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03/2012; , ISBN: 978-953-51-0248-9
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ABSTRACT: To compare plasma levels of oxidative stress biomarkers in patients with age-related macular degeneration (AMD) and controls and to evaluate a potential relationship between biochemical markers of oxidative stress and AMD susceptibility genotypes.
Prospective case-control study.
Plasma levels of oxidative stress biomarkers were determined in 77 AMD patients and 75 controls recruited from a clinical practice. Cysteine, cystine (CySS), glutathione, isoprostane, and isofuran were measured, and participants were genotyped for polymorphisms in the complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes.
CySS was elevated in cases compared with controls (P = .013). After adjustment for age, sex, and smoking, this association was not significant. In all participants, CySS levels were associated with the CFH polymorphism rs3753394 (P = .028) as well as an 8-allele CFH haplotype (P = .029) after correction for age, gender, and smoking. None of the other plasma markers was related to AMD status in our cohort.
Our investigation of the gene-environment interaction involved in AMD revealed a relationship between a plasma biomarker of oxidative stress, CySS, and CFH genotype. These data suggest a potential association between inflammatory regulators and redox status in AMD pathogenesis.
American journal of ophthalmology 03/2012; 153(3):460-467.e1. · 3.83 Impact Factor
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ABSTRACT: To determine if short-term Age-Related Eye Disease Study (AREDS) antioxidant and zinc supplementation affects biomarkers of oxidative stress, possibly serving as a predictor of their efficacy.
Prospective interventional case series.
Nineteen subjects, 12 with intermediate or advanced age-related macular degeneration (AMD) (AREDS categories 3 or 4) and 7 non-AMD controls, were admitted to the Vanderbilt General Clinical Research Center and placed on a controlled diet for 7 days. Antioxidant and zinc supplements were stopped 2 weeks prior to study enrollment. Dietary supplementation with 500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, 80 mg zinc oxide, and 2 mg cupric oxide per day was instituted on study day 2. Blood was drawn on study days 2 and 7, and plasma concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were determined.
Short-term AREDS supplementation significantly lowered mean plasma levels of CySS in participants on a regulated diet (P = .034). No significant differences were observed for Cys, GSH, IsoP, or IsoF. There were no significant differences between AMD patients and controls.
This pilot interventional study shows that a 5-day course of antioxidant and zinc supplements can modify plasma levels of CySS, suggesting that this oxidative stress biomarker could help predict how likely an individual is to benefit from AREDS supplementation. Further, CySS may be useful for the evaluation of new AMD therapies, particularly those hypothesized to affect redox status.
American journal of ophthalmology 02/2012; 153(6):1104-9.e2. · 3.83 Impact Factor
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ABSTRACT: Oxidative stress is a contributing factor to the development and progression of diabetic retinopathy, a leading cause of blindness in people at working age worldwide. Recent studies showed that Müller cells play key roles in diabetic retinopathy and produce vascular endothelial growth factor (VEGF) that regulates retinal vascular leakage and proliferation. Melatonin is a potent antioxidant capable of protecting variety of retinal cells from oxidative damage. In addition to the pineal gland, the retina produces melatonin. In the current study, we investigated whether melatonin protects against hyperglycemia-induced oxidative injury to Müller cells and explored the potential underlying mechanisms. Our results show that both melatonin membrane receptors, MT1 and MT2, are expressed in cultured primary Müller cells and are upregulated by elevated glucose levels. Both basal and high glucose-induced VEGF production was attenuated by melatonin treatment in a dose-dependent manner. Furthermore, we found that melatonin is a potent activator of Akt in Müller cells. Our findings suggest that in addition to functioning as a direct free radical scavenger, melatonin can elicit cellular signaling pathways that are protective against retinal injury during diabetic retinopathy.
PLoS ONE 01/2012; 7(12):e50661. · 4.09 Impact Factor
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ABSTRACT: The decision to remove or refold oxidized, denatured, or misfolded proteins by heat shock protein 70 and its binding partners is critical to determine cell fate under pathophysiological conditions. Overexpression of the ubiquitin ligase C-terminus of HSC70 interacting protein (CHIP) can compensate for failure of other ubiquitin ligases and enhance protein turnover and survival under chronic neurological stress. The ability of CHIP to alter cell fate after acute neurological injury has not been assessed. Using postmortem human tissue samples, we provide the first evidence that cortical CHIP expression is increased after ischemic stroke. Oxygen glucose deprivation in vitro led to rapid protein oxidation, antioxidant depletion, proteasome dysfunction, and a significant increase in CHIP expression. To determine if CHIP upregulation enhances neural survival, we overexpressed CHIP in vitro and evaluated cell fate 24 h after acute oxidative stress. Surprisingly, CHIP overexpressing cells fared worse against oxidative injury, accumulated more ubiquitinated and oxidized proteins, and experienced decreased proteasome activity. Conversely, using small interfering RNA to decrease CHIP expression in primary neuronal cultures improved survival after oxidative stress, suggesting that increases in CHIP observed after stroke like injuries are likely correlated with diminished survival and may negatively impact the neuroprotective potential of heat shock protein 70.
Antioxidants & Redox Signaling 05/2011; 14(10):1787-801. · 8.20 Impact Factor
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ABSTRACT: Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.
Eyes of both wild type and Nrf2(-/-) mice were examined in vivo by fundus photography and electroretinography (ERG). Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/-) mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE). Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV) and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/-) mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/-) mice.
Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/-) mice can provide a novel model for mechanistic and translational research on AMD.
PLoS ONE 01/2011; 6(4):e19456. · 4.09 Impact Factor
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ABSTRACT: To assess the degree of laser-induced choroidal neovascular membrane formation in wild-type (WT) and COX-2 null mice and to measure vascular endothelial growth factor (VEGF), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α levels in the retina and choroid.
Four laser burns were placed in each eye of WT and COX-2 null mice to induce choroidal neovascularization. Fluorescein angiography (FA) was performed at 14 days, and retinal pigment epithelium-choroid-sclera (choroidal) flat mounts were prepared. The retina and choroid were isolated from WT and COX-2 null mice at 24, 72, and 168 hours after laser photocoagulation and from unlasered eyes and were tested for VEGF, IL-1β, and TNF-α.
COX-2 null mice demonstrated 58% (P = 0.001) and 48% (P = 0.001) reductions in CNV formation on FA and choroidal flat mounts, respectively, compared with WT mice. For unlasered mice, mean VEGF concentrations in the retina and choroid were 1.2 ± 0.42 pg/mg protein for WT but only 0.42 ± 0.2 pg/mg protein for COX-2 null mice (P < 0.05). After laser photocoagulation, WT mice showed significantly greater VEGF and IL-β expression in the retina and choroid by 168 hours (P < 0.05) and 72 hours (P < 0.05), respectively, compared with COX-2 null mice.
COX-2 null mice exhibited significantly less choroidal neovascular membrane formation associated with reduced expression of VEGF. The results of this study suggest that COX-2 modulates VEGF expression in CNV and implicates a potential therapeutic role for nonsteroidal anti-inflammatory drugs.
Investigative ophthalmology & visual science 09/2010; 52(2):701-7. · 3.43 Impact Factor
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ABSTRACT: The neurotoxicity of methylmercury (MeHg) is well documented in both humans and animals. MeHg causes acute and chronic damage to multiple organs, most profoundly the central nervous system (CNS). Microglial cells are derived from macrophage cell lineage, making up approximately 12% of cells in the CNS, yet their role in MeHg-induced neurotoxicity is not well defined. The purpose of the present study was to characterize microglial vulnerability to MeHg and their potential adaptive response to acute MeHg exposure. We examined the effects of MeHg on microglial viability, reactive oxygen species (ROS) generation, glutathione (GSH) level, redox homeostasis, and Nrf2 protein expression. Our data showed that MeHg (1-5 microM) treatment caused a rapid (within 1 min) concentration- and time-dependent increase in ROS generation, accompanied by a statistically significant decrease in the ratio of GSH and its oxidized form glutathione disulfide (GSSG) (GSH:GSSG ratio). MeHg increased the cytosolic Nrf2 protein level within 1 min of exposure, followed by its nuclear translocation after 10 min of treatment. Consistent with the nuclear translocation of Nrf2, quantitative real-time PCR revealed a concentration-dependent increase in the messenger RNA level of Ho-1, Nqo1, and xCT 30 min post MeHg exposure, whereas Nrf2 knockdown greatly reduced the upregulation of these genes. Furthermore, we observed increased microglial death upon Nrf2 knockdown by the small hairpin RNA approach. Taken together, our study has demonstrated that microglial cells are exquisitely sensitive to MeHg and respond rapidly to MeHg by upregulating the Nrf2-mediated antioxidant response.
Toxicological Sciences 08/2010; 116(2):590-603. · 4.65 Impact Factor
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ABSTRACT: Mammalian target of rapamycin (mTOR)-mediated pathways play central roles in regulating aging. The purpose of the present study was to characterize the mTOR cascade in human retinal pigment epithelial (RPE) cells and to investigate its potential roles in controlling RPE senescence.
Expression of major components of the mTOR signaling networks was evaluated by Western blot analyses. Formations of the two signaling complexes of mTOR, mTORC1, and mTORC2 were determined by coimmunoprecipitation. The activation of mTORC1 was monitored by measuring the phosphorylation status of the downstream substrate protein S6. Senescence of the cultured human RPE cells was assessed by measuring both the senescence associated-β-galactosidase (SA-β-Gal) activity and the expression level of p16, a cyclin-dependent kinase inhibitor.
Human RPE cells contained functional mTORC1 and mTORC2 signaling complexes. The assembly and activity of mTORC1 were regulated by upstream nutrient and growth factor signals. The sensitivity of mTORC1 to extracellular nutrient stimuli increased in RPE cells that had developed in vitro senescence. Suppression of the mTORC1 by rapamycin prevented the appearance of senescence markers in the RPE.
The mTOR pathway presented age-associated changes in human RPE cells, and downregulation of mTORC1 could delay the aging process of the RPE.
Investigative ophthalmology & visual science 05/2010; 51(10):5314-9. · 3.43 Impact Factor
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ABSTRACT: Methylmercury (MeHg) is a potent neurotoxicant and preferentially induces oxidative injury in astrocytes. In neuronal tissues, nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor determining the protective antioxidant response against various environmental toxicants. Nrf2 is subjected to regulation by many other signaling pathways. The purpose of this study is to characterize its interaction with the phosphatidylinositol 3 (PI3) kinase in cultured rat neonatal primary astrocytes. The results showed that at pathologically relevant concentrations, exposure of primary astrocytes to MeHg led to Nrf2 activation and upregulation of its downstream antioxidant genes. Inhibition of the PI3 kinase resulted in decreased Nrf2 activity, decreased cellular glutathione, and increased cell death to high-dose MeHg. The functional interaction between the two signaling pathways underlined an important mechanism for astrocyte protection against MeHg toxicity. Modulation of Nrf2 by pharmacological modalities should afford a treatment to attenuate MeHg-induced neurotoxicity.
Toxicological Sciences 10/2008; 107(1):135-43. · 4.65 Impact Factor
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ABSTRACT: 4-Hydroxy-2-nonenal (4-HNE) is a major lipid peroxidation product in the retina and the retinal pigment epithelium. The purpose of the present study was to investigate how NF-E2-related factor-2 (Nrf2) and phosphatidylinositol 3 (PI3K) pathways affect the responses of cultured human retinal pigment epithelial (RPE) cells to 4-HNE.
Cultured ARPE-19 cells were treated with different concentrations of 4-HNE and a PI3K inhibitor, LY294002. Intracellular glutathione (GSH) was measured by high-performance liquid chromatography (HPLC). The transcriptional activity of Nrf2 was measured by dual luciferase assay after transient transfection with reporter plasmids. The mRNA level of glutamate cysteine ligase (GCL) was quantified by real-time RT-PCR. Formation of HNE adduct on heat shock cognate protein 70 (Hsc70) was measured by immunoprecipitation and Western blot analyses.
Treatment with 4-HNE increased Nrf2 activity and GSH synthesis in a dose-dependent manner in cultured RPE cells. The modulatory subunit of GCL was upregulated by 4-HNE. Antioxidant responses were largely abolished by pretreatment with LY294002. The modification of Hsc70 by 4-HNE was increased when PI3K was inhibited.
The Nrf2-dependent antioxidant response protects against 4-HNE toxicity, and this protective mechanism is dependent on the functions of the PI3K pathway.
Investigative ophthalmology & visual science 10/2008; 50(2):936-42. · 3.43 Impact Factor
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ABSTRACT: Thioredoxin-2 (Trx2) is a multifunctional, mitochondria-specific protein, which inhibits cell death. The mitochondrial permeability transition (MPT) is a distinct mechanism for cell death activated by oxidants and linked to both necrotic and apoptotic morphologies. We studied mitochondria from Trx2 transgenic mice to determine whether Trx2 protects against oxidant-induced MPT. All experiments were performed in isolated mitochondria. Results showed that Trx2 protected against MPT induced by exogenously added peroxide. Unexpectedly, Trx2 also protected against the MPT induced by Ca(2+) in the absence of added peroxide. The results indicate that in addition to protecting against oxidative stress, Trx2 is an endogenous regulator of the MPT.
Toxicological Sciences 07/2008; 105(1):44-50. · 4.65 Impact Factor
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ABSTRACT: Thioredoxin 2 (Trx2) is a mitochondrially localized antioxidant and antiapoptotic protein, whose functions are mainly dependent on the conserved cysteines at its redox active center. In the current study, we showed by mass spectrometry that a thiol alkylating agent, N-ethylmaleimide (NEM), alkylated a single cysteine residue in the active center of Trx2. The interaction between NEM and Trx2 in intact cells was confirmed by redox Western analysis. Overexpression of Trx2 in cultured 143B osteosarcoma cells caused increased sensitivity to NEM. Covalent modification by NEM resulted in a dominant-negative effect and increased the interaction between Trx2 and peroxiredoxin 3 (Prx3). Our data suggest that the alkylation of the essential thiol(s) of Trx2 has profound impact on the mitochondrial redox circuitry and that such effects are distinct from the responses to agents causing reversible disulfide bond formation between the vicinal dithiols in the active center.
Chemical Research in Toxicology 06/2008; 21(6):1205-10. · 3.78 Impact Factor
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ABSTRACT: To evaluate the associations between plasma-soluble Fas ligand (sFasL) and age-related macular degeneration (AMD).
Plasma samples were obtained from 230 individuals (age range, 45-85), with or without AMD. The concentrations of sFasL were determined by an enzyme-linked immunosorbent assay (ELISA). The measured sFasL levels were transformed into cubic roots and were fitted into linear regression models against AMD status, with adjustment for age and sex.
Plasma sFasL increased with age and AMD. There was a linear correlation between age and the cubic roots of sFasL. The plasma sFasL concentrations in non-AMD subjects ranged from 0 to 1.63 ng/mL (median, 0.69 ng/mL), whereas in patients with AMD, sFasL ranged from 0 to 2.43 ng/mL (median, 0.18 ng/mL). Between the ages of 61 and 84, the subjects with AMD had significantly higher sFasL than did the non-AMD subjects. There was a sexual dimorphism of the plasma sFasL levels. In non-AMD subjects, sFasL was lower in the females. In patients with AMD, sFasL was higher in the females.
An elevation of plasma sFasL with aging may play a role in the development of AMD and is a potential peripheral marker for monitoring disease progression.
Investigative Ophthalmology & Visual Science 05/2008; 49(4):1345-9. · 3.60 Impact Factor
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ABSTRACT: To characterize the involvement of Zip2, a zinc transporter protein, in the antioxidant functions of cultured human retinal pigment epithelial (RPE) cells.
The expression of zinc transporter proteins was determined by RT-PCR. Intracellular zinc concentration was assessed by staining with a zinc-sensitive dye followed by flow cytometry. Stable overexpression of the transporter protein Zip2 was achieved by transducing ARPE-19 cells with a retroviral vector containing the open reading frame of the human Zip2 gene. Activity of nuclear factor erythroid 2-related factor 2 (Nrf2) was measured using a dual luciferase assay after transient transfection of reporter plasmids containing the antioxidant response element (ARE). Glutamate-cysteine ligase (GCL) expression was measured by quantitative real-time RT-PCR.
Cultured RPE cells could transport zinc with Zip2 as an influx transporter expressed in ARPE-19 cells and human RPE cells isolated from postmortem donor eyes. The mRNA level of Zip2 was influenced by intracellular and extracellular zinc concentrations. Overexpression of Zip2 resulted in increased Nrf2 activity, higher GCL expression, and increased glutathione synthesis.
RPE cells can actively uptake zinc through the transporter Zip2, and the increased intracellular zinc upregulates the Nrf2-dependent antioxidant function.
Investigative Ophthalmology & Visual Science 05/2008; 49(4):1665-70. · 3.60 Impact Factor
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ABSTRACT: To investigate functional interactions between the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant system in cultured human retinal pigment epithelium (RPE) cells.
Cultured ARPE-19 cells were treated with different concentrations of PI3K inhibitors, followed by exposure to sulforaphane, an Nrf2 inducer. Akt phosphorylation was detected by Western blot analysis. Intracellular glutathione (GSH) content was measured by HPLC. Expression of genes downstream of Nrf2, including glutamate-cysteine ligase (GCL) and glutathione S-transferase, was measured by quantitative RT-PCR. Nrf2 activity was measured by a dual luciferase assay after transfection of a reporter plasmid containing the antioxidant response element (ARE). The small interference RNA approach was used to knock down Nrf2 in the RPE. Nrf2 localization was determined by subcellular fractionation and Western blot analyses.
PI3K inhibitors wortmannin and LY294002 caused dose-dependent cellular and mitochondrial GSH depletion and downregulation of the modulatory subunit of GCL in cultured RPE cells. Both the basal and the induced Nrf2 activities were inhibited by wortmannin and LY294002. Overexpression of a constitutively active form of Akt potentiated Nrf2 activation, and the effect of Akt was blocked by siRNA that knocked down Nrf2. LY294002 also inhibited sulforaphane-induced Nrf2 nuclear translocation.
The PI3K/Akt pathway plays key roles in regulating Nrf2-ARE-dependent protection against oxidative stress in the RPE.
Investigative Ophthalmology & Visual Science 05/2008; 49(4):1671-8. · 3.60 Impact Factor
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ABSTRACT: The immunophilin protein FKBP8 interacts with Bcl2/Bcl-XL and is essential for mouse eye development. The purpose of this study was to define the expression of the FKBP8 gene in cultured human RPE cells and explore its involvement in the control of apoptosis.
Rapid amplification of cDNA ends (RACE) was performed on RNA isolated from human RPE cells. The existence of FKBP8 and a splice variant was confirmed by RT-PCR. The interaction between Bcl-XL and FKBP8 was measured by coimmunoprecipitation. ARPE-19 cells stably overexpressing FKBP8 and its splice variant were established. Their responses to thapsigargin and t-butyl hydroperoxide-induced cell death were measured by flow cytometry. Apoptosis was determined by terminal deoxyribonucleotidyl transferase-mediated fluorescein-dUTP nick-end labeling (TUNEL) assay. The activities of the nuclear factor of activated T cells (NFAT) were measured by reporter assay after transient transfection.
RACE and RT-PCR identified a splice variant of FKBP8 lacking exons 3, 4, and 5 in human RPE cells. Both the full-length and the short form of FKBP8 proteins showed mitochondrial distribution and directly interacted with Bcl-XL. Overexpression of FKBP8 caused increased sensitivity to apoptosis induced by thapsigargin. The transcriptional activity of NFAT was not affected by FKBP8.
FKBP8 and its novel splice variant are Bcl-XL-interacting proteins and regulate the apoptotic signaling pathways in the RPE.
Investigative Ophthalmology & Visual Science 05/2008; 49(4):1721-7. · 3.60 Impact Factor
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ABSTRACT: Depleted uranium (DU) is an extremely dense metal that is used in radiation shielding, counterbalances, armor, and ammunition. In light of the public concerns about exposure to DU and its potential role in Gulf War Syndrome (GWS), this study evaluated the neurotoxic potential of DU using focused studies on primary rat cortical neurons and the nematode Caenorhabditis elegans. We examined cell viability, cellular energy metabolism, thiol metabolite oxidation, and lipid peroxidation following exposure of cultured neurons to DU, in the form of uranyl acetate. We concurrently evaluated the neurotoxicity of uranyl acetate in C. elegans using various neuronal-green fluourescent protein reporter strains to visualize neurodegeneration. Our studies indicate that uranyl acetate has low cytotoxic potential, and uranium exposure does not result in significant changes in cellular energy metabolism, thiol metabolite oxidation, or lipid peroxidation. Furthermore, our C. elegans studies do not show any significant neurodegeneration following uranyl acetate exposure. Together, these studies suggest that DU, in the form of uranyl acetate, has low neurotoxic potential. These findings should alleviate the some of public concerns regarding DU as an etiologic agent of neurodegenerative conditions associated with GWS.
Toxicological Sciences 11/2007; 99(2):553-65. · 4.65 Impact Factor
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ABSTRACT: Mitochondrial thioredoxin (mtTrx) can be oxidized in response to inducers of oxidative stress; yet the functional consequences of the oxidation have not been determined. This study evaluated the redox status of mtTrx and its association to oxidant-induced apoptosis. Results showed that mtTrx was oxidized after exposure to peroxides and diamide. Overexpression of mtTrx protected against diamide-induced oxidation and cytotoxicity. Oxidation of mtTrx was also achieved by knocking down its reductase; and lead to increased susceptibility to cell death. The data indicate that the redox status of mtTrx is a regulatory mechanism underlying the vulnerability of mitochondria to oxidative injury.
FEBS Letters 01/2007; 580(28-29):6596-602. · 3.54 Impact Factor
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ABSTRACT: Mitochondrial oxidative stress plays important roles in aging and age-related degenerative disorders. The newly identified mitochondrial thioredoxin (mtTrx; Trx2) is a key component of the mitochondrial antioxidant system which is responsible for the clearance of reactive intermediates and repairs proteins with oxidative damage. Here, we show that in cultured SH-SY5Y human neuroblastoma 1cells, overexpression of mtTrx inhibited apoptosis and loss of mitochondrial membrane potential induced by a chemical oxidant, tert-butylhydroperoxide (tBH). The effects of calcium ionophore (Br-A23187) were not affected by mtTrx, suggesting the protection was specific against oxidative injury. The mitochondrial glutathione pool was oxidized by tBH, and this oxidation was not inhibited by increased mtTrx. Consequently, the antioxidant function of mtTrx is not redundant, but rather in addition, to that of GSH. Mutations of Cys90 and Cys93 to serines rendered mtTrx ineffective in protection against tBH-induced cytoxicity. These data indicate that mtTrx controls the mitochondrial redox status independently of GSH and is a key component of the defensive mechanism against oxidative stress in cultured neuronal cells.
Toxicology and Applied Pharmacology 11/2006; 216(2):256-62. · 4.45 Impact Factor
