scholarly journals Therapeutic effect of Keap1-Nrf2-ARE pathway-related drugs on age-related eye diseases through anti-oxidative stress

2021 ◽  
Vol 14 (8) ◽  
pp. 1260-1273
Author(s):  
Zi-Yan Cai ◽  
◽  
Ke Liu ◽  
Xuan-Chu Duan ◽  
◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vision Loss ◽  
Eye Diseases ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Classical Pathway ◽  
Age Related ◽  
Important Relationship

Age-related eye diseases, including cataract, glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD), are the leading causes of vision loss in the world. Several studies have shown that the occurrence and development of these diseases have an important relationship with oxidative stress in the eye. The Keap1-Nrf2-ARE pathway is a classical pathway that resists oxidative stress and inflammation in the body. This pathway is also active in the development of age-related eye diseases. A variety of drugs have been shown to treat age-related eye diseases through the Keap1-Nrf2-ARE (Kelch-like ECH-Associating protein 1- nuclear factor erythroid 2 related factor 2-antioxidant response element) pathway. This review describes the role of oxidative stress in the development of age-related eye diseases, the function and regulation of the Keap1-Nrf2-ARE pathway, and the therapeutic effects of drugs associated with this pathway on age-related eye diseases.

scholarly journals A review of the role of oxidative stress in the pathogenesis of eye diseases

2011 ◽  
Vol 70 (4) ◽  
Author(s):  
O. A. Oduntan ◽  
K. P. Masige
Keyword(s):  
Oxidative Stress ◽  
Free Radicals ◽  
Open Angle Glaucoma ◽  
Epidemiological Studies ◽  
Eye Diseases ◽  
The Body ◽  
Alpha Tocopherol ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Unpaired Electrons

Free radicals, referred to as oxidants are molecules in the body with unpaired electrons, hence are unstable and ready to bond with other molecules with unpaired electrons.  They include Reactive Oxygen Species (ROS) such as superoxide anion radicals (·O¯), hydrogen peroxide (H202), and hydroxyl free radicals (·OH).  Endogenous sources of ROS include metabolic and other organic processes, while exogenous sources include ultraviolet radiation and environmental toxins such as smoke.  Antioxidants (oxidant scavengers) such as ascorbate, alpha-tocopherol and glutathione as well as various enzymatic compounds such as superoxide dismutase (SOD), catalase and glutathione reductase are also present in the body and in manyfoods or food supplements.  An imbalance between oxidants and antioxidants in favour of oxidantsis termed oxidative stress and can lead to cell or tissue damage and aging. Oxidative stress has been implicated in the pathogenesis of many serious systemic diseases such as diabetes, cancer and neurological disorders.  Also, laboratory and epidemiological studies have implicated oxidative stress in the pathogenesis of the majority of common serious eye diseases such as cataract, primary open angle glaucoma and age-related macular degeneration. In this article, we reviewed the current information on the roles of oxidative stress in the pathogenesis of various eye diseases and the probable roles of antioxidants.  Eye care practitioners will find this article useful as it provides information on the pathogenesis of common eye diseases. (S Afr Optom 2011 70(4) 182-190)

scholarly journals Lutein, Zeaxanthin, andmeso-Zeaxanthin in the Clinical Management of Eye Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Nicole K. Scripsema ◽  
Dan-Ning Hu ◽  
Richard B. Rosen
Keyword(s):  
Clinical Trials ◽  
Animal Studies ◽  
Serum Levels ◽  
Epidemiological Studies ◽  
Eye Diseases ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Therapeutic Effects ◽  
Age Related ◽  
Risk Of Progression

Lutein, zeaxanthin, andmeso-zeaxanthin are xanthophyll carotenoids found within the retina and throughout the visual system. The retina is one of the most metabolically active tissues in the body. The highest concentration of xanthophylls is found within the retina, and this selective presence has generated many theories regarding their role in supporting retinal function. Subsequently, the effect of xanthophylls in the prevention and treatment of various eye diseases has been examined through epidemiological studies, animal studies, and clinical trials. This paper attempts to review the epidemiological studies and clinical trials investigating the effects of xanthophylls on the incidence and progression of various eye diseases. Observational studies have reported that increased dietary intake and higher serum levels of lutein and zeaxanthin are associated with lower risk of age-related macular degeneration (AMD), especially late AMD. Randomized, placebo-controlled clinical trials have demonstrated that xanthophyll supplementation increases macular pigment levels, improves visual function, and decreases the risk of progression to late AMD, especially neovascular AMD. Current publications on the preventive and therapeutic effects of lutein and zeaxanthin on cataracts, diabetic retinopathy, and retinopathy of prematurity have reported encouraging results.

scholarly journals Age-Related Macular Degeneration: New Paradigms for Treatment and Management of AMD

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Luis Fernando Hernández-Zimbrón ◽  
Ruben Zamora-Alvarado ◽  
Lenin Ochoa-De la Paz ◽  
Raul Velez-Montoya ◽  
Edgar Zenteno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Visual Disability ◽  
Cellular Mechanisms ◽  
Cell Dysfunction ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is a well-characterized and extensively studied disease. It is currently considered the leading cause of visual disability among patients over 60 years. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss. There are two forms of AMD: the “dry” and the “wet” form that is less frequent but is responsible for 90% of acute blindness due to AMD. Risk factors have been associated with AMD progression, and they are taking relevance to understand how AMD develops: (1) advanced age and the exposition to environmental factors inducing high levels of oxidative stress damaging the macula and (2) this damage, which causes inflammation inducing a vicious cycle, altogether causing central vision loss. There is neither a cure nor treatment to prevent AMD. However, there are some treatments available for the wet form of AMD. This article will review some molecular and cellular mechanisms associated with the onset of AMD focusing on feasible treatments for each related factor in the development of this pathology such as vascular endothelial growth factor, oxidative stress, failure of the clearance of proteins and organelles, and glial cell dysfunction in AMD.

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

Antioxidants ◽  
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.

scholarly journals Oxidative Stress and Mitochondrial Damage in Dry Age-Related Macular Degeneration Like NFE2L2/PGC-1α -/- Mouse Model Evoke Complement Component C5a Independent of C3

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 622
Author(s):  
Iswariyaraja Sridevi Gurubaran ◽  
Hanna Heloterä ◽  
Stephen Marry ◽  
Ali Koskela ◽  
Juha M. T. Hyttinen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Macular Degeneration ◽  
Complement Component ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Complement Factor ◽  
Age Related ◽  
Dry Amd

Aging-associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g., age-related macular degeneration (AMD). Previously, we reported the presence of dry AMD-like signs, such as elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the retinal pigment epithelial (RPE) cells of nuclear factor erythroid 2-related factor 2, and a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (NFE2L2/PGC1α) double knockout (dKO) mouse model. Here, we investigated the dynamics of inflammatory markers in one-year-old NFE2L2/PGC1α dKO mice. Immunohistochemical analysis revealed an increase in levels of Toll-like receptors 3 and 9, while those of NOD-like receptor 3 were decreased in NFE2L2/PGC1α dKO retinal specimens as compared to wild type animals. Further analysis showed a trend towards an increase in complement component C5a independent of component C3, observed to be tightly regulated by complement factor H. Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detected an increase in primary acute phase C-reactive protein and receptor for advanced glycation end products in NFE2L2/PGC1α dKO retina. Our main data show C5 and thrombin upregulation together with decreased C3 levels in this dry AMD-like model. In general, the retina strives to mount an orchestrated inflammatory response while attempting to maintain tissue homeostasis and resolve inflammation.

scholarly journals Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

2021 ◽  
Vol 22 (19) ◽  
pp. 10279
Author(s):  
Gabriella D. Hartman ◽  
Nathan A. Lambert-Cheatham ◽  
Mark R. Kelley ◽  
Timothy W. Corson
Keyword(s):  
Vision Loss ◽  
Eye Diseases ◽  
Age Related Macular Degeneration ◽  
Neuroprotective Effects ◽  
Multifunctional Protein ◽  
Age Related ◽  
Transcription Factor Activation ◽  
Molecule Inhibitor ◽  
Orally Bioavailable ◽  
Endothelial Growth Factor

Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.

scholarly journals Superoxide Dismutase-1 Induced Oxidative Stress Mediated Apoptosis in Murine Retinal Pigment Epithelial Cells

2019 ◽  
Vol 8 (4S2) ◽  
pp. 463-466
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Vision Loss ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Superoxide Dismutase 1 ◽  
Central Vision Loss ◽  
Age Related ◽  
Pigment Epithelial Cells

Age related macular degeneration (AMD) is a complicated ocular disease which occurs in elderly people and leads to central vision loss. The AMD generated because of overproduction of oxidative stress which leads to RPE cell death. The present study investigates whether SOD1 induced MRPE cell death based on that overexpression of SOD1 in MRPE cells which induced cell death. The SOD1 gradually increased ROS production and fragmentation of nuclei. To explore the ER stress persuaded UPR via GRP78, and CHOP, protein expression level analyses were carried out by western blotting. Together, our results represent that SOD1 could possibly produce the oxidant induced MRPE cell death.

scholarly journals PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

2018 ◽  
Vol 19 (8) ◽  
pp. 2317 ◽  
Author(s):  
Kai Kaarniranta ◽  
Jakub Kajdanek ◽  
Jan Morawiec ◽  
Elzbieta Pawlowska ◽  
Janusz Blasiak
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sirtuin 1 ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

scholarly journals Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Samuel Abokyi ◽  
Chi-Ho To ◽  
Tim T. Lam ◽  
Dennis Y. Tse
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Macular Degeneration ◽  
Molecular Mechanisms ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Vascular Endothelial ◽  
Age Related ◽  
Endothelial Growth Factor

Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

scholarly journals Polyphenol Stilbenes: Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-24 ◽  
Author(s):  
Mika Reinisalo ◽  
Anna Kårlund ◽  
Ali Koskela ◽  
Kai Kaarniranta ◽  
Reijo O. Karjalainen
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Damage ◽  
Age Related Macular Degeneration ◽  
Related Factor ◽  
Age Related ◽  
Cellular Defence ◽  
The Impact ◽  
Stilbene Compounds

Numerous studies have highlighted the key roles of oxidative stress and inflammation in aging-related diseases such as obesity, type 2 diabetes, age-related macular degeneration (AMD), and Alzheimer’s disease (AD). In aging cells, the natural antioxidant capacity decreases and the overall efficiency of reparative systems against cell damage becomes impaired. There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases. This review highlights recent data helping to clarify the molecular mechanisms involved in the stilbene-mediated protection against oxidative stress. The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized. The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

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