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Yan Y, Wu Y, Zhao Y, Yang Y, An G, Liu Z, Qi D. A review on eye diseases induced by blue light: pathology, model, active ingredients and mechanisms. Front Pharmacol 2025; 16:1513406. [PMID: 39917620 PMCID: PMC11798942 DOI: 10.3389/fphar.2025.1513406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 01/02/2025] [Indexed: 02/09/2025] Open
Abstract
Blue light induced eye damage (BLED) belongs to modern diseases. It is an ophthalmic disease caused by prolonged exposure to electronic devices or screens containing a large amount of high-energy short waves (blue light). Specific symptoms include dryness and discomfort in the eyes, blurred vision, headache, insomnia, and in severe cases, it may also cause various eye diseases such as cataracts and glaucoma. At present, the development of health products and drugs for eye blue light injury faces many difficulties. Therefore, further exploration and research are needed on the pathogenesis, pathophysiology, and pharmacological mechanisms of blue light injury. Natural medicine ingredients and preparations have unique advantages in targeting eye blue light injury fatigue products due to their multi-component synergistic effects, overall regulation, and mild and safe characteristics. Starting from the disease-related mechanisms and pathophysiological characteristics of eye blue light injury, this article elucidates the pharmacological mechanisms of various drugs for treating eye blue light injury. At the same time, it reviews the research on in vitro cultured cell and animal model conditions for blue light injury eyes, in order to provide reference for subsequent blue light injury modeling experiments. And explore future research directions to provide new ideas and methods for the prevention and treatment of BLED.
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Affiliation(s)
- Yuan Yan
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yiyao Wu
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yu Zhao
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yaguang Yang
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guangtao An
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhidong Liu
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- College of Chinese Medicine, Tianjin University of Chinese Medicine, Tianjin, China
| | - Dongli Qi
- Haihe Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Cai J, Liao F, Mao Y, Liu S, Wu X, Tang S, Wang S, Shan G, Wu S. Regulation of LAMTOR1 by oxidative stress in retinal pigment epithelium: Implications for age-related macular degeneration pathogenesis. Exp Eye Res 2024; 249:110129. [PMID: 39424220 DOI: 10.1016/j.exer.2024.110129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/23/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Oxidative stress is a critical pathogenic factor for age-related macular degeneration (AMD). Autophagy serves as a mechanism to counteract oxidative stress. LAMTOR1 regulates mTORC1 activity by recruiting or disassembling it on the lysosome under the addition or deprivation of amino acids. This regulation inhibits or enhances autophagy. Our study investigates whether oxidative stress impacts LAMTOR1, thereby adapting to oxidative conditions. We employed oxidative stressors, menadione (VK3) and 4-hydroxynonenal (4-HNE), and observed a reduction of LAMTOR1 in both human and mouse retinal pigment epithelium (RPE) following short-term (1h) and prolonged exposures (24h). Nrf2 overexpression increased both lamtor1 mRNA and LAMTOR1 protein in the RPE. To determine if Nrf2 regulates lamtor1 transcription, we cloned the deletion mutants of the lamtor1 promoter into a luciferase reporter. Although the promoter contained antioxidant response elements, transcriptional activity depended on the interaction between Nrf2 and the constructs containing the transcriptional start site. Moreover, Nrf2-driven transcription was significantly reduced by an inhibitor of histone acetyltransferase, p300. Correspondingly, Nrf2 overexpression increased levels of acetylated histone 3 and p300. The reduction in LAMTOR1 by 4-HNE was reversed by pepstatin A and NH4Cl which block lysosomal degradation. 4-HNE increased TFEB nuclear translocation which was reversed by LAMTOR1 overexpression. In vivo, LAMTOR1 levels decreased in the photoreceptor and RPE layers of NaIO3-injected mice, compared to PBS-injected controls. In conclusion, oxidative injury reduces LAMTOR1, predominantly through lysosomal degradation although Nrf2-mediated histone acetylation enhances lamtor1 transcription. This study reveals a previously unrecognized regulatory mechanism of lamtor1 by oxidative stress, suggesting a novel role for LAMTOR1 in the pathogenesis of AMD.
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Affiliation(s)
- Jingjing Cai
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Fei Liao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Yandie Mao
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Shuyi Liu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiong Wu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Shiqi Tang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Simin Wang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ge Shan
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, 230027, China
| | - Shengzhou Wu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
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Seol A, Kim JE, Jin YJ, Song HJ, Roh YJ, Kim TR, Park ES, Park KH, Park SH, Uddin MS, Lee SW, Choi YW, Hwang DY. Novel Therapeutic Effects of Euphorbia heterophylla L. Methanol Extracts in Macular Degeneration Caused by Blue Light in A2E-Laden ARPE-19 Cells and Retina of BALB/c Mice. Pharmaceuticals (Basel) 2024; 17:1193. [PMID: 39338355 PMCID: PMC11435363 DOI: 10.3390/ph17091193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/05/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
Natural products with high antioxidant activity are considered as innovative prevention strategies to effectively prevent age-related macular degeneration (AMD) in the early stage because the generation of reactive oxygen species (ROS) leading to the development of drusen is reported as an important cause of this disease. To investigate the prevention effects of the methanol extracts of Euphorbia heterophylla L. (MEE) on AMD, its effects on the antioxidant activity, inflammatory response, apoptosis pathway, neovascularization, and retinal tissue degeneration were analyzed in N-retinylidene-N-retinylethanolamine (A2E)-landed spontaneously arising retinal pigment epithelia (ARPE)-19 cells and BALB/c mice after exposure to blue light (BL). The MEE contained 10 active components and showed high free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and nitric oxide (NO) radicals. The pretreatments of high-dose MEE remarkably suppressed the production of intracellular ROS (88.2%) and NO (25.2%) and enhanced (SOD) activity (84%) and the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2) in A2E + BL-treated ARPE-19 cells compared to Vehicle-treated group. The activation of the inducible nitric oxide synthase (iNOS)-induced cyclooxygenase-2 (COX-2) mediated pathway, inflammasome activation, and expression of inflammatory cytokines was significantly inhibited in A2E + BL-treated ARPE-19 cells after the MEE pretreatment. The activation of the apoptosis pathway and increased expression of neovascular proteins (36% for matrix metalloproteinase (MMP)-9) were inhibited in the MEE pretreated groups compared to the Vehicle-treated group. Furthermore, the thickness of the whole retina (31%), outer nuclear layer (ONL), inner nuclear layer (INL), and photoreceptor layer (PL) were significantly increased by the MEE pretreatment of BALB/c mice with BL-induced retinal degeneration. Therefore, these results suggest that the MEE, with its high antioxidative activity, protects against BL-induced retinal degeneration through the regulation of the antioxidative system, inflammatory response, apoptosis, and neovascularization in the AMD mouse model.
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Affiliation(s)
- Ayun Seol
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Ji-Eun Kim
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - You-Jeong Jin
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Hee-Jin Song
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Yu-Jeong Roh
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Tae-Ryeol Kim
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Eun-Seo Park
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Ki-Ho Park
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - So-Hae Park
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | | | - Sang-Woo Lee
- International Biological Material Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Young-Woo Choi
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
| | - Dae-Youn Hwang
- Department of Biomaterials Science (BK21 FOUR Program), Life and Industry Convergence Research Institute, College of Natural Resources and Life Science, Pusan National University, Miryang 50463, Republic of Korea
- Longevity & Wellbeing Research Center, Laboratory Animals Resources Center, Pusan National University, Miryang 50463, Republic of Korea
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Cervantes-Paz B, Yahia EM. Avocado oil: Production and market demand, bioactive components, implications in health, and tendencies and potential uses. Compr Rev Food Sci Food Saf 2021; 20:4120-4158. [PMID: 34146454 DOI: 10.1111/1541-4337.12784] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/06/2021] [Accepted: 05/17/2021] [Indexed: 12/30/2022]
Abstract
Avocado is a subtropical/tropical fruit with creamy texture, peculiar flavor, and high nutritional value. Due to its high oil content, a significant quantity of avocado fruit is used for the production of oil using different methods. Avocado oil is rich in lipid-soluble bioactive compounds, but their content depends on different factors. Several phytochemicals in the oil have been linked to prevention of cancer, age-related macular degeneration, and cardiovascular diseases and therefore have generated an increase in consumer demand for avocado oil. The aim of this review is to critically and systematically analyze the worldwide production and commercialization of avocado oil, its extraction methods, changes in its fat-soluble phytochemical content, health benefits, and new trends and applications. There is a lack of information on the production and commercialization of the different types of avocado oil, but there are abundant data on extraction methods using solvents, centrifugation-assisted aqueous extraction, mechanical extraction by cold pressing (varying concentration and type of enzymes, temperature and time of reaction, and dilution ratio), ultrasound-assisted extraction, and supercritical fluid to enhance the yield and quality of oil. Extensive information is available on the content of fatty acids, although it is limited on carotenoids and chlorophylls. The effect of avocado oil on cancer, diabetes, and cardiovascular diseases has been demonstrated through in vitro and animal studies, but not in humans. Avocado oil continues to be of interest to the food, pharmaceutical, and cosmetic industries and is also generating increased attention in other areas including structured lipids, nanotechnology, and environmental care.
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Affiliation(s)
- Braulio Cervantes-Paz
- Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Juriquilla, México.,Instituto de Investigación de Zonas Desérticas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México
| | - Elhadi M Yahia
- Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Juriquilla, México
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Vagge A, Ferro Desideri L, Del Noce C, Di Mola I, Sindaco D, Traverso CE. Blue light filtering ophthalmic lenses: A systematic review. Semin Ophthalmol 2021; 36:541-548. [PMID: 33734926 DOI: 10.1080/08820538.2021.1900283] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background: Blue blocking (BB) lenses, including spectacles and intraocular lenses, work by attenuating short-wavelength light. BB glasses are being marketed with the aim to reduce eye fatigue symptoms when using digital devices, improve sleep quality and potentially confer protection from retinal phototoxicity. BB intraocular lenses following cataract surgery may be implanted because they are thought to prevent age-related macular degeneration (AMD) progression.Methods: The present study is a systematic review aiming to analyze BB lenses clinical efficacy in preventing blue light-related ocular disorders, including AMD progression, eye fatigue, and their impact on sleep quality. We searched Medline, PubMed, Web of Science and the Cochrane Library until May 2020.Results:Although several studies have been performed investigating BB lenses, clinical efficacy for preventing or attenuating the above-mentioned ocular disorders is often theorical or based on laboratory or animal experiments. Conclusions: To date, there is a lack of consistent evidence for a larger-sclale introduction of BB lenses in the routine clinical practice.
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Affiliation(s)
- Aldo Vagge
- IRCCS Polyclinic Hospital San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
| | - Lorenzo Ferro Desideri
- IRCCS Polyclinic Hospital San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
| | - Chiara Del Noce
- IRCCS Polyclinic Hospital San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
| | - Ilaria Di Mola
- IRCCS Polyclinic Hospital San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
| | - Daniele Sindaco
- IRCCS Polyclinic Hospital San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
| | - Carlo E Traverso
- IRCCS Polyclinic Hospital San Martino, Genoa, Italy.,Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (Dinogmi), University of Genoa, Italy
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Gao XD, Liu SL, Fei GT, Zhang LD, Men DD, Zhang Y, Xu SH, Li XH. Plasmonic ordered pore array Ag film coated glass: transparent and solar heat reflective material. NANOTECHNOLOGY 2020; 31:145203. [PMID: 31860897 DOI: 10.1088/1361-6528/ab646a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
In this paper, we fabricate ordered pore array (OPA) Ag film coated glass with the aid of polystyrene sphere (PS) array templates. This kind of OPA Ag coated glass has optical advantages of visible transparency, blue and near-infrared resistance. The average visible transmittance is 68%, including a transmission peak of 78% located at 570 nm, and low average transmittance of 48% in the blue light region that is not damaging to the eyes. The near-infrared light blocking rate is 67%, among which 40% light is reflected directly, indicating the reflection domination.
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Affiliation(s)
- Xu Dong Gao
- Key Laboratory of Materials Physics and Anhui Key Laboratory of Nanomaterials and Nanotechnology, Institute of Solid State Physics, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, People's Republic of China
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Che L, Song JY, Lou Y, Li GY. Analysis from the perspective of cilia: the protective effect of PARP inhibitors on visual function during light-induced damage. Int Ophthalmol 2019; 40:1017-1027. [PMID: 31802371 DOI: 10.1007/s10792-019-01245-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 11/23/2019] [Indexed: 12/26/2022]
Abstract
PURPOSE To analyze the protective effect of PARP inhibitors on light-damaged retina and explore its possible mechanism from the perspective of ciliopathy. METHODS A systematic review of the literature was performed to investigate the protection of PARP inhibition on light-damaged cilia. PubMed database was retrieved to find the relevant studies and 119 literatures were involved in the review. RESULTS In retina, the outer segment of photoreceptor is regarded as a special type of primary cilium, so various retinal diseases actually belong to a type of ciliopathy. The retina is the only central nervous tissue exposed to light, but poly (ADP-ribose) polymerase (PARP), as a nuclear enzyme repairing DNA breaks, is overactivated during the light-induced DNA damage, and is involved in the cell death cascade. Studies show that both ATR and phosphorylated Akt colocalize with cilium and play an important role in regulating ciliary function. PARP may function at ATR or PI3K/Akt signal to exert protective effect on cilia. CONCLUSION PARP inhibitors may protect the cilia/OS of photoreceptor during light-induced damage, which the possible mechanism may be involved in the activation of ATR and PI3K/Akt signal.
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Affiliation(s)
- Lin Che
- Department of Ophthalmology, Second Hospital of Jilin University, Changchun, 130041, China
| | - Jing-Yao Song
- Department of Ophthalmology, Second Hospital of Jilin University, Changchun, 130041, China
| | - Yan Lou
- Department of Nephropathy, Second Hospital of Jilin University, Changchun, 130041, China
| | - Guang-Yu Li
- Department of Ophthalmology, Second Hospital of Jilin University, Changchun, 130041, China.
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Chen JL, Hung CT, Keller JJ, Lin HC, Wu YJ. Proteomic analysis of retinal pigment epithelium cells after exposure to UVA radiation. BMC Ophthalmol 2019; 19:168. [PMID: 31375076 PMCID: PMC6679551 DOI: 10.1186/s12886-019-1151-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 06/24/2019] [Indexed: 01/09/2023] Open
Abstract
Background Age-related macular degeneration (AMD) is the primary cause of blindness and severe vision loss in developed countries and is responsible for 8.7% of blindness globally. Ultraviolet radiation can induce DNA breakdown, produce reactive oxygen species, and has been implicated as a risk factor for AMD. This study investigated the effects of UVA radiation on Human retinal pigment epithelial cell (ARPE-19) growth and protein expression. Methods ARPE-19 cells were irradiated with a UVA lamp at different doses (5, 10, 20, 30 and 40 J/cm2) from 10 cm. Cell viability was determined by MTT assay. Visual inspection was first achieved with inverted light microscopy and then the DeadEnd™ Fluorometric TUNEL System was used to observe nuclear DNA fragmentation. Flow cytometry based-Annexin V-FITC/PI double-staining was used to further quantify cellular viability. Mitochondrial membrane potential was assessed with JC-1 staining. 2D electrophoresis maps of exposed cells were compared to nonexposed cells and gel images analyzed with PDQuest 2-D Analysis Software. Spots with greater than a 1.5-fold difference were selected for LC-MS/MS analysis and some confirmed by western blot. We further investigated whether caspase activation, apoptotic-related mitochondrial proteins, and regulators of ER stress sensors were involved in UVA-induced apoptosis. Results We detected 29 differentially expressed proteins (9 up-regulated and 20 down-regulated) in the exposed cells. Some of these proteins such as CALR, GRP78, NPM, Hsp27, PDI, ATP synthase subunit alpha, PRDX1, and GAPDH are associated with anti-proliferation, induction of apoptosis, and oxidative-stress protection. We also detected altered protein expression levels among caspases (caspase 3 and 9) and in the mitochondrial (cytosolic cytochrome C, AIF, Mcl-1, Bcl-2, Bcl-xl, Bax, Bad, and p-Bad) and ER stress-related (p-PERK, p-eIF2α, ATF4 and CHOP) apoptotic pathways. Conclusions UVA irradiation suppressed the proliferation of ARPE-19 cells in a dose-dependent manner, caused quantitative loses in transmembrane potential (ΔΨm), and induced both early and late apoptosis.
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Affiliation(s)
- Jiunn-Liang Chen
- Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
| | - Chun-Tzu Hung
- Department of Ophthalmology, Yuan's General Hospital, Kaohsiung, Taiwan
| | - Joseph Jordan Keller
- College of Medicine, The Ohio State University, Columbus, OH, USA.,School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan.,International Master's Program, College of Health Technology, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Hsien-Chung Lin
- Department of Ophthalmology, Yuan's General Hospital, Kaohsiung, Taiwan. .,Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Yu-Jen Wu
- Department of Beauty Science, Meiho University, Pingtung, Taiwan.
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Gea M, Schilirò T, Iacomussi P, Degan R, Bonetta S, Gilli G. Cytotoxicity and genotoxicity of light emitted by incandescent, halogen, and LED bulbs on ARPE-19 and BEAS-2B cell lines. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2018; 81:998-1014. [PMID: 30325709 DOI: 10.1080/15287394.2018.1510350] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
LED technology has the extraordinary ability to reduce energy consumption, constituting an economic and ecological advantage, so it is planned to replace incandescent, halogen and other inefficient bulbs for public and domestic lighting with LEDs. LEDs present specific spectral and energetic characteristics compared with those of other domestic light sources, so the potential risks for human health of these bulbs need to be explored. The aim of this study was to assess cytotoxicity and genotoxicity of light emitted by different commercial light bulbs: incandescent, halogen, and two LED bulbs with different correlated color temperatures. The evaluation was done on ARPE-19 as a specific cell model for eye toxicity and on BEAS-2B as a good cell model for toxicology tests. Light induced mainly cytotoxic effects on ARPE-19 and DNA damage on BEAS-2B, so different cell lines showed different biological responses. Moreover, our findings indicate that among the four bulbs, cold LED caused the highest cytotoxic effect on ARPE-19 and the highest genotoxic and oxidative effect on BEAS-2B. Cold LED is probably able to cause more cellular damage because it contains more high-energy radiations (blue). These results suggest that LED technology could be a safe alternative to older technologies, but the use of warm LED should be preferred to cold LED, which can potentially cause adverse effects on retinal cells.
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Affiliation(s)
- Marta Gea
- a Department of Public Health and Pediatrics , University of Torino , Torino , Italy
| | - Tiziana Schilirò
- a Department of Public Health and Pediatrics , University of Torino , Torino , Italy
| | - Paola Iacomussi
- b Italian National Metrological Institute , INRIM , Torino , Italy
| | - Raffaella Degan
- a Department of Public Health and Pediatrics , University of Torino , Torino , Italy
| | - Sara Bonetta
- a Department of Public Health and Pediatrics , University of Torino , Torino , Italy
| | - Giorgio Gilli
- a Department of Public Health and Pediatrics , University of Torino , Torino , Italy
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Bernstein PS, Li B, Vachali PP, Gorusupudi A, Shyam R, Henriksen BS, Nolan JM. Lutein, zeaxanthin, and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease. Prog Retin Eye Res 2016; 50:34-66. [PMID: 26541886 PMCID: PMC4698241 DOI: 10.1016/j.preteyeres.2015.10.003] [Citation(s) in RCA: 340] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 10/04/2015] [Accepted: 10/29/2015] [Indexed: 12/31/2022]
Abstract
The human macula uniquely concentrates three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. Lutein and zeaxanthin must be obtained from dietary sources such as green leafy vegetables and orange and yellow fruits and vegetables, while meso-zeaxanthin is rarely found in diet and is believed to be formed at the macula by metabolic transformations of ingested carotenoids. Epidemiological studies and large-scale clinical trials such as AREDS2 have brought attention to the potential ocular health and functional benefits of these three xanthophyll carotenoids consumed through the diet or supplements, but the basic science and clinical research underlying recommendations for nutritional interventions against age-related macular degeneration and other eye diseases are underappreciated by clinicians and vision researchers alike. In this review article, we first examine the chemistry, biochemistry, biophysics, and physiology of these yellow pigments that are specifically concentrated in the macula lutea through the means of high-affinity binding proteins and specialized transport and metabolic proteins where they play important roles as short-wavelength (blue) light-absorbers and localized, efficient antioxidants in a region at high risk for light-induced oxidative stress. Next, we turn to clinical evidence supporting functional benefits of these carotenoids in normal eyes and for their potential protective actions against ocular disease from infancy to old age.
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Affiliation(s)
- Paul S Bernstein
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
| | - Binxing Li
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
| | - Preejith P Vachali
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
| | - Aruna Gorusupudi
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
| | - Rajalekshmy Shyam
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
| | - Bradley S Henriksen
- Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
| | - John M Nolan
- Macular Pigment Research Group, Vision Research Centre, School of Health Science, Carriganore House, Waterford Institute of Technology West Campus, Carriganore, Waterford, Ireland.
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11
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Funk RHW, Schumann U, Engelmann K, Becker KA, Roehlecke C. Blue light induced retinal oxidative stress: Implications for macular degeneration. World J Ophthalmol 2014; 4:29-34. [DOI: 10.5318/wjo.v4.i3.29] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 03/19/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
A number of studies have shown that oxidative stress can be harmful for the retina. The real causal circumstances that lead to degenerative diseases like age related macular degeneration remain obscure. Whether light induced radical stress is a direct interaction of light with photoreceptors or a secondary mechanism within the pigment epithelium or choroid is in discussion. Among the molecular mechanisms involved are production of reactive oxygen species (ROS), secondary lipid peroxidation, protein oxidation and DNA-damage. The initial trigger to write this review was first a recent finding of our group that the photoreceptor outer segments produce great amounts of ROS and second the detection of ectopic enzymes of the respiratory chain localized there - in addition to the hitherto known ROS sources like the visual pigments with their intermediates and the photoreceptor mitochondria harbouring the respiratory chain.
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12
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Meyers KJ, Mares JA, Igo RP, Truitt B, Liu Z, Millen AE, Klein M, Johnson EJ, Engelman CD, Karki CK, Blodi B, Gehrs K, Tinker L, Wallace R, Robinson J, LeBlanc ES, Sarto G, Bernstein PS, SanGiovanni JP, Iyengar SK. Genetic evidence for role of carotenoids in age-related macular degeneration in the Carotenoids in Age-Related Eye Disease Study (CAREDS). Invest Ophthalmol Vis Sci 2014; 55:587-99. [PMID: 24346170 DOI: 10.1167/iovs.13-13216] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
PURPOSE We tested variants in genes related to lutein and zeaxanthin status for association with age-related macular degeneration (AMD) in the Carotenoids in Age-Related Eye Disease Study (CAREDS). METHODS Of 2005 CAREDS participants, 1663 were graded for AMD from fundus photography and genotyped for 424 single nucleotide polymorphisms (SNPs) from 24 candidate genes for carotenoid status. Of 337 AMD cases 91% had early or intermediate AMD. The SNPs were tested individually for association with AMD using logistic regression. A carotenoid-related genetic risk model was built using backward selection and compared to existing AMD risk factors using the area under the receiver operating characteristic curve (AUC). RESULTS A total of 24 variants from five genes (BCMO1, BCO2, NPCL1L1, ABCG8, and FADS2) not previously related to AMD and four genes related to AMD in previous studies (SCARB1, ABCA1, APOE, and ALDH3A2) were associated independently with AMD, after adjusting for age and ancestry. Variants in all genes (not always the identical SNPs) were associated with lutein and zeaxanthin in serum and/or macula, in this or other samples, except for BCO2 and FADS2. A genetic risk score including nine variants significantly (P = 0.002) discriminated between AMD cases and controls beyond age, smoking, CFH Y402H, and ARMS2 A69S. The odds ratio (95% confidence interval) for AMD among women in the highest versus lowest quintile for the risk score was 3.1 (2.0-4.9). CONCLUSIONS Variants in genes related to lutein and zeaxanthin status were associated with AMD in CAREDS, adding to the body of evidence supporting a protective role of lutein and zeaxanthin in risk of AMD.
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Affiliation(s)
- Kristin J Meyers
- Department of Ophthalmology and Visual Sciences, McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
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Klein BEK, McElroy JA, Klein R, Howard KP, Lee KE. Nitrate-nitrogen levels in rural drinking water: Is there an association with age-related macular degeneration? JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART A, TOXIC/HAZARDOUS SUBSTANCES & ENVIRONMENTAL ENGINEERING 2013; 48:1757-1763. [PMID: 24007430 PMCID: PMC4068731 DOI: 10.1080/10934529.2013.823323] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
We examined the association of nitrate-nitrogen exposure from rural private drinking water and incidence of age-related macular degeneration (AMD). All participants in the Beaver Dam Eye Study (53916 improvement plan code) completed a questionnaire and had an ocular examination including standardized, graded fundus photographs at five examinations. Only information from rural residents in that study are included in this report. Data from an environmental monitoring study with probabilistic-based agro-chemical sampling, including nitrate-nitrogen, of rural private drinking water were available. Incidence of early AMD was associated with elevated nitrate-nitrogen levels in rural private drinking water supply (10.0% for low, 19.2% for medium, and 26.1% for high nitrate-nitrogen level in the right eye). The odds ratios (ORs) were 1.77 (95% confidence interval [CI]: 1.12-2.78) for medium and 2.88 (95% CI: 1.59-5.23) for high nitrate-nitrogen level. Incidence of late AMD was increased for those with medium or high levels of nitrate-nitrogen compared to low levels (2.3% for low and 5.1% for the medium or high nitrate-nitrogen level, for the right eye). The OR for medium or high nitrate-nitrogen groups was 2.80 (95% CI: 1.07-7.31) compared to the low nitrate-nitrogen group.
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Affiliation(s)
- Barbara E K Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53726-2336, USA.
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14
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Walls HL, Walls KL, Benke G. Eye disease resulting from increased use of fluorescent lighting as a climate change mitigation strategy. Am J Public Health 2011; 101:2222-5. [PMID: 22021286 DOI: 10.2105/ajph.2011.300246] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Increased use of fluorescent lighting as a climate change mitigation strategy may increase eye disease. The safe range of light to avoid exposing the eye to potentially damaging ultraviolet (UV) radiation is 2000 to 3500K and greater than 500 nanometers. Some fluorescent lights fall outside this safe range. Fluorescent lighting may increase UV-related eye diseases by up to 12% and, according to our calculations, may cause an additional 3000 cases of cataracts and 7500 cases of pterygia annually in Australia. Greater control of UV exposure from fluorescent lights is required. This may be of particular concern for aging populations in developed countries and countries in northern latitudes where there is a greater dependence on artificial lighting.
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Affiliation(s)
- Helen L Walls
- Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
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15
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Millen AE, Voland R, Sondel SA, Parekh N, Horst RL, Wallace RB, Hageman GS, Chappell R, Blodi BA, Klein ML, Gehrs KM, Sarto GE, Mares JA. Vitamin D status and early age-related macular degeneration in postmenopausal women. ACTA ACUST UNITED AC 2011; 129:481-9. [PMID: 21482873 DOI: 10.1001/archophthalmol.2011.48] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE The relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated in participants of the Carotenoids in Age-Related Eye Disease Study. METHODS Stereoscopic fundus photographs, taken from 2001 to 2004, assessed AMD status. Baseline (1994-1998) serum samples were available for 25(OH)D assays in 1313 women with complete ocular and risk factor data. Odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD (n = 241) of 1287 without advanced disease were estimated with logistic regression and adjusted for age, smoking, iris pigmentation, family history of AMD, cardiovascular disease, diabetes, and hormone therapy use. RESULTS In multivariate models, no significant relationship was observed between early AMD and 25(OH)D (OR for quintile 5 vs 1, 0.79; 95% CI, 0.50-1.24; P for trend = .47). A significant age interaction (P = .002) suggested selective mortality bias in women aged 75 years and older: serum 25(OH)D was associated with decreased odds of early AMD in women younger than 75 years (n = 968) and increased odds in women aged 75 years or older (n = 319) (OR for quintile 5 vs 1, 0.52; 95% CI, 0.29-0.91; P for trend = .02 and OR, 1.76; 95% CI, 0.77-4.13; P for trend = .05, respectively). Further adjustment for body mass index and recreational physical activity, predictors of 25(OH)D, attenuated the observed association in women younger than 75 years. Additionally, among women younger than 75 years, intake of vitamin D from foods and supplements was related to decreased odds of early AMD in multivariate models; no relationship was observed with self-reported time spent in direct sunlight. CONCLUSIONS High serum 25(OH)D concentrations may protect against early AMD in women younger than 75 years.
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Affiliation(s)
- Amy E Millen
- Department of Social and Preventive Medicine, University at Buffalo, Buffalo, NY 14214, USA.
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16
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Roller AB, Mahajan VB, Boldt HC, Abramoff MD, Russell SR, Folk JC. Effects of vitrectomy on age-related macular degeneration. Ophthalmology 2010; 117:1381-6. [PMID: 20176401 DOI: 10.1016/j.ophtha.2009.11.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2009] [Revised: 10/09/2009] [Accepted: 11/03/2009] [Indexed: 01/29/2023] Open
Abstract
PURPOSE To determine whether vitrectomy alters the long-term progression of age-related macular degeneration (AMD). DESIGN Retrospective case-control study. PARTICIPANTS Forty-four eyes of 22 patients with AMD who underwent vitrectomy in 1 eye were included in the study. The progression of AMD at follow-up in the 22 eyes that underwent vitrectomy was compared with the 22 fellow, nonvitrectomized eyes. METHODS The charts and photographs of subjects with Age-Related Eye Disease Study category 3 AMD in both eyes who previously underwent vitrectomy surgery for an epiretinal membrane or macular hole were reviewed. Subjects were excluded if they had had a vitrectomy in both eyes, had <2 years of follow-up, had previous choroidal neovascularization (CNV), retinal detachment, diabetic retinopathy, angioid streaks, high myopia, vascular occlusions, or extensive macular scarring in either eye, or insufficient hospital records or photographs to determine the extent of AMD. Clinical notes throughout the follow-up interval were reviewed. Two vitreoretinal specialists independently graded pre- and postvitrectomy fundus photographs of all eyes in a masked fashion. MAIN OUTCOME MEASURES The development or progression of geographic atrophy of the retinal pigment epithelium and the development of CNV. RESULTS Twenty-two patients were included. The average follow up interval was 5.5 years (range, 2-15). Choroidal neovascularization developed in 5 control eyes and in 2 vitrectomized eyes, and atrophy developed in 7 control and 4 vitrectomized eyes. The difference between vitrectomized eyes and fellow eyes for the combined end points of RPE geographic atrophy or CNV was significant (P = 0.02). CONCLUSIONS In this pilot study, we did not detect that vitrectomy increased the progression of AMD. In fact, it was associated with a reduced progression to geographic atrophy or CNV. Additional studies are needed to confirm or refute this association. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any of the materials discussed in this article.
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Affiliation(s)
- A Brock Roller
- Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals & Clinics, Iowa City, Iowa 52242, USA.
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Wielgus AR, Collier RJ, Martin E, Lih FB, Tomer KB, Chignell CF, Roberts JE. Blue light induced A2E oxidation in rat eyes – experimental animal model of dry AMD. Photochem Photobiol Sci 2010; 9:1505-12. [DOI: 10.1039/c0pp00133c] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Sheu SJ, Wu TT. Resveratrol Protects Against Ultraviolet A-Mediated Inhibition of the Phagocytic Function of Human Retinal Pigment Epithelial Cells Via Large-Conductance Calcium-Activated Potassium Channels. Kaohsiung J Med Sci 2009; 25:381-8. [DOI: 10.1016/s1607-551x(09)70531-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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19
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Transmittance characteristics of ultraviolet and blue-light-filtering intraocular lenses. J Cataract Refract Surg 2008; 34:1161-6. [PMID: 18571086 DOI: 10.1016/j.jcrs.2008.03.039] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2007] [Accepted: 03/20/2008] [Indexed: 10/21/2022]
Abstract
PURPOSE To record the spectral transmittance curves of various ultraviolet (UV) and blue-light-filtering intraocular lenses (IOLs), evaluate their UV and blue-light-radiation- absorption capacities, and compare them with those of the natural crystalline lens. SETTING Department of Ophthalmology, Duisburg-Essen University, Essen, Germany. METHODS Eight IOLs from 6 manufacturers were evaluated. The transmittance of wavelengths from 200 nm to 800 nm was measured using a high-performance spectrophotometer with a diffuse transmittance accessory through a 1.5 mm aperture. RESULTS All assessed IOLs provided good UVC (200 to 280 nm) and UVB (280 to 320 nm) protection, but 2 IOLs lacked sufficient UVA (320 to 400 nm) protection. Major differences in the absorption capacities were observed in the blue-light range (400 to 500 nm). CONCLUSIONS The absorption characteristics of some UV and blue-light-filtering IOLs resembled those of the crystalline lens, but some differed. Long-term clinical trials should be performed to determine how blue-blocking IOLs affect the risk for progression of age-related macular degeneration.
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20
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Javitt NB. Oxysterols: novel biologic roles for the 21st century. Steroids 2008; 73:149-57. [PMID: 18068744 DOI: 10.1016/j.steroids.2007.10.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2007] [Revised: 09/17/2007] [Accepted: 10/12/2007] [Indexed: 01/17/2023]
Abstract
A major focus for the 21st century are the sterol intermediates in cholesterol synthesis and their metabolites. No longer considered inactive way stations in their transformation to cholesterol, both physiologic and pathophysiologic studies, though early in their development, indicate novel biologic roles for these sterols, and their oxysterol metabolites that bypass cholesterol, the expected end product. A major impetus for further inquiry is the recognition that in genetically determined errors in cholesterol synthesis such as Smith-Lemil-Opitz syndrome, the phenotypic effects on the developing fetus are not solely attributable to the lack of cholesterol but the accumulation of 7-dehydrocholesterol and its 27-hydroxy metabolite. This view is now supported by a new mouse model, the double knockout Insig1 & 2 (insulin-induced genes 1 & 2) in which lack of the protein product results in a greater production of lanosterol compared to cholesterol during fetal life with severe dysmorphic consequences. Further support can be derived from in vitro studies of the Sonic hedgehog signaling pathway, essential for normal morphogenesis in the central nervous system and perhaps other organs, which may require the local presence of oxysterols for full expression. Future studies that can delineate the specific role of a sterol intermediate or its metabolite require a paradigm shift away from the generic use of oxysterols as a class of compounds to a focus on specific sterols that can be expected in tissues and techniques for mimicking the local environment. Another class of oxysterols are those arising by photoxidation, now considered to be an expected event generated by the photons of visible blue light and therefore pari passu with normal vision. The sequence of events from peroxides of cholesterol to hydroxy and keto derivatives is the signature of singlet oxygen as opposed to free radicals and other mechanisms for generating reactive oxygen species. Perhaps surprisingly, the retina expresses CYP 27A1 and CYP 46A1, enzymes with broad substrate specificity for ring-modified sterols, implying that, in addition to a rich blood supply for disposing of potentially toxic oxysterols, they can be detoxified locally. Recognition that the retina has nuclear receptors similar to those found in other tissues raises the possibility that the sterols that are generated may function in their traditional role as ligands for modulating gene expression but other, nonligand, activities can be expected since other proteins such as the oxysterol-binding proteins exist and are considered to have biologic activities. To critically evaluate these potentially new biologic roles for oxysterols a need exists for the synthesis and utilization of the expected naturally occurring metabolites rather than available surrogates that may not be truly representative of their tissue effects and to utilize analytical techniques that can identify their existence at the expected concentrations in tissues.
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Affiliation(s)
- Norman B Javitt
- Department of Pediatrics and Medicine, NYU School of Medicine, 550 First Avenue, New York, NY 10016, United States.
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Glazer-Hockstein C, Dunaief JL. Could blue light-blocking lenses decrease the risk of age-related macular degeneration? Retina 2006; 26:1-4. [PMID: 16395131 DOI: 10.1097/00006982-200601000-00001] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Epidemiologic and experimental evidence suggests that blue light-blocking lenses could theoretically benefit patients with age-related macular degeneration. Clinical trials are needed to determine the effect of yellow lenses in preventing the progression of age-related macular degeneration.
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23
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Gollapalli DR, Rando RR. The specific binding of retinoic acid to RPE65 and approaches to the treatment of macular degeneration. Proc Natl Acad Sci U S A 2004; 101:10030-5. [PMID: 15218101 PMCID: PMC454159 DOI: 10.1073/pnas.0401936101] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
RPE65 is essential in the operation of the visual cycle and functions as a chaperone for all-trans-retinyl esters, the substrates for isomerization in the visual cycle. RPE65 stereospecifically binds all-trans-retinyl esters with a K(D) of 47 nM. It is shown here by using a quantitative fluorescence technique, that Accutane (13-cis-retinoic acid), a drug used in the treatment of acne but that causes night blindness, binds to RPE65 with a K(D) of 195 nM. All-trans-retinoic acid binds with a K(D) of 109 nM. The binding of the retinoic acids to RPE65 is competitive with all-trans-retinyl ester binding, and this competition inhibits visual cycle function. A retinoic acid analog that binds weakly to RPE65 is not inhibitory. These data suggest that RPE65 function is rate-limiting in visual cycle function. They also reveal the target through which the retinoic acids induce night blindness. Finally, certain forms of retinal and macular degeneration are caused by the accumulation of vitamin A-based retinotoxic products, called the retinyl pigment epithelium-lipofuscin. These retinotoxic products accumulate during the normal course of rhodopsin bleaching and regeneration after the operation of the visual cycle. Drugs such as Accutane may represent an important approach to reducing the accumulation of the retinotoxic lipofuscin by inhibiting visual cycle function. The identification of RPE65 as the visual cycle target for the retinoic acids makes it feasible to develop useful drugs to treat retinal and macular degeneration while avoiding the substantial side effects of the retinoic acids.
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Affiliation(s)
- Deviprasad R Gollapalli
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 45 Shattuck Street, Boston, MA 02115, USA
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24
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Jockusch S, Ren RX, Jang YP, Itagaki Y, Vollmer-Snarr HR, Sparrow JR, Nakanishi K, Turro NJ. Photochemistry of A1E, a Retinoid with a Conjugated Pyridinium Moiety: Competition between Pericyclic Photooxygenation and Pericyclization. J Am Chem Soc 2004; 126:4646-52. [PMID: 15070381 DOI: 10.1021/ja039048d] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The photochemistry of the retinoid analogue A1E shows an oxygen and solvent dependence. Irradiation of A1E with visible light (lambda(irr) = 425 nm) in methanol solutions resulted in pericyclization to form pyridinium terpenoids. Although the quantum yield for this cyclization is low (approximately 10(-4)), nevertheless the photochemical transformation occurs with quantitative chemical yield with remarkable chemoselectivity and diastereoselectivity. Conversely, irradiation of A1E under the same irradiation conditions in air-saturated carbon tetrachloride or deuterated chloroform produced a cyclic 5,8-peroxide as the major product. Deuterium solvent effects, experiments utilizing endoperoxide, phosphorescence, and chemiluminescence quenching studies strongly support the involvement of singlet oxygen in the endoperoxide formation. It is proposed that, upon irradiation, in the presence of oxygen, A1E acts as a sensitizer for generation of singlet oxygen from triplet oxygen present in the solution; the singlet oxygen produced reacts with A1E to produce cyclic peroxide. Thus, the photochemistry of A1E is characterized by two competing reactions, cyclization and peroxide formation. The dominant reaction is determined by the concentration of oxygen, the concentration of A1E, and the lifetime of singlet oxygen in the solvent employed. If the lifetime of singlet oxygen in a given solvent is long enough, then oxidation (peroxide formation) is the major reaction. If the singlet oxygen produced is quenched by the protonated solvent molecules faster than singlet oxygen reacts with A1E, then cyclization dominates.
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Affiliation(s)
- Steffen Jockusch
- Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, USA
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25
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Abstract
The presence of lipofuscin in postmitotic cells is considered a hallmark of the aging process. In the retinal pigment epithelium (RPE), lipofuscin is found as micrometer-sized spherical particles and characterized by its yellow autofluorescence when exposed to blue light. This exposure to light is also known to produce reactive oxygen intermediates (ROI), but the particular molecular constituent(s) responsible for this phototoxicity have yet to be completely identified. Resulting mostly from the autophagocytosis of intracellular organelles, the composition of lipofuscin is poorly defined but known to contain protein, lipids and several fluorophores. The subsequent identification of one of the fluorophores in lipofuscin, A2E, generated much interest and resulted in a variety of studies to understand its potential role in the phototoxicity of lipofuscin. Several modes of toxicity have been suggested through which A2E can affect the health of RPE cells. These modes include photoinduced production of ROI, which places additional oxidative stress on RPE cells, the disruption of membrane integrity through its natural role as an amphiphilic detergent and inhibition of key cellular functions. This article presents the current understanding of the photochemistry of A2E and its involvement as a phototoxic agent in RPE cells.
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Affiliation(s)
- Laura E Lamb
- Department of Chemistry, Duke University, Durham, NC 27708-0346, USA
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Krinsky NI, Landrum JT, Bone RA. Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye. Annu Rev Nutr 2003; 23:171-201. [PMID: 12626691 DOI: 10.1146/annurev.nutr.23.011702.073307] [Citation(s) in RCA: 521] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The macular region of the primate retina is yellow in color due to the presence of the macular pigment, composed of two dietary xanthophylls, lutein and zeaxanthin, and another xanthophyll, meso-zeaxanthin. The latter is presumably formed from either lutein or zeaxanthin in the retina. By absorbing blue-light, the macular pigment protects the underlying photoreceptor cell layer from light damage, possibly initiated by the formation of reactive oxygen species during a photosensitized reaction. There is ample epidemiological evidence that the amount of macular pigment is inversely associated with the incidence of age-related macular degeneration, an irreversible process that is the major cause of blindness in the elderly. The macular pigment can be increased in primates by either increasing the intake of foods that are rich in lutein and zeaxanthin, such as dark-green leafy vegetables, or by supplementation with lutein or zeaxanthin. Although increasing the intake of lutein or zeaxanthin might prove to be protective against the development of age-related macular degeneration, a causative relationship has yet to be experimentally demonstrated.
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Affiliation(s)
- Norman I Krinsky
- Department of Biochemistry, School of Medicine and the USDA Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111-1837, USA.
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Abstract
Singlet-oxygen generation was measured in solutions containing equilibrium mixtures of the retinal lipofuscins, 2-[2, 6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 1E,3E,5E,7Eoctatetraenyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) and double bond isomer of A2E (iso-A2E), using steady-state irradiation and using cholesterol as a singlet-oxygen trap. The amount of singlet oxygen generated by equilibrium mixtures of A2E and iso-A2E was compared with that generated by tetraphenylporphine (TPP) under the same conditions. Studies were carried out in ethanol-d6, acetone-d6, 80% cyclohexane-d(12)-20% acetone-d6 (vol/vol) and hexafluorobenzene. Using 420 nm irradiation and assuming a singlet-oxygen quantum yield of 0.60 +/- 0.12 for TPP, the singlet-oxygen quantum yields were 0.8 +/- 0.3 x 10(-3), 1.2 +/- 0.4 x 10(-3), 2 +/- 1 x 10(-3) and 4 + 1 x 10(-3), respectively. In acetone-d6, the quantum yields were smaller at longer wavelengths, with values of 0.3 +/- 0.1 x 10(-3) and 0.4 +/- 0.2 x 10(-3) at 461 and 493 nm, respectively. Singlet-oxygen generation was greatest in solvents with the lowest dielectric constants. In view of the relatively small quantum yields, the contribution of singlet-oxygen generation to the phototoxic properties of A2E and of iso-A2E will require further study.
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Affiliation(s)
- Jeffrey R Kanofsky
- Medical Service, Edward Hines Jr., Department of Veterans Affairs Hospital, Hines, IL 60141, USA.
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Haralampus-Grynaviski NM, Lamb LE, Clancy CMR, Skumatz C, Burke JM, Sarna T, Simon JD. Spectroscopic and morphological studies of human retinal lipofuscin granules. Proc Natl Acad Sci U S A 2003; 100:3179-84. [PMID: 12612344 PMCID: PMC152266 DOI: 10.1073/pnas.0630280100] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
The emission properties of ocular lipofuscin granules isolated from human retinal pigment epithelial cells are examined by using steady-state fluorescence spectroscopy and spectrally resolved confocal microscopy. The shape of the emission spectrum of a thick sample of lipofuscin granules dried on glass varies with excitation energy. The polarization of this emission is wavelength-dependent, exhibiting significant polarization near the excitation wavelength and becoming mostly depolarized over the majority of the emission spectrum. These results show that the yellow-emitting fluorophores [e.g., A2E (2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hydroxyethyl)-4-[4-methyl-6-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium)] are excited as a result of energy transfer within the granules and therefore are not the dominant blue-absorbing chromophores within lipofuscin granules. Atomic force microscopy images show lipofuscin granules to be an aggregated structure. Bulk and in vivo emission measurements must therefore take into account the effect of Raleigh scattering. When corrected for scattering, the emission spectrum of a thick lipofuscin deposit or intracellular lipofuscin resembles that for A2E. The sum of the emission spectra of a collection of individual granules also resembles the emission spectrum of A2E, but the spectrum of individual granules varies significantly. This result suggests that the agreement between the emission spectra of lipofuscin and A2E is fortuitous, and the collective data indicate the presence of several blue-absorbing chromophores in lipofuscin and show A2E is not the dominant yellow-emitting fluorophore in many of the granules studied.
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Abstract
Singlet-oxygen generation was measured in solutions containing equilibrium mixtures of the retinal lipofuscins, 2-[2, 6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)- 1E,3E,5E,7Eoctatetraenyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) and double bond isomer of A2E (iso-A2E), using steady-state irradiation and using cholesterol as a singlet-oxygen trap. The amount of singlet oxygen generated by equilibrium mixtures of A2E and iso-A2E was compared with that generated by tetraphenylporphine (TPP) under the same conditions. Studies were carried out in ethanol-d6, acetone-d6, 80% cyclohexane-d(12)-20% acetone-d6 (vol/vol) and hexafluorobenzene. Using 420 nm irradiation and assuming a singlet-oxygen quantum yield of 0.60 +/- 0.12 for TPP, the singlet-oxygen quantum yields were 0.8 +/- 0.3 x 10(-3), 1.2 +/- 0.4 x 10(-3), 2 +/- 1 x 10(-3) and 4 + 1 x 10(-3), respectively. In acetone-d6, the quantum yields were smaller at longer wavelengths, with values of 0.3 +/- 0.1 x 10(-3) and 0.4 +/- 0.2 x 10(-3) at 461 and 493 nm, respectively. Singlet-oxygen generation was greatest in solvents with the lowest dielectric constants. In view of the relatively small quantum yields, the contribution of singlet-oxygen generation to the phototoxic properties of A2E and of iso-A2E will require further study.
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Affiliation(s)
- Jeffrey R Kanofsky
- Medical Service, Edward Hines Jr., Department of Veterans Affairs Hospital, Hines, IL 60141, USA.
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van den Bergh H, Ballini JP, Sickenberg M. Photodynamic Therapy for Subfoveal Choroidal Neovascularisation in Various Diseases among which Age-related Macular Degeneration: An Update. ACTA ACUST UNITED AC 2003. [DOI: 10.1078/1615-1615-00089] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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Shaban H, Borrás C, Viña J, Richter C. Phosphatidylglycerol potently protects human retinal pigment epithelial cells against apoptosis induced by A2E, a compound suspected to cause age-related macula degeneration. Exp Eye Res 2002; 75:99-108. [PMID: 12123641 DOI: 10.1006/exer.2001.1192] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Age-related macular degeneration (AMD) affects about one fifth of the population older than 65 years and is one of the main causes of poor vision in the elderly in industrialized nations. The endogenous lipophilic and cationic compound N-retinyl-N-retinylidene ethanolamine (A2E) is suspected to cause the dry form of the disease, which currently cannot be treated. The authors recently reported that A2E induces apoptosis in several cell types including porcine retinal pigment epithelial cells, detaches pro-apoptotic proteins from mitochondria, and inhibits cytochrome c oxidase. A2E acts primarily at the level of cardiolipin/cytochrome c oxidase, which in the light becomes permanently inactivated by A2E. The authors now report that A2E at low concentrations causes apoptosis in cultured human retinal pigment epithelial cells. These cells are more sensitive to A2E in the light than in the dark. Phosphatidylglycerol, a negatively charged phospholipid and immediate biosynthetic precursor of cardiolipin readily inhibits apoptosis. Exposure of cells to A2E results in the formation of reactive oxygen and nitrogen species, and exposure of mitochondria to A2E results in oxidative stress. Accordingly, the potent antioxidant coenzyme Q also protects cells against A2E-induced apoptosis. These findings are highly relevant for the treatment and/or prevention of AMD.
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Affiliation(s)
- Hamdy Shaban
- Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), Universitätstr, 16, CH-8092, Zurich, Switzerland
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