant levels did not vary with body mass index. The findings conclude that free radical-mediated oxidative stress and DNA damage accelerate with lifestyle variations under reduced antioxidant potential.

Damage to Lipids, Proteins, DNA, and RNA in Mild Cognitive Impairment

Free radical-mediated oxidative damage is thought to play a role in the pathogenesis of Alzheimer disease. Previous studies have shown oxidative damage to lipids, proteins, DNA, and RNA in multiple brain regions in late-stage Alzheimer disease. Recent studies on patients with amnestic mild cognitive impairment who have undergone autopsy have shown increased lipid peroxidation as well as protein, DNA, and RNA oxidation in multiple brain regions. These studies establish oxidative damage as an early event in the pathogenesis of Alzheimer disease that can serve as a therapeutic target to slow the progression or perhaps the onset of the disease.

Can malondialdehyde be used as a biological marker of progression in neurodegenerative disease?

There is a large body of evidence that free radical-mediated oxidative damage is involved in the pathogenesis of neurodegenerative disease. Although it is unlikely that markers of such damage will have any diagnostic value, they might be of considerable interest in following disease progression and monitoring the efficacy of different treatments. Among such markers, there is evidence for the elevation of peripheral malondialdehyde levels in several neurodegenerative diseases, including Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease. The measurement of malondialdehyde levels, which is both simple and cheap to perform, can and should be incorporated into future clinical trials. This will allow a clearer picture to emerge as to whether malondialdehyde can be considered as a marker for the evolution of these diseases.

Prospective study of cataract extraction and risk of coronary heart disease in women.

Oxidative damage to proteins in the human lens is believed to be important in the etiology of age-related cataract. Because free radical-mediated oxidative damage to lipoproteins may accelerate atherosclerosis, the authors hypothesized that the development of cataract might be a marker for such damage and therefore might be associated with future risk of coronary heart disease (CHD). The authors followed 60,657 women aged 45--63 years and without known coronary disease, stroke, or cancer in 1984. During 10 years of follow-up (674,283 person-years), the authors documented 887 incident cases of CHD and 2,322 deaths. After adjustment for age, smoking, and other coronary risk factors, cataract extraction was significantly associated with higher risk of CHD (relative risk (RR) = 1.88, 95% confidence interval (CI): 1.41, 2.50) for total CHD, 2.44 (95% CI: 1.54, 3.89) for fatal CHD, and 1.63 (95% CI: 1.14, 2.34) for nonfatal myocardial infarction). The positive association between cataract extraction and total CHD was stronger among women with a history of diabetes (RR = 2.80, 95% CI: 1.77, 4.42) than among those without reported diabetes (RR = 1.51, 95 percent CI: 1.04, 2.18). In multivariate analyses, cataract extraction was associated with significantly increased overall mortality (RR = 1.37, 95 percent CI: 1.13, 1.66), which was entirely explained by the increased mortality from cardiovascular disease (RR = 1.84, 95% CI: 1.29, 2.64). These findings are compatible with current hypotheses relating oxidative damage and tissue aging to the development of cataract and CHD.