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1
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Cocksedge SP, Mantecón L, Castaño E, Infante C, Bailey SJ. The Potential of Superoxide Dismutase-Rich Tetraselmis chuii as a Promoter of Cellular Health. Int J Mol Sci 2025; 26:1693. [PMID: 40004157 PMCID: PMC11855123 DOI: 10.3390/ijms26041693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Tetraselmis chuii (T. chuii) is a green, marine, eukaryotic, microalgae that was authorized in the European Union (EU) as a novel food for human consumption in 2014, and as a food supplement in 2017. This narrative review will provide an overview of preclinical and clinical trials assessing the efficacy of a T. chuii-derived ingredient, characterized by a high superoxide dismutase (SOD) activity (SOD-rich T. chuii), to improve various aspects of cellular health. Collectively, results from in vitro, and more importantly in vivo research, support SOD-rich T. chuii as a potential promoter of cellular health. Principally, the ingredient appears to function as an indirect antioxidant by boosting intracellular antioxidant systems. Moreover, it can positively modulate inflammatory status by up-regulating anti-inflammatory and down-regulating pro-inflammatory cytokines and factors. In addition, SOD-rich T. chuii appears to promote cellular health though protecting from DNA damage, boosting immune function, strengthening cell structure and integrity, and positively modulating cell signaling pathways. There is also some evidence to suggest that SOD-rich T. chuii may improve aspects of mitochondrial function through the up-regulation of genes linked to mitochondrial biogenesis and ATP synthesis. From the trials conducted to date, transcriptional activation of nuclear factor erythroid 2-related factor 2 (NRF2) and sirtuin 1 (SIRT1) appear to be important in mediating the effects of SOD-rich T. chuii on cellular health. These exciting preliminary observations suggest that SOD-rich T. chuii may represent a natural blue food supplement with the potential to enhance various aspects of cellular health.
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Affiliation(s)
- Stuart P. Cocksedge
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK;
- Centre for Physical Activity, Sport and Exercise Sciences, Coventry University, Coventry CV1 5FB, UK
| | - Lalia Mantecón
- Fitoplancton Marino, S.L., Dársena Comercial s/n, 11500 El Puerto de Santa María, Cádiz, Spain; (L.M.); (E.C.); (C.I.)
| | - Enrique Castaño
- Fitoplancton Marino, S.L., Dársena Comercial s/n, 11500 El Puerto de Santa María, Cádiz, Spain; (L.M.); (E.C.); (C.I.)
| | - Carlos Infante
- Fitoplancton Marino, S.L., Dársena Comercial s/n, 11500 El Puerto de Santa María, Cádiz, Spain; (L.M.); (E.C.); (C.I.)
| | - Stephen J. Bailey
- School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough LE11 3TU, UK;
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2
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Qin Y, Liu H, Wu H. Cellular Senescence in Health, Disease, and Lens Aging. Pharmaceuticals (Basel) 2025; 18:244. [PMID: 40006057 PMCID: PMC11859104 DOI: 10.3390/ph18020244] [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: 01/13/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Cellular senescence is a state of irreversible cell cycle arrest that serves as a critical regulator of tissue homeostasis, aging, and disease. While transient senescence contributes to development, wound healing, and tumor suppression, chronic senescence drives inflammation, tissue dysfunction, and age-related pathologies, including cataracts. Lens epithelial cells (LECs), essential for maintaining lens transparency, are particularly vulnerable to oxidative stress-induced senescence, which accelerates lens aging and cataract formation. This review examines the dual role of senescence in LEC function and its implications for age-related cataractogenesis, alongside emerging senotherapeutic interventions. Methods: This review synthesizes findings on the molecular mechanisms of senescence, focusing on oxidative stress, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). It explores evidence linking LEC senescence to cataract formation, highlighting key studies on stress responses, DNA damage, and antioxidant defense. Recent advances in senotherapeutics, including senolytics and senomorphics, are analyzed for their potential to mitigate LEC senescence and delay cataract progression. Conclusions: LEC senescence is driven by oxidative damage, mitochondrial dysfunction, and impaired redox homeostasis. These factors activate senescence path-ways, including p53/p21 and p16/Rb, resulting in cell cycle arrest and SASP-mediated inflammation. The accumulation of senescent LECs reduces regenerative capacity, disrupts lens homeostasis, and contributes to cataractogenesis. Emerging senotherapeutics, such as dasatinib, quercetin, and metformin, show promise in reducing the senescent cell burden and modulating the SASP to preserve lens transparency.
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Affiliation(s)
- Ying Qin
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (Y.Q.); (H.L.)
| | - Haoxin Liu
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (Y.Q.); (H.L.)
| | - Hongli Wu
- Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; (Y.Q.); (H.L.)
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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3
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Gao W, Wang Y, Wang F, Wu X, Lu F, Liu F. Ergothioneine exerts neuroprotective effects in Parkinson's disease: Targeting α-synuclein aggregation and oxidative stress. Food Res Int 2025; 201:115590. [PMID: 39849723 DOI: 10.1016/j.foodres.2024.115590] [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: 08/26/2024] [Revised: 11/16/2024] [Accepted: 12/28/2024] [Indexed: 01/25/2025]
Abstract
Ergothioneine (EGT) is a natural dietary antioxidant derived from certain edible mushrooms, commonly used as a food additive and supplement, but its effects on Parkinson's Disease (PD) are still unclear. The accumulation of α-synuclein (α-syn) plays a pivotal role in the pathogenesis and development of PD. Here, this study demonstrated that EGT effectively inhibits α-syn aggregation, disrupts mature fibers, and reduces associated cytotoxicity and oxidative stress. The beneficial effects of EGT were confirmed in Caenorhabditis elegans, where it protected dopaminergic neurons, prolonged lifespan and enhanced behavioral functions by reducing α-syn plaque accumulation and associated oxidative stress. Molecular dynamics simulation revealed that EGT interacts directly with α-syn pentamer through van der Waals and electrostatic forces, disrupting the structural stability of the preformed pentamer. Furthermore, animal studies validated that EGT alleviated neuronal damage and improved behavioral deficits by reducing α-syn aggregation, oxidative stress and inflammatory response. In conclusion, EGT presents promising potential as a dietary supplement for preventing and alleviating PD.
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Affiliation(s)
- Wen Gao
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, PR China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, PR China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China
| | - Yang Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, PR China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, PR China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China
| | - Fuhao Wang
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, PR China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, PR China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China
| | - Xinni Wu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, PR China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, PR China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China
| | - Fuping Lu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, PR China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, PR China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China
| | - Fufeng Liu
- Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, Tianjin 300457, PR China; Tianjin Key Laboratory of Industrial Microbiology, Tianjin 300457, PR China; College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China.
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4
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Parmar UPS, Surico PL, Mori T, Singh RB, Cutrupi F, Premkishore P, Gallo Afflitto G, Di Zazzo A, Coassin M, Romano F. Antioxidants in Age-Related Macular Degeneration: Lights and Shadows. Antioxidants (Basel) 2025; 14:152. [PMID: 40002339 PMCID: PMC11852319 DOI: 10.3390/antiox14020152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/13/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Age-related macular degeneration (AMD) is a leading cause of vision impairment worldwide, primarily driven by oxidative stress and inflammation. This review examines the role of antioxidants in mitigating oxidative damage, emphasizing both their therapeutic potential and limitations in AMD management. Key findings underscore the efficacy of specific antioxidants, including vitamins C and E, lutein, zeaxanthin, and Coenzyme Q10, in slowing AMD progression. Landmark studies such as AREDS and AREDS2 have shaped current antioxidant formulations, although challenges persist, including patient variability and long-term safety concerns. Emerging therapies, such as mitochondrial-targeted antioxidants and novel compounds like saffron and resveratrol, offer promising avenues for AMD treatment. Complementary lifestyle interventions, including antioxidant-rich diets and physical activity, further support holistic management approaches. This review highlights the critical role of antioxidants in AMD therapy, advocating for personalized strategies to optimize patient outcomes.
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Affiliation(s)
| | - Pier Luigi Surico
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
- Department of Sense Organs, La Sapienza University, 00185 Rome, Italy
| | - Tommaso Mori
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Rohan Bir Singh
- Department of Health and Medical Sciences, Adelaide Medical School, Adelaide, SA 5000, Australia
| | - Francesco Cutrupi
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Pramila Premkishore
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
| | - Gabriele Gallo Afflitto
- Ophthalmology Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00128 Rome, Italy
| | - Antonio Di Zazzo
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Marco Coassin
- Department of Ophthalmology, Campus Bio-Medico University Hospital, 00128 Rome, Italy
| | - Francesco Romano
- Eye Clinic, Department of Biomedical and Clinical Sciences, Ospedale Luigi Sacco, University of Milan, 20157 Milan, Italy
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Emeka PM, Badger-Emeka LI, Thirugnanasambantham K, Alatawi AS. Rutin-Activated Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Attenuates Corneal and Heart Damage in Mice. Pharmaceuticals (Basel) 2024; 17:1523. [PMID: 39598433 PMCID: PMC11597448 DOI: 10.3390/ph17111523] [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: 09/30/2024] [Revised: 11/06/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
Background: Corneal degeneration is a form of progressive cell death caused by multiple factors, such as diabetic retinopathy. It is the most well-known neural degenerative disease caused by macular degeneration in the aged and those with retinitis pigmentosa. Myocardial infarction is becoming a more common burden, causing cardiomyocyte degeneration, ischemia, and heart tissue death. This study examined the preventive effects of rutin on isoproterenol (ISO)-induced oxidative damage (that is, inflammation) on rabbit corneal epithelial cells and mouse heart injuries. Methods: These investigations involved a cytotoxicity test, biochemical analysis, qRT-PCR, Western blotting, and mouse cardiac histopathology. Results: The results showed that rutin enhanced ADH7 and ALDH1A1, retinoic acid signaling components in SIRC1 rabbit corneal cell lines. The production of NO by ocular epithelial cells was significantly reduced. It reduced cTnT and cTnI, CK-MB, and LDH contents in mouse cardiac tissue. The nuclear expressions of Nrf2, Sirt, and HO-1 were all increased by rutin. Docking studies revealed a good interaction between rutin and the Keap protein, enhancing Nrf2 nuclear activity. Conclusions: This showed that rutin can potentially enhance ADH7 and ALDH1A1 corneal signaling components, preventing corneal degeneration and mitigating ISO-induced myocardial infarction (MI) via Keap/Nrf2 expressions.
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Affiliation(s)
- Promise M. Emeka
- Department of Pharmaceutical Science, College of Clinical Pharmacy, King Faisal University, Al Ahsa 31982, Saudi Arabia;
| | - Lorina I. Badger-Emeka
- Department of Biomedical Science, College of Medicine, King Faisal University, Al Ahsa 31982, Saudi Arabia;
| | | | - Abdulaziz S. Alatawi
- Department of Pharmaceutical Science, College of Clinical Pharmacy, King Faisal University, Al Ahsa 31982, Saudi Arabia;
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Huang KC, Chiang YF, Ali M, Hsia SM. Oleocanthal mitigates CoCl 2-induced oxidative damage and apoptosis via regulating MAPK pathway in human retinal pigment epithelial cells. Biomed Pharmacother 2024; 180:117582. [PMID: 39467472 DOI: 10.1016/j.biopha.2024.117582] [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: 07/31/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 10/30/2024] Open
Abstract
Retinal hypoxia causes severe visual impairment and dysfunction in retinal pigment epithelial (RPE) cells, triggering a cascade of events leading to cellular apoptosis. Oxidative stress induced by hypoxia plays a significant role in the development of retinal diseases; however, the precise pathogenesis remains unclear. Oleocanthal, a phenolic compound in extra virgin olive oil, is known for its diverse biological properties. This study aims to investigate the potential anti-oxidative effects of oleocanthal against CoCl2-induced hypoxia in ARPE-19 cells. The cell culture model enabled the evaluation of apoptosis, DNA damage, and ROS levels using MTT assay, Western blot, Annexin V/PI staining, JC-1 staining, MitoSOX, H2DCFDA, immunocytochemistry, and comet assays. Our results showed that oleocanthal effectively protected RPE cells against CoCl2-induced damage by enhancing cell viability, reducing DNA damage, and decreasing ROS levels. Moreover, oleocanthal attenuated CoCl2-induced MMP loss by elevating the JC-1 aggregate/monomer ratio. Furthermore, CoCl2-induced cell apoptosis via up-regulating MAPK signaling, while oleocanthal mitigated this effect. These findings shed light on the molecular mechanisms underlying oleocanthal's protection against oxidative stress induced by hypoxia, offering potential insights for the development of novel therapeutic agents for retinal hypoxia.
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Affiliation(s)
- Ko-Chieh Huang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Yi-Fen Chiang
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Mohamed Ali
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Clinical Pharmacy Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA
| | - Shih-Min Hsia
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan; School of Food and Safety, Taipei Medical University, Taipei 11031, Taiwan; Nutrition Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan; TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei 110301, Taiwan.
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7
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Bresciani G, Manai F, Felszeghy S, Smedowski A, Kaarniranta K, Amadio M. VEGF and ELAVL1/HuR protein levels are increased in dry and wet AMD patients. A new tile in the pathophysiologic mechanisms underlying RPE degeneration? Pharmacol Res 2024; 208:107380. [PMID: 39216841 DOI: 10.1016/j.phrs.2024.107380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
Age-related macular degeneration (AMD) is a common retinal pathology characterized by degeneration of macula's retinal pigment epithelium (RPE) and photoreceptors, visual impairment, or loss. Compared to wet AMD, dry AMD is more common, but lacks cures; therefore, identification of new potential therapeutic targets and treatments is urgent. Increased oxidative stress and declining antioxidant, detoxifying systems contribute to the pathophysiologic mechanisms underlying AMD. The present work shows that the Embryonic Lethal Abnormal Vision-Like 1/Human antigen R (ELAVL1/HuR) and the Vascular Endothelial Growth Factor (VEGF) protein levels are higher in the RPE of both dry and wet AMD patients compared to healthy subjects. Moreover, increased HuR protein levels are detected in the retina, and especially in the RPE layer, of a dry AMD model, the nuclear factor erythroid 2-related factor 2 (Nrf2) / peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) double knock-out mouse. The crosstalk among Nrf2, HuR and VEGF has been also studied in ARPE-19 cells in basal and stressful conditions related to the AMD context (i.e., oxidative stress, autophagy impairment, Nrf2 deficit), offering new evidence of the mutual influence between Nrf2 and HuR, of the dependence of VEGF expression and secretion by these two factors, and of the increased susceptibility of cells to stressful conditions in Nrf2- or HuR-impaired contexts. Overall, this study shows evidence of the interplay among Nrf2, HuR and VEGF, essential factors for RPE homeostasis, and represents an additional piece in the understanding of the complex pathophysiologic mechanisms underlying AMD.
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Affiliation(s)
| | - Federico Manai
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy
| | - Szabolcs Felszeghy
- Institute of Dentistry, University of Eastern Finland, Kuopio, Finland; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Adrian Smedowski
- Department of Ophthalmology, Professor K. Gibinski University Clinical Center, Medical University of Silesia, Katowice, Poland; GlaucoTech Co., Katowice, Poland; Department of Ophthalmology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland; Department of Molecular Genetics, University of Lodz, Lodz, Poland
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8
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Staehlke S, Mahajan S, Thieme D, Trosan P, Fuchsluger TA. Suppressing Pro-Apoptotic Proteins by siRNA in Corneal Endothelial Cells Protects against Cell Death. Biomedicines 2024; 12:1439. [PMID: 39062012 PMCID: PMC11274739 DOI: 10.3390/biomedicines12071439] [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: 05/30/2024] [Revised: 06/20/2024] [Accepted: 06/23/2024] [Indexed: 07/28/2024] Open
Abstract
Corneal endothelial cells (CE) are critical for the cornea's transparency. For severe corneal damage, corneal tissue transplantation is the most promising option for restoring vision. However, CE apoptotic cell death occurs during the storage of donor corneas for transplantation. This study used small interfering (si)RNA-mediated silencing of pro-apoptotic proteins as a novel strategy to protect CE against apoptosis. Therefore, the pro-apoptotic proteins Bax and Bak were silenced in the human corneal endothelial cell line (HCEC-12) by transfection with Accell™siRNA without any adverse effects on cell viability. When apoptosis was induced, e.g., etoposide, the caspase-3 activity and Annexin V-FITC/PI assay indicated a significantly reduced apoptosis rate in Bax+Bak-siRNA transfected HCECs compared to control (w/o siRNA). TUNEL assay in HCECs exposed also significantly lower cell death in Bax+Bak-siRNA (7.5%) compared to control (w/o siRNA: 32.8%). In ex vivo donor corneas, a significant reduction of TUNEL-positive CEs in Bax+Bak-siRNA corneas (8.1%) was detectable compared to control-treated corneas (w/o siRNA: 27.9%). In this study, we demonstrated that suppressing pro-apoptotic siRNA leads to inhibiting CE apoptosis. Gene therapy with siRNA may open a new translational approach for corneal tissue treatment in the eye bank before transplantation, leading to graft protection and prolonged graft survival.
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Affiliation(s)
- Susanne Staehlke
- Department of Ophthalmology, Rostock University Medical Center, 18057 Rostock, Germany;
- Institute for Cell Biology, Rostock University Medical Center, 18057 Rostock, Germany
| | - Siddharth Mahajan
- Department of Ophthalmology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
| | - Daniel Thieme
- Department of Ophthalmology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
- Institute of Polymer Materials, University of Erlangen-Nuremberg, 91058 Erlangen, Germany
| | - Peter Trosan
- Department of Ophthalmology, Rostock University Medical Center, 18057 Rostock, Germany;
| | - Thomas A. Fuchsluger
- Department of Ophthalmology, Rostock University Medical Center, 18057 Rostock, Germany;
- Department of Ophthalmology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany
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9
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Dolar-Szczasny J, Drab A, Rejdak R. Biochemical Changes in Anterior Chamber of the Eye in Diabetic Patients-A Review. J Clin Med 2024; 13:2581. [PMID: 38731110 PMCID: PMC11084197 DOI: 10.3390/jcm13092581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/15/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
This article aims to provide a comprehensive review of the biochemical changes observed in the anterior chamber of the eye in diabetic patients. The increased levels of inflammatory markers, alterations in antioxidant defense mechanisms, and elevated levels of advanced glycation end products (AGEs) in the aqueous humor (AH) are explored. Additionally, the impact of these biochemical changes on diabetic retinopathy progression, increased intraocular pressure, and cataract formation is discussed. Furthermore, the diagnostic and therapeutic implications of these findings are presented. This study explores potential biomarkers for detecting diabetic eye disease at an early stage and monitoring its progression. An investigation of the targeting of inflammatory and angiogenic pathways as a potential treatment approach and the role of antioxidant agents in managing these biochemical changes is performed.
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Affiliation(s)
- Joanna Dolar-Szczasny
- Department of General and Pediatric Ophtalmology, Medical University of Lublin, 20-079 Lublin, Poland;
| | - Agnieszka Drab
- Department of Medical Informatics and Statistics with e-Health Lab, Medical University of Lublin, 20-954 Lublin, Poland;
| | - Robert Rejdak
- Department of General and Pediatric Ophtalmology, Medical University of Lublin, 20-079 Lublin, Poland;
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10
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Somayajulu M, Muhammed FS, Wright R, McClellan SA, Hazlett LD. Mechanisms of PM 10 Disruption of the Nrf2 Pathway in Cornea. Int J Mol Sci 2024; 25:3754. [PMID: 38612568 PMCID: PMC11011424 DOI: 10.3390/ijms25073754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
We have previously shown that PM10 exposure causes oxidative stress and reduces Nrf2 protein levels, and SKQ1 pre-treatment protects against this damage in human corneal epithelial cells (HCE-2). The current study focuses on uncovering the mechanisms underlying acute PM10 toxicity and SKQ1-mediated protection. HCE-2 were pre-treated with SKQ1 and then exposed to 100 μg/mL PM10. Cell viability, oxidative stress markers, programmed cell death, DNA damage, senescence markers, and pro-inflammatory cytokines were analyzed. Nrf2 cellular location and its transcriptional activity were determined. Effects of the Nrf2 inhibitor ML385 were similarly evaluated. Data showed that PM10 decreased cell viability, Nrf2 transcriptional activity, and mRNA levels of antioxidant enzymes, but increased p-PI3K, p-NFκB, COX-2, and iNOS proteins levels. Additionally, PM10 exposure significantly increased DNA damage, phosphor-p53, p16 and p21 protein levels, and β-galactosidase (β-gal) staining, which confirmed the senescence. SKQ1 pre-treatment reversed these effects. ML385 lowered the Nrf2 protein levels and mRNA levels of its downstream targets. ML385 also abrogated the protective effects of SKQ1 against PM10 toxicity by preventing the restoration of cell viability and reduced oxidative stress. In conclusion, PM10 induces inflammation, reduces Nrf2 transcriptional activity, and causes DNA damage, leading to a senescence-like phenotype, which is prevented by SKQ1.
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Affiliation(s)
| | | | | | | | - Linda D. Hazlett
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA; (M.S.); (F.S.M.); (R.W.); (S.A.M.)
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11
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Bighinati A, Adani E, Stanzani A, D’Alessandro S, Marigo V. Molecular mechanisms underlying inherited photoreceptor degeneration as targets for therapeutic intervention. Front Cell Neurosci 2024; 18:1343544. [PMID: 38370034 PMCID: PMC10869517 DOI: 10.3389/fncel.2024.1343544] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 01/16/2024] [Indexed: 02/20/2024] Open
Abstract
Retinitis pigmentosa (RP) is a form of retinal degeneration characterized by primary degeneration of rod photoreceptors followed by a secondary cone loss that leads to vision impairment and finally blindness. This is a rare disease with mutations in several genes and high genetic heterogeneity. A challenging effort has been the characterization of the molecular mechanisms underlying photoreceptor cell death during the progression of the disease. Some of the cell death pathways have been identified and comprise stress events found in several neurodegenerative diseases such as oxidative stress, inflammation, calcium imbalance and endoplasmic reticulum stress. Other cell death mechanisms appear more relevant to photoreceptor cells, such as high levels of cGMP and metabolic changes. Here we review some of the cell death pathways characterized in the RP mutant retina and discuss preclinical studies of therapeutic approaches targeting the molecular outcomes that lead to photoreceptor cell demise.
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Affiliation(s)
- Andrea Bighinati
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Elisa Adani
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Agnese Stanzani
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Sara D’Alessandro
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valeria Marigo
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
- Center for Neuroscience and Neurotechnology, Modena, Italy
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12
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Chen J, Wang Q, Li R, Li Z, Jiang Q, Yan F, Ye J. The role of Keap1-Nrf2 signaling pathway during the progress and therapy of diabetic retinopathy. Life Sci 2024; 338:122386. [PMID: 38159594 DOI: 10.1016/j.lfs.2023.122386] [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: 10/19/2023] [Revised: 12/09/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2024]
Abstract
Diabetic retinopathy is a complex and progressive ocular complication of diabetes mellitus and is a leading cause of blindness in people of working age worldwide. The pathophysiology of diabetic retinopathy involves multifactorial processes, including oxidative stress, inflammation and vascular abnormalities. Understanding the underlying molecular mechanisms involved in its pathogenesis is essential for the development of effective therapeutic interventions. One of the pathways receiving increasing attention is the Keap1-Nrf2 signaling pathway, which regulates the cellular response to oxidative stress by activating Nrf2. In this review, we analyze the current evidence linking Keap1-Nrf2 signaling pathway dysregulation to diabetic retinopathy. In addition, we explore the potential therapeutic implications and the challenges of targeting this pathway for disease management. A comprehensive understanding of the molecular mechanisms of diabetic retinopathy and the therapeutic potential of the Keap1-Nrf2 pathway may pave the way for innovative and effective interventions to combat this vision-threatening disease.
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Affiliation(s)
- Jiawen Chen
- State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing 211198, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China; Department of Ophthalmology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, China
| | - Qi Wang
- Department of Ophthalmology, The First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, China
| | - Ruiyan Li
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Zhe Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular research Institute, Wuhan University, Wuhan 430060, China
| | - Qizhou Jiang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China
| | - Fangrong Yan
- State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Junmei Ye
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China.
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13
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Xue R, Fan XL, Yang Q, Yu C, Lu TY, Wan GM. Protective effect of ethyl ferulate against hypoxic injury in retinal cells and retinal neovascularization in an oxygen-induced retinopathy model. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 121:155097. [PMID: 37778248 DOI: 10.1016/j.phymed.2023.155097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 09/10/2023] [Accepted: 09/16/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND Pathological neovascularization is a major cause of visual impairment in hypoxia-induced retinopathy. Ethyl ferulate (EF), the natural ester derivative of ferulic acid commonly found in Ferula and Angelica Sinensis, has been shown to exert antioxidant, neuroprotective, and anti-inflammatory properties. However, whether EF exerts a protective effect on retinal neovascularization and the underlying mechanisms are not well known. PURPOSE The aim of the study was to investigate the effect of EF on retinal neovascularization and explore its underlying molecular mechanisms. STUDY-DESIGN/METHODS We constructed hypoxia models induced by cobalt chloride (CoCl2) in ARPE-19 cells and Rhesus choroid-retinal vascular endothelial (RF/6A) cells in vitro, as well as a retinal neovascularization model in oxygen-induced retinopathy (OIR) mice in vivo. RESULTS In this work, we demonstrated that EF treatment inhibited hypoxia-induced vascular endothelial growth factor A (VEGFA) expression in ARPE-19 cells and abrogated hypoxia-induced tube formation in RF/6A cells. As expected, intravitreal injection of EF significantly suppressed retinal neovascularization in a dose-dependent manner in OIR retinas. We also found that hypoxia increased VEGFA expression by blocking autophagic flux, whereas EF treatment enhanced autophagic flux, thereby reducing VEGFA expression. Furthermore, EF activated the sequestosome 1 (p62) / nuclear factor E2-related factor 2 (Nrf-2) pathway via upregulating oxidative stress-induced growth inhibitor 1 (OSGIN1) expression, thus alleviating oxidative stress and reducing VEGFA expression. CONCLUSION As a result of our findings, EF has an inhibitory effect on retinal neovascularization, implying a potential therapeutic strategy for hypoxia-induced retinopathy.
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Affiliation(s)
- Rong Xue
- Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, No.1 East Jianshe Road, Zhengzhou, Henan 450052, PR China
| | - Xia-Lian Fan
- Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, No.1 East Jianshe Road, Zhengzhou, Henan 450052, PR China
| | - Qian Yang
- Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, No.1 East Jianshe Road, Zhengzhou, Henan 450052, PR China
| | - Chuan Yu
- Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, No.1 East Jianshe Road, Zhengzhou, Henan 450052, PR China
| | - Tai-Ying Lu
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Zhengzhou, Henan 450052, PR China.
| | - Guang-Ming Wan
- Department of Ophthalmology, First Affiliated Hospital of Zhengzhou University, Henan Province Eye Hospital, No.1 East Jianshe Road, Zhengzhou, Henan 450052, PR China.
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14
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Naguib S, Backstrom JR, Artis E, Ghose P, Stahl A, Hardin R, Haider AA, Ang J, Calkins DJ, Rex TS. NRF2/ARE mediated antioxidant response to glaucoma: role of glia and retinal ganglion cells. Acta Neuropathol Commun 2023; 11:171. [PMID: 37875948 PMCID: PMC10594672 DOI: 10.1186/s40478-023-01663-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/04/2023] [Indexed: 10/26/2023] Open
Abstract
Glaucoma, the second leading cause of irreversible blindness worldwide, is associated with age and sensitivity to intraocular pressure (IOP). We have shown that elevated IOP causes an early increase in levels of reactive oxygen species (ROS) in the microbead occlusion mouse model. We also detected an endogenous antioxidant response mediated by Nuclear factor erythroid 2-Related Factor 2 (NRF2), a transcription factor that binds to the antioxidant response element (ARE) and increases transcription of antioxidant genes. Our previous studies show that inhibiting this pathway results in earlier and greater glaucoma pathology. In this study, we sought to determine if this endogenous antioxidant response is driven by the retinal ganglion cells (RGCs) or glial cells. We used Nrf2fl/fl mice and cell-type specific adeno-associated viruses (AAVs) expressing Cre to alter Nrf2 levels in either the RGCs or glial cells. Then, we quantified the endogenous antioxidant response, visual function and optic nerve histology after IOP elevation. We found that knock-down of Nrf2 in either cell type blunts the antioxidant response and results in earlier pathology and vision loss. Further, we show that delivery of Nrf2 to the RGCs is sufficient to provide neuroprotection. In summary, both the RGCs and glial cells contribute to the antioxidant response, but treatment of the RGCs alone with increased Nrf2 is sufficient to delay onset of vision loss and axon degeneration in this induced model of glaucoma.
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Affiliation(s)
- Sarah Naguib
- Neuroscience Program, Vanderbilt University, Nashville, TN, USA
| | - Jon R Backstrom
- Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA
| | - Elisabeth Artis
- Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA
| | - Purnima Ghose
- Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA
| | - Amy Stahl
- Neuroscience Program, Vanderbilt University, Nashville, TN, USA
| | - Rachael Hardin
- Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA
| | - Ameer A Haider
- Neuroscience Program, Vanderbilt University, Nashville, TN, USA
| | - John Ang
- Neuroscience Program, Vanderbilt University, Nashville, TN, USA
| | - David J Calkins
- Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA
| | - Tonia S Rex
- Vanderbilt University Medical Center, Vanderbilt Eye Institute, Nashville, TN, USA.
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15
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Nita M, Grzybowski A. Antioxidative Role of Heterophagy, Autophagy, and Mitophagy in the Retina and Their Association with the Age-Related Macular Degeneration (AMD) Etiopathogenesis. Antioxidants (Basel) 2023; 12:1368. [PMID: 37507908 PMCID: PMC10376332 DOI: 10.3390/antiox12071368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/09/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Age-related macular degeneration (AMD), an oxidative stress-linked neurodegenerative disease, leads to irreversible damage of the central retina and severe visual impairment. Advanced age and the long-standing influence of oxidative stress and oxidative cellular damage play crucial roles in AMD etiopathogenesis. Many authors emphasize the role of heterophagy, autophagy, and mitophagy in maintaining homeostasis in the retina. Relevantly modifying the activity of both macroautophagy and mitophagy pathways represents one of the new therapeutic strategies in AMD. Our review provides an overview of the antioxidative roles of heterophagy, autophagy, and mitophagy and presents associations between dysregulations of these molecular mechanisms and AMD etiopathogenesis. The authors performed an extensive analysis of the literature, employing PubMed and Google Scholar, complying with the 2013-2023 period, and using the following keywords: age-related macular degeneration, RPE cells, reactive oxygen species, oxidative stress, heterophagy, autophagy, and mitophagy. Heterophagy, autophagy, and mitophagy play antioxidative roles in the retina; however, they become sluggish and dysregulated with age and contribute to AMD development and progression. In the retina, antioxidative roles also play in RPE cells, NFE2L2 and PGC-1α proteins, NFE2L2/PGC-1α/ARE signaling cascade, Nrf2 factor, p62/SQSTM1/Keap1-Nrf2/ARE pathway, circulating miRNAs, and Yttrium oxide nanoparticles performed experimentally in animal studies.
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Affiliation(s)
- Małgorzata Nita
- Domestic and Specialized Medicine Centre "Dilmed", 40-231 Katowice, Poland
| | - Andrzej Grzybowski
- Institute for Research in Ophthalmology, Foundation for Ophthalmology Development, Gorczyczewskiego 2/3, 61-553 Poznań, Poland
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16
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Liang Q, Guo R, Tsao JR, He Y, Wang C, Jiang J, Zhang D, Chen T, Yue T, Hu K. Salidroside alleviates oxidative stress in dry eye disease by activating autophagy through AMPK-Sirt1 pathway. Int Immunopharmacol 2023; 121:110397. [PMID: 37302369 DOI: 10.1016/j.intimp.2023.110397] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/14/2023] [Accepted: 05/24/2023] [Indexed: 06/13/2023]
Abstract
Dry eye disease (DED) is a multifactorial disease, and oxidative stress plays a crucial role in its pathogenesis. Recently, multiple studies have shown that upregulation of autophagy can protect the cornea from oxidative stress damage. The present study investigated the therapeutic effects of salidroside, the main component of Rhodiola crenulata, in both in vivo and in vitro dry eye models. The results showed that topical eye drop treatment with salidroside restored corneal epithelium damage, increased tear secretion, and reduced cornea inflammation in the DED mice. Salidroside activated autophagy through AMP-activated protein kinase (AMPK)-sirtuin-1 (Sirt1) signaling pathway, which promoted the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant factors heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). This process restored antioxidant enzyme activity, reduced reactive oxygen species (ROS) accumulation, and alleviated oxidative stress. The application of autophagy inhibitor chloroquine and AMPK inhibitor Compound C reversed the therapeutic efficacy of salidroside, validating the above findings. In conclusion, our data suggest that salidroside is a promising candidate for DED treatment.
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Affiliation(s)
- Qi Liang
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Rongjie Guo
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Jia-Ruei Tsao
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Yun He
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Chenchen Wang
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, 618 Fengqi East Rd, Hangzhou, Zhejiang, China
| | - Jiaxuan Jiang
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Di Zhang
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Taige Chen
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China; Department of Rheumatology and Immunology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China
| | - Tingting Yue
- Department of Neurosurgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China.
| | - Kai Hu
- Department of Ophthalmology, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Rd, Nanjing, Jiangsu, China.
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17
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Ma DY, Liu JX, Wang LD, Zhi XY, Luo L, Zhao JY, Qin Y. GSK-3β-dependent Nrf2 antioxidant response modulates ferroptosis of lens epithelial cells in age-related cataract. Free Radic Biol Med 2023; 204:161-176. [PMID: 37156294 DOI: 10.1016/j.freeradbiomed.2023.04.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 04/05/2023] [Accepted: 04/29/2023] [Indexed: 05/10/2023]
Abstract
Oxidative stress-induced lens epithelial cells (LECs) death plays a pivotal role in age-related cataract (ARC) with severe visual impairment, in which ferroptosis is gradually receiving numerous attention resulting from lipid peroxide accumulation and reactive oxygen species (ROS) overproduction. However, the essential pathogenic factors and the targeted medical strategies still remain skeptical and indistinct. In this work, by transmission electron microscopy (TEM) analysis, the major pathological courses in the LECs of ARC patients have been identified as ferroptosis, which was manifested with remarkable mitochondrial alterations, and similar results were found in aged mice (24-month-old). Furthermore, the primary pathological processes in the NaIO3-induced mice and HLE-B3 cell model have also been verified to be ferroptosis with an irreplaceable function of Nrf2, proved by the increased sensitivity to ferroptosis when Nrf2 was blocked in Nrf2-KO mice and si-Nrf2-treated HLE-B3 cells. Importantly, it has been found that an increased expression of GSK-3β was indicated in low-Nrf2-expressed tissues and cells. Subsequently, the contributions of abnormal GSK-3β expression to NaIO3-induced mice and HLE-B3 cell model were further evaluated, inhibition of GSK-3β utilizing SB216763 significantly alleviated LECs ferroptosis with less iron accumulation and ROS generation, as well as reversed expression alterations of ferroptosis markers, including GPX4, SLC7A11, SLC40A1, FTH1 and TfR1, in vitro and in vivo. Collectively, our findings conclude that targeting GSK-3β/Nrf2 balance might be a promising therapeutic strategy to mitigate LECs ferroptosis and thus probably delay the pathogenesis and development of ARC.
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Affiliation(s)
- Dong-Yue Ma
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China
| | - Jin-Xia Liu
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China
| | - Lu-di Wang
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China
| | - Xin-Yu Zhi
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China
| | - Li Luo
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China
| | - Jiang-Yue Zhao
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China
| | - Yu Qin
- Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China.
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18
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Chhunchha B, Kubo E, Krueger RR, Singh DP. Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response. Antioxidants (Basel) 2023; 12:140. [PMID: 36671002 PMCID: PMC9854670 DOI: 10.3390/antiox12010140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/10/2023] Open
Abstract
A major hallmark of aging-associated diseases is the inability to evoke cellular defense responses. Transcriptional protein Nrf2 (nuclear factor erythroid-derived 2-related factor) plays a pivotal role in the oxidative stress response, cellular homeostasis, and health span. Nrf2's activation has been identified as a therapeutic target to restore antioxidant defense in aging. Here, we demonstrated that FDA-approved drug, hydralazine (Hyd), was a reactivator of the Nrf2/ARE (antioxidant response element) pathway in various ages and types of mouse (m) or human (h) lens epithelial cells (LECs) and mice lenses in-vitro/in-vivo. This led to Hyd-driven abatement of carbonyls, reduced reactive oxygen species (ROS), and reduced 4-HNE/MDA-adducts with cytoprotection, and extended lens healthspan by delaying/preventing lens opacity against aging/oxidative stress. We elucidated that Hyd activated the protective signaling by inducing Nrf2 to traverse from the cytoplasm to the nucleus and potentiated the ARE response by direct interaction of Nrf2 and ARE sequences of the promoter. Loss-of-function study and cotreatment of Hyd and antioxidant, N-acetyl cysteine (NAC) or Peroxiredoxin (Prdx)6, specified that Nrf2/ARE-driven increase in the promoter activity was Hyd-dependent. Our study provides proof-of concept evidence and, thereby, paves the way to repurposing Hyd as a therapeutic agent to delay/prevent aging and oxidative-related disorders.
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Affiliation(s)
- Bhavana Chhunchha
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Eri Kubo
- Department of Ophthalmology, Kanazawa Medical University, Kanazawa 9200293, Japan
| | - Ronald R. Krueger
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Dhirendra P. Singh
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA
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19
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Manai F, Govoni S, Amadio M. The Challenge of Dimethyl Fumarate Repurposing in Eye Pathologies. Cells 2022; 11:cells11244061. [PMID: 36552824 PMCID: PMC9777082 DOI: 10.3390/cells11244061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/28/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Dimethyl fumarate (DMF) is a small molecule currently approved and used in the treatment of psoriasis and multiple sclerosis due to its immuno-modulatory, anti-inflammatory, and antioxidant properties. As an Nrf2 activator through Keap1 protein inhibition, DMF unveils a potential therapeutical use that is much broader than expected so far. In this comprehensive review we discuss the state-of-art and future perspectives regarding the potential repositioning of this molecule in the panorama of eye pathologies, including Age-related Macular Degeneration (AMD). The DMF's mechanism of action, an extensive analysis of the in vitro and in vivo evidence of its beneficial effects, together with a search of the current clinical trials, are here reported. Altogether, this evidence gives an overview of the new potential applications of this molecule in the context of ophthalmological diseases characterized by inflammation and oxidative stress, with a special focus on AMD, for which our gene-disease (KEAP1-AMD) database search, followed by a protein-protein interaction analysis, further supports the rationale of DMF use. The necessity to find a topical route of DMF administration to the eye is also discussed. In conclusion, the challenge of DMF repurposing in eye pathologies is feasible and worth scientific attention and well-focused research efforts.
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Affiliation(s)
- Federico Manai
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
| | - Stefano Govoni
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy
| | - Marialaura Amadio
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy
- Correspondence: ; Tel.: +39-0382-987888
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20
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Ren X, Léveillard T. Modulating antioxidant systems as a therapeutic approach to retinal degeneration. Redox Biol 2022; 57:102510. [PMID: 36274523 PMCID: PMC9596747 DOI: 10.1016/j.redox.2022.102510] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/11/2022] [Accepted: 10/11/2022] [Indexed: 11/21/2022] Open
Abstract
The human retina is facing a big challenge of reactive oxygen species (ROS) from endogenous and exogenous sources. Excessive ROS can cause damage to DNA, lipids, and proteins, triggering abnormal redox signaling, and ultimately lead to cell death. Thus, oxidative stress has been observed in inherited retinal diseases as a common hallmark. To counteract the detrimental effect of ROS, cells are equipped with various antioxidant defenses. In this review, we will focus on the antioxidant systems in the retina and how they can protect retina from oxidative stress. Both small antioxidants and antioxidant enzymes play a role in ROS removal. Particularly, the thioredoxin and glutaredoxin systems, as the major antioxidant systems in mammalian cells, exert functions in redox signaling regulation via modifying cysteines in proteins. In addition, the thioredoxin-like rod-derived cone viability factor (RdCVFL) and thioredoxin interacting protein (TXNIP) can modulate metabolism in photoreceptors and promote their survival. In conclusion, elevating the antioxidant capacity in retina is a promising therapy to curb the progress of inherited retinal degeneration.
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Affiliation(s)
- Xiaoyuan Ren
- Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 17177, Sweden.
| | - Thierry Léveillard
- Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France.
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21
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Yang X, Zhang F, Liu X, Meng J, Du S, Shao J, Liu J, Fang M. FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling. Exp Cell Res 2022; 420:113340. [PMID: 36075446 DOI: 10.1016/j.yexcr.2022.113340] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 08/06/2022] [Accepted: 08/31/2022] [Indexed: 11/19/2022]
Abstract
Oxidative stress damage to the lens is a key factor in most cataracts. Forkhead box O 4 (FOXO4), a member of the forkhead box O family, plays a pivotal role in oxidative stress. FOXO4 is upregulated in lens of age-related cataract patients, but its role in cataract has not been elucidated. Herein, we investigated the role and mechanism of FOXO4 during oxidative stress damage in lens epithelial cells. H2O2 treatment enhanced FOXO4 expression in HLEpiC cells. Short hairpin RNAs mediated FOXO4 silence aggravated H2O2-induced cell apoptosis. In addition, upon H2O2 exposure, silencing of FOXO4 reduced SOD and CAT activities, as well as increased intracellular MDA and ROS levels. FOXO4 silencing also inhibited Nrf2 nuclear translocation, followed by reducing the expressions of Nrf2-governed antioxidant genes HO-1 and NOQ-1. Exogenous overexpression of FOXO4 was also involved in this study and exhibited opposite effects of FOXO4-silencing. Mechanistically, FOXO4 directly bound the promoter of TRIM25 and regulated its transcription, thereby activating the Nrf2 signaling. Taken together, in the condition of oxidative stress, the expression of FOXO4 showed a compensatory upregulation and it exhibited an anti-oxidative effect by modulating the transcription of TRIM25, thus activating the Nrf2 signaling. The FOXO4/TRIM25/Nrf2 axis may be associated with the pathological mechanisms of cataract.
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Affiliation(s)
- Xin Yang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Fengyan Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Xuhui Liu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Jia Meng
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Shanshan Du
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Jingzhi Shao
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Jingjing Liu
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Mengyuan Fang
- Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
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22
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Manai F, Amadio M. Dimethyl Fumarate Triggers the Antioxidant Defense System in Human Retinal Endothelial Cells through Nrf2 Activation. Antioxidants (Basel) 2022; 11:antiox11101924. [PMID: 36290650 PMCID: PMC9598343 DOI: 10.3390/antiox11101924] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/22/2022] [Accepted: 09/24/2022] [Indexed: 12/06/2022] Open
Abstract
Dimethyl fumarate (DMF) is a well-known activator of Nrf2 (NF-E2-related factor 2), used in the treatment of psoriasis and multiple sclerosis. The mechanism of action consists in the modification of the cysteine residues on the Nrf2-inhibitor Keap1, thus leading to the dissociation of these two proteins and the consequent activation of Nrf2. Considering the paucity of evidence of DMF effects in the context of retinal endothelium, this in vitro study investigated the role of DMF in human retinal endothelial cells (HREC). Here, we show for the first time in HREC that DMF activates the Nrf2 pathway, thus leading to an increase in HO-1 protein levels and a decrease in intracellular ROS levels. Furthermore, this molecule also shows beneficial properties in a model of hyperglucose stress, exerting cytoprotective prosurvival effects. The overall collected results suggest that DMF-mediated activation of the Nrf2 pathway may also be a promising strategy in ocular diseases characterized by oxidative stress. This study opens a new perspective on DMF and suggests its potential repositioning in a broader therapeutical context.
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Affiliation(s)
- Federico Manai
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy
| | - Marialaura Amadio
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, 27100 Pavia, Italy
- Correspondence: ; Tel.: +39-0382-987888
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Krstić L, Jarho P, Ruponen M, Urtti A, González-García MJ, Diebold Y. Improved ocular delivery of quercetin and resveratrol: A comparative study between binary and ternary cyclodextrin complexes. Int J Pharm 2022; 624:122028. [PMID: 35853567 DOI: 10.1016/j.ijpharm.2022.122028] [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: 03/31/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 11/19/2022]
Abstract
The number of patients affected by Dry Eye Disease (DED) had notably increased worldwide, addressing the need of novel therapeutic approaches. Polyphenols, quercetin (QUE) and resveratrol (RSV) show necessary antioxidant and anti-inflammatory properties to manage DED, but their application as topical eyedrops is restricted by low aqueous solubility and low chemical stability. Cyclodextrins (CD) are widely used to improve physicochemical characteristics of drugs. Consequently, the aim of this study was to make a comparison between binary complexes with quercetin, resveratrol and cyclodextrins and tertiary complexes adding hyaluronic acid (HA). Both complexes were able to enhance solubility and stability of QUE and RSV. AFM imaging and DLS measurements disclose the formation of spherical nanoaggregates within tertiary complexes of both QUE and RSV with mean diameters of 103 and 82 nm. Neither complex demonstrated cytotoxic effect in in vitro studies in corneal (HCE) and conjunctival (IM-ConjEpi) cell lines. In HCE cells, complexes containing QUE or RSV at their highest concentrations were able to scavenge more than 95 % of the ROS that were produced intracellularly (p < 0.005). Similar response was observed with IM-ConjEpi cells. The antioxidant effect was maintained in the complexes with HA. This confirmed their potential as viable topical treatment for DED.
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Affiliation(s)
- Luna Krstić
- Insituto de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, 47011 Valladolid, Spain
| | - Pekka Jarho
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland
| | - Marika Ruponen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland
| | - Arto Urtti
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland; Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014 Helsinki, Finland
| | - María J González-García
- Insituto de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, 47011 Valladolid, Spain; Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.
| | - Yolanda Diebold
- Insituto de Oftalmobiología Aplicada (IOBA), Universidad de Valladolid, 47011 Valladolid, Spain; Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Yu B, Li C, Gu L, Zhang L, Wang Q, Zhang Y, Lin J, Hu L, Jia Y, Yin M, Zhao G. Eugenol protects against Aspergillus fumigatus keratitis by inhibiting inflammatory response and reducing fungal load. Eur J Pharmacol 2022; 924:174955. [DOI: 10.1016/j.ejphar.2022.174955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 03/26/2022] [Accepted: 04/11/2022] [Indexed: 11/03/2022]
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Hsu WH, Chung CP, Wang YY, Kuo YH, Yeh CH, Lee IJ, Lin YL. Dendrobium nobile protects retinal cells from UV-induced oxidative stress damage via Nrf2/HO-1 and MAPK pathways. JOURNAL OF ETHNOPHARMACOLOGY 2022; 288:114886. [PMID: 34856359 DOI: 10.1016/j.jep.2021.114886] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/19/2021] [Accepted: 11/27/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Excessive UV irradiation and ROS exposure are the main contributors of ocular pathologies. Pseudobulb of Dendrobium nobile Lindl. is one of the sources of Shihu and has long been used in traditional Chinese medicine as a tonic to nourish stomach, replenish body fluid, antipyretic and anti-inflammation. AIM OF STUDY This study aimed to investigate whether D. nobile could protect ocular cells against oxidative stress damage. MATERIALS AND METHODS Retinal-related cell lines, ARPE-19 and RGC-5 cells, were pretreated with D. nobile extracts before H2O2- and UV-treatment. Cell viability and the oxidative stress were monitored by sulforhodamine B (SRB) and SOD1 and CAT assay kits, respectively. The oxidative stress related proteins were measured by Western blotting. RESULTS Under activity-guided fractionation, a sesquiterpene-enriched fraction (DN-2) and a major component (1) could ameliorate H2O2- and UV-induced cytotoxicity and SOD1 and CAT activity, but not dendrobine, the chemical marker of D. nobile. Western blotting showed both DN-2 and compound 1 protected ARPE-19 cells against UV-induced oxidative stress damage by regulating MAPK and Nrf2/HO-1 signaling. CONCLUSION Our results suggest D. nobile extract protects retinal pigment epithelia cells from UV- and oxidative stress-damage, which may have a beneficial effect on eye diseases.
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Affiliation(s)
- Wei-Hsiang Hsu
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan
| | - Cheng-Pei Chung
- Department of Nutrition and Health Science, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan
| | | | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan; Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan
| | - Chih-Hsin Yeh
- Taoyuan District Agricultural Research and Extension Station, Council of Agriculture, Executive Yuan, Taoyuan 32754, Taiwan
| | - I-Jung Lee
- Herbal Medicine Department, Yokohama University of Pharmacy, Yokohama Kanagawa 245-0046, Japan
| | - Yun-Lian Lin
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan; Department of Pharmacy, National Taiwan University, Taipei 10050, Taiwan.
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Chowdhury A, Balogh E, Ababneh H, Tóth A, Jeney V. Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells. Pharmaceuticals (Basel) 2022; 15:ph15050493. [PMID: 35631320 PMCID: PMC9145770 DOI: 10.3390/ph15050493] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/16/2022] [Indexed: 02/04/2023] Open
Abstract
Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron.
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Affiliation(s)
- Arpan Chowdhury
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Enikő Balogh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
| | - Haneen Ababneh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Andrea Tóth
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Viktória Jeney
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Correspondence:
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Yingrui W, Zheng L, Guoyan L, Hongjie W. Research progress of active ingredients of Scutellaria baicalensis in the treatment of type 2 diabetes and its complications. Biomed Pharmacother 2022; 148:112690. [DOI: 10.1016/j.biopha.2022.112690] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/21/2022] [Accepted: 02/02/2022] [Indexed: 12/13/2022] Open
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Cell-Based Antioxidant Properties and Synergistic Effects of Natural Plant and Algal Extracts Pre and Post Intestinal Barrier Transport. Antioxidants (Basel) 2022; 11:antiox11030565. [PMID: 35326215 PMCID: PMC8944961 DOI: 10.3390/antiox11030565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 12/10/2022] Open
Abstract
In this work, both direct and indirect cell-based antioxidant profiles were established for 27 plant extracts and 1 algal extract. To evaluate the direct antioxidant effects, fluorescent AOP1 cell assay was utilized, which measures the ability of different samples to neutralize intracellular free radicals produced by a cell-based photo-induction process. As the intestinal barrier is the first cell line crossed by the product, dose response curves obtained from Caco-2 cells were used to establish EC50 values for 26 out of the 28 natural extracts. Among them, 11 extracts from Vitis, Hamamelis, Syzygium, Helichrysum, Ilex and Ribes genera showed remarkable EC50s in the range of 10 µg/mL. In addition to this, a synergistic effect was found when combinations of the most potent extracts (S. aromaticum, H. italicum, H. virginiana, V. vinifera) were utilized compared to extracts alone. Indirect antioxidant activities (i.e., the ability of cells to trigger antioxidant defenses) were studied using the ARE/Nrf2 luminescence reporter-gene assay in HepG2 cells, as liver is the first organ crossed by an edible ingredient once it enters in the bloodstream. Twelve extracts were subjected to an intestinal epithelial barrier passage in order to partially mimic intestinal absorption and show whether basolateral compartments could maintain direct or indirect antioxidant properties. Using postepithelial barrier samples and HepG2 cells as a target model, we demonstrate that indirect antioxidant activities are maintained for three extracts, S. aromaticum, H. virginiana and H. italicum. Our experimental work also confirms the synergistic effects of combinations of post-intestinal barrier compartments issued from apical treatment with these three extracts. By combining cell-based assays together with an intestinal absorption process, this study demonstrates the power of cell systems to address the issue of antioxidant effects in humans.
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Kim MJ, Jeon JH. Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases. Int J Mol Sci 2022; 23:ijms23052846. [PMID: 35269986 PMCID: PMC8910922 DOI: 10.3390/ijms23052846] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice.
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Affiliation(s)
- Min-Ji Kim
- Department of Endocrinology in Internal Medicine, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Jae-Han Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea
- Correspondence: ; Tel.: +82-(53)-200-3182; Fax: +82-(53)-200-3155
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Wang L, Zhao Z, Zhao L, Zhao Y, Yang G, Wang C, Gao L, Niu C, Li S. Lactobacillus plantarum DP189 Reduces α-SYN Aggravation in MPTP-Induced Parkinson's Disease Mice via Regulating Oxidative Damage, Inflammation, and Gut Microbiota Disorder. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:1163-1173. [PMID: 35067061 DOI: 10.1021/acs.jafc.1c07711] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
This study aimed to evaluate the attenuating effect of Lactobacillus plantarum DP189 on α-synuclein (α-SYN) aggregates in the substantia nigra (SN) of Parkinson's disease (PD) mice via 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced. Our results indicated that L. plantarum DP189 increased the levels of superoxide dismutase (SOD), glutathione peroxide (GSH-Px), and interleukin-10 (IL-10) and decreased the levels of malondialdehyde (MDA), reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). Moreover, L. plantarum DP189 reduced the α-SYN accumulation in SN. Mechanistically, L. plantarum DP189 activated the expression of nuclear factor erythroid 2-related factor (Nrf2)/ARE and PGC-1α pathways and suppressed the NLRP3 inflammasome. Furthermore, fecal analysis showed that L. plantarum DP189 reshaped the gut microbiota in PD mice by reducing the number of pathogenic bacteria (Proteobacteria and Actinobacteria) and increased the abundance of probiotics (Lactobacillus and Prevotella). Our results suggested that L. plantarum DP189 could delay the neurodegeneration caused by the accumulation of α-SYN in the SN of PD mice via suppressing oxidative stress, repressing proinflammatory response, and modulating gut microbiota.
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Affiliation(s)
- Lei Wang
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, P. R. China
| | - Zijian Zhao
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
| | - Lei Zhao
- School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun 130117, P. R. China
| | - Yujuan Zhao
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
| | - Ge Yang
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
| | - Chao Wang
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
| | - Lei Gao
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
| | - Chunhua Niu
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
| | - Shengyu Li
- Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Changchun 130033, P. R. China
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Du J, Kang Z, Huang L, Zhou F, Feng X, Huang J. Protective effects of Hirudin against compartment syndrome in rabbits through the activation of Nrf2/HO-1. Injury 2022; 53:408-415. [PMID: 34872701 DOI: 10.1016/j.injury.2021.11.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 02/02/2023]
Abstract
Compartment syndrome generates an oxidative condition causing the death of skeletal muscle cells. Hirudin has antioxidant and anti-inflammatory properties. However, its correlation with the pathway of Nrf2/HO-1 for the protection of the skeletal muscle is unknown. We aimed to evaluate the protective efficacy of double-doses of hirudin in compartment syndrome and its association with Nrf2/HO-1 expression. Compartment syndrome was induced in rabbits and double-doses of hirudin (0-8 ATU/kg) were locally administered to select an optimal Hirudin concentration that protects skeletal muscle from damage. The tissue structural changes, W/D ratio, lipid peroxidation level by MDA assay and inflammatory factors were determined in the skeletal muscle. To determine the musculoprotective efficacy of H8 at 72 h timepoint after compartment syndrome, and its association with the Nrf2/HO-1 pathway, the following assays were performed by TUNEL assay and immunofluorescence: necrosis (high-mobility group box-1; HMGB1), Nrf2, and HO-1. In addition, the HO-1 mRNA was evaluated by qPCR. Hirudin in a dose of 8 ATU/kg (H8) presented the lowest levels of histological damage, fibrosis, W/D ratio and oxidative stress in the studied groups. Moreover, treatment with H8 markedly downregulated the level of inflammatory factors including TNF-a, IL-1β and IL-6. H8 showed a protective effect at 72 h timepoint after compartment syndrome, as revealed by a decrease in the levels of all damage markers. Nuclear translocation Nrf2 and HO-1 staining in cytoplasm were increased, and the levels of HO-1 mRNA were also increased. In conclusion, double-doses of H8 alleviate the death of muscle cells induced by oxidative stress 72 h after compartment syndrome in rabbits. This protective effect is associated with the nuclear translocation of Nrf2 and an elevated expression of HO-1.
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Affiliation(s)
- Jianhang Du
- Department of Orthopaedic, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Zhanrong Kang
- Department of Orthopaedic, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Libiao Huang
- Department of Orthopaedic, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China.
| | - Fei Zhou
- Department of Traditional Chinese Medicine, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Xu Feng
- Department of Orthopaedic, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China
| | - Jianming Huang
- Department of Orthopaedic, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Huinan Town, Pudong, Shanghai 201399, China.
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Wang L, Zou H, Xiao X, Wu H, Zhu Y, Li J, Liu X, Shen Q. Abscisic acid inhibited reactive oxygen species-mediated endoplasmic reticulum stress by regulating the PPAR-γ signaling pathway in ARDS mice. Phytother Res 2021; 35:7027-7038. [PMID: 34791723 DOI: 10.1002/ptr.7326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 10/27/2021] [Accepted: 10/29/2021] [Indexed: 11/10/2022]
Abstract
Acute respiratory distress syndrome (ARDS) is a life-threatening form of a respiratory disorder, and there are few effective therapies. Abscisic acid (ABA) has been proven to be effective in influenza and asthma. Herein, we explored the protective effect of ABA on the resolution of ARDS and the underlying mechanism. Mice were challenged with lipopolysaccharide (LPS) to establish an ARDS model. We found that ABA reduced pulmonary injury, with concomitant suppression of endoplasmic reticulum (ER) stress and reduction of reactive oxygen species (ROS) production. Furthermore, after the elimination of ROS by the specific inhibitor N-acetyl-L-cysteine (NAC), ABA did not further inhibit airway inflammation or ER stress in ARDS mice. In addition, ABA inhibited ROS production through nuclear factor erythroid 2-related factor 2 (Nrf2) activation in parallel with elevated levels of peroxisome proliferator activated receptor γ (PPAR-γ). Furthermore, the addition of a PPAR-γ antagonist abrogated the suppressive action of ABA on inflammation as well as on ER stress and oxidative stress, while NAC restored the protective effect of ABA in ARDS mice treated with a PPAR-γ antagonist. Collectively, ABA protects against LPS-induced lung injury through PPAR-γ signaling, and this effect may be associated with its inhibitory effect on ROS-mediated ER stress.
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Affiliation(s)
- Lixia Wang
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hongyun Zou
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xueying Xiao
- Department of Anesthesiology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Huimei Wu
- Department of Geriatric Respiratory and Critical Care, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Hefei, China
| | - Yan Zhu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xuesheng Liu
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China
| | - Qiying Shen
- Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.,Department of Anesthesiology, The Fourth Affiliated Hospital of Anhui Medical University, Hefei, China
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Ryu J, Gulamhusein H, Oh JK, Chang JH, Chen J, Tsang SH. Nutrigenetic reprogramming of oxidative stress. Taiwan J Ophthalmol 2021; 11:207-215. [PMID: 34703735 PMCID: PMC8493979 DOI: 10.4103/tjo.tjo_4_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/17/2021] [Indexed: 12/30/2022] Open
Abstract
Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the complex mechanisms underlying these processes. In the photoreceptors, we highlight that Nrf2 preserves their survival and function by maintaining oxidation homeostasis. In the retinal pigment epithelium, Nrf2 similarly plays a critical role in oxidative stabilization but also maintains mitochondrial motility and autophagy-related lipid metabolic processes. In endothelial cells, Nrf2 seems to promote proper vascularization and revascularization through concurrent activation of antioxidative and angiogenic factors as well as inhibition of inflammatory cytokines. Finally, Nrf2 protects retinal ganglion cells against apoptotic cell death. Importantly, we show that Nrf2-mediated protection of the various retinal tissues corresponds to a preservation of functional vision. Altogether, this review underscores the potential of the Nrf2-Keap1 pathway as a powerful tool against retinal degeneration. Key insights into this elegant oxidative defense mechanism may ultimately pave the path toward a universal therapy for various inherited and environmental retinal disorders.
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Affiliation(s)
- Joseph Ryu
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA
| | - Huzeifa Gulamhusein
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Institute of Human Nutrition, Columbia University, New York, NY, USA.,Department of Ophthalmology, The University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA
| | - Jin Kyun Oh
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, State University of New York at Downstate Medical Center, Brooklyn, USA
| | - Joseph H Chang
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Institute of Human Nutrition, Columbia University, New York, NY, USA
| | - Jocelyn Chen
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Columbia University, New York, USA
| | - Stephen H Tsang
- Department of Ophthalmology, Jonas Children's Vision Care and the Bernard and Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Columbia University, New York, NY, USA.,Department of Ophthalmology, Institute of Human Nutrition, Columbia University, New York, NY, USA.,Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute of Human Nutrition, Columbia University, NY, USA
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Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy. Int J Mol Sci 2021; 22:ijms221910279. [PMID: 34638620 PMCID: PMC8508814 DOI: 10.3390/ijms221910279] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 01/05/2023] Open
Abstract
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.
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Rodríguez ML, Millán I, Ortega ÁL. Cellular targets in diabetic retinopathy therapy. World J Diabetes 2021; 12:1442-1462. [PMID: 34630899 PMCID: PMC8472497 DOI: 10.4239/wjd.v12.i9.1442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/08/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.
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Affiliation(s)
- María Lucía Rodríguez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
| | - Iván Millán
- Neonatal Research Group, Health Research Institute La Fe, Valencia 46026, Valencia, Spain
| | - Ángel Luis Ortega
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
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Dammak A, Huete-Toral F, Carpena-Torres C, Martin-Gil A, Pastrana C, Carracedo G. From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment. Pharmaceutics 2021; 13:1376. [PMID: 34575451 PMCID: PMC8467715 DOI: 10.3390/pharmaceutics13091376] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/16/2021] [Accepted: 08/20/2021] [Indexed: 12/17/2022] Open
Abstract
Most irreversible blindness observed with glaucoma and retina-related ocular diseases, including age-related macular degeneration and diabetic retinopathy, have their origin in the posterior segment of the eye, making their physiopathology both complex and interconnected. In addition to the age factor, these diseases share the same mechanism disorder based essentially on oxidative stress. In this context, the imbalance between the production of reactive oxygen species (ROS) mainly by mitochondria and their elimination by protective mechanisms leads to chronic inflammation. Oxidative stress and inflammation share a close pathophysiological process, appearing simultaneously and suggesting a relationship between both mechanisms. The biochemical end point of these two biological alarming systems is the release of different biomarkers that can be used in the diagnosis. Furthermore, oxidative stress, initiating in the vulnerable tissue of the posterior segment, is closely related to mitochondrial dysfunction, apoptosis, autophagy dysfunction, and inflammation, which are involved in each disease progression. In this review, we have analyzed (1) the oxidative stress and inflammatory processes in the back of the eye, (2) the importance of biomarkers, detected in systemic or ocular fluids, for the diagnosis of eye diseases based on recent studies, and (3) the treatment of posterior ocular diseases, based on long-term clinical studies.
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Affiliation(s)
- Azza Dammak
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain; (A.D.); (F.H.-T.); (C.C.-T.); (A.M.-G.); (C.P.)
| | - Fernando Huete-Toral
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain; (A.D.); (F.H.-T.); (C.C.-T.); (A.M.-G.); (C.P.)
| | - Carlos Carpena-Torres
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain; (A.D.); (F.H.-T.); (C.C.-T.); (A.M.-G.); (C.P.)
| | - Alba Martin-Gil
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain; (A.D.); (F.H.-T.); (C.C.-T.); (A.M.-G.); (C.P.)
| | - Cristina Pastrana
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain; (A.D.); (F.H.-T.); (C.C.-T.); (A.M.-G.); (C.P.)
| | - Gonzalo Carracedo
- Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain; (A.D.); (F.H.-T.); (C.C.-T.); (A.M.-G.); (C.P.)
- Department of Optometry and Vsiion, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain
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Rossino MG, Amato R, Amadio M, Rosini M, Basagni F, Cammalleri M, Dal Monte M, Casini G. A Nature-Inspired Nrf2 Activator Protects Retinal Explants from Oxidative Stress and Neurodegeneration. Antioxidants (Basel) 2021; 10:1296. [PMID: 34439544 PMCID: PMC8389314 DOI: 10.3390/antiox10081296] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 01/02/2023] Open
Abstract
Oxidative stress (OS) plays a key role in retinal dysfunctions and acts as a major trigger of inflammatory and neurodegenerative processes in several retinal diseases. To prevent OS-induced retinal damage, approaches based on the use of natural compounds are actively investigated. Recently, structural features from curcumin and diallyl sulfide have been combined in a nature-inspired hybrid (NIH1), which has been described to activate transcription nuclear factor erythroid-2-related factor-2 (Nrf2), the master regulator of the antioxidant response, in different cell lines. We tested the antioxidant properties of NIH1 in mouse retinal explants. NIH1 increased Nrf2 nuclear translocation, Nrf2 expression, and both antioxidant enzyme expression and protein levels after 24 h or six days of incubation. Possible toxic effects of NIH1 were excluded since it did not alter the expression of apoptotic or gliotic markers. In OS-treated retinal explants, NIH1 strengthened the antioxidant response inducing a massive and persistent expression of antioxidant enzymes up to six days of incubation. These effects resulted in prevention of the accumulation of reactive oxygen species, of apoptotic cell death, and of gliotic reactivity. Together, these data indicate that a strategy based on NIH1 to counteract OS could be effective for the treatment of retinal diseases.
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Affiliation(s)
- Maria Grazia Rossino
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.R.); (R.A.); (M.C.)
| | - Rosario Amato
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.R.); (R.A.); (M.C.)
| | - Marialaura Amadio
- Section of Pharmacology, Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy;
| | - Michela Rosini
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (M.R.); (F.B.)
| | - Filippo Basagni
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy; (M.R.); (F.B.)
| | - Maurizio Cammalleri
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.R.); (R.A.); (M.C.)
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56124 Pisa, Italy
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.R.); (R.A.); (M.C.)
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56124 Pisa, Italy
| | - Giovanni Casini
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.G.R.); (R.A.); (M.C.)
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56124 Pisa, Italy
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Rasoulinejad SA, Akbari A, Nasiri K. Interaction of miR-146a-5p with oxidative stress and inflammation in complications of type 2 diabetes mellitus in male rats: Anti-oxidant and anti-inflammatory protection strategies in type 2 diabetic retinopathy. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:1078-1086. [PMID: 34804425 PMCID: PMC8591764 DOI: 10.22038/ijbms.2021.56958.12706] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/12/2021] [Indexed: 11/24/2022]
Abstract
OBJECTIVES This study aimed to evaluate the role of miR-146a-5p in the pathogenesis of diabetic retinopathy and its interaction with oxidative stress and inflammation in the ocular tissue of rats with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS Twenty adult male Sprague Dawley rats (220 ±20 g) were randomly assigned to control and diabetic groups. A high-fat diet was used for three months to induce T2DM which was confirmed by the HOMA-IR index. After that, the levels of glucose and insulin in serum, HOMA-IR as an indicator of insulin resistance, the ocular level of oxidative markers, TNF-α, IL-1β, MIPs, and MCP-1 along with ocular gene expression of NF-κB, Nrf2, and miR-146a-5p were evaluated. RESULTS The level of lipid peroxidation along with metabolic and inflammatory factors significantly increased and the antioxidant enzyme activity significantly decreased in diabetic rats (P<0.05). The ocular expression of NF-κB and TNF-α increased and Nrf2, HO-1, and miR-146a-5p expression decreased in diabetic rats (P<0.05). In addition, a negative correlation between miR-146a-5p expression with NF-κB and HOMA-IR and a positive correlation between miR-146a-5p with Nrf2 were observed. CONCLUSION It can be concluded that miR-146a-5p may regulate Nrf2 and NF-κB expression and inflammation and oxidative stress in the ocular tissue of diabetic rats.
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Affiliation(s)
- Seyed Ahmad Rasoulinejad
- Department of Ophthalmology, Ayatollah Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Abolfazl Akbari
- Department of Physiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - Khadijeh Nasiri
- Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Iran,Corresponding author: Khadijeh Nasiri. Department of Exercise Physiology, Faculty of Sport Sciences, University of Mazandaran, Babolsar, Iran. Babolsar, Iran.
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Dhingra A, Sharp RC, Kim T, Popov AV, Ying GS, Pietrofesa RA, Park K, Christofidou-Solomidou M, Boesze-Battaglia K. Assessment of a Small Molecule Synthetic Lignan in Enhancing Oxidative Balance and Decreasing Lipid Accumulation in Human Retinal Pigment Epithelia. Int J Mol Sci 2021; 22:5764. [PMID: 34071220 PMCID: PMC8198017 DOI: 10.3390/ijms22115764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 01/03/2023] Open
Abstract
Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. The daily phagocytosis of the photoreceptor outer segment tips by the overlaying RPE provides essential nutrients for the RPE itself and photoreceptors through intricate metabolic synergy. Age-related retinal changes are often characterized by metabolic dysregulation contributing to increased lipid accumulation and peroxidation as well as the release of proinflammatory cytokines. LGM2605 is a synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant and anti-inflammatory properties demonstrated in diverse in vitro and in vivo inflammatory disease models. In these studies, we tested the hypothesis that LGM2605 may be an attractive small-scale therapeutic that protects RPE against inflammation and restores its metabolic capacity under lipid overload. Using an in vitro model in which loss of the autophagy protein, LC3B, results in defective phagosome degradation and metabolic dysregulation, we show that lipid overload results in increased gasdermin cleavage, IL-1 β release, lipid accumulation and decreased oxidative capacity. The addition of LGM2605 resulted in enhanced mitochondrial capacity, decreased lipid accumulation and amelioration of IL-1 β release in a model of defective lipid homeostasis. Collectively, these studies suggest that lipid overload decreases mitochondrial function and increases the inflammatory response, with LGM2605 acting as a protective agent.
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Affiliation(s)
- Anuradha Dhingra
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (A.D.); (R.C.S.)
| | - Rachel C. Sharp
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (A.D.); (R.C.S.)
| | - Taewan Kim
- Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Anatoliy V. Popov
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;
| | - Gui-Shuang Ying
- Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (G.-S.Y.); (K.P.)
| | - Ralph A. Pietrofesa
- Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (R.A.P.); (M.C.-S.)
| | - Kyewon Park
- Center for Preventive Ophthalmology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (G.-S.Y.); (K.P.)
| | - Melpo Christofidou-Solomidou
- Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (R.A.P.); (M.C.-S.)
| | - Kathleen Boesze-Battaglia
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; (A.D.); (R.C.S.)
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Raga-Cervera J, Bolarin JM, Millan JM, Garcia-Medina JJ, Pedrola L, Abellán-Abenza J, Valero-Vello M, Sanz-González SM, O’Connor JE, Galarreta-Mira D, Bendala-Tufanisco E, Mayordomo-Febrer A, Pinazo-Durán MD, Zanón-Moreno V. miRNAs and Genes Involved in the Interplay between Ocular Hypertension and Primary Open-Angle Glaucoma. Oxidative Stress, Inflammation, and Apoptosis Networks. J Clin Med 2021; 10:jcm10112227. [PMID: 34063878 PMCID: PMC8196557 DOI: 10.3390/jcm10112227] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/10/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
Glaucoma has no cure and is a sight-threatening neurodegenerative disease affecting more than 100 million people worldwide, with primary open angle glaucoma (POAG) being the most globally prevalent glaucoma clinical type. Regulation of gene expression and gene networks, and its multifactorial pathways involved in glaucoma disease are landmarks for ophthalmic research. MicroRNAs (miRNAs/miRs) are small endogenous non-coding, single-stranded RNA molecules (18–22 nucleotides) that regulate gene expression. An analytical, observational, case-control study was performed in 42 patients of both sexes, aged 50 to 80 years, which were classified according to: (1) suffering from ocular hypertension (OHT) but no glaucomatous neurodegeneration (ND) such as the OHT group, or (2) have been diagnosed of POAG such as the POAG group. Participants were interviewed for obtaining sociodemographic and personal/familial records, clinically examined, and their tear samples were collected and frozen at 80 °C until processing for molecular-genetic assays. Tear RNA extraction, libraries construction, and next generation sequencing were performed. Here, we demonstrated, for the first time, the differential expression profiling of eight miRNAs when comparing tears from the OHT versus the POAG groups: the miR-26b-5p, miR-152-3p, miR-30e-5p, miR-125b-2-5p, miR-224-5p, miR-151a-3p, miR-1307-3p, and the miR-27a-3p. Gene information was set up from the DIANA-TarBase v7, DIANA-microT-CDS, and TargetScan v7.1 databases. To build a network of metabolic pathways, only genes appearing in at least four of the following databases: DisGeNet, GeneDistiller, MalaCards, OMIM PCAN, UniProt, and GO were considered. We propose miRNAs and their target genes/signaling pathways as candidates for a better understanding of the molecular-genetic bases of glaucoma and, in this way, to gain knowledge to achieve optimal diagnosis strategies for properly identifying HTO at higher risk of glaucoma ND. Further research is needed to validate these miRNAs to discern the potential role as biomarkers involved in oxidative stress, immune response, and apoptosis for the diagnosis and/or prognosis of OHT and the prevention of glaucoma ND.
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Affiliation(s)
| | - Jose M. Bolarin
- Technological Centre of Information and Communication Technologies (CENTIC), 30100 Murcia, Spain; (J.M.B.); (J.A.-A.)
| | - Jose M. Millan
- Sequencing Service at the University and Polytechnic Hospital La Fe, 46026 Valencia, Spain; (J.M.M.); (L.P.)
| | - Jose J. Garcia-Medina
- Ophthalmic Research Unit “Santiago Grisolía”/FISABIO, 46017 Valencia, Spain; (J.J.G.-M.); (M.V.-V.); (M.D.P.-D.); (V.Z.-M.)
- Department of Ophthalmology, General University Hospital “Morales Meseguer”, 30007 Murcia, Spain
- Department of Ophthalmology and Optometry, University of Murcia, 30120 Murcia, Spain
- Spanish Net of Ophthalmic Research OFTARED RD16/0008/0022, Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.-T.); (A.M.-F.)
| | - Laia Pedrola
- Sequencing Service at the University and Polytechnic Hospital La Fe, 46026 Valencia, Spain; (J.M.M.); (L.P.)
| | - Javier Abellán-Abenza
- Technological Centre of Information and Communication Technologies (CENTIC), 30100 Murcia, Spain; (J.M.B.); (J.A.-A.)
| | - Mar Valero-Vello
- Ophthalmic Research Unit “Santiago Grisolía”/FISABIO, 46017 Valencia, Spain; (J.J.G.-M.); (M.V.-V.); (M.D.P.-D.); (V.Z.-M.)
| | - Silvia M. Sanz-González
- Ophthalmic Research Unit “Santiago Grisolía”/FISABIO, 46017 Valencia, Spain; (J.J.G.-M.); (M.V.-V.); (M.D.P.-D.); (V.Z.-M.)
- Spanish Net of Ophthalmic Research OFTARED RD16/0008/0022, Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.-T.); (A.M.-F.)
- Cellular and Molecular Ophthalmobiology Group, Department of Surgery, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain
- Correspondence:
| | - José E. O’Connor
- Laboratory of Cytomics, Joint Research Unit Principe Felipe Research Center and University of Valencia, 46010 Valencia, Spain;
| | | | - Elena Bendala-Tufanisco
- Spanish Net of Ophthalmic Research OFTARED RD16/0008/0022, Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.-T.); (A.M.-F.)
- Mixed Research Unit for Visual Health and Veterinary Ophthalmology CEU/FISABIO, 46020 Valencia, Spain
- Physiology Department, Faculty of Health Sciences, CEU University, Alfara del Patriarca, 46115 Valencia, Spain
| | - Aloma Mayordomo-Febrer
- Spanish Net of Ophthalmic Research OFTARED RD16/0008/0022, Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.-T.); (A.M.-F.)
- Mixed Research Unit for Visual Health and Veterinary Ophthalmology CEU/FISABIO, 46020 Valencia, Spain
- Animal Medicine and Surgery Department, Veterinary Medicine Faculty, CEU University, Alfara del Patriarca, 46115 Valencia, Spain
| | - Maria D. Pinazo-Durán
- Ophthalmic Research Unit “Santiago Grisolía”/FISABIO, 46017 Valencia, Spain; (J.J.G.-M.); (M.V.-V.); (M.D.P.-D.); (V.Z.-M.)
- Spanish Net of Ophthalmic Research OFTARED RD16/0008/0022, Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.-T.); (A.M.-F.)
- Cellular and Molecular Ophthalmobiology Group, Department of Surgery, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain
| | - Vicente Zanón-Moreno
- Ophthalmic Research Unit “Santiago Grisolía”/FISABIO, 46017 Valencia, Spain; (J.J.G.-M.); (M.V.-V.); (M.D.P.-D.); (V.Z.-M.)
- Spanish Net of Ophthalmic Research OFTARED RD16/0008/0022, Institute of Health Carlos III, 28029 Madrid, Spain; (E.B.-T.); (A.M.-F.)
- Faculty of Health Sciences, Valencian International University, 46002 Valencia, Spain
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Dimethyl Fumarate Promotes the Survival of Retinal Ganglion Cells after Optic Nerve Injury, Possibly through the Nrf2/HO-1 Pathway. Int J Mol Sci 2020; 22:ijms22010297. [PMID: 33396673 PMCID: PMC7795407 DOI: 10.3390/ijms22010297] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/28/2020] [Indexed: 12/18/2022] Open
Abstract
This study aimed to verify whether dimethyl fumarate (DMF) promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush (ONC) accompanied by activation of the NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. We examined changes in the densities of tubulin β3 (TUBB3)-positive RGCs and the amplitudes of the positive scotopic threshold response (pSTR), reflecting the functional activity of RGCs, recorded on an electroretinogram, with daily administration of DMF, on day 7 after ONC. Furthermore, immunohistochemical and immunoblotting analyses were performed to study the activation of the Nrf2/HO-1 pathway using retinas treated with daily administration of DMF. Daily administration of DMF increasedthe density of TUBB3-positive RGCs in a dose-dependent fashion and significantly increased the amplitude of the pSTR. Immunohistochemical analysis showed that DMF administration increased the immunoreactivity for Nrf2 and HO-1, a potent antioxidant enzyme, in RGCs immunolabeled with RNA-binding protein with multiple splicing (RBPMS). Immunoblotting analysis revealed an increase in the nuclear expression of Nrf2 and marked upregulation of HO-1 after DMF administration. These results suggest that DMF has survival-promoting effects in RGC after ONC, possibly via the Nrf2/HO-1 pathway.
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Ananth S, Miyauchi S, Thangaraju M, Jadeja RN, Bartoli M, Ganapathy V, Martin PM. Selenomethionine (Se-Met) Induces the Cystine/Glutamate Exchanger SLC7A11 in Cultured Human Retinal Pigment Epithelial (RPE) Cells: Implications for Antioxidant Therapy in Aging Retina. Antioxidants (Basel) 2020; 10:antiox10010009. [PMID: 33374239 PMCID: PMC7823377 DOI: 10.3390/antiox10010009] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/15/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022] Open
Abstract
Oxidative damage has been identified as a major causative factor in degenerative diseases of the retina; retinal pigment epithelial (RPE) cells are at high risk. Hence, identifying novel strategies for increasing the antioxidant capacity of RPE cells, the purpose of this study, is important. Specifically, we evaluated the influence of selenium in the form of selenomethionine (Se-Met) in cultured RPE cells on system xc- expression and functional activity and on cellular levels of glutathione, a major cellular antioxidant. ARPE-19 and mouse RPE cells were cultured with and without selenomethionine (Se-Met), the principal form of selenium in the diet. Promoter activity assay, uptake assay, RT-PCR, northern and western blots, and immunofluorescence were used to analyze the expression of xc-, Nrf2, and its target genes. Se-Met activated Nrf2 and induced the expression and function of xc- in RPE. Other target genes of Nrf2 were also induced. System xc- consists of two subunits, and Se-Met induced the subunit responsible for transport activity (SLC7A11). Selenocysteine also induced xc- but with less potency. The effect of Se-met on xc- was associated with an increase in maximal velocity and an increase in substrate affinity. Se-Met increased the cellular levels of glutathione in the control, an oxidatively stressed RPE. The Se-Met effect was selective; under identical conditions, taurine transport was not affected and Na+-coupled glutamate transport was inhibited. This study demonstrates that Se-Met enhances the antioxidant capacity of RPE by inducing the transporter xc- with a consequent increase in glutathione.
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Affiliation(s)
- Sudha Ananth
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
| | - Seiji Miyauchi
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
| | - Muthusamy Thangaraju
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
| | - Ravirajsinh N. Jadeja
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
- Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA;
| | - Manuela Bartoli
- Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech Health Science Center, Lubbock, TX 79430, USA;
| | - Pamela M. Martin
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA; (S.A.); (S.M.); (M.T.); (R.N.J.)
- Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, USA;
- Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Correspondence: ; Tel.: +706-721-4220; Fax: +706-721-6608
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Ajith TA. Alpha-lipoic acid: A possible pharmacological agent for treating dry eye disease and retinopathy in diabetes. Clin Exp Pharmacol Physiol 2020; 47:1883-1890. [PMID: 32621549 DOI: 10.1111/1440-1681.13373] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 06/22/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022]
Abstract
Alpha-lipoic acid (ALA) is a naturally occurring dithiol micronutrient which acts as a cofactor for mitochondrial enzyme activity. Due to its potential antioxidant activity, it is considered as "universal antioxidant". Previous studies reported the pharmacological benefits of ALA such as glycaemic control, improved insulin sensitivity and alleviation of diabetic complications such as neuropathy and cardiovascular diseases. Dry eye disease and retinopathy are prevalent in diabetic patients. Experimental studies demonstrated the beneficial effects of ALA in dry eye and diabetic retinopathy. ALA can prevent the dry eye by down regulating the expression of matrix metalloproteinase-9 in the corneal epithelial cells and activating the antioxidant status of the ocular surface. Furthermore, its direct antioxidant effect can also prevent oxidative stress-induced corneal surface erosion and lachrymal gland damage. ALA prevents diabetic retinopathy through inhibition of O-linked β-N-acetylglucosamine transferase and nuclear factor-kappa B activity and alleviation of oxidative stress. It can activate the nuclear factor erythroid-2-related factor 2 and AMP-activated protein kinase in retinal ganglion cells. Clinical trials conducted in pre-retinopathic diabetic patients showed ALA with genistein and vitamins could protect the retinal cells and decline the inflammatory effect in diabetic patients. However, studies are scant to explore its beneficial effects in dry eye disease and diabetic retinopathy. Therefore, this review article discusses an update on the role of ALA in dry eye disease and diabetic retinopathy, two ocular diseases prevalent in diabetic patients.
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The Protective Effects of Flavonoids in Cataract Formation through the Activation of Nrf2 and the Inhibition of MMP-9. Nutrients 2020; 12:nu12123651. [PMID: 33261005 PMCID: PMC7759919 DOI: 10.3390/nu12123651] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/11/2022] Open
Abstract
Cataracts account for over half of global blindness. Cataracts formations occur mainly due to aging and to the direct insults of oxidative stress and inflammation to the eye lens. The nuclear factor-erythroid-2-related factor 2 (Nrf2), a transcriptional factor for cell cytoprotection, is known as the master regulator of redox homeostasis. Nrf2 regulates nearly 600 genes involved in cellular protection against contributing factors of oxidative stress, including aging, disease, and inflammation. Nrf2 was reported to disrupt the oxidative stress that activates Nuclear factor-κB (NFκB) and proinflammatory cytokines. One of these cytokines is matrix metalloproteinase 9 (MMP-9), which participates in the decomposition of lens epithelial cells (LECs) extracellular matrix and has been correlated with cataract development. Thus, during inflammatory processes, MMP production may be attenuated by the Nrf2 pathway or by the Nrf2 inhibition of NFκB pathway activation. Moreover, plant-based polyphenols have garnered attention due to their presumed safety and efficacy, nutritional, and antioxidant effects. Polyphenol compounds can activate Nrf2 and inhibit MMP-9. Therefore, this review focuses on discussing Nrf2's role in oxidative stress and cataract formation, epigenetic effect in Nrf2 activity, and the association between Nrf2 and MMP-9 in cataract development. Moreover, we describe the protective role of flavonoids in cataract formation, targeting Nrf2 activation and MMP-9 synthesis inhibition as potential molecular targets in preventing cataracts.
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Zhang Y, An Y, He X, Zhang D, He W. Esculetin protects human corneal epithelial cells from oxidative stress through Nrf-2 signaling pathway. Exp Eye Res 2020; 202:108360. [PMID: 33220236 DOI: 10.1016/j.exer.2020.108360] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 10/18/2020] [Accepted: 11/10/2020] [Indexed: 12/27/2022]
Abstract
Dry eye formation often originates from oxidative damage to the ocular surface, which can be caused by external environment or internal pathologic factors. Esculetin (6, 7-dihydroxycoumarin) is a natural product found in many plants, and has been reported to have multiple pharmacological activities. The objective of our present study is to investigate if esculetin could protect the corneal epithelial cells from oxidative damages and its underlying antioxidant molecular mechanisms. Our experimental results demonstrated that pretreatment with esculetin markedly increased the cell viability while decreased the apoptosis in H2O2-treated human corneal epithelial (HCE) cells, by regulating Bcl-2, Bax and caspase-3 protein expressions and by altering the imbalance of activities of intracellular reactive oxygen species (ROS) and superoxide dismutase (SOD). Our data revealed that esculetin played an antioxidant role not only through its antioxidant activity, but also by highly inducing Nrf-2 translocation to the nucleus, which in turn, enhanced Nrf2 signaling regulated antioxidant genes (HO-1, NQO1, GCLM, SOD1 and SOD2) mRNA expression levels in H2O2-treated HCE cells. In the present study, the protective effects of esculetin on the corneal epithelium were also confirmed by a murine desiccating stress induced dry eye model in vivo. These data illustrated, for the first time, that esculetin may have the ability to protect human corneal epithelial cells from oxidative damages through its scavenging of free radical properties and through the activation of Nrf2 signaling.
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Affiliation(s)
- Yingjun Zhang
- The School of Pharmacy, He University, Shenyang, 110163, China
| | - Yuanlong An
- The School of Pharmacy, He University, Shenyang, 110163, China
| | - Xiangdong He
- The School of Pharmacy, He University, Shenyang, 110163, China; Shenyang Industrial Technology Institute of Ophthalmology, Shenyang, 110163, China
| | - Donglei Zhang
- The School of Pharmacy, He University, Shenyang, 110163, China.
| | - Wei He
- The School of Pharmacy, He University, Shenyang, 110163, China; Shenyang Industrial Technology Institute of Ophthalmology, Shenyang, 110163, China.
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Shinde V, Hu N, Mahale A, Maiti G, Daoud Y, Eberhart CG, Maktabi A, Jun AS, Al-Swailem SA, Chakravarti S. RNA sequencing of corneas from two keratoconus patient groups identifies potential biomarkers and decreased NRF2-antioxidant responses. Sci Rep 2020; 10:9907. [PMID: 32555404 PMCID: PMC7303170 DOI: 10.1038/s41598-020-66735-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 04/17/2020] [Indexed: 12/21/2022] Open
Abstract
Keratoconus is a highly prevalent (1 in 2000), genetically complex and multifactorial, degenerative disease of the cornea whose pathogenesis and underlying transcriptomic changes are poorly understood. To identify disease-specific changes and gene expression networks, we performed next generation RNA sequencing from individual corneas of two distinct patient populations - one from the Middle East, as keratoconus is particularly severe in this group, and the second from an African American population in the United States. We conducted a case: control RNA sequencing study of 7 African American, 12 Middle Eastern subjects, and 7 controls. A Principal Component Analysis of all expressed genes was used to ascertain differences between samples. Differentially expressed genes were identified using Cuffdiff and DESeq2 analyses, and identification of over-represented signaling pathways by Ingenuity Pathway Analysis. Although separated by geography and ancestry, key commonalities in the two patient transcriptomes speak of disease - intrinsic gene expression networks. We identified an overwhelming decrease in the expression of anti-oxidant genes regulated by NRF2 and those of the acute phase and tissue injury response pathways, in both patient groups. Concordantly, NRF2 immunofluorescence staining was decreased in patient corneas, while KEAP1, which helps to degrade NRF2, was increased. Diminished NRF2 signaling raises the possibility of NRF2 activators as future treatment strategies in keratoconus. The African American patient group showed increases in extracellular matrix transcripts that may be due to underlying profibrogenic changes in this group. Transcripts increased across all patient samples include Thrombospondin 2 (THBS2), encoding a matricellular protein, and cellular proteins, GAS1, CASR and OTOP2, and are promising biomarker candidates. Our approach of analyzing transcriptomic data from different populations and patient groups will help to develop signatures and biomarkers for keratoconus subtypes. Further, RNA sequence data on individual patients obtained from multiple studies may lead to a core keratoconus signature of deregulated genes and a better understanding of its pathogenesis.
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Affiliation(s)
- Vishal Shinde
- Department of Ophthalmology, NYU Langone Medical Center, New York, NY, USA
| | - Nan Hu
- Department of Ophthalmology, NYU Langone Medical Center, New York, NY, USA
| | - Alka Mahale
- King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - George Maiti
- Department of Ophthalmology, NYU Langone Medical Center, New York, NY, USA
| | - Yassine Daoud
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Charles G Eberhart
- Ophthalmology and Oncology Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Azza Maktabi
- King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
| | - Albert S Jun
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Shukti Chakravarti
- Department of Ophthalmology, NYU Langone Medical Center, New York, NY, USA.
- Department of Pathology, NYU Langone Medical Center, New York, NY, USA.
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Catanzaro M, Lanni C, Basagni F, Rosini M, Govoni S, Amadio M. Eye-Light on Age-Related Macular Degeneration: Targeting Nrf2-Pathway as a Novel Therapeutic Strategy for Retinal Pigment Epithelium. Front Pharmacol 2020; 11:844. [PMID: 32581803 PMCID: PMC7291861 DOI: 10.3389/fphar.2020.00844] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022] Open
Abstract
Age-related macular degeneration (AMD) is a common disease with a multifactorial aetiology, still lacking effective and curative therapies. Among the early events triggering AMD is the deterioration of the retinal pigment epithelium (RPE), whose fundamental functions assure good health of the retina. RPE is physiologically exposed to high levels of oxidative stress during its lifespan; thus, the integrity and well-functioning of its antioxidant systems are crucial to maintain RPE homeostasis. Among these defensive systems, the Nrf2-pathway plays a primary role. Literature evidence suggests that, in aged and especially in AMD RPE, there is an imbalance between the increased pro-oxidant stress, and the impaired endogenous detoxifying systems, finally reverberating on RPE functions and survival. In this in vitro study on wild type (WT) and Nrf2-silenced (siNrf2) ARPE-19 cells exposed to various AMD-related noxae (H2O2, 4-HNE, MG132 + Bafilomycin), we show that the Nrf2-pathway activation is a physiological protective stress response, leading downstream to an up-regulation of the Nrf2-targets HO1 and p62, and that a Nrf2 impairment predisposes the cells to a higher vulnerability to stress. In search of new pharmacologically active compounds potentially useful for AMD, four nature-inspired hybrids (NIH) were individually characterized as Nrf2 activators, and their pharmacological activity was investigated in ARPE-19 cells. The Nrf2 activator dimethyl-fumarate (DMF; 10 μM) was used as a positive control. Three out of the four tested NIH (5 μM) display both direct and indirect antioxidant properties, in addition to cytoprotective effects in ARPE-19 cells under pro-oxidant stimuli. The observed pro-survival effects require the presence of Nrf2, with the exception of the lead compound NIH1, able to exert a still significant, albeit lower, protection even in siNrf2 cells, supporting the concept of the existence of both Nrf2-dependent and independent pathways mediating pro-survival effects. In conclusion, by using some pharmacological tools as well as a reference compound, we dissected the role of the Nrf2-pathway in ARPE-19 stress response, suggesting that the Nrf2 induction represents an efficient defensive strategy to prevent the stress-induced damage.
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Affiliation(s)
- Michele Catanzaro
- Section of Pharmacology, Department of Drug Sciences, University of Pavia, Pavia, Italy
| | - Cristina Lanni
- Section of Pharmacology, Department of Drug Sciences, University of Pavia, Pavia, Italy
| | - Filippo Basagni
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Michela Rosini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Stefano Govoni
- Section of Pharmacology, Department of Drug Sciences, University of Pavia, Pavia, Italy
| | - Marialaura Amadio
- Section of Pharmacology, Department of Drug Sciences, University of Pavia, Pavia, Italy
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Clementi ME, Sampaolese B, Sciandra F, Tringali G. Punicalagin Protects Human Retinal Pigment Epithelium Cells from Ultraviolet Radiation-Induced Oxidative Damage by Activating Nrf2/HO-1 Signaling Pathway and Reducing Apoptosis. Antioxidants (Basel) 2020; 9:antiox9060473. [PMID: 32498245 PMCID: PMC7346122 DOI: 10.3390/antiox9060473] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/25/2020] [Accepted: 05/29/2020] [Indexed: 12/29/2022] Open
Abstract
The oxidative damage of the retinal pigment epithelium (RPE) is the early event that underlies the pathogenesis of maculopathies. Numerous studies have shown that punicalagin (PUN), a polyphenol present in pomegranate, can protect several cell types from oxidative stress. Our study aims to establish if PUN protects RPE from UV radiation-induced oxidative damage. We used an experimental model which involves the use of a human-RPE cell line (ARPE-19) exposed to UV-A radiation for 1, 3, and 5 h. ARPE-19 cells were pre-treated with PUN (24 h) followed by UV-A irradiation; controls were treated identically, except for UV-A. Effects of pre-treatment with PUN on cell viability, intracellular reactive oxygen species ROS levels, modulation of Nrf2 and its antioxidant target genes, and finally apoptosis were examined. We found that pre-treatment with PUN: (1) antagonized the decrease in cell viability and reduced high levels of ROS associated with UV-A-induced oxidative stress; (2) activated Nrf2 signaling pathway by promoting Nrf2 nuclear translocation and upregulating its downstream antioxidant target genes (HO-1 and NQO1); (3) induced an anti-apoptotic effect by decreasing Bax/Bcl-2 ratio. These findings provide the first evidence that PUN can prevent UV-A-induced oxidative damage in RPE, offering itself as a possible antioxidant agent capable of contrasting degenerative eye diseases.
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Affiliation(s)
- Maria Elisabetta Clementi
- National Research Council (CNR), Istituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC)—c/o Istituto di Biochimica e Biochimica Clinica Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy; (M.E.C.); (B.S.); (F.S.)
| | - Beatrice Sampaolese
- National Research Council (CNR), Istituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC)—c/o Istituto di Biochimica e Biochimica Clinica Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy; (M.E.C.); (B.S.); (F.S.)
| | - Francesca Sciandra
- National Research Council (CNR), Istituto di Scienze e Tecnologie Chimiche “Giulio Natta” (SCITEC)—c/o Istituto di Biochimica e Biochimica Clinica Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy; (M.E.C.); (B.S.); (F.S.)
| | - Giuseppe Tringali
- Pharmacology Section, Department of Health Care Surveillance and Bioethics, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma—Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy
- Correspondence: ; Tel.: +39-063-015-4367
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Rivera-Pérez J, Martínez-Rosas M, Conde-Castañón CA, Toscano-Garibay JD, Ruiz-Pérez NJ, Flores PL, Mera Jiménez E, Flores-Estrada J. Epigallocatechin 3-Gallate Has a Neuroprotective Effect in Retinas of Rabbits with Ischemia/Reperfusion through the Activation of Nrf2/HO-1. Int J Mol Sci 2020; 21:E3716. [PMID: 32466215 PMCID: PMC7279438 DOI: 10.3390/ijms21103716] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/12/2020] [Accepted: 05/17/2020] [Indexed: 01/20/2023] Open
Abstract
Retinal ischemia-reperfusion (rI/R) generates an oxidative condition causing the death of neuronal cells. Epigallocatechin 3-gallate (EGCG) has antioxidant and anti-inflammatory properties. Nonetheless, its correlation with the pathway of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) for the protection of the retina is unknown. We aimed to evaluate the neuroprotective efficacy of single-doses of EGCG in rI/R and its association with Nrf2/Ho-1 expression. In albino rabbits, rI/R was induced and single-doses of EGCG in saline (0-30 mg/kg) were intravenously administered to select an optimal EGCG concentration that protects from retina damage. To reach this goal, retinal structural changes, gliosis by glial fibrillary acidic protein (GFAP) immunostaining, and lipid peroxidation level by TBARS (thiobarbituric acid reactive substance) assay were determined. EGCG in a dose of 15 mg/kg (E15) presented the lowest levels of histological damage, gliosis, and oxidative stress in the studied groups. To determine the neuroprotective efficacy of E15 in a timeline (6, 24, and 48 h after rI/R), and its association with the Nrf2/HO-1 pathway, the following assays were done by immunofluorescence: apoptosis (TUNEL assay), necrosis (high-mobility group box-1; HMGB1), Nrf2, and HO-1. In addition, the Ho-1 mRNA (qPCR) and lipid peroxidation levels were evaluated. E15 showed a protective effect during the first 6 h, compared to 24 and 48 h after rI/R, as revealed by a decrease in the levels of all damage markers. Nuclear translocation Nrf2 and HO-1 staining were increased, including Ho-1 mRNA levels. In conclusion, a single dose of E15 decreases the death of neuronal cells induced by oxidative stress during the first 6 h after rI/R. This protective effect is associated with the nuclear translocation of Nrf2 and with an elevation of Ho-1 expression.
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Affiliation(s)
- Josué Rivera-Pérez
- Instituto de Neurobiología, Universidad Nacional Autónoma de Mexico (UNAM), Campus UNAM-Juriquilla, CP 76230 Querétaro, Mexico;
| | - Martín Martínez-Rosas
- Departamento de Fisiología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección 16, Tlalpan, CP 14080 Ciudad de Mexico, Mexico;
| | - César A. Conde-Castañón
- Departamento de Oftalmología, Centro Médico Nacional La Raza, Paseo de las Jacarandas S/N, La Raza, Azcapotzalco, CP 02990 Ciudad de Mexico, Mexico;
| | - Julia D. Toscano-Garibay
- División de Investigación, Hospital Juárez de Mexico, Av. Instituto Politécnico Nacional 5160, Magdalena de las Salinas, Gustavo A. Madero, CP 07760 Ciudad de Mexico, Mexico; (J.D.T.-G.); (N.J.R.-P.)
| | - Nancy J. Ruiz-Pérez
- División de Investigación, Hospital Juárez de Mexico, Av. Instituto Politécnico Nacional 5160, Magdalena de las Salinas, Gustavo A. Madero, CP 07760 Ciudad de Mexico, Mexico; (J.D.T.-G.); (N.J.R.-P.)
| | - Pedro L. Flores
- Departamento de Instrumentación Electromecánica, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección 16, Tlalpan, CP 14080 Ciudad de Mexico, Mexico;
| | - Elvia Mera Jiménez
- Laboratorio de Cultivo Celular, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Casco de Santo Tomas, Miguel Hidalgo, CP 11340 Ciudad de Mexico, Mexico;
| | - Javier Flores-Estrada
- División de Investigación, Hospital Juárez de Mexico, Av. Instituto Politécnico Nacional 5160, Magdalena de las Salinas, Gustavo A. Madero, CP 07760 Ciudad de Mexico, Mexico; (J.D.T.-G.); (N.J.R.-P.)
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50
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Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9410952. [PMID: 32273949 PMCID: PMC7125500 DOI: 10.1155/2020/9410952] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 02/05/2020] [Indexed: 12/19/2022]
Abstract
Nuclear factor- (erythroid-derived 2-) like 2 (Nrf2) is a regulator of many processes of life, and it plays an important role in antioxidant, anti-inflammatory, and antifibrotic responses and in cancer. This review is focused on the potential mechanism of Nrf2 in the occurrence and development of ocular diseases. Also, several Nrf2 inducers, including noncoding RNAs and exogenous compounds, which control the expression of Nrf2 through different pathways, are discussed in ocular disease models and ocular cells, protecting them from dysfunctional changes. Therefore, Nrf2 might be a potential target of protecting ocular cells from various stresses and preventing ocular diseases.
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