Mechanism Of Oxidative Damage Research Articles

Rat liver mitochondrial dysfunction by addition of copper(II) or iron(III) ions

Increased copper (Cu) and iron (Fe) levels in liver and brain are associated to oxidative stress and damage with increased phospholipid oxidation process. The aim of this work was to assess the toxic effects of Cu2+ and Fe3+ addition to rat liver mitochondria by determining mitochondrial respiration in states 3 (active respiration) and 4 (resting respiration), and phospholipid peroxidation. Both, Cu2+ and Fe3+ produced decreases in O2 consumption in a concentration-dependent manner in active state 3: both ions by 42% with malate-glutamate as complex I substrate (concentration for half maximal response (C50) 60μM Cu2+ and 1.25mM Fe3+), and with succinate as complex II substrate: 64–69% with C50 of 50μM Cu2+ and with C50 of 1.25mM of Fe3+. Respiratory control decreased with Cu2+ (C50 50μM) and Fe3+ (C50 1.25-1-75mM) with both substrates. Cu2+ produced a 2-fold increase and Fe3+ a 5-fold increase of thiobarbituric acid-reactive substances (TBARS) content from 25μM Cu2+ (C50 40μM) and from 100μM Fe3+ (C50 1.75mM). Supplementations with Cu2+ and Fe3+ ions induce mitochondrial dysfunction with phospholipid peroxidation in rat liver mitochondria. Although is proved that a Fenton/Haber Weiss mechanism of oxidative damage occurs in metal-ion induced mitochondrial toxicity, slightly different responses to the metal ions suggest some differences in the mechanism of intracellular toxicity. The decreased rates of mitochondrial respiration and the alteration of mitochondrial function by phospholipid and protein oxidations lead to mitochondrial dysfunction, cellular dyshomeostasis and cell death.

GW27-e0271 A study on the mechanism of the oxidative damage in Ginsenoside Rb1 against the intrinsic aging of mouse brain

To study the mechanism of the oxidative damage in Ginsenoside Rb1 against the intrinsic aging of mouse brain. Female C57BL/6 mice were divided into three groups randomly: control group(4 months, n=12); model group(24 months, n=12) and drug group(24 months, n=12). In drug group, ginsenoside Rb1(20mg

The influence of heavy metal ions, spermine and sodium nitroprusside on ATP-hydrolases of cell membranes of rat colon smooth muscle.

The specific features of functional lability of the rat colon smooth muscle (CSM) АТР-hydrolases were studied. Na+,K+-AТРase activity is effectively inhibited by divalent ions of both transition (≥ 0,1 µM) and nontransition (≥ 1 µM) heavy metals in succession by efficiency: Cu2+ > Fe2+ ≥ Cd2+ (10 µM). Polyamine spermine (0,5-1,0 mM) is a weak Na+,K+-AТРase inhibitor at saturation concentrations of ions and substrate. Sodium nitroprusside (1 mM) as nitric oxide-generating compound exhibits weak Na+,K+-AТРase inhibition only after prolonged preincubation with membranes. Mg2+-АТР-hydrolase activity in all cases is much more resistant to studied agents. Considering the example of the CSM Na+,K+-AТРase it is assumed that enzyme has specific biochemical features that contribute to its role as a potential target and redox-sensor, mediating the pathological mechanisms of heavy metal intoxication and cell oxidative damage.

Arsenic-induced mitochondrial oxidative damage is mediated by decreased PGC-1α expression and its downstream targets in rat brain

The present study was carried out to investigate the molecular mechanism of arsenic-induced mitochondrial oxidative damage and its relation to biogenesis in rat brain. Chronic sodium arsenite (25 ppm, orally) administration for 12 weeks decreased mitochondrial complexes activities and mRNA expression of selective complexes subunits. The expression of mitochondrial biogenesis regulator PGC-1α, and its downstream targets NRF-1, NRF-2 and Tfam were decreased significantly both at mRNA and protein levels suggesting impaired biogenesis following chronic arsenic-exposure. In addition to this, protein expression analysis also revealed activation of Bax and caspase-3, leading to translocation of cytochrome c from mitochondria to cytosol suggesting induction of apoptotic pathway under oxidative stress. This was further confirmed by electron microscopy study which depicted morphological changes in mitochondria in terms of altered nuclear and mitochondrial shape and chromatin condensation in arsenic-treated rats. The immunohistochemical studies showed both nuclear and cytosolic localization of NRF-1 and NRF-2 in arsenic-exposed rat brain further suggesting regulatory role of these transcription factors under arsenic neurotoxicity. The results of present study indicate that arsenic-induced mitochondrial oxidative damage is associated with decreased mitochondrial biogenesis in rat brain that may present as important target to reveal the mechanism for arsenic-induced neurotoxicity.

Changes in Serum Ceruloplasmin Levels Based on Immunomodulatory Treatments and Melatonin Supplementation in Multiple Sclerosis Patients

BackgroundThe cause of multiple sclerosis (MS) is currently unknown, but it is thought that oxidative damage and iron metabolism mechanisms are involved. The aim of this study was to examine ceruloplasmin concentration in MS patients based on various immunomodifying therapies and to test the effect of antioxidative melatonin on ceruloplasmin levels.Material/MethodsThis prospective study included 102 MS patients and 15 healthy controls. Patients were divided into groups according to different immunomodifying therapies: interferons beta 1a, interferons beta 1b, glatiramer acetate, mitoxantrone, and immunomodifying pre-treatment (A, B, G, Mx, and P groups, respectively), and the relapse R group. MS patients were supplemented with melatonin for 3 months. Serum ceruloplasmin concentrations, EDSS, brain MRI, serum C-reactive protein level, and white blood cell count were examined.ResultsThe results indicated significantly increased levels of ceruloplasmin in MS patients. No differences in ceruloplasmin concentrations between the relapse group and controls were observed. In A and G groups, ceruloplasmin levels before and after melatonin were similar to levels in controls. In group B, ceruloplasmin concentration was significantly higher vs. control and relapse groups. After melatonin administration in group B, ceruloplasmin levels decreased. Ceruloplasmin concentrations in the Mx group were significantly higher compared to controls.ConclusionsWe found for the first time that ceruloplasmin concentration in MS patients varies depending on different immunomodulatory treatment and decrease after 3 months of melatonin administration. Ceruloplasmin could be a valuable serum marker for the chronic demyelinating process participating in oxidative stress mechanisms, as well as a neurodegenerative marker, but not a marker of acute-phase MS.

Mechanism of protein oxidative damage that is coupled to long-range electron transfer to high-valent haems.

In the absence of its substrate, the auto-reduction of the high-valent bis-Fe(IV) state of the dihaem enzyme MauG is coupled to oxidative damage of a methionine residue. Transient kinetic and solvent isotope effect studies reveal that this process occurs via two sequential long-range electron transfer (ET) reactions from methionine to the haems. The first ET is coupled to proton transfer (PT) to the haems from solvent via an ordered water network. The second ET is coupled to PT at the methionine site and occurs during the oxidation of the methionine to a sulfoxide. This process proceeds via Compound I- and Compound II-like haem intermediates. It is proposed that the methionine radical is stabilized by a two-centre three-electron (2c3e) bond. This provides insight into how oxidative damage to proteins may occur without direct contact with a reactive oxygen species, and how that damage can be propagated through the protein.

Anaesthesia Management of a Young Patient with Homocystinuria

Homocystinurea is a rare autosomal recessive genetic disease. It is caused by deficiency in cystathionine-beta synthase leading to defect in methionine metabolism. HIGH LEVEL of plasma homocysteine are associated with vascular injury via mechanism of oxidative damage. Vascular smooth muscle proliferation, promotion of platelet activation and aggregation and disruption of normal procoagulant-anticoagulant balance favoring thrombosis. This is a case of seventeen-year-old girl. Known case of homocystinurea who scheduled for cataract surgery for her dislocated lens. The major anesthetic consideration includes the development of thromboembolism, need to avoid nitrous oxide in balance anesthesia and avoid dehydration, long fasting, hypoglycemia.

Anaesthesia Management of a Young Patient with Homocystinuria

Homocystinurea is a rare autosomal recessive genetic disease. It is caused by deficiency in cystathionine-beta synthase leading to defect in methionine metabolism. HIGH LEVEL of plasma homocysteine are associated with vascular injury via mechanism of oxidative damage. Vascular smooth muscle proliferation, promotion of platelet activation and aggregation and disruption of normal procoagulant-anticoagulant balance favoring thrombosis. This is a case of seventeen-year-old girl. Known case of homocystinurea who scheduled for cataract surgery for her dislocated lens. The major anesthetic consideration includes the development of thromboembolism, need to avoid nitrous oxide in balance anesthesia and avoid dehydration, long fasting, hypoglycemia.

Expression changes of brain-derived neurotrophic factor in retina of oxygen-induced retinopathy

Background Neovascular diseases such as retinopathy of prematurity often leads to irreversible vision loss.The study on oxidative damage mechanism is becoming more and more important.Whether brain derived neurotrophic factor (BNDF) has protection to retinal ganglion cells(RGCs) has few research reports. Objective The study was to investigate the expression changes of BDNFin mouse retinas of oxygen-induced retinopathy (OIR). Methods Thirty SPF C57BL/6J immature rats were divided into OIR group and normal control group and to fifteen rats for each group.OIR models were established by raising 7-day-old (P7) mice together with maternal mouse in (75±3)% oxygen environment for 5 days and then returned to the normal air environment, and the mice of the normal control group were raised in the normal air environment.The P17 mice were sacrificed for retinal histopathological examination by hematoxylin and eosin staining, and the number of vascular endothelial cell nucleus extending the inner limiting membrane was counted.Whole retinal mounts were prepared after fluorescein isothiacyanate-dextran (FITC-dextran) (9 ml/kg) was retrosorbitally injected, and the distribution of retinal vessels was observed in P17 mice.The relative expression levels of BNDF in retinas were detected in P13, P15, P17 mice, and the results were compared between the normal control group and the OIR group. Results Histopathological examination showed that retinal inner limiting membrane was smooth in the normal control group, but a lots of vascular endothelial cell nucleus extending the inner limiting membrane were seen under the optical microscope in the OIR group.The number of the vascular endothelial cell nucleus extending the inner limiting membrane was 1.70±0.68 in the normal group and 45.3±3.13 in the OIR group, showing significant difference between them (t=86.5, P=0.00). Whole retinal mount revealed that normal retinal vessels and network-like capillaries were exhibited in the mice in the normal group, while tortuous vessels, capillary loss and non-perfusion areas were revealed in the OIR group on the whole retina mounts.The relative expressing levels of BDNF in retinas were 263.992±9.451 and 218.432±9.710 in P15 and P17 mice in the OIR group, which were significantly higher than 230.324±7.779 and 115.846±7.305 in the normal control group (t=14.2, 42.3, P<0.05). Conclusions OIR can be inhibited by increasing the expression of BNDF. Key words: Brain-derived neurotrophic factor; Hyperoxia/complications; Retinal neovascularization/pathology; Disease models, animal; Mice, inbred C57BL

Oxidative Stress Related Diseases in Newborns.

We review oxidative stress-related newborn disease and the mechanism of oxidative damage. In addition, we outline diagnostic and therapeutic strategies and future directions. Many reports have defined oxidative stress as an imbalance between an enhanced reactive oxygen/nitrogen species and the lack of protective ability of antioxidants. From that point of view, free radical-induced damage caused by oxidative stress seems to be a probable contributing factor to the pathogenesis of many newborn diseases, such as respiratory distress syndrome, bronchopulmonary dysplasia, periventricular leukomalacia, necrotizing enterocolitis, patent ductus arteriosus, and retinopathy of prematurity. We share the hope that the new understanding of the concept of oxidative stress and its relation to newborn diseases that has been made possible by new diagnostic techniques will throw light on the treatment of those diseases.

Time course and mechanism of brain oxidative stress and damage for redox active and inactive transition metals overload

Time course and mechanism of brain oxidative stress and damage for redox active and inactive transition metals overload

Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of the Akt/Nrf2 pathway

Parkinson's disease (PD) is an age-related complex neurodegenerative disease that affects ≤ 80% of dopaminergic neurons in the substantia nigra pars compacta (SNpc). It has previously been suggested that mitochondrial dysfunction, oxidative stress and oxidative damage underlie the pathogenesis of PD. Curcumin, which is a major active polyphenol component extracted from the rhizomes of Curcuma longa (Zingiberaceae), has been reported to exert neuroprotective effects on an experimental model of PD. The present study conducted a series of in vivo experiments, in order to investigate the effects of curcumin on behavioral deficits, oxidative damage and related mechanisms. The results demonstrated that curcumin was able to significantly alleviate motor dysfunction and increase suppressed tyrosine hydroxylase (TH) activity in the SNpc of rotenone (ROT)-injured rats. Biochemical measurements indicated that rats pretreated with curcumin exhibited increased glutathione (GSH) levels, and reduced reactive oxygen species activity and malondialdehyde content. Mechanistic studies demonstrated that curcumin significantly restored the expression levels of heme oxygenase-1 and quinone oxidoreductase 1, thus ameliorating ROT-induced damage in vivo, via the phosphorylation of Akt and nuclear factor erythroid 2-related factor 2 (Nrf2). Further studies indicated that the Akt/Nrf2 signaling pathway was associated with the protective role of curcumin in ROT-treated rats. Inhibiting the Akt/Nrf2 pathway using a lentiviral vector containing Nrf2-specific short hairpin RNA, or the phosphoinositide 3-kinase inhibitor LY294002, markedly reduced the expression levels of TH and GSH, ultimately attenuating the neuroprotective effects of curcumin against oxidative damage. These results indicated that curcumin was able to significantly ameliorate ROT-induced dopaminergic neuronal oxidative damage in the SNpc of rats via activation of the Akt/Nrf2 signaling pathway.

Evaluation of Oxidative Damage and Antioxidant Mechanisms in COPD, Lung Cancer, and Obstructive Sleep Apnea Syndrome.

Oxidative damage is a major contributing factor to carcinogenesis and obstructive disorders in lungs. Current evidence suggests that the inflammatory processes yield to oxidative mechanisms, which underlie COPD, lung cancer, and obstructive sleep apnea syndrome (OSAS). This study aimed to evaluate the oxidative damage in these diseases by evaluating the oxidative and antioxidant biomarkers. Malondialdehyde, 8-oxo-7,8-dihydro-2'-deoxyguanosine, and coenzyme Q10 levels were evaluated in the blood samples of subjects with COPD, lung cancer, and OSAS by high-pressure liquid chromatography. A total of 111 participants (35 females, 76 males) with OSAS (n = 29), COPD (n = 26), and lung cancer (n = 28) and healthy controls (n = 28) were included in the study. The malondialdehyde and coenzyme Q10 levels were significantly higher in all 3 diseases when compared with controls (P < .01), whereas 8-oxo-7,8-dihydro-2'-deoxyguanosine levels were only significantly higher than in healthy controls in subjects with lung cancer (P = .005). The highest levels of malondialdehyde and coenzyme Q10 were determined in subjects with OSAS and lung cancer, respectively. The highest 8-oxo-7,8-dihydro-2'-deoxyguanosine levels were also observed in subjects with lung cancer, but the differences of this biomarker with other diagnoses were not statistically significant (P = .56). Oxidative damage was observed in all 3 diagnoses, and, as a response to oxidative stress, antioxidant mechanisms were also active in these diseases. Malondialdehyde and 8-oxo-7,8-dihydro-2'-deoxyguanosine were found to be efficiently usable in the evaluation of oxidative damage in chronic respiratory diseases. (ClinicalTrials.gov registration NCT02406053.).

Monosodium glutamate-induced oxidative kidney damage and possible mechanisms: a mini-review.

Animal studies suggest that chronic monosodium glutamate (MSG) intake induces kidney damage by oxidative stress. However, the underlying mechanisms are still unclear, despite the growing evidence and consensus that α-ketoglutarate dehydrogenase, glutamate receptors and cystine-glutamate antiporter play an important role in up-regulation of oxidative stress in MSG-induced renal toxicity. This review summaries evidence from studies into MSG-induced renal oxidative damage, possible mechanisms and their importance from a toxicological viewpoint.

Study on efficacy and accompanying toxic and side effects of volatile oil of Evodia Fructus based on stomach cold syndrome model

To preliminarily study the effective dosage range and mechanism of the abirritation of volatile oil of Evodia Fructus on the stomach cold syndrome model in mice, and discuss the correlation between its accompanying toxicity and oxidative damage mechanism, in order to provide the experimental basis for explaining the efficacy-syndrome-toxicity correlation. The stomach cold-syndrome model in mice was induced by the classic hot plate test by orally administrating with different doses of volatile oil of Evodia Fructus, in order to observe its abirritation and companying toxic and side effects and detect serum ALT, AST, PGE2, NO, NOS, MDA, SOD, GSH, GSH-Px, BUN, CR and hepatic ALT, AST. The companying toxic symptoms in mice were recorded in toxic reaction integral table. Volatile oil of Evodia Fructus had an obvious analgesic effect at 30 min after the oral administration and reached the peak effect at 60 min, with certain "dose-effect" and "time-effect" relations, rises in serum and hepatic ALT and AST levels, serum PGE2, MDA, NO and NOS and hepatic indexes, decreases in SOD, GSH and GSH-Px and no notable change in BUN, CR levels and kidney weight/body ratio. Conclusion: The abirritation mechanism of volatile oil of Evodia Fructus was related to the inhibition of pain transmitter release, peroxidative damage and NO damage, which is accompanied by certain hepatotoxicity, mainly mainly oxidative damage, with a concurrent "dose-time-toxicity" relationship.

Oxidative Stress Induced by Cadmium and Copper in Brassica rapa Leaves: Indicators of Stress, Oxidative Damage, and Antioxidant Mechanisms

Brassica rapa is frequently used as a vegetable for human consumption and can accumulate metals that are bioavailable in soils. We studied the oxidative stress induced by 25 μM cadmium (Cd) and 50 μM copper (Cu) on Brassica rapa leaves and evaluated the intracellular antioxidative plant response mechanisms and the accumulation of these metals. With this purpose, hydrogen peroxide (H2O2) concentration, lipid peroxidation, and enzymatic and nonenzymatic responses was determined. The obtained results indicate that Cd and Cu induced different plant responses. Oxidative stress induced by Cu was characterized by increased lipid peroxidation and free proline levels. Guaiacol peroxidase and ascorbate peroxidase showed a relevant role in H2O2 removal. Cadmium did not influence lipid peroxidation, H2O2, proline and glutathione contents, and the enzymatic response mainly involves superoxide dismutase and ascorbate peroxidase. It was concluded that both excess Cu and Cd induced oxidative stress but plant response is characterized by different antioxidative response mechanisms.

Effects of The Hydroxyurea Derivative 1, 3 ,4 - Thiadiazoles on Antioxidant Vitamins and MDA in Serums of Rats and Cell Viability of MCF-7 Breast Cancer Cells

In this study, the effects of as used ligand [1-hydroxy - 2 - (5 - (trifluoromethyl) - 1, 3, 4- thiadiazole- 2 - yl) guanidine] and its Mn, Cd, Cr complexes on the antioxidant vitamins and MDA levels in the serums of rats and antitumor activity of these chemical compounds on the MCF-7 breast cancer cells at different concentrations were investigated. When the results were compared between the levels of control and experimental groups of antioxidant vitamins and MDA statistically, it was observed that there were decreased levels of A, E, and C vitamins in groups of applied Cd (II) and Cr (II) complexes compared with the control group, whereas MDA levels were increased. The antioxidant vitamins and MDA levels in serum were determined by HPLC. It was clearly observed that the subcutaneously MCF-7 breast cancer cells treated Ligand (L), Mn (L) 2, Cd (L) 2 and Cr (L) 2 complexes had the low levels of cell viability activity when compared to the untreated control cells clearly increased according to the control group for after incubation 24 h onwards to 48 h. Cell vialities measured by electronic microscope. As a result, it suggested that thiadiazole compounds exhibit antitumor activity with reduction in serum antioxidant vitamins of rats can cause cytotoxic effect depending on the mechanism of oxidative damage.

Study on efficacy accompanied by side effects of water extraction components of Evodiae Fructus based on syndrome model

The range of effective dose and mechanism of abirritation about water extraction components of Evodiae Fructus on the stomach cold syndrome model in mice were preliminary studied. The method of stomach cold-syndrome model in mice was built, which were administrated with different doses water extraction components of Evodiae Fructus, observing abirritation and toxicity by the classical hot plate method, detecting the level of ALT, AST, PGE2, NO, NOS, MDA, SOD, GSH, GSH-Px, BUN, CR in serum and ALT, AST in hepatic tissue, and recording toxicity symptoms in mice according to the list of relevant toxicity reaction. The water extraction component of Evodiae Fructus has obvious analgesic action after administration 30 min, arriving peak effect after administration 60 min, showing certain "dose-time-toxicity" relationship. ALT and AST levels in mice serum and liver tissue enhanced; PGE2, MDA, NO, NOS enhanced in mice serum; SOD, GSH, GSH-Px reduced; the BUN, CR levels was no significant alteration; liver weight/ body weight enhanced; kidney weight/body weight was no significant alteration. The a irritation mechanism of volatile oil of Evodiae Fructus was connected with suppressing pain transmitters release, per oxidative damage mechanism and NO damage, which also induced hepatotoxicity and the mechanism of hepatotoxicity is main lyoxidative damage, showing certain "dose-time-toxicity" relationship in accordance to hepato-toxicity injury.

Evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: preliminary results of a randomised study

This study aimed to investigate oxidative stress in etiopathogenesis by analyzing serum total antioxidant capacity (TAC), total oxidant status (TOS), binding capacity of exogenous cobalt to human albumin (IMA), serum advanced oxidation protein products (AOPP), paraoxonase (PON), arylesterase, IgE, and C-reactive protein (CRP) in bladder pain syndrome/interstitial cystitis (BPS/IC). The study included 16 female patients diagnosed with BPS/IC and 25 healthy female subjects forming the control group. A bladder biopsy was performed on all patients in the BPS/IC group by carrying out cystoscopy with hydrodistention under general anesthesia. The results of serum TAC, TOS, IMA, AOPP, PON, arylesterase, IgE, and CRP of the subjects in both groups were compared. The mean age of the 16 female patients in the BPS/IC group was 43.6 ± 14.5 years, and the mean age of the 25 healthy subjects in the control group was 42.0 ± 10.3 years. According to the criteria of International Society for the Study of Interstitial Cystitis (ESSIC), eight patients were classified as Type 2A, three patients as Type 2B, four patients as Type 2C, and one patient as Type 3C. In the BPS/IC group, while TAC was found significantly lower than in the control group, IMA, IgE, and CRP were found significantly higher (P < 0.05). When binary logistic regression analysis was performed, the created model was determined to have 81.3 % sensitivity and 80 % specifity. In the etiology of BPS/IC, mechanism of oxidative damage comes into prominence. In the diagnosis of BPS/IC, IgE, CRP, and TAC are not specific markers when used separately; however, a higher specifity and sensitivity could be reached when used jointly in the suspected patients.

Cardioprotective Effect of Exercise Training in Heart Failure Rats: Exercise Training Reduces Oxidative Stress Induced Nuclear Genomic Fragmentation

Alterations in energy metabolism are hallmarks of heart failure (HF) following myocardial infarction (MI). The failing heart is commonly described as an energy-starved engine that has run out of fuel, and myocardial energetics is therefore a topic of considerable interest. Markers of oxidative stress are elevated in HF and have been correlated with myocardial dysfunction. Increased oxidative stress can induce DNA damage, and the main repair mechanism of oxidative DNA damage is Base excision repair (BER) and Single strand break repair (SSBR). Defects in SSBR in post-mitotic cells have been associated with human diseases. Exercise training is an effective treatment for HF. Therefore we aimed to investigate the effect of exercise training on the nuclear genomic integrity in HF rats.MI was induced in 30 female Sprague Dawley rats by surgical ligation of the descending coronary artery. HF was present 4 weeks after ligation. HF rats were then randomized to remain sedentary (n=10) or exposed to either moderate (n=10) or high intensity (n=10) aerobic interval training. Sham sedentary rats (n=10) acted as controls. After 6 weeks of exercise training, H2O2 induced genomic DNA fragmentation was studied in isolated left ventricular cardiomyocytes through an alkaline single cell gel electrophoresis assay. Cardiomyocytes from HF sedentary rats had an increase in H2O2 induced genomic fragmentation by 29% relative to sham, exercise training reduced the genomic fragmentation towards sham levels. 31P NMR experiments revealed reduced PCr concentration in HF and exercise training did not change the PCr levels. However, both moderate- and high intensity training resulted in an increase in cardiac ATP concentration in HF rats. Exercise training seems to induce a cardioprotective effect to increased oxidative stress in HF rats and possibly affects BER/SSBR pathways.