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Cappellani F, Foti R, Malaguarnera G, D’Esposito F, Musumeci C, Rapisarda L, Tognetto D, Gagliano C, Zeppieri M. Nutrients and Natural Substances for Hypoglycemic Effects and Management in Diabetic Retinopathy. Nutrients 2025; 17:1207. [PMID: 40218965 PMCID: PMC11990073 DOI: 10.3390/nu17071207] [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: 03/14/2025] [Revised: 03/26/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
UNLABELLED Diabetic retinopathy (DR) is a significant microvascular consequence of diabetes mellitus (DM), resulting in visual impairment and blindness. Controlling hyperglycemia is essential for avoiding and alleviating diabetic retinopathy. Nutrients and natural compounds possessing hypoglycemic characteristics present promising supplementary approaches to conventional therapies. This review assesses the influence of nutrients and natural substances on glycemic regulation and their possible effects on diabetic retinopathy. GOAL To investigate and consolidate knowledge about nutrients and natural compounds exhibiting hypoglycemic properties and their processes in the prevention and management of diabetic retinopathy. APPROACHES Extensive reviews were conducted on pertinent studies from databases including PubMed, Scopus, and Web of Science. Selection criteria encompassed papers that examined natural substances, nutrients, or dietary supplements exhibiting effects on blood glucose levels and pathways associated to diabetic retinopathy. Principal findings were encapsulated according to their mechanisms, efficacy, and safety. OUTCOMES Numerous foods, including omega-3 fatty acids, vitamin D, and polyphenols (e.g., curcumin, resveratrol), have hypoglycemic properties by improving insulin sensitivity and diminishing oxidative stress. Natural substances like berberine, quercetin, and flavonoids demonstrate analogous effects, influencing pathways associated with inflammation, advanced glycation end products (AGEs), and angiogenesis, which are critical factors in the evolution of diabetic retinopathy (DR). The synergistic benefits of integrating natural medicines with conventional antidiabetic medications may enhance glycemic control and reduce retinal damage. The safety profiles of these therapies are predominantly positive; nonetheless, clinical trials are still constrained in both breadth and scale. CONCLUSIONS Nutrients and natural compounds are promising supplementary approaches for glycemic regulation and the therapy of diabetic retinopathy. Additional research, encompassing extensive clinical studies, is required to substantiate their efficacy, determine optimal dose, and verify long-term safety. The use of these natural substances into clinical practice may improve comprehensive management of diabetes and associated consequences.
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Affiliation(s)
- Francesco Cappellani
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (F.C.)
| | - Roberta Foti
- Division of Rheumatology, A.O.U. “Policlinico San Marco”, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, 153-173 Marylebone Rd., London NW1 5QH, UK
- Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, Via Pansini 5, 80131 Napoli, Italy
| | - Carlo Musumeci
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (F.C.)
| | - Lorenzo Rapisarda
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
| | - Daniele Tognetto
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
- Mediterranean Foundation “G.B. Morgagni”, 95125 Catania, Italy
| | - Marco Zeppieri
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
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Seo H, Park SJ, Song M. Diabetic Retinopathy (DR): Mechanisms, Current Therapies, and Emerging Strategies. Cells 2025; 14:376. [PMID: 40072104 PMCID: PMC11898816 DOI: 10.3390/cells14050376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/21/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025] Open
Abstract
Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes, affecting nearly one-third of patients with diabetes mellitus and remaining a leading cause of blindness worldwide. Among the various diabetes-induced complications, DR is of particular importance due to its direct impact on vision and the irreversible damage to the retina. DR is characterized by multiple pathological processes, primarily a hyperglycemia-induced inflammatory response and oxidative stress. Current gold standard therapies, such as anti-VEGF injections and photocoagulation, have shown efficacy in slowing disease progression. However, challenges such as drug resistance, partial therapeutic responses, and the reliance on direct eye injections-which often result in low patient compliance-remain unresolved. This review provides a comprehensive overview of the underlying molecular mechanisms in DR, the current therapies, and their unmet needs for DR treatment. Additionally, emerging therapeutic strategies for improving DR treatment outcomes are discussed.
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Affiliation(s)
| | | | - Minsoo Song
- New Drug Development Center, Daegu-Gyeongbukk Medical Innovation Foundation (K-MEDI hub), 80 Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea; (H.S.); (S.-J.P.)
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Zhou X, Hou G, Wang X, Peng Z, Yin X, Yang J, Wang S, He Y, Wang Y, Sui J, Qiang W, Guo H, Wang Y, Lin L, Shi B, He M. Metabolomic studies reveal and validate potential biomarkers of diabetic retinopathy in two Chinese datasets with type 2 diabetes: a cross-sectional study. Cardiovasc Diabetol 2024; 23:439. [PMID: 39696333 PMCID: PMC11657842 DOI: 10.1186/s12933-024-02535-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/02/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus and causes vision impairment and blindness. The presence of major risk factors for DR, such as high levels of HbA1c, does not predict all DR pathogenesis in the clinic, which suggests that uncovering the underlying mechanisms and identifying novel markers are needed. Previous evidence has shown that the serum metabolic signature of DR is unique and detectable compared with that of diabetes mellitus (DM). Here, we aimed to identify serum metabolites as reliable biomarkers for the presence of DR in type 2 DM (T2DM) patients. METHODS We performed untargeted and targeted metabolomic studies using liquid chromatography‒mass spectrometry (LC‒MS) and multiple reaction monitoring (MRM) methods on the serum samples of T2DM patients. For the discovery dataset, 39 DR patients and 39 non-DR (NDR) patients were included. For the validation dataset, 95 DR patients and 95 non-DR (NDR) patients were included. Receiver operating characteristic curve analysis was performed to evaluate the discriminating power of the metabolites. Binary logistic regression models were fit to evaluate the associations of metabolite peak areas or neurotransmitter concentrations with the presence of DR and adjusted for known risk factors. RESULTS A total of 7123 metabolites were tested. The 39 DR patients had a mean age of 56 years with an average diabetes duration of 12 years, and the 39 NDR patients had a mean age of 57 years with an average diabetes duration of 11 years. Nine serum candidate markers were further identified. Six out of nine markers were associated with DR after we adjusted for covariates, including blood pressure, HbA1c, diabetes duration, fasting blood glucose, triglyceride, eGFR etc. Among them, eicosapentaenoic acid (EPA) and L-tyrosine were validated in an independent, risk factor-matched sample set. The serum L-tyrosine concentration was decreased in DR group by 47% (-0.22 ± 0.87 vs. 0.48 ± 1.05, P < 0.001), of which the cutoff value was 0.10 mg/ml, with 86% sensitivity and 40% specificity (AUC = 0.62, 95% CI = 0.54-0.70, P = 0.005). CONCLUSIONS Low levels of circulating L-Tyrosine indicate retinopathy occurrence in T2DM population.
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Affiliation(s)
- Xingchen Zhou
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Guixue Hou
- BGI-SHENZHEN, Building NO.7, BGI Park, No. 21 Hongan 3rd Street, Yantian District, Shenzhen, Guangdong, 518083, People's Republic of China
| | - Xin Wang
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an JiaoTong University, Xi'an JiaoTong university, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Zhaoyi Peng
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Xiaoming Yin
- Chengdu HuiXin Life Technology, Chengdu, Sichuan, 610091, People's Republic of China
| | - Jing Yang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an JiaoTong University, Xi'an JiaoTong university, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Shan Wang
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an JiaoTong University, Xi'an JiaoTong university, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yayi He
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yue Wang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Jing Sui
- Department of Endocrinology and International Medical Center, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Wei Qiang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Hui Guo
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Yanan Wang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an JiaoTong University, Xi'an JiaoTong university, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Liang Lin
- BGI-SHENZHEN, Building NO.7, BGI Park, No. 21 Hongan 3rd Street, Yantian District, Shenzhen, Guangdong, 518083, People's Republic of China.
| | - Bingyin Shi
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China.
| | - Mingqian He
- Department of Endocrinology, The First Affiliated Hospital of Xi'an JiaoTong University, No.277, West Yanta Road, Xi'an, Shaanxi, 710061, People's Republic of China.
- Med-X Institute, Center for Immunological and Metabolic Diseases, The First Affiliated Hospital of Xi'an JiaoTong University, Xi'an JiaoTong university, Xi'an, Shaanxi, 710061, People's Republic of China.
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Sugasini D, Yalagala PCR, Park JC, Ma G, Farooq Z, Baccouche B, Sawant OB, McAnany JJ, Yao X, Kazlauskas A, Layden BT, Subbaiah PV. Retinal Docosahexaenoic Acid Is Significantly Reduced in Diabetic Humans and Mice: Possible Relationship to Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2024; 65:39. [PMID: 39728692 DOI: 10.1167/iovs.65.14.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Purpose The retina contains the highest concentration of the omega 3 fatty acid, docosahexaenoic acid (DHA), in the body. Although epidemiologic studies showed an inverse correlation between the consumption of omega 3 fatty acids and the prevalence of diabetic retinopathy, there are no data showing the effect of diabetes on retinal DHA in humans. In this study, we measured the DHA content of the retina in diabetic and non-diabetic humans as well as mice and determined the effect of diabetes on retinal thickness and function in mice. Methods Fatty acid composition was determined by gas chromatography/mass spectroscopy. Retinal thickness in mice was measured by optical coherence tomography and retinal function was measured by electroretinogram (ERG). Expression of selected genes involved in inflammation and lipid metabolism was determined by quantitative real-time PCR (qRT-PCR). Results We found a 40% reduction of DHA in peripheral retina and a 25% reduction in the macula of diabetic humans compared with nondiabetic controls. There was a 24% reduction in retinal DHA of type 2 diabetic mice (db/db) compared with the controls (db/+). The retinal thickness was significantly decreased in db/db mice, especially in the inner retina, and the ERG b-wave amplitudes were significantly attenuated. Increased expression of proinflammatory genes was observed in both human and mouse diabetic retinas. Conclusions Retinal DHA is reduced in diabetic humans and mice, which is associated with a thinning of retina and functional defects in diabetic mice. Enriching retinal DHA through diet may be beneficial in the prevention and treatment of diabetic retinopathy.
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Affiliation(s)
- Dhavamani Sugasini
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Poorna C R Yalagala
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Jason C Park
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Guangying Ma
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Zeenat Farooq
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Basma Baccouche
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Onkar B Sawant
- Center for Vision and Eye Banking Research, Eversight, Cleveland, Ohio, United States
| | - J Jason McAnany
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Xincheng Yao
- Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Andrius Kazlauskas
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Brian T Layden
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
- Jesse Brown VA Medical Center, Chicago, Illinois, United States
| | - Papasani V Subbaiah
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
- Jesse Brown VA Medical Center, Chicago, Illinois, United States
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Burns ME, Contini FM, Michaud JM, Waring CT, Price JC, McFarland AT, Burke SG, Murphy CA, Guindon GE, Krevosky MK, Seggio JA. Obesity alters circadian and behavioral responses to constant light in male mice. Physiol Behav 2024; 287:114711. [PMID: 39395627 DOI: 10.1016/j.physbeh.2024.114711] [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: 06/28/2024] [Revised: 10/03/2024] [Accepted: 10/04/2024] [Indexed: 10/14/2024]
Abstract
Exposure to artificial light during the night is known to promote disruption to the biological clock, which can lead to impaired mood and metabolism. Metabolic hormone secretion is modulated by the circadian pacemaker and recent research has shown that hormones such as insulin and leptin can also directly affect behavioral outcomes and the circadian clock. In turn, obesity itself is known to modulate the circadian rhythm and alter emotionality. This study investigated the behavioral and metabolic effects of constant light exposure in two models of obesity - a leptin null mutant (OB) and diet-induced obesity via high-fat diet. For both experiments, mice were placed into either a standard Light:Dark cycle (LD) or constant light (LL) and their circadian locomotor rhythms were continuously monitored. After 10 weeks of exposure to their respective lighting conditions, all mice were subjected to an open field assay to assess their explorative behaviors. Their metabolic hormone levels and inflammation levels were also measured. Behaviorally, exposure to constant light led to increased period lengthening and open field activity in the lean mice compared to both obesity models. Metabolically, LL led to increased cytokine levels and poorer metabolic outcomes in both lean and obese mice, sometimes exacerbating the metabolic issues in the obese mice, independent of weight gain. This study illustrates that LL can produce altered behavioral and physiological outcomes, even in lean mice. These results also indicate that obesity induced by different reasons can lead to shortened circadian rhythmicity and exploratory activity when exposed to chronic light.
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Affiliation(s)
- Meredith E Burns
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA
| | - Fernanda Medeiros Contini
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA; Now at Harvard University Medical School, Neurobiology Department
| | - Julie M Michaud
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA
| | - Caitlin T Waring
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA; Now at Colorado State University, College of Veterinary Medicine & Biomedical Sciences
| | - John C Price
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA
| | - Alexander T McFarland
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA; Now at Georgia Southern University, Department of Biology
| | - Samantha G Burke
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA; Now at Cummings School of Veterinary Medicine at Tufts University
| | - Cloey A Murphy
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA
| | - Grace E Guindon
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA
| | - Merideth K Krevosky
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA
| | - Joseph A Seggio
- Department of Biological Sciences, Bridgewater State University, 24 Park Ave., Bridgewater, MA 02325, USA.
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Jovanovic Macura I, Milanovic D, Tesic V, Major T, Perovic M, Adzic M, Ivkovic S. The Impact of High-Dose Fish Oil Supplementation on Mfsd2a, Aqp4, and Amyloid-β Expression in Retinal Blood Vessels of 5xFAD Alzheimer's Mouse Model. Int J Mol Sci 2024; 25:9400. [PMID: 39273347 PMCID: PMC11394872 DOI: 10.3390/ijms25179400] [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: 07/27/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
In patients with Alzheimer's disease (AD) and in animal models, the increased accumulation of amyloid β (Aβ) in retinal blood vessels strongly correlates with brain amyloid deposits and cognitive decline. The accumulation of Aβ in blood vessels may result from impaired transcytosis and a dysfunctional ocular glymphatic system in AD. High-dose fish oil (FO) supplementation has been shown to significantly change the expression of major facilitator superfamily domain-containing protein 2a (Mfsd2a), a key regulator of transcytosis, and Aquaporin 4 (Aqp4), an essential component of the glymphatic system in the retinas of WT mice. We examined the expression of Mfsd2a and Aqp4 in the retinas of 4-month-old 5xFAD female mice supplemented with high-dose FO for three weeks. There was a significant increase in Mfsd2a expression in 5xFAD retinas supplemented with FO compared to control 5xFAD mice. Additionally, the increase in Aqp4 expression observed in 4-month-old 5xFAD retinas, indicative of an impaired glymphatic system, was significantly decreased. Simultaneously, Aβ accumulation in 5xFAD retinal blood vessels was reduced following FO supplementation. These findings suggest that high-dose FO supplementation could serve as an adjunct in developing new treatments aimed at improving the regulation of transcytosis or the function of the glymphatic system in the AD retina.
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Affiliation(s)
- Irena Jovanovic Macura
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Desanka Milanovic
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Vesna Tesic
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Tamara Major
- Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia
| | - Milka Perovic
- Institute for Biological Research "Sinisa Stankovic", National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Miroslav Adzic
- Vinca-Institute for Nuclear Sciences, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
| | - Sanja Ivkovic
- Vinca-Institute for Nuclear Sciences, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
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Zhang J, Li H, Deng Q, Huang AM, Qiu W, Wang L, Xiang Z, Yang R, Liang J, Liu Z. Correlation between omega-3 intake and the incidence of diabetic retinopathy based on NHANES from 2005 to 2008. Acta Diabetol 2024; 61:997-1005. [PMID: 38625392 DOI: 10.1007/s00592-024-02267-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 02/28/2024] [Indexed: 04/17/2024]
Abstract
AIMS To identify correlations between omega-3 intake and incidence of diabetic retinopathy (DR). METHODS This was a cross-sectional study using data from participants over age 40 in the National Health and Nutrition Examination Survey (NHANES) 2005-2008. Metrics included participants' intake of omega-3 fatty acids, specifically three types of representative polyunsaturated fatty acids, DR prevalence, and demographic characteristics. Multiple logistic regression models were used to assess the relationship between omega-3 intake and DR. RESULTS Of the 1243 participants included in this study, omega-3 intake was lower in patients with DR relative to those without DR. Of the three polyunsaturated fatty acids within the omega-3 fatty acid family that we focused on, participants without DR consumed more docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) than those with DR. In contrast, there was no significant difference in the intake of eicosapentaenoic acid (EPA). Higher omega-3 intake was associated with a decreased risk of DR. In a crude model, the odds ratio (OR) was 0.548 (95% CI 0.315, 0.951; p = 0.033). In the fully adjusted model of omega-3 (model II), the adjusted OR was 0.525 (95% CI 0.306, 0.901; p = 0.021). DPA and DHA were also associated with a decreased risk of DR. In the full adjustment model (model II) of DPA and DHA, the adjusted ORs were 0.0002 (95% CI 0.000, 0.166; p = 0.014) and 0.293 (95% CI 0.105, 0.819; p = 0.020). Subgroup analysis showed that the protective effect of omega-3 against DR was more significant in younger patients (p value = 0.015). CONCLUSIONS In this cross-sectional study of the U.S. general population, we found that increased intake of omega-3 and its components, specifically DPA and DHA were negatively associated with DR incidence. This suggests that omega-3 may be a potential protective factor for DR and may help to prevent or delay the onset and progression of DR.
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Affiliation(s)
- Jingyu Zhang
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Huangdong Li
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Qian Deng
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
- Zhejiang Provincal People's Hospital Bijie Hospital, Bijie, 551700, Guizhou, China
| | - Amy Michelle Huang
- Department of Ophthalmology, University of Colorado, Aurora, CO, 80045, USA
| | - Wangjian Qiu
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
- Department of Ophthalmology, Shenzhen Songgang District People's Hospital, Shenzhen, 518105, China
| | - Li Wang
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Zheng Xiang
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Ruiming Yang
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Jiamian Liang
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China
| | - Zhiping Liu
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China.
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Augustine-Wofford K, Connaughton VP, McCarthy E. Are Hyperglycemia-Induced Changes in the Retina Associated with Diabetes-Correlated Changes in the Brain? A Review from Zebrafish and Rodent Type 2 Diabetes Models. BIOLOGY 2024; 13:477. [PMID: 39056672 PMCID: PMC11273949 DOI: 10.3390/biology13070477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/23/2024] [Accepted: 06/24/2024] [Indexed: 07/28/2024]
Abstract
Diabetes is prevalent worldwide, with >90% of the cases identified as Type 2 diabetes. High blood sugar (hyperglycemia) is the hallmark symptom of diabetes, with prolonged and uncontrolled levels contributing to subsequent complications. Animal models have been used to study these complications, which include retinopathy, nephropathy, and peripheral neuropathy. More recent studies have focused on cognitive behaviors due to the increased risk of dementia/cognitive deficits that are reported to occur in older Type 2 diabetic patients. In this review, we collate the data reported from specific animal models (i.e., mouse, rat, zebrafish) that have been examined for changes in both retina/vision (retinopathy) and brain/cognition, including db/db mice, Goto-Kakizaki rats, Zucker Diabetic Fatty rats, high-fat diet-fed rodents and zebrafish, and hyperglycemic zebrafish induced by glucose immersion. These models were selected because rodents are widely recognized as established models for studying diabetic complications, while zebrafish represent a newer model in this field. Our goal is to (1) summarize the published findings relevant to these models, (2) identify similarities in cellular mechanisms underlying the disease progression that occur in both tissues, and (3) address the hypothesis that hyperglycemic-induced changes in retina precede or predict later complications in brain.
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Affiliation(s)
| | - Victoria P. Connaughton
- Department of Biology, American University, Washington, DC 20016, USA; (K.A.-W.); (E.M.)
- Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
| | - Elizabeth McCarthy
- Department of Biology, American University, Washington, DC 20016, USA; (K.A.-W.); (E.M.)
- Center for Neuroscience and Behavior, American University, Washington, DC 20016, USA
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Lee D, Fu Z, Hellstrom A, Smith LEH. Therapeutic Effects of Anti-Inflammatory and Anti-Oxidant Nutritional Supplementation in Retinal Ischemic Diseases. Int J Mol Sci 2024; 25:5503. [PMID: 38791541 PMCID: PMC11122288 DOI: 10.3390/ijms25105503] [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: 04/17/2024] [Revised: 05/15/2024] [Accepted: 05/16/2024] [Indexed: 05/26/2024] Open
Abstract
Appropriate nutrients are essential for cellular function. Dietary components can alter the risk of systemic metabolic diseases, including cardiovascular diseases, cancer, diabetes, and obesity, and can also affect retinal diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Dietary nutrients have been assessed for the prevention or treatment of retinal ischemic diseases and the diseases of aging. In this article, we review clinical and experimental evidence concerning the potential of some nutritional supplements to prevent or treat retinal ischemic diseases and provide further insights into the therapeutic effects of nutritional supplementation on retinopathies. We will review the roles of nutrients in preventing or protecting against retinal ischemic diseases.
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Affiliation(s)
- Deokho Lee
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Zhongjie Fu
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Ann Hellstrom
- The Sahlgrenska Centre for Pediatric Ophthalmology Research, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 416 85 Gothenburg, Sweden
| | - Lois E. H. Smith
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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10
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Elbarbary NS, Ismail EAR, Mohamed SA. Omega-3 fatty acids supplementation improves early-stage diabetic nephropathy and subclinical atherosclerosis in pediatric patients with type 1 diabetes: A randomized controlled trial. Clin Nutr 2023; 42:2372-2380. [PMID: 37862823 DOI: 10.1016/j.clnu.2023.10.007] [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: 08/05/2023] [Revised: 09/21/2023] [Accepted: 10/07/2023] [Indexed: 10/22/2023]
Abstract
BACKGROUND Numerous studies have evaluated the beneficial effects of omega-3 fatty acids on inflammatory, autoimmune and renal diseases. However, data about the effects of omega-3 fatty acids on diabetic kidney disease in type 1 diabetes mellitus (T1DM) are lacking. OBJECTIVES This randomized-controlled trial assessed the effect of oral omega-3 supplementation on glycemic control, lipid profile, albuminuria level, kidney injury molecule-1 (KIM-1) and carotid intima media thickness (CIMT) in pediatric patients with T1DM and diabetic nephropathy. METHODS Seventy T1DM patients and diabetic nephropathy were enrolled with a mean age 15.2 ± 1.96 years and median disease duration 7 years. Patients were randomly assigned into two groups; intervention group which received oral omega-3 fatty acids capsules (1 g daily). The other group received a matching placebo and served as a control group. Both groups were followed-up for 6 months with assessment of fasting blood glucose (FBG), HbA1c, fasting lipids, urinary albumin creatinine ratio (UACR), KIM-1 and CIMT. RESULTS After 6 months, omega-3 fatty acids adjuvant therapy for the intervention group resulted in a significant decrease in FBG, HbA1c, triglycerides, total cholesterol, LDL-cholesterol, UACR, KIM-1 and CIMT, whereas, HDL-cholesterol was significantly higher post-therapy compared with baseline levels and compared with the control group (p < 0.05). Baseline KIM-1 levels were positively correlated to HbA1c, UACR and CIMT. Supplementation with omega-3 fatty acids was safe and well-tolerated. CONCLUSIONS Omega-3 fatty acids as an adjuvant therapy in pediatric T1DM patients with diabetic nephropathy improved glycemic control, dyslipidemia and delayed disease progression and subclinical atherosclerosis among those patients. This trial was registered under ClinicalTrials.gov Identifier no. NCT05980026.
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11
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Bora K, Kushwah N, Maurya M, Pavlovich MC, Wang Z, Chen J. Assessment of Inner Blood-Retinal Barrier: Animal Models and Methods. Cells 2023; 12:2443. [PMID: 37887287 PMCID: PMC10605292 DOI: 10.3390/cells12202443] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 10/07/2023] [Accepted: 10/08/2023] [Indexed: 10/28/2023] Open
Abstract
Proper functioning of the neural retina relies on the unique retinal environment regulated by the blood-retinal barrier (BRB), which restricts the passage of solutes, fluids, and toxic substances. BRB impairment occurs in many retinal vascular diseases and the breakdown of BRB significantly contributes to disease pathology. Understanding the different molecular constituents and signaling pathways involved in BRB development and maintenance is therefore crucial in developing treatment modalities. This review summarizes the major molecular signaling pathways involved in inner BRB (iBRB) formation and maintenance, and representative animal models of eye diseases with retinal vascular leakage. Studies on Wnt/β-catenin signaling are highlighted, which is critical for retinal and brain vascular angiogenesis and barriergenesis. Moreover, multiple in vivo and in vitro methods for the detection and analysis of vascular leakage are described, along with their advantages and limitations. These pre-clinical animal models and methods for assessing iBRB provide valuable experimental tools in delineating the molecular mechanisms of retinal vascular diseases and evaluating therapeutic drugs.
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Affiliation(s)
| | | | | | | | | | - Jing Chen
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
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12
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Rusciano D, Bagnoli P. Pharmacotherapy and Nutritional Supplements for Neovascular Eye Diseases. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1334. [PMID: 37512145 PMCID: PMC10383223 DOI: 10.3390/medicina59071334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/27/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023]
Abstract
In this review, we aim to provide an overview of the recent findings about the treatment of neovascular retinal diseases. The use of conventional drugs and nutraceuticals endowed with antioxidant and anti-inflammatory properties that may support conventional therapies will be considered, with the final aim of achieving risk reduction (prevention) and outcome improvement (cooperation between treatments) of such sight-threatening proliferative retinopathies. For this purpose, we consider a medicinal product one that contains well-defined compound(s) with proven pharmacological and therapeutic effects, usually given for the treatment of full-blown diseases. Rarely are prescription drugs given for preventive purposes. A dietary supplement refers to a compound (often an extract or a mixture) used in the prevention or co-adjuvant treatment of a given pathology. However, it must be kept in mind that drug-supplement interactions may exist and might affect the efficacy of certain drug treatments. Moreover, the distinction between medicinal products and dietary supplements is not always straightforward. For instance, melatonin is formulated as a medicinal product for the treatment of sleep and behavioral problems; at low doses (usually below 1 mg), it is considered a nutraceutical, while at higher doses, it is sold as a psychotropic drug. Despite their lower status with respect to drugs, increasing evidence supports the notion of the beneficial effects of dietary supplements on proliferative retinopathies, a major cause of vision loss in the elderly. Therefore, we believe that, on a patient-by-patient basis, the administration of nutraceuticals, either alone or in association, could benefit many patients, delaying the progression of their disease and likely improving the efficacy of pharmaceutical drugs.
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Affiliation(s)
| | - Paola Bagnoli
- Department of Biology, University of Pisa, 56123 Pisa, Italy
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13
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Sugasini D, Park JC, McAnany JJ, Kim TH, Ma G, Yao X, Antharavally B, Oroskar A, Oroskar AA, Layden BT, Subbaiah PV. Improvement of retinal function in Alzheimer disease-associated retinopathy by dietary lysophosphatidylcholine-EPA/DHA. Sci Rep 2023; 13:9179. [PMID: 37280266 PMCID: PMC10244360 DOI: 10.1038/s41598-023-36268-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 05/31/2023] [Indexed: 06/08/2023] Open
Abstract
Alzheimer disease (AD) is the most prevalent cause of dementia in the elderly. Although impaired cognition and memory are the most prominent features of AD, abnormalities in visual functions often precede them, and are increasingly being used as diagnostic and prognostic markers for the disease. Retina contains the highest concentration of the essential fatty acid docosahexaenoic acid (DHA) in the body, and its deficiency is associated with several retinal diseases including diabetic retinopathy and age related macular degeneration. In this study, we tested the hypothesis that enriching retinal DHA through a novel dietary approach could ameliorate symptoms of retinopathy in 5XFAD mice, a widely employed model of AD. The results show that 5XFAD mice have significantly lower retinal DHA compared to their wild type littermates, and feeding the lysophosphatidylcholine (LPC) form of DHA and eicosapentaenoic acid (EPA) rapidly normalizes the DHA levels, and increases retinal EPA by several-fold. On the other hand, feeding similar amounts of DHA and EPA in the form of triacylglycerol had only modest effects on retinal DHA and EPA. Electroretinography measurements after 2 months of feeding the experimental diets showed a significant improvement in a-wave and b-wave functions by the LPC-diet, whereas the TAG-diet had only a modest benefit. Retinal amyloid β levels were decreased by about 50% by the LPC-DHA/EPA diet, and by about 17% with the TAG-DHA/EPA diet. These results show that enriching retinal DHA and EPA through dietary LPC could potentially improve visual abnormalities associated with AD.
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Affiliation(s)
- Dhavamani Sugasini
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois, Chicago, IL, 60612, USA.
| | - Jason C Park
- Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago, IL, 60612, USA
| | - J Jason McAnany
- Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago, IL, 60612, USA
| | - Tae-Hoon Kim
- Department of Biomedical Engineering, University of Illinois, Chicago, IL, 60607, USA
| | - Guangying Ma
- Department of Biomedical Engineering, University of Illinois, Chicago, IL, 60607, USA
| | - Xincheng Yao
- Department of Ophthalmology and Visual Sciences, University of Illinois, Chicago, IL, 60612, USA
- Department of Biomedical Engineering, University of Illinois, Chicago, IL, 60607, USA
| | | | - Anil Oroskar
- Orochem Technologies, Inc, Naperville, IL, 60563, USA
| | | | - Brian T Layden
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois, Chicago, IL, 60612, USA
- Jesse Brown VA Medical Center, Chicago, IL, 60612, USA
| | - Papasani V Subbaiah
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois, Chicago, IL, 60612, USA.
- Jesse Brown VA Medical Center, Chicago, IL, 60612, USA.
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14
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Weir NL, Guan W, Karger AB, Klein BEK, Meuer SM, Cotch MF, Guo X, Li X, Tan J, Genter P, Chen YDI, Rotter JI, Ipp E, Tsai MY. OMEGA-3 FATTY ACIDS ARE ASSOCIATED WITH DECREASED PRESENCE AND SEVERITY OF DIABETIC RETINOPATHY: A Combined Analysis of MESA and GOLDR Cohorts. Retina 2023; 43:984-991. [PMID: 36735419 DOI: 10.1097/iae.0000000000003745] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
PURPOSE Inflammation is associated with diabetic retinopathy development and progression, and previous studies have demonstrated that omega-3 polyunsaturated fatty acids have anti-inflammatory properties. Therefore, the goal of this study was to determine if omega-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are associated with decreased risk and severity of retinopathy in individuals with type 2 diabetes. METHODS In a combined population of 1,356 individuals with type 2 diabetes from the Multi-Ethnic Study of Atherosclerosis and Genetics of Latino Diabetic Retinopathy cohorts, odds ratios using logistic regression were determined to assess the association between polyunsaturated fatty acids and retinopathy. RESULTS In 1,356 participants with type 2 diabetes, individuals in the fourth quartile of DHA were 17% less likely to have retinopathy compared with the first quartile ( P = 0.009, CI: 0.72-0.95). Secondary analysis revealed 38% lower severity of retinopathy in individuals in the fourth quartile compared with the first quartile of DHA ( P = 0.006; CI: 0.44-0.87) and EPA + DHA ( P = 0.004; CI: 0.44-0.85). No significant associations were observed between EPA and retinopathy. CONCLUSION DHA is inversely associated with the presence and severity of diabetic retinopathy. Increased intake of dietary sources of DHA may provide some protection against retinopathy in individuals with type 2 diabetes and warrants more research as a preventative option.
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Affiliation(s)
- Natalie L Weir
- Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Weihua Guan
- School of Public Health, University of Minnesota, Minnesota
| | - Amy B Karger
- Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Barbara E K Klein
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin
| | - Stacy M Meuer
- Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin
| | - Mary Frances Cotch
- Division of Epidemiology and Clinical Applications, National Eye Institute (NEI), Bethesda, Maryland
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California; and
| | - Xiaohui Li
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California; and
| | - Jingyi Tan
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California; and
| | - Pauline Genter
- Division of Endocrinology and Metabolism, Department of Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
| | - Yii-Der Ida Chen
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California; and
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California; and
| | - Eli Ipp
- Division of Endocrinology and Metabolism, Department of Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
| | - Michael Y Tsai
- Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, Minnesota
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15
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Georgiou M, Prokopiou E. Diabetic retinopathy and the role of Omega-3 PUFAs: A narrative review. Exp Eye Res 2023; 231:109494. [PMID: 37149278 DOI: 10.1016/j.exer.2023.109494] [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: 12/22/2022] [Revised: 04/07/2023] [Accepted: 04/29/2023] [Indexed: 05/08/2023]
Abstract
Diabetes mellitus has been a major cause of concern for the past few decades. As the number of diabetic patients increases, so too does the occurrence of its complications. Diabetic retinopathy (DR) is one of these and constitutes the most common cause of blindness amongst working-age individuals. Chronic exposure to a hyperglycaemic environment remains the driving force of a cascade of molecular events that disrupt the microvasculature of the retina and if left untreated can lead to blindness. In this review, we identify oxidative stress as a major implication in the pathway to the development of DR and speculate that it plays a central role especially in the early stages of the disease. Cells lose their antioxidant capacity under a hyperglycaemic state, free radicals are formed and eventually apoptosis ensues. The polyol pathway; advanced glycation end-product formation; the protein kinase C pathway, and the hexosamine pathway are found to contribute to the increase in oxidative stress observed in diabetic patients. We also investigate the use of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in DR. These molecules possess antioxidant and anti-inflammatory properties and have been previously investigated for use in other ocular pathologies with promising results. In this review we present the latest findings in pre-clinical and clinical studies for the use of ω-3 PUFAs in DR. We hypothesise that ω-3 PUFAs could be beneficial for DR in ways of reducing the oxidative stress and limiting the progression of the disease that threatens the eyesight of the patient, in conjunction with conventional therapy.
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Affiliation(s)
- Maria Georgiou
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, 2414, Nicosia, Cyprus
| | - Ekatherine Prokopiou
- Department of Basic and Clinical Sciences, University of Nicosia Medical School, 2414, Nicosia, Cyprus; Ophthalmos Research and Educational Institute, 2417, Nicosia, Cyprus.
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16
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Sharif N. Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors. Neural Regen Res 2023; 18:5-17. [PMID: 35799502 PMCID: PMC9241399 DOI: 10.4103/1673-5374.343887] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and thromboxane-A2 interact with five major receptors (and their sub-types) to elicit specific downstream cellular and tissue actions. In general, prostaglandins have been associated with pain, inflammation, and edema when they are present at high local concentrations and involved on a chronic basis. However, in acute settings, certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation, providing cellular protection, regulating sleep, and enhancing blood flow, to lowering intraocular pressure to prevent the development of glaucoma, a blinding disease. Several classes of prostaglandins are implicated (or are considered beneficial) in certain central nervous system dysfunctions (e.g., Alzheimer’s, Parkinson’s, and Huntington’s diseases; amyotrophic lateral sclerosis and multiple sclerosis; stroke, traumatic brain injuries and pain) and in ocular disorders (e.g., ocular hypertension and glaucoma; allergy and inflammation; edematous retinal disorders). This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease, and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists, polyunsaturated fatty acids, and cyclooxygenase inhibitors.
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17
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Jovanovic Macura I, Djuricic I, Major T, Milanovic D, Brkic M, Sobajic S, Kanazir S, Ivkovic S. The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
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18
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Metabolomics and Biomarkers in Retinal and Choroidal Vascular Diseases. Metabolites 2022; 12:metabo12090814. [PMID: 36144219 PMCID: PMC9503269 DOI: 10.3390/metabo12090814] [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: 07/26/2022] [Revised: 08/25/2022] [Accepted: 08/27/2022] [Indexed: 11/17/2022] Open
Abstract
The retina is one of the most important structures in the eye, and the vascular health of the retina and choroid is critical to visual function. Metabolomics provides an analytical approach to endogenous small molecule metabolites in organisms, summarizes the results of “gene-environment interactions”, and is an ideal analytical tool to obtain “biomarkers” related to disease information. This study discusses the metabolic changes in neovascular diseases involving the retina and discusses the progress of the study from the perspective of metabolomics design and analysis. This study advocates a comparative strategy based on existing studies, which encompasses optimization of the performance of newly identified biomarkers and the consideration of the basis of existing studies, which facilitates quality control of newly discovered biomarkers and is recommended as an additional reference strategy for new biomarker discovery. Finally, by describing the metabolic mechanisms of retinal and choroidal neovascularization, based on the results of existing studies, this study provides potential opportunities to find new therapeutic approaches.
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19
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Chen S, Zou H. Key Role of 12-Lipoxygenase and Its Metabolite 12-Hydroxyeicosatetraenoic Acid (12-HETE) in Diabetic Retinopathy. Curr Eye Res 2022; 47:329-335. [PMID: 35129022 DOI: 10.1080/02713683.2021.1995003] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Abnormal lipid metabolism has been proved to be implicated in the complex pathogenesis of diabetic retinopathy (DR). 12-lipoxygenase (12-LOX) is a member of lipoxygenase family responsible for the oxygenation of cellular polyunsaturated fatty acids to produce lipid mediators which modulate cell inflammation. This review explores the role of 12-lipoxygenase and its products in the pathogenesis of DR. METHODS A comprehensive medical literature search was conducted on PubMed till September 2021. RESULTS Emerging evidence has demonstrated that 12-LOX and its main product 12- hydroxyeicosatetraenoic acid (12-HETE) activate retinal cells, especially retinal vascular endothelial cells, through the activation of NADPH oxidase and the subsequent generation of reactive oxygen species (ROS), mediating multiple pathological changes during DR. Genetic deletion or pharmacological inhibition models of 12-LOX in mice show protection from DR. CONCLUSION 12-LOX and its product 12-HETE take important part in DR pathogenesis and show their potential as future therapeutic targets for DR. Further studies are needed on the specific mechanism including 12-LOX pathway related molecules, 12-HETE receptors and downstream signaling pathways.
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Affiliation(s)
- Shuli Chen
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Haidong Zou
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Eye Disease Prevention and Treatment Center, Shanghai Eye Hospital, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
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20
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Tomita Y, Usui-Ouchi A, Nilsson AK, Yang J, Ko M, Hellström A, Fu Z. Metabolism in Retinopathy of Prematurity. Life (Basel) 2021; 11:1119. [PMID: 34832995 PMCID: PMC8620873 DOI: 10.3390/life11111119] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/11/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Retinopathy of prematurity is defined as retinal abnormalities that occur during development as a consequence of disturbed oxygen conditions and nutrient supply after preterm birth. Both neuronal maturation and retinal vascularization are impaired, leading to the compensatory but uncontrolled retinal neovessel growth. Current therapeutic interventions target the hypoxia-induced neovessels but negatively impact retinal neurons and normal vessels. Emerging evidence suggests that metabolic disturbance is a significant and underexplored risk factor in the disease pathogenesis. Hyperglycemia and dyslipidemia correlate with the retinal neurovascular dysfunction in infants born prematurely. Nutritional and hormonal supplementation relieve metabolic stress and improve retinal maturation. Here we focus on the mechanisms through which metabolism is involved in preterm-birth-related retinal disorder from clinical and experimental investigations. We will review and discuss potential therapeutic targets through the restoration of metabolic responses to prevent disease development and progression.
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Affiliation(s)
- Yohei Tomita
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (Y.T.); (J.Y.); (M.K.)
| | - Ayumi Usui-Ouchi
- Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba 279-0021, Japan;
| | - Anders K. Nilsson
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 413 19 Gothenburg, Sweden; (A.K.N.); (A.H.)
| | - Jay Yang
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (Y.T.); (J.Y.); (M.K.)
| | - Minji Ko
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (Y.T.); (J.Y.); (M.K.)
| | - Ann Hellström
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 413 19 Gothenburg, Sweden; (A.K.N.); (A.H.)
| | - Zhongjie Fu
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (Y.T.); (J.Y.); (M.K.)
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21
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Zhang CL, Wang HL, Li PC, Hong CD, Chen AQ, Qiu YM, Zeng AP, Zhou YF, Hu B, Li YN. Mfsd2a overexpression alleviates vascular dysfunction in diabetic retinopathy. Pharmacol Res 2021; 171:105755. [PMID: 34229049 DOI: 10.1016/j.phrs.2021.105755] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 06/30/2021] [Accepted: 06/30/2021] [Indexed: 11/30/2022]
Abstract
Diabetic retinopathy (DR) is one of the common complications in diabetic patients. Nowadays, VEGF pathway is subject to extensive research. However, about 27% of the patients have a poor visual outcome, with 50% still having edema after two years' treatment of diabetic macular edema (DME) with ranibizumab. Docosahexaenoic acid (DHA), the primary ω-3 long-chain polyunsaturated fatty acid (LC-PUFA), reduces abnormal neovascularization and alleviates neovascular eye diseases. A study reported that fish oil reduced the incidence of retinopathy of prematurity (ROP) by about 27.5% in preterm infants. Although ω-3 LC-PUFAs protects against pathological retinal neovascularization, the treatment effectiveness is low. It is interesting to investigate why DHA therapy fails in some patients. In human vitreous humor samples, we found that the ratio of DHA and DHA-derived metabolites to total fatty acids was higher in vitreous humor from DR patients than that from macular hole patients; however, the ratio of DHA metabolites to DHA and DHA-derived metabolites was lower in the diabetic vitreous humor. The expression of Mfsd2a, the LPC-DHA transporter, was reduced in the oxygen-induced retinopathy (OIR) model and streptozotocin (STZ) model. In vitro, Mfsd2a overexpression inhibited endothelial cell proliferation, migration and vesicular transcytosis. Moreover, Mfsd2a overexpression in combination with the DHA diet obviously reduced abnormal retinal neovascularization and vascular leakage, which is more effective than Mfsd2a overexpression alone. These results suggest that DHA therapy failure in some DR patients is linked to low expression of Mfsd2a, and the combination of Mfsd2a overexpression and DHA therapy may be an effective treatment.
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Affiliation(s)
- Chun-Lin Zhang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hai-Ling Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Peng-Cheng Li
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Can-Dong Hong
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - An-Qi Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan-Mei Qiu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ai-Ping Zeng
- Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yi-Fan Zhou
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Ya-Nan Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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22
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Okamura T, Nakajima H, Hashimoto Y, Majima S, Senmaru T, Ushigome E, Nakanishi N, Hamaguchi M, Asano M, Yamazaki M, Takakuwa H, Fukui M. Low circulating dihomo-gamma-linolenic acid is associated with diabetic retinopathy: a cross sectional study of KAMOGAWA-DM cohort study. Endocr J 2021; 68:421-428. [PMID: 33361692 DOI: 10.1507/endocrj.ej20-0564] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Diabetic retinopathy (DR), one of the major complications of diabetes, can cause blindness and reduce quality of life. Dyslipidemia is reported to be associated with DR, whereas arachidonic acid may have a protective effect against DR. We aimed to investigate the association of circulating n-3 and n-6 polyunsaturated fatty acids (PUFAs) with DR. In this cross-sectional study, 190 Japanese patients with type 2 diabetes were classified as no diabetic retinopathy (NDR), simple diabetic retinopathy (SDR), or proliferative diabetic retinopathy (PDR) including pre-proliferative diabetic retinopathy. Circulating fatty acids (FAs) were measured by gas chromatograph-mass spectrometry. Logistic regression analysis was performed to investigate the association between the levels of FAs and the presence of DR. The average age, body mass index and the duration of diabetes were 62.7 ± 12.1 years, 25.0 ± 4.5 kg/m2, and 9.8 ± 8.7 years, respectively. Twenty-seven patients were diagnosed with DR. Circulating levels of dihomo-gamma-linolenic acid (DGLA) in the NDR (n = 163), SDR (n = 13) and PDR (n = 14) groups were 28.3 ± 11.0 μg/mL, 24.4 ± 9.7 μg/mL, and 21.8 ± 6.2 μg/mL, respectively (p = 0.032). The logarithm of circulating DGLA levels was associated with the presence of DR after adjusting for covariates (OR of 1-unit increment: 0.79, 95% CI: 0.62-1.00, p = 0.049). Circulating DGLA was negatively associated with the presence of DR.
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Affiliation(s)
- Takuro Okamura
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hanako Nakajima
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Yoshitaka Hashimoto
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Saori Majima
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takafumi Senmaru
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Emi Ushigome
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Naoko Nakanishi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Mai Asano
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Masahiro Yamazaki
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hiroshi Takakuwa
- Agilent Technologies, Chromatography Mass Spectrometry Sales Department, Life Science and Applied Markets Group, Tokyo 192-8510, Japan
| | - Michiaki Fukui
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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Rao H, Jalali JA, Johnston TP, Koulen P. Emerging Roles of Dyslipidemia and Hyperglycemia in Diabetic Retinopathy: Molecular Mechanisms and Clinical Perspectives. Front Endocrinol (Lausanne) 2021; 12:620045. [PMID: 33828528 PMCID: PMC8020813 DOI: 10.3389/fendo.2021.620045] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/25/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetic retinopathy (DR) is a significant cause of vision loss and a research subject that is constantly being explored for new mechanisms of damage and potential therapeutic options. There are many mechanisms and pathways that provide numerous options for therapeutic interventions to halt disease progression. The purpose of the present literature review is to explore both basic science research and clinical research for proposed mechanisms of damage in diabetic retinopathy to understand the role of triglyceride and cholesterol dysmetabolism in DR progression. This review delineates mechanisms of damage secondary to triglyceride and cholesterol dysmetabolism vs. mechanisms secondary to diabetes to add clarity to the pathogenesis behind each proposed mechanism. We then analyze mechanisms utilized by both triglyceride and cholesterol dysmetabolism and diabetes to elucidate the synergistic, additive, and common mechanisms of damage in diabetic retinopathy. Gathering this research adds clarity to the role dyslipidemia has in DR and an evaluation of the current peer-reviewed basic science and clinical evidence provides a basis to discern new potential therapeutic targets.
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Affiliation(s)
- Hussain Rao
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
| | - Jonathan A. Jalali
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
| | - Thomas P. Johnston
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri – Kansas City, Kansas City, MO, United States
| | - Peter Koulen
- Department of Ophthalmology, School of Medicine, Vision Research Center, University of Missouri – Kansas City, Kansas City, MO, United States
- Department of Biomedical Sciences, School of Medicine, University of Missouri – Kansas City, Kansas City, MO, United States
- *Correspondence: Peter Koulen,
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24
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Sugasini D, Yalagala PCR, Subbaiah PV. Efficient Enrichment of Retinal DHA with Dietary Lysophosphatidylcholine-DHA: Potential Application for Retinopathies. Nutrients 2020; 12:nu12103114. [PMID: 33053841 PMCID: PMC7601701 DOI: 10.3390/nu12103114] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/03/2020] [Accepted: 10/06/2020] [Indexed: 12/29/2022] Open
Abstract
Although decreased retinal docosahexaenoic acid (DHA) is a known risk factor for retinopathy, currently available omega-3 fatty acid supplements, which are absorbed as triacylglycerol (TAG), do not significantly enrich retinal DHA. We tested the hypothesis that lysophospahtidylcholine (LPC)-DHA which is absorbed as phospholipid, would efficiently increase retinal DHA because of the presence of LPC-specific transporter at the blood–retina barrier. In normal rats, LPC-DHA and di-DHA phosphatidylcholine (PC), which generates LPC-DHA during digestion, increased retinal DHA by 101% and 45%, respectively, but TAG-DHA had no significant effect at the same dose (40 mg/kg, 30 days). In normal mice, both sn-1 DHA LPC and sn-2 DHA LPC increased retinal DHA by 80%, but free DHA had no effect. Lipase-treated krill oil (which contains LPC-DHA and LPC-EPA (eicosapentaenoic acid), but not normal krill oil (which has little LPC), increased both retinal DHA (+76%) and EPA (100-fold). Fish oil, however, had no effect, whether lipase-treated or not. These studies show that retinal DHA can be efficiently increased by dietary LPC-DHA, but not by TAG-DHA or free DHA. Since DHA is known to be protective against retinopathy and other eye diseases, this study provides a novel nutraceutical approach for the prevention/treatment of these diseases.
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Affiliation(s)
- Dhavamani Sugasini
- Department of Medicine, Section of Endocrinology and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA; (D.S.); (P.C.R.Y.)
| | - Poorna C. R. Yalagala
- Department of Medicine, Section of Endocrinology and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA; (D.S.); (P.C.R.Y.)
| | - Papasani V. Subbaiah
- Department of Medicine, Section of Endocrinology and Metabolism, University of Illinois at Chicago, Chicago, IL 60612, USA; (D.S.); (P.C.R.Y.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA
- Correspondence: ; Tel.: +1-312-996-8212; Fax: +1-312-413-0437
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25
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Suzumura A, Terao R, Kaneko H. Protective Effects and Molecular Signaling of n-3 Fatty Acids on Oxidative Stress and Inflammation in Retinal Diseases. Antioxidants (Basel) 2020; 9:E920. [PMID: 32993153 PMCID: PMC7600094 DOI: 10.3390/antiox9100920] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Oxidative stress and inflammation play crucial roles in the development and progression of retinal diseases. Retinal damage by various etiologies can result in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). n-3 fatty acids are essential fatty acids and are necessary for homeostasis. They are important retinal membrane components and are involved in energy storage. n-3 fatty acids also have antioxidant and anti-inflammatory properties, and their suppressive effects against ROP, DR, and AMD have been previously evaluated. α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their metabolites have been shown to alleviate retinal oxidative stress and inflammation involving various biological signaling pathways. In this review, we summarize the current understanding of the n-3 fatty acids effects on the mechanisms of these retinal diseases and how they exert their therapeutic effects, focusing on ALA, EPA, DHA, and their metabolites. This knowledge may provide new remedial strategies for n-3 fatty acids in the prevention and treatment of retinal diseases associated with oxidative stress and inflammation.
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Affiliation(s)
- Ayana Suzumura
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
| | - Ryo Terao
- Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan;
| | - Hiroki Kaneko
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan;
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Saenz de Viteri M, Hernandez M, Bilbao-Malavé V, Fernandez-Robredo P, González-Zamora J, Garcia-Garcia L, Ispizua N, Recalde S, Garcia-Layana A. A Higher Proportion of Eicosapentaenoic Acid (EPA) When Combined with Docosahexaenoic Acid (DHA) in Omega-3 Dietary Supplements Provides Higher Antioxidant Effects in Human Retinal Cells. Antioxidants (Basel) 2020; 9:E828. [PMID: 32899655 PMCID: PMC7555332 DOI: 10.3390/antiox9090828] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/24/2020] [Accepted: 09/01/2020] [Indexed: 12/15/2022] Open
Abstract
Retinal pigment epithelium (RPE) is a key regulator of retinal function and is directly related to the transport, delivery, and metabolism of long-chain n-3 polyunsaturated fatty acids (n3-PUFA), in the retina. Due to their functions and location, RPE cells are constantly exposed to oxidative stress. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown to have antioxidant effects by different mechanisms. For this reason, we designed an in vitro study to compare 10 formulations of DHA and EPA supplements from different origins and combined in different proportions, evaluating their effect on cell viability, cell proliferation, reactive oxygen species production, and cell migration using ARPE-19 cells. Furthermore, we assessed their ability to rescue RPE cells from the oxidative conditions seen in diabetic retinopathy. Our results showed that the different formulations of n3-PUFAs have a beneficial effect on cell viability and proliferation and are able to restore oxidative induced RPE damage. We observed that the n3-PUFA provided different results alone or combined in the same supplement. When combined, the best results were obtained in formulations that included a higher proportion of EPA than DHA. Moreover, n3-PUFA in the form of ethyl-esters had a worse performance when compared with triglycerides or phospholipid based formulations.
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Affiliation(s)
- Manuel Saenz de Viteri
- Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.S.d.V.); (V.B.-M.); (J.G.-Z.); (A.G.-L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa Sanitaria en Enfermedades Oculares (Oftared), 31008 Pamplona, Spain
| | - María Hernandez
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
| | - Valentina Bilbao-Malavé
- Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.S.d.V.); (V.B.-M.); (J.G.-Z.); (A.G.-L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
| | - Patricia Fernandez-Robredo
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa Sanitaria en Enfermedades Oculares (Oftared), 31008 Pamplona, Spain
| | - Jorge González-Zamora
- Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.S.d.V.); (V.B.-M.); (J.G.-Z.); (A.G.-L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
| | - Laura Garcia-Garcia
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
| | - Nahia Ispizua
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
| | - Sergio Recalde
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa Sanitaria en Enfermedades Oculares (Oftared), 31008 Pamplona, Spain
| | - Alfredo Garcia-Layana
- Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.S.d.V.); (V.B.-M.); (J.G.-Z.); (A.G.-L.)
- Retinal Pathologies and New Therapies Group, Experimental Ophthalmology Laboratory, Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain; (M.H.); (L.G.-G.); (N.I.); (S.R.)
- Navarra Institute for Health Research, IdiSNA, 31008 Pamplona, Spain
- Red Temática de Investigación Cooperativa Sanitaria en Enfermedades Oculares (Oftared), 31008 Pamplona, Spain
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O'Mahoney LL, Dunseath G, Churm R, Holmes M, Boesch C, Stavropoulos-Kalinoglou A, Ajjan RA, Birch KM, Orsi NM, Mappa G, Price OJ, Campbell MD. Omega-3 polyunsaturated fatty acid supplementation versus placebo on vascular health, glycaemic control, and metabolic parameters in people with type 1 diabetes: a randomised controlled preliminary trial. Cardiovasc Diabetol 2020; 19:127. [PMID: 32787879 PMCID: PMC7425064 DOI: 10.1186/s12933-020-01094-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/25/2020] [Indexed: 12/11/2022] Open
Abstract
Background The role of omega-3 polyunsaturated fatty acids (n-3PUFA), and the potential impact of n-3PUFA supplementation, in the treatment and management of type 1 diabetes (T1D) remains unclear and controversial. Therefore, this study aimed to examine the efficacy of daily high-dose-bolus n-3PUFA supplementation on vascular health, glycaemic control, and metabolic parameters in subjects with T1D. Methods Twenty-seven adults with T1D were recruited to a 6-month randomised, double-blind, placebo-controlled trial. Subjects received either 3.3 g/day of encapsulated n-3PUFA or encapsulated 3.0 g/day corn oil placebo (PLA) for 6-months, with follow-up at 9-months after 3-month washout. Erythrocyte fatty acid composition was determined via gas chromatography. Endpoints included inflammation-associated endothelial biomarkers (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule-1 [ICAM-1], E-selectin, P-selectin, pentraxin-3, vascular endothelial growth factor [VEGF]), and their mediator tumor necrosis factor alpha [TNFα] analysed via immunoassay, vascular structure (carotid intima-media thickness [CIMT]) and function (brachial artery flow mediated dilation [FMD]) determined via ultrasound technique, blood pressure, glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial metabolism. Results Twenty subjects completed the trial in full. In the n-3PUFA group, the mean ± SD baseline n-3PUFA index of 4.93 ± 0.94% increased to 7.67 ± 1.86% (P < 0.001) after 3-months, and 8.29 ± 1.45% (P < 0.001) after 6-months. Total exposure to n-3PUFA over the 6-months (area under the curve) was 14.27 ± 3.05% per month under n-3PUFA, and 9.11 ± 2.74% per month under PLA (P < 0.001). VCAM-1, ICAM-1, E-selectin, P-selectin, pentraxin-3, VEGF, TNFα, CIMT, FMD, blood pressure, HbA1c, FPG, and postprandial metabolism did not differ between or within groups after treatment (P > 0.05). Conclusions This study indicates that daily high-dose-bolus of n-3PUFA supplementation for 6-months does not improve vascular health, glucose homeostasis, or metabolic parameters in subjects with T1D. The findings from this preliminary RCT do not support the use of therapeutic n-3PUFA supplementation in the treatment and management of T1D and its associated complications. Trial Registration ISRCTN, ISRCTN40811115. Registered 27 June 2017, http://www.isrctn.com/ISRCTN40811115.
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Affiliation(s)
| | - Gareth Dunseath
- Diabetes Research Group, Swansea University Medical School, Swansea University, Swansea, UK
| | - Rachel Churm
- Applied Sports, Technology, Exercise and Medicine (A-STEM) Research Centre, Swansea University, Swansea, UK
| | - Mel Holmes
- School of Food Science and Nutrition, Faculty of Environment, University of Leeds, Leeds, LS2 9JT, UK
| | - Christine Boesch
- School of Food Science and Nutrition, Faculty of Environment, University of Leeds, Leeds, LS2 9JT, UK
| | | | - Ramzi A Ajjan
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK
| | - Karen M Birch
- School of Biomedical Sciences, University of Leeds, Leeds, UK
| | - Nicolas M Orsi
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Leeds, UK
| | - Georgia Mappa
- Leeds Institute of Medical Research at St James's, St James's University Hospital, Leeds, UK
| | - Oliver J Price
- Carnegie School of Sport, Leeds Beckett University, Leeds, UK
| | - Matthew D Campbell
- School of Food Science and Nutrition, Faculty of Environment, University of Leeds, Leeds, LS2 9JT, UK.
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THREE-YEAR OUTCOMES IN A RANDOMIZED SINGLE-BLIND CONTROLLED TRIAL OF INTRAVITREAL RANIBIZUMAB AND ORAL SUPPLEMENTATION WITH DOCOSAHEXAENOIC ACID AND ANTIOXIDANTS FOR DIABETIC MACULAR EDEMA. Retina 2020; 39:1083-1090. [PMID: 29474306 PMCID: PMC6553973 DOI: 10.1097/iae.0000000000002114] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The decrease in macular thickness observed at 24 months was maintained at Month 36 in patients with diabetic macular edema treated with a combination of intravitreal ranibizumab and oral supplementation with high-dose docosahexaenoic acid and antioxidants. Purpose: To report 3-year results of a randomized single-blind controlled trial of intravitreal ranibizumab combined with oral docosahexaenoic acid (DHA) supplementation versus ranibizumab alone in patients with diabetic macular edema. Methods: There were 26 patients (31 eyes) in the DHA group and 29 (38 eyes) in the control group. Ranibizumab (0.5 mg) was administered monthly for the first 4 months followed by a pro re nata (PRN) regimen. In the experimental group, patients received oral DHA supplementation (1,050 mg/day) (Brudyretina 1.5 g). Results: At 36 months, mean decrease of central subfield macular thickness was higher in the DHA-supplementation group than in controls (275 ± 50 μm vs. 310 ± 97 μm) with significant differences at Months 25, 30, 33, and 34. Between-group differences in best-corrected visual acuity were not found, but the percentages of ETRDS gains >5 and >10 letters were higher in the DHA-supplementation group. Differences serum HbA1c, plasma total antioxidant capacity values, erythrocyte DHA content, and serum IL-6 levels were all significant in favor of the DHA-supplementation group. Conclusion: The addition of a high-rich DHA dietary supplement to intravitreal ranibizumab was effective to achieve better sustained improvement of central subfield macular thickness outcomes after 3 years of follow-up as compared with intravitreal ranibizumab alone.
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Huang CP, Lin YW, Huang YC, Tsai FJ. Mitochondrial Dysfunction as a Novel Target for Neuroprotective Nutraceuticals in Ocular Diseases. Nutrients 2020; 12:nu12071950. [PMID: 32629966 PMCID: PMC7400242 DOI: 10.3390/nu12071950] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 06/23/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022] Open
Abstract
The eyes require a rich oxygen and nutrient supply; hence, the high-energy demand of the visual system makes it sensitive to oxidative stress. Excessive free radicals result in mitochondrial dysfunction and lead to retinal neurodegeneration, as an early stage of retinal metabolic disorders. Retinal cells are vulnerable because of their coordinated interaction and intricate neural networks. Nutraceuticals are believed to target multiple pathways and have shown neuroprotective benefits by scavenging free radicals and promoting mitochondrial gene expression. Furthermore, encouraging results demonstrate that nutraceuticals improve the organization of retinal cells and visual functions. This review discusses the mitochondrial impairments of retinal cells and the mechanisms underlying the neuroprotective effects of nutraceuticals. However, some unsolved problems still exist between laboratory study and clinical therapy. Poor bioavailability and bioaccessibility strongly limit their development. A new delivery system and improved formulation may offer promise for health care applications.
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Affiliation(s)
- Chun-Ping Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan;
| | - Yi-Wen Lin
- Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan;
| | - Yu-Chuen Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan;
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
- Correspondence: (Y.-C.H.); (F.-J.T.)
| | - Fuu-Jen Tsai
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan;
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
- Children’s Hospital of China Medical University, Taichung 404, Taiwan
- Department of Medical Genetics, China Medical University Hospital, Taichung 404, Taiwan
- Correspondence: (Y.-C.H.); (F.-J.T.)
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30
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Suzumura A, Kaneko H, Funahashi Y, Takayama K, Nagaya M, Ito S, Okuno T, Hirakata T, Nonobe N, Kataoka K, Shimizu H, Namba R, Yamada K, Ye F, Ozawa Y, Yokomizo T, Terasaki H. n-3 Fatty Acid and Its Metabolite 18-HEPE Ameliorate Retinal Neuronal Cell Dysfunction by Enhancing Müller BDNF in Diabetic Retinopathy. Diabetes 2020; 69:724-735. [PMID: 32029482 DOI: 10.2337/db19-0550] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 01/22/2020] [Indexed: 11/13/2022]
Abstract
Diabetic retinopathy (DR) is a widespread vision-threatening disease, and neuroretinal abnormality should be considered as an important problem. Brain-derived neurotrophic factor (BDNF) has recently been considered as a possible treatment to prevent DR-induced neuroretinal damage, but how BDNF is upregulated in DR remains unclear. We found an increase in hydrogen peroxide (H2O2) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H2O2 by high glucose, and H2O2 reduced cell viability of MIO-M1, Müller glia cell line, PC12D, and the neuronal cell line and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Müller glia cell. Oral intake of eicosapentaenoic acid ethyl ester (EPA-E) ameliorated BDNF reduction and oscillatory potentials (OPs) in electroretinography (ERG) in DR. Mass spectrometry revealed an increase in several EPA metabolites in the eyes of EPA-E-fed rats. In particular, an EPA metabolite, 18-hydroxyeicosapentaenoic acid (18-HEPE), induced BDNF upregulation in Müller glia cells and recovery of OPs in ERG. Our results indicated diabetes-induced oxidative stress attenuates neuroretinal function, but oral EPA-E intake prevents retinal neurodegeneration via BDNF in Müller glia cells by increasing 18-HEPE in the early stages of DR.
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Affiliation(s)
- Ayana Suzumura
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kaneko
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhito Funahashi
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kei Takayama
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan
| | - Masatoshi Nagaya
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seina Ito
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Toshiaki Okuno
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Toshiaki Hirakata
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
- Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Norie Nonobe
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keiko Kataoka
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideyuki Shimizu
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Rina Namba
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuhisa Yamada
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fuxiang Ye
- Department of Ophthalmology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yoko Ozawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroko Terasaki
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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31
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Thebeau C, Zhang S, Kolesnikov AV, Kefalov VJ, Semenkovich CF, Rajagopal R. Light deprivation reduces the severity of experimental diabetic retinopathy. Neurobiol Dis 2020; 137:104754. [PMID: 31978605 DOI: 10.1016/j.nbd.2020.104754] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/13/2020] [Accepted: 01/20/2020] [Indexed: 12/30/2022] Open
Abstract
Illumination of the retina is a major determinant of energy expenditure by its neurons. However, it remains unclear whether light exposure significantly contributes to the pathophysiology of common retinal disease. Driven by the premise that light exposure reduces the metabolic demand of the retina, recent clinical trials failed to demonstrate a benefit for constant illumination in the treatment of diabetic retinopathy. Here, we instead ask whether light deprivation or blockade of visual transduction could modulate the severity of this common cause of blindness. We randomized adult mice with two different models of diabetic retinopathy to 1-3 months of complete dark housing. Unexpectedly, we find that diabetic mice exposed to short or prolonged light deprivation have reduced diabetes-induced retinal pathology, using measures of visual function, compared to control animals in standard lighting conditions. To corroborate these results, we performed assays of retinal vascular health in diabetic Gnat1-/- and Rpe65-/- mice, which lack phototransduction. Both mutants displayed less diabetes-associated retinal vascular disease compared to respective wild-type controls. Collectively, these results suggest that light-induced visual transduction promotes the development of diabetic retinopathy and implicate photoreceptors as an early source of visual pathology in diabetes.
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Affiliation(s)
- Christina Thebeau
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Sheng Zhang
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Alexander V Kolesnikov
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Vladimir J Kefalov
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Clay F Semenkovich
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Rithwick Rajagopal
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA.
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Abstract
PURPOSE OF REVIEW To introduce recent advances in the understanding of diabetic retinopathy and to summarize current and emerging strategies to treat this common and complex cause of vision loss. RECENT FINDINGS Advances in retinal imaging and functional analysis indicate that retinal vascular and neural pathologies exist long before the development of clinically visible retinopathy. Such diagnostics could facilitate risk stratification and selective early intervention in high-risk patients. Antagonists of the vascular endothelial growth factor pathway effectively reduce vision loss in diabetes and promote regression of disease severity. Promising new strategies to treat diabetic retinopathy involve novel systemic diabetes therapy and ocular therapies that antagonize angiogenic growth factor signaling, improve blood-retina barrier function and neurovascular coupling, modulate neuroretinal metabolism, or provide neuroprotection. Long considered a pure microvasculopathy, diabetic retinopathy in fact affects the neural and vascular retina as well as neurovascular communication. Emerging therapies include those that target neuroretinal dysfunction in addition to those modulating vascular biology.
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Affiliation(s)
- Avinash Honasoge
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave. 8096, St. Louis, MO, 63108, USA
| | - Eric Nudleman
- Shiley Eye Institute, University of California, San Diego, La Jolla, CA, USA
| | - Morton Smith
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave. 8096, St. Louis, MO, 63108, USA
| | - Rithwick Rajagopal
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave. 8096, St. Louis, MO, 63108, USA.
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33
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Fu Z, Chen CT, Cagnone G, Heckel E, Sun Y, Cakir B, Tomita Y, Huang S, Li Q, Britton W, Cho SS, Kern TS, Hellström A, Joyal JS, Smith LE. Dyslipidemia in retinal metabolic disorders. EMBO Mol Med 2019; 11:e10473. [PMID: 31486227 PMCID: PMC6783651 DOI: 10.15252/emmm.201910473] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 06/10/2019] [Accepted: 08/15/2019] [Indexed: 12/24/2022] Open
Abstract
The light‐sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid‐rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders.
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Affiliation(s)
- Zhongjie Fu
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.,Manton Center for Orphan Disease, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Chuck T Chen
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Gael Cagnone
- Department of Pediatrics, Pharmacology and Ophthalmology, CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, University of Montreal, Montreal, QC, Canada
| | - Emilie Heckel
- Department of Pediatrics, Pharmacology and Ophthalmology, CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, University of Montreal, Montreal, QC, Canada
| | - Ye Sun
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Bertan Cakir
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Yohei Tomita
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Shuo Huang
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Qian Li
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - William Britton
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Steve S Cho
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Timothy S Kern
- Center for Translational Vision Research, Gavin Herbert Eye Institute, Irvine, CA, USA
| | - Ann Hellström
- Section for Ophthalmology, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Jean-Sébastien Joyal
- Department of Pediatrics, Pharmacology and Ophthalmology, CHU Sainte-Justine Research Center, Université de Montréal, Montreal, QC, Canada.,Department of Pharmacology and Therapeutics, University of Montreal, Montreal, QC, Canada
| | - Lois Eh Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
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34
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Cecilia OM, José Alberto CG, José NP, Ernesto Germán CM, Ana Karen LC, Luis Miguel RP, Ricardo Raúl RR, Adolfo Daniel RC. Oxidative Stress as the Main Target in Diabetic Retinopathy Pathophysiology. J Diabetes Res 2019; 2019:8562408. [PMID: 31511825 PMCID: PMC6710812 DOI: 10.1155/2019/8562408] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 06/17/2019] [Accepted: 07/15/2019] [Indexed: 12/12/2022] Open
Abstract
Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM) causing vision impairment even at young ages. There are numerous mechanisms involved in its development such as inflammation and cellular degeneration leading to endothelial and neural damage. These mechanisms are interlinked thus worsening the diabetic retinopathy outcome. In this review, we propose oxidative stress as the focus point of this complication onset.
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Affiliation(s)
- Olvera-Montaño Cecilia
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Mexico
| | - Castellanos-González José Alberto
- Department of Ophthalmology, Specialties Hospital of the National Occidental Medical Center, Mexican Institute of Social Security, Mexico
| | - Navarro-Partida José
- Tecnológico de Monterrey Institute, School of Medicine and Health Sciences, Campus Guadalajara, Mexico
| | - Cardona-Muñoz Ernesto Germán
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Mexico
| | - López-Contreras Ana Karen
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Mexico
| | | | - Robles-Rivera Ricardo Raúl
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Mexico
| | - Rodríguez-Carrizalez Adolfo Daniel
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Mexico
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35
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Gorusupudi A, Chang FY, Nelson K, Hageman GS, Bernstein PS. n-3 PUFA Supplementation Alters Retinal Very-Long-Chain-PUFA Levels and Ratios in Diabetic Animal Models. Mol Nutr Food Res 2019; 63:e1801058. [PMID: 31106474 DOI: 10.1002/mnfr.201801058] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 04/16/2019] [Indexed: 12/26/2022]
Abstract
SCOPE Long-chain (LC)-PUFAs act as precursors for the special class of retinal lipids known as very-long-chain (VLC)-PUFAs and the effect of diabetes on retinal VLC-PUFA levels is unexplored. In order to understand the supplemental effect of omega-3 (n-3) LC-PUFAs on decreasing levels of VLC-PUFAs due to diabetes, Nile rats, which develop diabetes spontaneously, and Akita mouse, a genetic diabetes model, are chosen. METHODS AND RESULTS Human retinal punches from donors are collected from an eye bank; lipids are extracted and analyzed to study the alterations in VLC-PUFAs and their omega-3/omega-6 (n-3/n-6) ratios. Nile rats are fed a high-fat diet to induce hyperglycemia, and then an n-3 PUFA-rich diet is fed to the experimental group for 2 months. Diabetic male Akita mice and WT mice are fed with 5% fish-oil mixed in with their chow for 2 months to observe the effect of n-3 PUFAs. Results indicate that VLC-PUFA levels are lower in human diabetic and retinopathic retinal punches compared to age-matched controls. With supplementation of n-3 PUFAs, there is a significant increase in n-3/n-6 VLC-PUFA ratios in both animal models compared to diabetic controls. CONCLUSION Dietary supplementation with n-3 LC-PUFAs helps to prevent progression of diabetes and associated retinopathy.
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Affiliation(s)
- Aruna Gorusupudi
- Department of Opthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, 84132, UT, USA
| | - Fu-Yen Chang
- Department of Opthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, 84132, UT, USA
| | - Kelly Nelson
- Department of Opthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, 84132, UT, USA
| | - Gregory S Hageman
- Department of Opthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, 84132, UT, USA.,Sharon Eccles Steele Center for Translational Medicine
| | - Paul S Bernstein
- Department of Opthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, 84132, UT, USA.,Sharon Eccles Steele Center for Translational Medicine
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36
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Abstract
The retina is one of the most metabolically active tissues in the body, consuming high levels of oxygen and nutrients. A well-organized ocular vascular system adapts to meet the metabolic requirements of the retina to ensure visual function. Pathological conditions affect growth of the blood vessels in the eye. Understanding the neuronal biological processes that govern retinal vascular development is of interest for translational researchers and clinicians to develop preventive and interventional therapeutics for vascular eye diseases that address early drivers of abnormal vascular growth. This review summarizes the current knowledge of the cellular and molecular processes governing both physiological and pathological retinal vascular development, which is dependent on the interaction among retinal cell populations, including neurons, glia, immune cells, and vascular endothelial cells. We also review animal models currently used for studying retinal vascular development.
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Affiliation(s)
- Ye Sun
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
| | - Lois E H Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
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37
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Fu Z, Löfqvist CA, Liegl R, Wang Z, Sun Y, Gong Y, Liu CH, Meng SS, Burnim SB, Arellano I, Chouinard MT, Duran R, Poblete A, Cho SS, Akula JD, Kinter M, Ley D, Pupp IH, Talukdar S, Hellström A, Smith LE. Photoreceptor glucose metabolism determines normal retinal vascular growth. EMBO Mol Med 2019; 10:76-90. [PMID: 29180355 PMCID: PMC5760850 DOI: 10.15252/emmm.201707966] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The neural cells and factors determining normal vascular growth are not well defined even though vision‐threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet‐derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon‐induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia‐associated retinal abnormalities and suppress phase I ROP in premature infants.
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Affiliation(s)
- Zhongjie Fu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Chatarina A Löfqvist
- Section for Ophthalmology, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Raffael Liegl
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Zhongxiao Wang
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ye Sun
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yan Gong
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Chi-Hsiu Liu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Steven S Meng
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Samuel B Burnim
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ivana Arellano
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Rubi Duran
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexander Poblete
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Steve S Cho
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - James D Akula
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael Kinter
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - David Ley
- Pediatrics, Department of Clinical Sciences, Skåne University Hospital and University of Lund, Lund, Sweden
| | - Ingrid Hansen Pupp
- Pediatrics, Department of Clinical Sciences, Skåne University Hospital and University of Lund, Lund, Sweden
| | | | - Ann Hellström
- Section for Ophthalmology, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden
| | - Lois Eh Smith
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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38
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Itsiopoulos C, Marx W, Mayr H, Tatucu-Babet O, Dash S, George E, Trakman G, Kelly J, Thomas C, Brazionis L. The role of omega-3 polyunsaturated fatty acid supplementation in the management of type 2 diabetes mellitus: A narrative review. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2018. [DOI: 10.1016/j.jnim.2018.02.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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Wong MYZ, Man REK, Fenwick EK, Gupta P, Li LJ, van Dam RM, Chong MF, Lamoureux EL. Dietary intake and diabetic retinopathy: A systematic review. PLoS One 2018; 13:e0186582. [PMID: 29324740 PMCID: PMC5764236 DOI: 10.1371/journal.pone.0186582] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/03/2017] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION The evidence linking dietary intake with diabetic retinopathy (DR) is growing but unclear. We conducted a systematic review of the association between dietary intake and DR. METHODS We systematically searched PubMed, Embase, Medline, and the Cochrane Central register of controlled trials, for publications between January 1967 and January 2017 using standardized criteria for diet and DR. Interventional and observational studies investigating micro- and macro-nutrient intakes; food and beverage consumptions; and dietary patterns were included. Study quality was evaluated using a modified Newcastle-Ottawa scale for observational studies, and the Cochrane collaboration tool for interventional studies. RESULTS Of 4265 titles initially identified, 31 studies (3 interventional, 28 Observational) were retained. Higher intakes of dietary fibre, oily fish, and greater adherence to a Mediterranean diet were protective of DR. Conversely, high total caloric intake was associated with higher risk of DR. No significant associations of carbohydrate, vitamin D, and sodium intake with DR were found. Associations of antioxidants, fatty acids, proteins and alcohol with DR remain equivocal. CONCLUSIONS Dietary fibre, oily fish, a Mediterranean diet and a reduced caloric intake are associated with lower risk of DR. Longitudinal data and interventional models are warranted to confirm our findings and better inform clinical guidelines.
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Affiliation(s)
- Mark Y. Z. Wong
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
| | - Ryan E. K. Man
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
| | - Eva K. Fenwick
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
- Duke-NUS Medical School, Office of Clinical Sciences, Singapore
| | - Preeti Gupta
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
| | - Ling-Jun Li
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
- Duke-NUS Medical School, Office of Clinical Sciences, Singapore
| | - Rob M. van Dam
- Singapore Institute for Clinical Sciences, A*STAR, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Mary F. Chong
- Singapore Institute for Clinical Sciences, A*STAR, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Ecosse L. Lamoureux
- Singapore Eye Research Institute, Singapore National Eye Center, Singapore
- Duke-NUS Medical School, Office of Clinical Sciences, Singapore
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40
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COMBINED INTRAVITREAL RANIBIZUMAB AND ORAL SUPPLEMENTATION WITH DOCOSAHEXAENOIC ACID AND ANTIOXIDANTS FOR DIABETIC MACULAR EDEMA: Two-Year Randomized Single-Blind Controlled Trial Results. Retina 2018; 37:1277-1286. [PMID: 27787443 DOI: 10.1097/iae.0000000000001363] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE To assess the 2-year effectiveness of intravitreal ranibizumab combined with a dietary supplement rich in docosahexaenoic acid (DHA) plus antioxidants in 62 patients with diabetic macular edema. METHODS In a randomized single-blind controlled study, 33 subjects (42 eyes) received intravitreal ranibizumab alone and 29 (34 eyes) combined with DHA (1,050 mg/day). Monthly ranibizumab (0.5 mg) was given for the first 4 months followed by on as-needed treatment. RESULTS At 24 months, the difference between groups in the decrease of central subfield macular thickness was significant in favor of the DHA supplementation group (95% confidence interval of the difference 7.20-97.656; P = 0.024), although improvement in best-corrected visual acuity measured in the Early Treatment Diabetic Retinopathy Study letters did not reach statistical significance (95% confidence interval 5.4-11.2, P < 0.66). At 24 months, gains of >5 and >10 letters were significantly higher in the DHA supplementation group as compared with controls when the worse and better seeing eyes were considered but other differences at 12 months and 24 months were not found. CONCLUSION Intravitreal ranibizumab combined with DHA supplementation reduced central subfield macular thickness after 2 years of follow-up as compared with ranibizumab alone in patients with diabetic macular edema. This anatomical improvement was accompanied by a trend for an amelioration of vision.
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41
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Oubaha M, Miloudi K, Dejda A, Guber V, Mawambo G, Germain MA, Bourdel G, Popovic N, Rezende FA, Kaufman RJ, Mallette FA, Sapieha P. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med 2017; 8:362ra144. [PMID: 27797960 DOI: 10.1126/scitranslmed.aaf9440] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 06/17/2016] [Indexed: 12/13/2022]
Abstract
Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.
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Affiliation(s)
- Malika Oubaha
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4 Canada
| | - Khalil Miloudi
- Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4 Canada
| | - Agnieszka Dejda
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Vera Guber
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Gaëlle Mawambo
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Marie-Anne Germain
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.,Department of Medicine, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Guillaume Bourdel
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Natalija Popovic
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Flavio A Rezende
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
| | - Frédérick A Mallette
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada. .,Department of Medicine, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
| | - Przemyslaw Sapieha
- Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada. .,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4 Canada.,Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, Montreal, Quebec H1T 2M4, Canada
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Joyal JS, Gantner ML, Smith LEH. Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Prog Retin Eye Res 2017; 64:131-156. [PMID: 29175509 DOI: 10.1016/j.preteyeres.2017.11.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/11/2017] [Accepted: 11/15/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Jean-Sébastien Joyal
- Department of Pediatrics, Pharmacology and Ophthalmology, CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Qc, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Qc, Canada.
| | - Marin L Gantner
- The Lowy Medical Research Institute, La Jolla, United States
| | - Lois E H Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston MA 02115, United States.
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Ghadge AA, Kuvalekar AA. Controversy of oral hypoglycemic agents in type 2 diabetes mellitus: Novel move towards combination therapies. Diabetes Metab Syndr 2017; 11 Suppl 1:S5-S13. [PMID: 27578618 DOI: 10.1016/j.dsx.2016.08.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/22/2016] [Indexed: 01/18/2023]
Abstract
AIM As diabetes mellitus is multi-factorial disease, use of several oral hypoglycemic agents (OHAs) is the main stay of pharmacological treatment. The treatment has become more challenging and controversial as OHAs are heterogeneous in their mode of action that causes unwanted side effects. Complementary approaches such as use of medicinal plants and dietary polyunsaturated fatty acids (PUFA) with hypoglycemic and hypolipidemic activities are therefore imperative. A vast literature has independently documented the effects of OHAs, medicinal plants and PUFA for management of diabetes. In the present article, we have reviewed the current literature to describe the effects of commonly used OHAs, their mechanisms of action and reported controversies. The antidiabetic potential of herbs and/or formulations and omega-3 PUFA with its potential benefits and mode of action is also discussed. METHODS PUBMED, MEDLINE, Cochrane Library etc., were searched for relevant articles using appropriate terms (until February 2015). Human and animal studies were selected for the review. Data extraction was carried out by one author and checked by second author. RESULTS There is still controversy over the safety profile of OHAs. Medicinal herbs with hypoglycemic activities are increasingly sought because of its natural origin, active constituents and minimal side effects. The current literature suggests that supplementation with PUFA improves macro- and microvascular complications. CONCLUSION There is a need for best possible individualized treatment based on variations in biochemical parameters with combinational therapy of nutritional/herbal supplementations. Such a combination may be helpful for better management of diabetes and its complications.
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Affiliation(s)
- Abhijit A Ghadge
- Diabetes Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra, 411043 India
| | - Aniket A Kuvalekar
- Diabetes Laboratory, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Pune, Maharashtra, 411043 India.
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Gong Y, Fu Z, Liegl R, Chen J, Hellström A, Smith LEH. ω-3 and ω-6 long-chain PUFAs and their enzymatic metabolites in neovascular eye diseases. Am J Clin Nutr 2017; 106:16-26. [PMID: 28515072 PMCID: PMC5486202 DOI: 10.3945/ajcn.117.153825] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 04/18/2017] [Indexed: 01/01/2023] Open
Abstract
Neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, threaten the visual health of children and adults. Current treatment options, including anti-vascular endothelial growth factor therapy and laser retinal photocoagulation, have limitations and are associated with adverse effects; therefore, the identification of additional therapies is highly desirable. Both clinical and experimental studies show that dietary ω-3 (n-3) long-chain polyunsaturated fatty acids (LC-PUFAs) reduce retinal and choroidal angiogenesis. The ω-3 LC-PUFA metabolites from 2 groups of enzymes, cyclooxygenases and lipoxygenases, inhibit [and the ω-6 (n-6) LC-PUFA metabolites promote] inflammation and angiogenesis. However, both of the ω-3 and the ω-6 lipid products of cytochrome P450 oxidase 2C promote neovascularization in both the retina and choroid, which suggests that inhibition of this pathway might be beneficial. This review summarizes our current understanding of the roles of ω-3 and ω-6 LC-PUFAs and their enzymatic metabolites in neovascular eye diseases.
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Affiliation(s)
- Yan Gong
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA; and
| | - Zhongjie Fu
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA; and
| | - Raffael Liegl
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA; and
| | - Jing Chen
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA; and
| | - Ann Hellström
- Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Lois EH Smith
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA; and
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Abstract
IMPORTANCE Diabetic retinopathy (DR) is a devastating complication of individuals with type 2 diabetes mellitus. The retina is rich in long-chain ω−3 polyunsaturated fatty acids (LCω3PUFAs), which are substrate for oxylipins with anti-inflammatory and antiangiogenic properties. Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking. OBJECTIVE To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR in individuals with type 2 diabetes older than 55 years. DESIGN, SETTING, AND PARTICIPANTS In late 2015, we conceived a prospective study within the randomized clinical trial Prevención con Dieta Mediterránea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3482 participants (48% men; mean age 67 years). EXPOSURES Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention, as assessed by a validated food-frequency questionnaire. MAIN OUTCOMES AND MEASURES The main outcome was incident DR requiring laser photocoagulation, vitrectomy, and/or antiangiogenic therapy confirmed by an external adjudication committee. RESULTS Of the 3482 participants, 48% were men and the mean age was 67 years. A total of 2611 participants (75%) met target LCω3PUFA recommendation. During a median follow-up of 6 years, we documented 69 new events. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (≥500 mg/d) compared with those not fulfilling this recommendation (<500 mg/d) showed a 48% relatively reduced risk of incident sight-threatening DR, with a hazard ratio of 0.52 (95% CI, 0.31–0.88; P = .001). This association was slightly stronger for yearly updated LCω3PUFA intake (relative risk, 0.48; 95% CI, 0.28–0.82; P = .007). CONCLUSIONS AND RELEVANCE In middle-aged and older individuals with type 2 diabetes, intake of at least 500 mg/d of dietary LCω3PUFA, easily achievable with 2 weekly servings of oily fish, is associated with a decreased risk of sight-threatening DR. Our results concur with findings from experimental models and the current model of DR pathogenesis. TRIAL REGISTRATION clinicaltrials.gov Identifier: ISRCTN35739639
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Affiliation(s)
- Emily Y Chew
- Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland
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Nutrition for diabetic retinopathy: plummeting the inevitable threat of diabetic vision loss. Eur J Nutr 2017; 56:2013-2027. [PMID: 28258307 DOI: 10.1007/s00394-017-1406-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 02/10/2017] [Indexed: 12/14/2022]
Abstract
Diabetic retinopathy (DR) is among the leading causes of preventable blindness. Hyperglycemia, hypertension, hyperlipidemia and anemia majorly predispose its pathogenesis. The current treatment modalities of DR include laser photocoagulation therapy, intravitreal corticosteroids, intravitreal anti-vascular endothelial growth factor (VEGF) agents and vitreo-retinal surgery which are costly, highly invasive, unproven for prolonged use and opted in advanced stages of DR. By then retina already encounters a vast damage. Nutrients by their natural physiological, biochemical and molecular action can preserve retinal structure and functions by interfering with the various pathological steps prompting DR incidence, thereby altering the risk of developing this ocular morbidity. Nutrients can also play a central role in DR patients resistant towards the conventional medical treatments. However due to the byzantine interplay existing between nutrients and DR, the worth of nutrition in curbing this vision-threatening ocular morbidity remains silent. This review highlights how nutrients can halt DR development. A nutritional therapy, if adopted in the initial stages, can provide superior-efficacy over the current treatment modalities and can be a complementary, inexpensive, readily available, anodyne option to the clinically unmet requirement for preventing DR. Assessment of nutritional status is presently considered relevant in various clinical conditions except DR. Body Mass Index (BMI) conferred inconclusive results in DR subjects. Subjective Global Assessment (SGA) of nutritional status has recently furnished relevant association with DR status. By integrating nutritional strategies, the risk of developing DR can be reduced substantially. This review summarizes the subsisting knowledge on nutrition, potentially beneficial for preventing DR and sustaining good vision among diabetic subjects.
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Ioannidou E, Tseriotis VS, Tziomalos K. Role of lipid-lowering agents in the management of diabetic retinopathy. World J Diabetes 2017; 8:1-6. [PMID: 28138358 PMCID: PMC5237812 DOI: 10.4239/wjd.v8.i1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 09/17/2016] [Accepted: 11/16/2016] [Indexed: 02/05/2023] Open
Abstract
Diabetic retinopathy affects a substantial proportion of patients with diabetes mellitus (DM) and is the leading cause of blindness in working-aged adults. Even though the incidence of diabetic retinopathy has declined in the last decades, its prevalence increased and is expected to rise further as a result of the increasing incidence of type 2 DM (T2DM) and the longer life expectancy of patients with DM. The pathogenesis of diabetic retinopathy is multifactorial. Some observational studies suggested an association between dyslipidemia and the development and progression of retinopathy in patients with DM but others did not confirm this association. Regarding lipid-lowering agents, studies that evaluated the role of statins in the management of these patients are mostly small and yielded discrepant results. Large randomized studies with statins in patients with T2DM showed no benefit of these agents on diabetic retinopathy but were not designed to address this effect. In contrast, both preclinical data and two large randomized controlled studies, the FIELD and the ACCORD trial, showed that fenofibrate delays the progression of diabetic retinopathy. Even though the mechanisms underpinning this favorable effect are not entirely clear, these findings suggest that fenofibrate might represent a useful tool for the management of diabetic retinopathy.
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Gong Y, Shao Z, Fu Z, Edin ML, Sun Y, Liegl RG, Wang Z, Liu CH, Burnim SB, Meng SS, Lih FB, SanGiovanni JP, Zeldin DC, Hellström A, Smith LEH. Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis. EBioMedicine 2016; 13:201-211. [PMID: 27720395 PMCID: PMC5264653 DOI: 10.1016/j.ebiom.2016.09.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 09/23/2016] [Accepted: 09/28/2016] [Indexed: 12/19/2022] Open
Abstract
Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)α agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs). While ω-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ω-3 and ω-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ω-3 LCPUFA (and ω-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPARα-/-mice and augmented ω-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ω-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPARα. Fenofibrate augmented the overall protective effects of ω-3 LCPUFAs on neovascular eye diseases.
Fenofibrate inhibits retinal and choroidal neovascularization by inhibiting CYP2C activity as well as by activating PPARα. Fenofibrate augments the protective effects of ω-3 LCPUFAs on pathological ocular angiogenesis. Inhibition of CYP2C is a potential therapeutic approach for treatment of proliferative retinopathy and neovascular AMD. Findings from clinical trials indicate that fenofibrate reduces the progression of proliferative diabetic retinopathy, but the mechanism of this effect is currently unknown. Dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) is generally associated with a suppression of proliferative retinopathy and age-related macular degeneration acting through LCPUFA cyclooxygenase and lipoxygenase metabolites. However, cytochrome P450 epoxygenase (CYP)2C ω-3 and ω-6 LCPUFA metabolites promote retinopathy. Fenofibrate is a potent inhibitor of CYP2C. Our findings suggested that fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition. Combination therapy of dietary ω-3 LCPUFA supplementation with fenofibrate may be a promising approach to prevent incidence or progression of neovascular eye diseases.
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Affiliation(s)
- Yan Gong
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Zhuo Shao
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Zhongjie Fu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Matthew L Edin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
| | - Ye Sun
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Raffael G Liegl
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Zhongxiao Wang
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Chi-Hsiu Liu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Samuel B Burnim
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Steven S Meng
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
| | - Fred B Lih
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
| | - John Paul SanGiovanni
- Section on Nutritional Neurosciences, Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, United States
| | - Darryl C Zeldin
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
| | - Ann Hellström
- Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg 40530, Sweden
| | - Lois E H Smith
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
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Fu Z, Gong Y, Löfqvist C, Hellström A, Smith LEH. Review: adiponectin in retinopathy. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1862:1392-400. [PMID: 27155572 PMCID: PMC4885769 DOI: 10.1016/j.bbadis.2016.05.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 03/23/2016] [Accepted: 05/03/2016] [Indexed: 02/06/2023]
Abstract
Neovascular eye diseases are a major cause of blindness including retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration in which new vessel formation is driven by hypoxia or metabolic abnormalities affecting the fuel supply. White-adipose-tissue derived adipokines such as adiponectin modulate metabolic responses. Increasing evidence shows that lack of adiponectin may result in retinal neovascularization. Activation of the adiponectin pathway may in turn restore energy metabolism, to suppress the drive for compensatory but ultimately pathological neovessels of retinopathy. In this review, we will summarize our current knowledge of the role of adiponectin in eye diseases of premature infants, diabetic patients as well as the elderly. Further investigations in this field are likely to lead to new preventative approaches for these diseases.
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Affiliation(s)
- Zhongjie Fu
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Yan Gong
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Chatarina Löfqvist
- Department of Ophthalmology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ann Hellström
- Department of Ophthalmology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lois E H Smith
- Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
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Gong Y, Fu Z, Edin ML, Liu CH, Wang Z, Shao Z, Fredrick TW, Saba NJ, Morss PC, Burnim SB, Meng SS, Lih FB, Lee KSS, Moran EP, SanGiovanni JP, Hellström A, Hammock BD, Zeldin DC, Smith LEH. Cytochrome P450 Oxidase 2C Inhibition Adds to ω-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization. Arterioscler Thromb Vasc Biol 2016; 36:1919-27. [PMID: 27417579 DOI: 10.1161/atvbaha.116.307558] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 06/27/2016] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSIONS Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.
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Affiliation(s)
- Yan Gong
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Zhongjie Fu
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Matthew L Edin
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Chi-Hsiu Liu
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Zhongxiao Wang
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Zhuo Shao
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Thomas W Fredrick
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Nicholas J Saba
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Peyton C Morss
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Samuel B Burnim
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Steven S Meng
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Fred B Lih
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Kin Sing Stephen Lee
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Elizabeth P Moran
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - John Paul SanGiovanni
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Ann Hellström
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Bruce D Hammock
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Darryl C Zeldin
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.)
| | - Lois E H Smith
- From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (M.L.E., F.B.L., D.C.Z.); Department of Entomology and Comprehensive Cancer Center, University of California, Davis (K.S.S.L., B.D.H.); Section on Nutritional Neurosciences in the Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD (J.P.S.G.); and Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden (A.H.).
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