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The molecular chaperone sigma 1 receptor mediates rescue of retinal cone photoreceptor cells via modulation of NRF2
摘要： Sigma 1 receptor (Sig1R), a putative molecular chaperone, has emerged as a novel therapeutic target for retinal degenerative disease. Earlier studies showed that activation of Sig1R via the high-affinity ligand (+)-pentazocine ((+)-PTZ) induced profound rescue of cone photoreceptor cells in the rd10 mouse model of retinitis pigmentosa; however the mechanism of rescue is unknown. Improved cone function in (+)-PTZ-treated mice was accompanied by reduced oxidative stress and normalization of levels of NRF2, a transcription factor that activates antioxidant response elements (AREs) of hundreds of cytoprotective genes. Here, we tested the hypothesis that modulation of NRF2 is central to Sig1R-mediated cone rescue. Activation of Sig1R in 661W cone cells using (+)-PTZ induced dose-dependent increases in NRF2-ARE binding activity and NRF2 gene/protein expression, whereas silencing Sig1R significantly decreased NRF2 protein levels and increased oxidative stress, although (+)-PTZ did not disrupt NRF2-KEAP1 binding. In vivo studies were conducted to investigate whether, in the absence of NRF2, activation of Sig1R rescues cones. (+)-PTZ was administered systemically for several weeks to rd10/nrf2+/+ and rd10/nrf2-/- mice. Through post-natal day 42, cone function was significant in rd10/nrf2+/+, but minimal in rd10/nrf2-/- mice as indicated by electroretinographic recordings using natural noise stimuli, optical coherence tomography and retinal histological analyses. Immunodetection of cones was limited in (+)-PTZ-treated rd10/nrf2-/-, though considerable in (+)-PTZ-treated rd10/nrf2+/+mice. The data suggest that Sig1R-mediated cone rescue requires NRF2 and provide evidence for a previously-unrecognized relationship between these proteins.
关键词： retinitis pigmentosa,NRF2-KEAP1,retinal neuroprotection,retina,rd10 mouse,NRF2-Neh luciferase assay,oxidative stress
更新于2025-11-21 11:08:12
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Simvastatin Protects Photoreceptors from all-trans-retinal Induced Oxidative Stress with Up-regulation of Interphotoreceptor Retinoid Binding Protein
摘要： Background and Purpose Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with multiple targets and effects. It protects neurons in the brain but its protective effects on photoreceptors are unclear. In this study, we evaluated the neuroprotective effect of simvastatin on photoreceptors exposed to stress induced by all-trans-retinal (atRAL). Experimental approach AlamarBlue and lactate dehydrogenase assays were used to evaluate the viability and metabolic activity of Y79 cells (a retinoblastoma cell line) exposed to atRAL-induced stress with or without simvastatin pre-treatment. Changes in cellular reactive oxygen species were evaluated using flow cytometry and mitochondrial stress markers JC-1 and HSP60. Changes in levels of the photoreceptor-specific markers cone-rod homeobox protein (CRX) and Interphotoreceptor Retinoid Binding Protein (IRBP) were evaluated with Western blotting. The results were validated in ex vivo human retinal explants and a mouse model of photoreceptor degeneration. Key results Simvastatin improved mitochondrial function, alleviated oxidative stress and upregulated the photoreceptor specific markers IRBP and its upstream regulator CRX in Y79 cells and ex vivo human retinal explants under atRAL-induced stress. Simvastatin attenuated photoreceptor degeneration in association with upregulation of IRBP and CRX expression after knockdown of IRBP in a murine model. Conclusion and implications Our findings suggest that simvastatin has a novel role in protecting photoreceptors from atRAL-induced stress. Simvastatin treatment resulted in upregulation of IRBP and its upstream transcription factor CRX in Y79 cells, ex vivo human retinal explants and murine retinas in vivo. Further studies of simvastatin to treat photoreceptor degeneration are warranted.
关键词： photoreceptors,IRBP,CRX,oxidative stress,all-trans-retinal,Simvastatin
更新于2025-11-21 11:08:12
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Chemically exfoliated 1T-phase transition metal dichalcogenide nanosheets for transparent antibacterial applications
摘要： Two-dimensional transition metal dichalcogenides (TMDs) are promising materials for a range of applications owing to their intriguing properties including the excellent electrical performance and biocompatibility. Strikingly, 1T-phase TMDs have attracted significant interest based on their metallic properties with octahedral metal coordination where the phase transition can occur from the semiconducting 2H-phase to metallic 1T-phase by chemical intercalation-induced exfoliation process. In this regard, 1T-phase TMDs have great potential in antibacterial agents in terms of effective charge transfer between the bacterial membrane and TMD nanosheets while their biological interactions have been underexplored. To bridge this gap, we herein investigate the antibacterial activities of various 1T-phase TMDs including molybdenum disulfide (MoS2), tungsten disulfide (WS2), and molybdenum diselenide (MoSe2) toward Gram-negative bacteria Escherichia coli that exhibit the reduction of bacterial viability caused by the production of reactive oxygen species, oxidation of glutathione and other chemical functionalities. The effective antibacterial capacity of metallic 1T-phase TMDs is observed and their bactericidal mechanisms are investigated in terms of their electrical conductivity and chemical oxidation property that induce the charge transfer from bacterial membrane to TMDs leading to the continuous disruption of bacteria and loss of cellular components. Furthermore, we demonstrated the transparent antibacterial films consisting of 1T-phase TMDs in which TMD nanosheets are immobilized on the surfaces and their basal planes play an important role in antibacterial actions for practical biomedical applications. Thus, our findings provide new insights into the great potential of 1T-phase TMDs as promising building blocks for antibacterial surfaces and contribute to the widespread use of 1T-phase TMDs for practical biomedical applications.
关键词： 1T-phase,charge transfer,antibacterial activity,oxidative stress,transition metal dichalcogenide
更新于2025-11-21 11:08:12
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Suppression of Light-Induced Oxidative Stress in the Retina by Mitochondria-Targeted Antioxidant
摘要： Light-induced oxidation of lipids and proteins provokes retinal injuries and results in progression of degenerative retinal diseases, such as, for instance, iatrogenic photic maculopathies. Having accumulated over years retinal injuries contribute to development of age-related macular degeneration (AMD). Antioxidant treatment is regarded as a promising approach to protecting the retina from light damage and AMD. Here, we examine oxidative processes induced in rabbit retina by excessive light illumination with or without premedication using mitochondria-targeted antioxidant SkQ1 (10-(6’-plastoquinonyl)decyltriphenyl-phosphonium). The retinal extracts obtained from animals euthanized within 1–7 days post exposure were analyzed for H2O2, malondialdehyde (MDA), total antioxidant activity (AOA), and activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) using colorimetric and luminescence assays. Oxidation of visual arrestin was monitored by immunoblotting. The light exposure induced lipid peroxidation and H2O2 accumulation in the retinal cells. Unexpectedly, it prominently upregulated AOA in retinal extracts although SOD and GPx activities were compromised. These alterations were accompanied by accumulation of disulfide dimers of arrestin revealing oxidative stress in the photoreceptors. Premedication of the eyes with SkQ1 accelerated normalization of H2O2 levels and redox-status of lipids and proteins, contemporarily enhancing AOA and, likely, sustaining normal activity of GPx. Thus, SkQ1 protects the retina from light-induced oxidative stress and could be employed to suppress oxidative damage of proteins and lipids contributing to AMD.
关键词： SkQ1,superoxide dismutase,glutathione peroxidase,disulfide dimerization of proteins,visual arrestin,age-related macular degeneration,mitochondria-targeted antioxidant,antioxidant activity,light-induced retinal damage,oxidative stress
更新于2025-09-23 15:23:52
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Isorhamnetin prevents H2O2?induced oxidative stress in human retinal pigment epithelial cells
摘要： Isorhamnetin, a 3-O-methylated metabolite of quercetin, exhibits antioxidant effects. However, to the best of our knowledge, no study to date has focused on the effects of isorhamnetin on retinal pigment epithelium (RPE) cells, and its underlying molecular mechanisms. Therefore, the present study aimed to examine the potential protective effect of isorhamnetin against oxidative stress in human RPE cells. The results demonstrated that pretreatment of RPE cells with isorhamnetin significantly protected cell viability against oxidative stress. In addition, isorhamnetin pretreatment inhibited hydrogen peroxide (H2O2)-induced reactive oxygen species (ROS) production and caspase-3 activation in RPE cells. Furthermore, isorhamnetin pretreatment significantly increased the phosphorylation of phosphoinositide 3-kinase (PI3K) and AKT serine/threonine kinase 1 (Akt) in RPE cells exposed to H2O2, compared with cells treated with H2O2 alone. Taken together, the present results demonstrated that isorhamnetin protected human RPE cells from oxidative stress-induced cell death, and this effect was associated with activation of the PI3K/Akt signaling pathway. Thus, isorhamnetin may be considered as a potential antioxidant useful for the prevention of age-related macular degeneration.
关键词： age-related macular degeneration,oxidative stress,isorhamnetin,retinal pigment epithelium cells
更新于2025-09-23 15:23:52
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Carteolol hydrochloride reduces visible light-induced retinal damage in?vivo and BSO/glutamate-induced oxidative stress in?vitro
摘要： The purpose of this study was to determine whether carteolol eye drops, a b-adrenoceptor antagonist used as an intraocular hypotensive agent, has protective effects against the light-induced oxidative stress in retina. Dark-adapted pigmented rats were pre-treated with topical carteolol ophthalmic solution or saline and then exposed to visible light. The effects on electroretinogram (ERG), morphology, oxidative stress, and expression of mRNAs in the retinas were determined. The L-buthionine-(S,R)-sulfoximine (BSO)/glutamate-induced oxidative stress in 661 W cells, a murine photoreceptor cell line, was evaluated by cell death assays, production of reactive oxygen species (ROS), and activation of caspase. In vivo studies showed that exposure to light caused a decrease in the amplitudes of ERGs and the outer nuclear layer (ONL) thickness and an increase of the 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive cells in the ONL. These changes were significantly reduced by pre-treatment with carteolol. Carteolol also significantly up-regulated the mRNA levels of thioredoxin 1 and glutathione peroxidase 1 compared to saline-treated group. Moreover, carteolol and timolol, another b-adrenoceptor antagonist, significantly inhibited BSO/glutamate-induced cell death and reduced caspase-3/7 activity and ROS production in vitro. Therefore, carteolol could protect retina from light-induced damage with multiple effects such as enhancing the antioxidative potential and decreasing the intracellular ROS production.
关键词： Antioxidative potential,Oxidative stress,Carteolol hydrochloride,Light-induced retinal damage,Reactive oxygen species
更新于2025-09-23 15:23:52
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Metal accumulation, biochemical and behavioral responses on the Mediterranean clams Ruditapes decussatus exposed to two photocatalyst nanocomposites (TiO2 NPs and AuTiO2NPs)
摘要： Nanoparticle decoration with noble metal represents a promising alternative to improve their photocatalytic and photovoltaic properties. However, toxicity can be influenced by such modification, as the bioavailability of these substances may be influenced. To understand how decoration influences the NP impacts in marine ecosystems, we exposed suspension-feeding clams, Ruditapes decussatus, to two photocatalyst nanocomposites, TiO2 NPs and AuTiO2 NPs, over 2 concentrations, 50 μg L?1 and 100 μg L?1, in a laboratory experiment. Accumulation of Au and Ti in gills and digestive gland was noted in clams after exposure to TiO2 NPs and AuTiO2 NPs using inductively coupled plasma optic emission spectroscopy (ICP-OES). TiO2 and AuTiO2 NPs alter the behavior of the clams Ruditapes decussatus by reducing filtration and respiration rates. Furthermore, the highest concentration of TiO2NPs induces an overproduction of H2O2 in gills and digestive gland and NO production only in gills. Superoxide dismutase (SOD), Catalase (CAT), Glutathione-S-transferase (GST) and acetylcholinesterase (AChE) activities were induced in gills and digestives gland in concentration and nanocomposite type dependent manner. Decorated form presented higher Malondialdehyde (MDA) levels in gills and digestive gland than the undecorated form, suggesting different mechanisms of action that may be mediated through oxidative stress. In conclusion, the considered parameters could represent reliable biomarkers for the assessment of NP toxicity on R. decussatus as biological biomonitoring model. In addition, based on the obtained results, nanoparticle decoration influences the toxicity of metal nanoparticles in marine organism.
关键词： Oxidative stress,Ruditapes decussatus,Biomarkers,TiO2 NPs,AuTiO2NPs
更新于2025-09-23 15:23:52
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Observation of Acetylcholinesterase in Stress-induced Depression Phenotypes by Two-photon Fluorescence Imaging in the Mouse Brain
摘要： Oxidative stress in depression is a prime cause of neurotransmitter metabolism dysfunction in the brain. Acetylcholinesterase (AChE), a key hydrolase in the cholinergic system, directly determines the degradation of neurotransmitters. However, due to the complexity of the brain and lack of appropriate in situ imaging tools, the mechanism underlying the changes in AChE activity in depression remains unclear. Hence, we generated a two-photon fluorescence probe (MCYN) for real-time visualization of AChE with excellent sensitivity and selectivity. AChE can specifically recognize and cleave the carbamic acid ester bond in MCYN, and MCYN emits bright fluorescence at 560 nm by two-photon excitation at 800 nm. By utilizing MCYN to monitor AChE, we discovered a significant increase in AChE activity in the brains of mice with depression phenotypes. Notably, with the assistance of a two-photon fluorescence imaging probe of the superoxide anion radical (O2??), in vivo visualization for the first time revealed the positive correlation between AChE and O2?? levels associated with depressive behaviors. This finding suggests that oxidative stress may induce AChE overactivation, leading to depression-related behaviors. This work provides a new and rewarding perspective to elucidate the role of oxidative stress regulating AChE in the pathology of depression.
关键词： acetylcholinesterase,depression,Two-photon fluorescence imaging,brain,oxidative stress
更新于2025-09-23 15:23:52
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Protective role of melatonin on retinal ganglionar cell: In vitro an in vivo evidences
摘要： Oxidative stress triggers ocular neurodegenerative diseases, such as glaucoma or macular degeneration. The increase of reactive oxygen and nitrogen species in retinal ganglion cells (RGCs) causes damage to the structure and function of the axons that make up the optic nerve, leading to cell death arising from apoptosis, necrosis or autophagy in the RCGs. The use of antioxidants to prevent visual neurodegenerative pathologies is a novel and possibly valuable therapeutic strategy. To investigate in vitro and in vivo neuroprotective efficacy of melatonin (MEL) in RGCs, we used a model of oxidative glutamate (GLUT) toxicity in combination with L-butionin-S, R-sulfoximine (BSO), which induces cell death by apoptosis through cytotoxicity and oxidative stress mechanisms. Histological sectioning and immunohistochemical assays using the TUNEL technique were performed to determine the damage generated in affected cells and to observe the death process of RGCs. Whit BSO-GLUT the results revealed a progressive RGCs death without any significant evidence of a decreased retinal function after 9 days of treatment. In this way, we were able to develop a retinal degeneration model in vivo to carry out treatment with MEL and observed an increase in the survival percentage of RGCs, showing that BSO-GLUT could not exert an oxidant effect on cells to counteract the effect of MEL. These findings reveal that MEL has a neuroprotective and antiapoptotic effect as evidenced by the reduction of oxidative stress damage. MEL demonstrated in this model makes it a promising neuroprotective agent for the treatment of ocular neurodegenerative diseases when administered locally.
关键词： Ganglion retinal cells (RGCs),Oxidative stress,Neuroprotection,Melatonin
更新于2025-09-23 15:23:52
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Effect of Anti-vascular Endothelial Growth Factor Antibody on the Survival of Cultured Retinal Ganglion Cells
摘要： Purpose: To investigate the effects of anti-vascular endothelial growth factor (VEGF) antibody on the survival of retinal ganglion cell (RGC)-5 cells differentiated with staurosporine under oxidative stress. Methods: We used real-time polymerase chain reaction and Western blot to confirm the expression of VEGF, VEGF receptor (VEGFR)-1 and VEGFR-2 in RGC-5 cells differentiated with staurosporine for 6 hours. The differentiated RGC-5 cells were treated with 800 μM hydrogen peroxide (H2O2) for 24 hours to induce oxidative stress. Then, the survival rate of RGC-5 was confirmed by lactate dehydrogenase assay at each concentration (0, 0.01, 0.1, and 1 mg) using bevacizumab as the anti-VEGF antibody. The expression of VEGF, VEGFR-1, and VEGFR-2 was confirmed using real-time polymerase chain reaction. Results: VEGF, VEGFR-1, and VEGFR-2 were all expressed in differentiated RGC-5 cells. When RGC-5 cells were simultaneously treated with bevacizumab and 800 μM H2O2, survival of RGC-5 decreased with bevacizumab concentration. VEGF expression in RGC-5 cells increased with increasing concentration of bevacizumab. Similar patterns were observed for VEGFR-1 and VEGFR-2, but the degree of increase was smaller than that for VEGF. Conclusions: When bevacizumab was administered to differentiated RGC-5 cells, the cell damage caused by oxidative stress increased. Therefore, given these in vitro study results, caution should be exercised with bevacizumab treatment.
关键词： Oxidative stress,RGC-5,Retinal ganglion cell,Anti-vascular endothelial growth factor,Bevacizumab
更新于2025-09-23 15:22:29