Different Doses of β-Cryptoxanthin May Secure the Retina from Photooxidative Injury Resulted from Common LED Sources

Retinal damage associated with loss of photoreceptors is a hallmark of eye diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. Potent nutritional antioxidants were previously shown to abate the degenerative process in AMD. β-Cryptoxanthin (BCX) is an essential dietary carotenoid with antioxidant, anti-inflammatory, and provitamin A activity. It is a potential candidate for developing intervention strategies to delay the development/progression of AMD. In the current study, the effect of a novel, highly purified BCX oral formulation on the rat retinal damage model was evaluated. Rats were fed with BCX for four weeks at the doses of 2 and 4 mg/kg body weight in the form of highly bioavailable oil suspension, followed by retinal damage by exposing to the bright light-emitting diode (LED) light (750 lux) for 48 hrs. Animals were sacrificed after 48 hours, and eyes and blood samples were collected and analyzed. BCX supplementations (2 and 4 mg/kg) showed improvements in the visual condition as demonstrated by histopathology of the retina and measured parameters such as total retinal thickness and outer nuclear layer thickness. BCX supplementation helped reduce the burden of oxidative stress as seen by decreased serum and retinal tissue levels of malondialdehyde (MDA) and restored the antioxidant enzyme activities in BCX groups. Further, BCX supplementation modulated inflammatory markers (IL-1β, IL-6, and NF-κB), apoptotic proteins (Bax, Bcl-2, caspase 3), growth proteins and factors (GAP43, VEGF), glial and neuronal proteins (GFAP, NCAM), and heme oxygenase-1 (HO-1), along with the mitochondrial stress markers (ATF4, ATF6, Grp78, Grp94) in the rat retinal tissue. This study indicates that oral supplementation of BCX exerts a protective effect on light-induced retinal damage in the rats via reducing oxidative stress and inflammation, also protected against mitochondrial DNA damage and cellular death.

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Dietary Supplementation with Beta-Cryptoxanthin (BCX) Protects Against Light-Induced Retinal Damage

Current Developments in Nutrition ◽

10.1093/cdn/nzaa041_030 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 126-126

Author(s):

Deshanie Rai ◽

Kazim Sahin ◽

Emre Sahin ◽

Mehmet Tuzcu ◽

...

Keyword(s):

Oxidative Stress ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Angiogenic Factor ◽

Retinal Damage ◽

Waste Products ◽

Health Technologies ◽

Retinal Tissue ◽

Age Related ◽

Markers Of Oxidative Stress

Abstract Objectives The retinal pigment epithelium (RPE) regulates the transport of nutrients and waste products to and from the retina and protects against light and oxidative stress. Structural or physiological dysfunction of RPE leads to retinal conditions such as age-related eye disease (ARED). It is well-established that artificial and natural light is an important factor in the progression of ARED as it can induce oxidative damage and photochemical lesions. Recently, the use of LED in general lighting has raised concerns regarding the effects of this light source on the RPE. The goal was to investigate whether beta-cryptoxanthin, an efficient pro-vitamin A carotenoid can exert protective effects against LED-induced RPE cell damage. Methods Rats were fed with BCX for 4 weeks at a dose of 2 and 4 mg/kg body weight followed by retinal damage by exposing the eye to bright LED light for 48 hrs. Commercially available white LED sources, which are widely used in rat housing studies was used to induce retinal damage. Animals were sacrificed at the end of the study and retinal tissue and blood samples were collected and evaluated for retinal damage and markers of oxidative stress. Results BCX supplementation significantly reduced retinal damage as demonstrated by histopathology measurements including total retinal thickness, outer nuclear layer thickness, and swelling. Similarly, markers of oxidative stress including serum and retinal tissue levels of malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase were beneficially modulated by BCX supplementation. In parallel, BCX supplementation reduced inflammatory markers (IL-1β, IL-6, NF-κB), angiogenic factor VEGF, apoptotic proteins (Caspase-3, GAP43, GFAP, NCAM, HO-1) and mitochondrial stress markers (ATF4, ATF6, Grp78, Grp97) in retinal tissue. Conclusions Our study supports that oral supplementation of BCX dose-dependently exerts a protective effect against retinal damage induced by high-intensity light in a rat model by reducing oxidative stress, inflammation, angigogenesis and protection against mitochondrial DNA damage. BCX dietary intakes and supplementation throughout all stages of life can help protect against ARED that may start early in life. Funding Sources OmniActive Health Technologies.

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The Protective Effects of α-Mangostin Attenuate Sodium Iodate-Induced Cytotoxicity and Oxidative Injury via Mediating SIRT-3 Inactivation via the PI3K/AKT/PGC-1α Pathway

Antioxidants ◽

10.3390/antiox10121870 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1870

Author(s):

Chen-Ju Chuang ◽

Meilin Wang ◽

Jui-Hsuan Yeh ◽

Tzu-Chun Chen ◽

Shang-Chun Tsou ◽

...

Keyword(s):

Oxidative Stress ◽

Caspase 3 ◽

Cell Damage ◽

Outer Nuclear Layer ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Dependent Manner ◽

Protective Effects ◽

Age Related

It is well known that age-related macular degeneration (AMD) is an irreversible neurodegenerative disease that can cause blindness in the elderly. Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a part of the pathogenesis of AMD. In this study, we evaluated the protective effect and mechanisms of alpha-mangostin (α-mangostin, α-MG) against NaIO3-induced reactive oxygen species (ROS)-dependent toxicity, which activates apoptosis in vivo and in vitro. MTT assay and flow cytometry demonstrated that the pretreatment of ARPE-19 cells with α-MG (0, 3.75, 7.5, and 15 μM) significantly increased cell viability and reduced apoptosis from NaIO3-induced oxidative stress in a concentration-dependent manner, which was achieved by the inhibition of Bax, cleaved PARP-1, cleaved caspase-3 protein expression, and enhancement of Bcl-2 protein. Furthermore, pre-incubation of ARPE-19 cells with α-MG markedly inhibited the intracellular ROS and extracellular H2O2 generation via blocking of the abnormal enzyme activities of superoxide dismutase (SOD), the downregulated levels of catalase (CAT), and the endogenous antioxidant, glutathione (GSH), which were regulated by decreasing PI3K-AKT-PGC-1α-STRT-3 signaling in ARPE-19 cells. In addition, our in vivo results indicated that α-MG improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer by inhibiting the expression of cleaved caspase-3 protein. Taken together, our results suggest that α-MG effectively protects human ARPE-19 cells from NaIO3-induced oxidative damage via antiapoptotic and antioxidant effects.

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Relationship between Oxidative Stress, Circadian Rhythms, and AMD

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7420637 ◽

2016 ◽

Vol 2016 ◽

pp. 1-18 ◽

Cited By ~ 30

Author(s):

María Luisa Fanjul-Moles ◽

Germán Octavio López-Riquelme

Keyword(s):

Oxidative Stress ◽

Circadian Rhythms ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Retinal Damage ◽

Cell Organelles ◽

Age Related ◽

Exogenous Factors ◽

The Relationship

This work reviews concepts regarding oxidative stress and the mechanisms by which endogenous and exogenous factors produce reactive oxygen species (ROS). It also surveys the relationships between oxidative stress, circadian rhythms, and retinal damage in humans, particularly those related to light and photodamage. In the first section, the production of ROS by different cell organelles and biomolecules and the antioxidant mechanisms that antagonize this damage are reviewed. The second section includes a brief review of circadian clocks and their relationship with the cellular redox state. In the third part of this work, the relationship between retinal damage and ROS is described. The last part of this work focuses on retinal degenerative pathology, age-related macular degeneration, and the relationships between this pathology, ROS, and light. Finally, the possible interactions between the retinal pigment epithelium (RPE), circadian rhythms, and this pathology are discussed.

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Catalpol Protects ARPE-19 Cells against Oxidative Stress via Activation of the Keap1/Nrf2/ARE Pathway

Cells ◽

10.3390/cells10102635 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2635

Author(s):

Longtai You ◽

Hulinyue Peng ◽

Jing Liu ◽

Mengru Cai ◽

Huimin Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Phase Cell ◽

Heme Oxygenase 1 ◽

Iridoid Glucoside ◽

Rpe Cells ◽

Expression Levels ◽

Cycle Arrest ◽

Age Related

Oxidative damage to retinal pigment epithelial (RPE) has been identified as one of the major regulatory factors in the pathogenesis of age-related macular degeneration (AMD). Catalpol is an iridoid glucoside compound that has been found to possess potential antioxidant activity. In the present study, we aimed to investigate the protective effect of catalpol on RPE cells under oxidative stress and to elucidate the potential molecular mechanism involved. We found that catalpol significantly attenuated hydrogen peroxide (H2O2)-induced cytotoxicity, G0/G1 phase cell cycle arrest, and apoptosis in RPE cells. The overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA) stimulated by oxidative stress and the corresponding reductions in antioxidant glutathione (GSH) and superoxide dismutase (SOD) levels were largely reversed by catalpol pretreatment. Moreover, catalpol pretreatment markedly activated the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its downstream antioxidant enzymes, catalase (CAT), heme oxygenase-1 (HO-1), and NADPH dehydrogenase (NQO1). It also increased the expression levels of cyclin E Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK2) and decreased the expression levels of Bax, Fas, cleaved PARP, p-p53, and p21 cleaved caspase-3, 8, and 9. The oxidative stress-induced formation of the Keap1/Nrf2 complex in the cytoplasm was significantly blocked by catalpol pretreatment. These results indicate that catalpol protected RPE cells from oxidative stress through a mechanism involving the activation of the Keap1/Nrf2/ARE pathways and the inactivation of oxidative stress-mediated pathways of apoptosis.

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Effects of Novel Nitric Oxide-Releasing Molecules against Oxidative Stress on Retinal Pigmented Epithelial Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/1420892 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 21

Author(s):

Valeria Pittalà ◽

Annamaria Fidilio ◽

Francesca Lazzara ◽

Chiara Bianca Maria Platania ◽

Loredana Salerno ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Epithelial Cells ◽

Cell Survival ◽

Retinal Pigment ◽

Covalent Bond ◽

Retinal Pigment Epithelial Cells ◽

Age Related Macular Degeneration ◽

Heme Oxygenase 1 ◽

Age Related

Oxidative stress is a hallmark of retinal degenerations such as age-related macular degeneration and diabetic retinopathy. Enhancement of heme oxygenase-1 (HO-1) activity in the retina would exert beneficial effects by protecting cells from oxidative stress, therefore promoting cell survival. Because a crosstalk exists between nitric oxide (NO) and HO-1 in promotion of cell survival under oxidative stress, we designed novel NO-releasing molecules also capable to induce HO-1. Starting from curcumin and caffeic acid phenethyl ester (CAPE), two known HO-1 inducers, the molecules were chemically modified by acylation with 4-bromo-butanoyl chloride and 2-chloro-propanoyl chloride, respectively, and then treated in the dark with AgNO3 to obtain the nitrate derivatives VP10/12 and VP10/39. Human retinal pigment epithelial cells (ARPE-19) subjected to H2O2-mediated oxidative stress were treated with the described NO-releasing compounds. VP10/39 showed significant (p<0.05) antioxidant and protecting activity against oxidative damage, in comparison to VP10/12, which in turn showed at 100 μM concentration a slight but significant cell toxicity. Only VP10/39 significantly (p<0.05) induced HO-1 in ARPE-19, most likely through covalent bond formation at Cys151 of the Keap1-BTB domain, as revealed from molecular docking analysis. In conclusion, the present data indicate VP10/39 as a promising candidate to protect ARPE-19 cells against oxidative stress.

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Oxidative Stress, Ocular Disease and Diabetes Retinopathy

Current Pharmaceutical Design ◽

10.2174/1381612825666190115121531 ◽

2019 ◽

Vol 24 (40) ◽

pp. 4726-4741 ◽

Cited By ~ 8

Author(s):

Orathai Tangvarasittichai ◽

Surapon Tangvarasittichai

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Cell Death ◽

Protein Modification ◽

Morphological Changes ◽

Corneal Dystrophy ◽

Age Related Macular Degeneration ◽

Ocular Diseases ◽

Retinal Light Damage ◽

Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

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Crosstalk between Long-Term Sublethal Oxidative Stress and Detrimental Inflammation as Potential Drivers for Age-Related Retinal Degeneration

Antioxidants ◽

10.3390/antiox10010025 ◽

2020 ◽

Vol 10 (1) ◽

pp. 25

Author(s):

Lara Macchioni ◽

Davide Chiasserini ◽

Letizia Mezzasoma ◽

Magdalena Davidescu ◽

Pier Luigi Orvietani ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Mechanisms ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factor ◽

Nuclear Factor ◽

Rpe Cells ◽

Age Related ◽

Oxidative Insult

Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.

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FHL-1 interacts with human RPE cells through the α5β1 integrin and confers protection against oxidative stress

Scientific Reports ◽

10.1038/s41598-021-93708-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rawshan Choudhury ◽

Nadhim Bayatti ◽

Richard Scharff ◽

Ewa Szula ◽

Viranga Tilakaratna ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Fate ◽

Retinal Pigment ◽

Factor H ◽

Age Related Macular Degeneration ◽

Bruch's Membrane ◽

Bruch’S Membrane ◽

Rpe Cells ◽

Age Related

AbstractRetinal pigment epithelial (RPE) cells that underlie the neurosensory retina are essential for the maintenance of photoreceptor cells and hence vision. Interactions between the RPE and their basement membrane, i.e. the inner layer of Bruch’s membrane, are essential for RPE cell health and function, but the signals induced by Bruch’s membrane engagement, and their contributions to RPE cell fate determination remain poorly defined. Here, we studied the functional role of the soluble complement regulator and component of Bruch’s membrane, Factor H-like protein 1 (FHL-1). Human primary RPE cells adhered to FHL-1 in a manner that was eliminated by either mutagenesis of the integrin-binding RGD motif in FHL-1 or by using competing antibodies directed against the α5 and β1 integrin subunits. These short-term experiments reveal an immediate protein-integrin interaction that were obtained from primary RPE cells and replicated using the hTERT-RPE1 cell line. Separate, longer term experiments utilising RNAseq analysis of hTERT-RPE1 cells bound to FHL-1, showed an increased expression of the heat-shock protein genes HSPA6, CRYAB, HSPA1A and HSPA1B when compared to cells bound to fibronectin (FN) or laminin (LA). Pathway analysis implicated changes in EIF2 signalling, the unfolded protein response, and mineralocorticoid receptor signalling as putative pathways. Subsequent cell survival assays using H2O2 to induce oxidative stress-induced cell death suggest hTERT-RPE1 cells had significantly greater protection when bound to FHL-1 or LA compared to plastic or FN. These data show a non-canonical role of FHL-1 in protecting RPE cells against oxidative stress and identifies a novel interaction that has implications for ocular diseases such as age-related macular degeneration.

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The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

Cells ◽

10.3390/cells10010064 ◽

2021 ◽

Vol 10 (1) ◽

pp. 64

Author(s):

Annamaria Tisi ◽

Marco Feligioni ◽

Maurizio Passacantando ◽

Marco Ciancaglini ◽

Rita Maccarone

Keyword(s):

Oxidative Stress ◽

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Blood Retinal Barrier ◽

Functional Changes ◽

Beneficial Effects ◽

Age Related ◽

The Impact

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch’s membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

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Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

International Journal of Molecular Sciences ◽

10.3390/ijms22031296 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1296

Author(s):

Yue Ruan ◽

Subao Jiang ◽

Adrian Gericke

Keyword(s):

Oxidative Stress ◽

Macular Degeneration ◽

Vascular Function ◽

Vascular Dysfunction ◽

Therapeutic Strategies ◽

Vision Impairment ◽

Age Related Macular Degeneration ◽

Oxygen Species ◽

Age Related

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

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