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Jeong S, Doo M, Sung K, Kim YJ, Lee JH, Ha JH. Aruncus Dioicus Var. Kamtschaticus Extract Prevents Ocular Endoplasmic Reticulum Stress, Inflammation, and Oxidative Stress In Vitro. J Med Food 2025; 28:281-293. [PMID: 39973273 DOI: 10.1089/jmf.2024.k.0240] [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] [Indexed: 02/21/2025] Open
Abstract
The aim of this study was to determine the anti-inflammatory and anti-endoplasmic reticulum (ER) stress effects of Aruncus dioicus var. kamtschaticus (ADK) extract on ARPE-19 cells. Pretreatment with ADK effectively mitigated thapsigargin (Tg)-induced increases in vascular endothelial growth factor protein secretion and intracellular calcium levels. Furthermore, pretreatment with ADK suppressed ocular ER stress-related protein expression in a dose-dependent manner, inhibited the loss of tight junctions, and suppressed interleukin-6 gene expression. Moreover, ADK pretreatment significantly prevented lipopolysaccharide-inducible proinflammatory cytokine gene expression at the transcription level and the phosphorylation of proteins involved in the mitogen-activated protein kinase-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) axis at the posttranslational level. Additionally, ADK extract enhanced antioxidant activity, as evidenced by increased heme oxygenase-1 protein expression and increased 2,2-diphenyl-1-picrylhydrazyl radical scavenging and ferric-reducing antioxidant power. In conclusion, ADK extract effectively protected ARPE-19 cells from ocular ER stress, inflammation, and oxidative stress, demonstrating its potential as a nutraceutical intervention for ocular diseases.
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Affiliation(s)
- Sunyoung Jeong
- Bioanalytical and Pharmacokinetic Research Group, Korea Institute of Toxicology, Daejeon, Korea
- Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon, Korea
| | - Miae Doo
- Department of Food and Nutrition, Kunsan National University, Gunsan, Korea
| | - Kihun Sung
- Department of Food Science and Nutrition, Dankook University, Cheonan, Korea
| | - Young Jun Kim
- Department of Food and Biotechnology, Korea University, Sejong, Korea
| | - Jong-Hwa Lee
- Bioanalytical and Pharmacokinetic Research Group, Korea Institute of Toxicology, Daejeon, Korea
- Department of Human and Environmental Toxicology, University of Science and Technology, Daejeon, Korea
| | - Jung-Heun Ha
- Department of Food Science and Nutrition, Dankook University, Cheonan, Korea
- Research Center for Industrialization of Natural Neutralization, Dankook University, Yongin, Korea
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Martín-Loro F, Cano-Cano F, Ortega MJ, Cuevas B, Gómez-Jaramillo L, González-Montelongo MDC, Freisenhausen JC, Lara-Barea A, Campos-Caro A, Zubía E, Aguilar-Diosdado M, Arroba AI. Arylphthalide Delays Diabetic Retinopathy via Immunomodulating the Early Inflammatory Response in an Animal Model of Type 1 Diabetes Mellitus. Int J Mol Sci 2024; 25:8440. [PMID: 39126007 PMCID: PMC11313200 DOI: 10.3390/ijms25158440] [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: 07/03/2024] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
Diabetic retinopathy (DR) is one of the most prevalent secondary complications associated with diabetes. Specifically, Type 1 Diabetes Mellitus (T1D) has an immune component that may determine the evolution of DR by compromising the immune response of the retina, which is mediated by microglia. In the early stages of DR, the permeabilization of the blood-retinal barrier allows immune cells from the peripheral system to interact with the retinal immune system. The use of new bioactive molecules, such as 3-(2,4-dihydroxyphenyl)phthalide (M9), with powerful anti-inflammatory activity, might represent an advance in the treatment of diseases like DR by targeting the immune systems responsible for its onset and progression. Our research aimed to investigate the molecular mechanisms involved in the interaction of specific cells of the innate immune system during the progression of DR and the reduction in inflammatory processes contributing to the pathology. In vitro studies were conducted exposing Bv.2 microglial and Raw264.7 macrophage cells to proinflammatory stimuli for 24 h, in the presence or absence of M9. Ex vivo and in vivo approaches were performed in BB rats, an animal model for T1D. Retinal explants from BB rats were cultured with M9. Retinas from BB rats treated for 15 days with M9 via intraperitoneal injection were analyzed to determine survival, cellular signaling, and inflammatory markers using qPCR, Western blot, or immunofluorescence approaches. Retinal structure images were acquired via Spectral-Domain-Optical Coherence Tomography (SD-OCT). Our results show that the treatment with M9 significantly reduces inflammatory processes in in vitro, ex vivo, and in vivo models of DR. M9 works by inhibiting the proinflammatory responses during DR progression mainly affecting immune cell responses. It also induces an anti-inflammatory response, primarily mediated by microglial cells, leading to the synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). Ultimately, in vivo administration of M9 preserves the retinal integrity from the degeneration associated with DR progression. Our findings demonstrate a specific interaction between both retinal and systemic immune cells in the progression of DR, with a differential response to treatment, mainly driven by microglia in the anti-inflammatory action. In vivo treatment with M9 induces a switch in immune cell phenotypes and functions that contributes to delaying the DR progression, positioning microglial cells as a new and specific therapeutic target in DR.
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Affiliation(s)
- Francisco Martín-Loro
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
| | - Fátima Cano-Cano
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
| | - María J. Ortega
- Departamento de Química Orgánica, Facultad de Ciencias del Mar y Ambientales, Universidad de Cádiz, 11510 Puerto Real, Spain; (M.J.O.); (E.Z.)
| | - Belén Cuevas
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
- Departamento de Química Orgánica, Facultad de Ciencias del Mar y Ambientales, Universidad de Cádiz, 11510 Puerto Real, Spain; (M.J.O.); (E.Z.)
| | - Laura Gómez-Jaramillo
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
| | - María del Carmen González-Montelongo
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
| | - Jan Cedric Freisenhausen
- Dermatology and Venereology Division, Department of Medicine, Karolinska Institute, SE-171 77 Solna, Sweden;
- Center for Molecular Medicine, Karolinska University Hospital, SE-171 76 Solna, Sweden
| | - Almudena Lara-Barea
- Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, 11009 Cádiz, Spain;
| | - Antonio Campos-Caro
- Área Genética, Departamento Biomedicina Biotecnología y Salud Pública, Universidad de Cádiz, 11510 Puerto Real, Spain;
| | - Eva Zubía
- Departamento de Química Orgánica, Facultad de Ciencias del Mar y Ambientales, Universidad de Cádiz, 11510 Puerto Real, Spain; (M.J.O.); (E.Z.)
| | - Manuel Aguilar-Diosdado
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
- Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, 11009 Cádiz, Spain;
| | - Ana I. Arroba
- Diabetes Mellitus Laboratory, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain; (F.M.-L.); (F.C.-C.); (B.C.); (L.G.-J.); (M.d.C.G.-M.); (M.A.-D.)
- Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, 11009 Cádiz, Spain;
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3
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Zheng J, Zhang W, Xu R, Liu L. The role of adiponectin and its receptor signaling in ocular inflammation-associated diseases. Biochem Biophys Res Commun 2024; 717:150041. [PMID: 38710142 DOI: 10.1016/j.bbrc.2024.150041] [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: 02/29/2024] [Revised: 04/13/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024]
Abstract
Ocular inflammation-associated diseases are leading causes of global visual impairment, with limited treatment options. Adiponectin, a hormone primarily secreted by adipose tissue, binds to its receptors, which are widely distributed throughout the body, exerting powerful physiological regulatory effects. The protective role of adiponectin in various inflammatory diseases has gained increasing attention in recent years. Previous studies have confirmed the presence of adiponectin and its receptors in the eyes. Furthermore, adiponectin and its analogs have shown potential as novel drugs for the treatment of inflammatory eye diseases. This article summarizes the evidence for the interplay between adiponectin and inflammatory eye diseases and provides new perspectives on the diagnostic and therapeutic possibilities of adiponectin.
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Affiliation(s)
- Jing Zheng
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China; Department of Optometry and Visual Science, West China Hospital, Sichuan University, Chengdu, China
| | - Wenqiu Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China; Department of Optometry and Visual Science, West China Hospital, Sichuan University, Chengdu, China
| | - Ran Xu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China; Department of Optometry and Visual Science, West China Hospital, Sichuan University, Chengdu, China
| | - Longqian Liu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China; Department of Optometry and Visual Science, West China Hospital, Sichuan University, Chengdu, China.
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Forini F, Nicolini G, Amato R, Balzan S, Saba A, Bertolini A, Andreucci E, Marracci S, Melecchi A, Terlizzi D, Zucchi R, Iervasi G, Lulli M, Casini G. Local modulation of thyroid hormone signaling in the retina affects the development of diabetic retinopathy. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166892. [PMID: 37758065 DOI: 10.1016/j.bbadis.2023.166892] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/05/2023] [Accepted: 09/19/2023] [Indexed: 10/01/2023]
Abstract
Thyroid hormone (TH) dyshomeostasis is associated with poor prognosis in acute and prolonged illness, but its role in diabetic retinopathy (DR) has never been investigated. Here, we characterized the TH system in the retinas of db/db mice and highlighted regulatory processes in MIO-M1 cells. In the db/db retinas, typical functional traits and molecular signatures of DR were paralleled by a tissue-restricted reduction of TH levels. A local condition of low T3 (LT3S) was also demonstrated, which was likely to be induced by deiodinase 3 (DIO3) upregulation, and by decreased expression of DIO2 and of TH receptors. Concurrently, T3-responsive genes, including mitochondrial markers and microRNAs (miR-133-3p, 338-3p and 29c-3p), were downregulated. In MIO-M1 cells, a feedback regulatory circuit was evidenced whereby miR-133-3p triggered the post-transcriptional repression of DIO3 in a T3-dependent manner, while high glucose (HG) led to DIO3 upregulation through a nuclear factor erythroid 2-related factor 2-hypoxia-inducible factor-1 pathway. Finally, an in vitro simulated condition of early LT3S and hyperglycemia correlated with reduced markers of both mitochondrial function and stress response, which was reverted by T3 replacement. Together, the data suggest that, in the early phases of DR, a DIO3-driven LT3S may be protective against retinal stress, while, in the chronic phase, it not only fails to limit HG-induced damage, but also increases cell vulnerability likely due to persistent mitochondrial dysfunction.
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Affiliation(s)
- Francesca Forini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
| | | | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy.
| | - Silvana Balzan
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Alessandro Saba
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy; Center for Instrument Sharing (CISUP), University of Pisa, Pisa, Italy.
| | - Andrea Bertolini
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
| | - Elena Andreucci
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
| | | | | | - Domiziana Terlizzi
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Riccardo Zucchi
- Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
| | - Giorgio Iervasi
- Department of Biomedical Sciences, National Research Council, Rome, Italy.
| | - Matteo Lulli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
| | - Giovanni Casini
- Department of Biology, University of Pisa, Pisa, Italy; Interdepartmental Research Center Nutrafood "Nutraceuticals and Food for Health", University of Pisa, Pisa, Italy; Center for Instrument Sharing (CISUP), University of Pisa, Pisa, Italy.
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5
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Ferreira LB, Williams KA, Best G, Haydinger CD, Smith JR. Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non-infectious uveitis. Clin Transl Immunology 2023; 12:e1479. [PMID: 38090668 PMCID: PMC10714664 DOI: 10.1002/cti2.1479] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 09/22/2023] [Accepted: 11/21/2023] [Indexed: 06/30/2024] Open
Abstract
Characterised by intraocular inflammation, non-infectious uveitis includes a large group of autoimmune and autoinflammatory diseases that either involve the eye alone or have both ocular and systemic manifestations. When non-infectious uveitis involves the posterior segment of the eye, specifically the retina, there is substantial risk of vision loss, often linked to breakdown of the inner blood-retinal barrier. This barrier is formed by non-fenestrated retinal vascular endothelial cells, reinforced by supporting cells that include pericytes, Müller cells and astrocytes. Across the published literature, a group of inflammatory cytokines stand out as prominent mediators of intraocular inflammation, with effects on the retinal endothelium that may contribute to breakdown of the inner blood-retinal barrier, namely tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, IL-17 and chemokine C-C motif ligand (CCL)2. This article reviews the function of each cytokine and discusses the evidence for their involvement in retinal endothelial barrier dysfunction in non-infectious uveitis, including basic laboratory investigations, studies of ocular fluids collected from patients with non-infectious uveitis, and results of clinical treatment trials. The review also outlines gaps in knowledge in this area. Understanding the disease processes at a molecular level can suggest treatment alternatives that are directed against appropriate biological targets to protect the posterior segment of eye and preserve vision in non-infectious uveitis.
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Affiliation(s)
| | - Keryn A Williams
- Flinders University College of Medicine and Public HealthAdelaideSAAustralia
| | - Giles Best
- Flinders University College of Medicine and Public HealthAdelaideSAAustralia
| | - Cameron D Haydinger
- Flinders University College of Medicine and Public HealthAdelaideSAAustralia
| | - Justine R Smith
- Flinders University College of Medicine and Public HealthAdelaideSAAustralia
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6
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Lv K, Ying H, Hu G, Hu J, Jian Q, Zhang F. Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy. Front Immunol 2022; 13:942768. [PMID: 36119084 PMCID: PMC9479211 DOI: 10.3389/fimmu.2022.942768] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/08/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among working-age people. Inflammation is recognized as a critical driver of the DR process. However, the main retina-specific cell type producing pro-inflammatory cytokines and its mechanism underlying DR are still unclear. Here, we used single-cell sequencing to identify microglia with metabolic pathway alterations that were the main source of IL-1β in STZ-induced DR mice. To profile the full extent of local metabolic shifts in activated microglia and to reveal the metabolic microenvironment contributing to immune mechanisms, we performed integrated metabolomics, lipidomics, and RNA profiling analyses in microglia cell line samples representative of the DR microenvironment. The results showed that activated microglia with IL-1β increase exhibited a metabolic bias favoring glycolysis, purine metabolism, and triacylglycerol synthesis, but less Tricarboxylic acid (TCA). In addition, some of these especially glycolysis was necessary to facilitate their pro-inflammation. These findings suggest that activated microglia with intracellular metabolic reprogramming in retina may contribute to pro-inflammation in the early DR.
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Affiliation(s)
- Kangjia Lv
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Ying
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guangyi Hu
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Hu
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qizhi Jian
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Zhang
- National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Fang Zhang,
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Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes. Int J Mol Sci 2021; 22:ijms222111876. [PMID: 34769307 PMCID: PMC8584492 DOI: 10.3390/ijms222111876] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 01/03/2023] Open
Abstract
We have previously reported that inhibition of the Janus kinase 1 (JAK1) signaling ameliorates IL-17A-mediated blood-retinal barrier (BRB) dysfunction. Higher levels of IL-17A have been observed in the blood and intraocular fluids in patients with diabetic retinopathy (DR), in particular those with diabetic macular oedema. This study aimed to understand whether JAK1 inhibition could prevent BRB dysfunction in db/db mice, a model of type 2 diabetes (T2D). An in vitro study showed that high glucose treatment disrupted the junctional distribution of claudin-5 in bEnd3 cells and ZO-1 in ARPE19 cells and that tofacitinib citrate treatment prevented high glucose-mediated tight junction disruption. Albumin leakage, accompanied by increased levels of the phosphorylated form of JAK1 (pJAK1), was observed in three-month-old db/db mice. Treatment of two-and-a-half-month-old db/db mice with tofacitinib citrate for two weeks significantly reduced retinal albumin leakage and reduced pJAK1 expression. pJAK1 expression was also detected in human DR retina. Our results suggest that JAK1 inhibition can ameliorate BRB dysfunction in T2D, and JAK1 inhibitors such as tofacitinib citrate may be re-purposed for the management of diabetic macular oedema.
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8
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Cano-Cano F, Alcalde-Estévez E, Gómez-Jaramillo L, Iturregui M, Sánchez-Fernández EM, García Fernández JM, Ortiz Mellet C, Campos-Caro A, López-Tinoco C, Aguilar-Diosdado M, Valverde ÁM, Arroba AI. Anti-Inflammatory (M2) Response Is Induced by a sp 2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy. Front Immunol 2021; 12:632132. [PMID: 33815384 PMCID: PMC8013727 DOI: 10.3389/fimmu.2021.632132] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 03/01/2021] [Indexed: 12/11/2022] Open
Abstract
Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (SS,1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp2-iminosugar glycolipid (sp2-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (SS)-DS-ONJ in microglia. (SS)-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR.
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Affiliation(s)
- Fátima Cano-Cano
- Research Unit, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.,Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, Cádiz, Spain
| | - Elena Alcalde-Estévez
- Department of Metabolism and Cell Signaling, Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), Madrid, Spain
| | - Laura Gómez-Jaramillo
- Research Unit, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.,Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, Cádiz, Spain
| | - Marta Iturregui
- Research Unit, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.,Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, Cádiz, Spain
| | | | | | - Carmen Ortiz Mellet
- Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, Spain
| | - Antonio Campos-Caro
- Research Unit, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.,Área Genética, Dpto. Biomedicina Biotecnología y Salud Pública, Universidad de Cádiz, Cádiz, Spain
| | - Cristina López-Tinoco
- Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, Cádiz, Spain
| | - Manuel Aguilar-Diosdado
- Research Unit, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.,Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, Cádiz, Spain
| | - Ángela M Valverde
- Department of Metabolism and Cell Signaling, Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), Madrid, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, Madrid, Spain
| | - Ana I Arroba
- Research Unit, Instituto de Investigación e Innovación en Ciencias Biomédicas de la Provincia de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.,Department of Endocrinology and Metabolism, University Hospital Puerta del Mar, Cádiz, Spain
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9
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Sharma DS, Wadhwa S, Gulati M, Kadukkattil Ramanunny A, Awasthi A, Singh SK, Khursheed R, Corrie L, Chitranshi N, Gupta VK, Vishwas S. Recent advances in intraocular and novel drug delivery systems for the treatment of diabetic retinopathy. Expert Opin Drug Deliv 2020; 18:553-576. [PMID: 33143473 DOI: 10.1080/17425247.2021.1846518] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Introduction: Diabetic retinopathy (DR) is associated with damage to the retinal blood vessels that lead eventually to vision loss. The existing treatments of DR are invasive, expensive, and cumbersome. To overcome challenges associated with existing therapies, various intraocular sustained release and novel drug delivery systems (NDDS) have been explored.Areas covered: The review discusses recently developed intraocular devices for sustained release of drugs as well as novel noninvasive drug delivery systems that have met a varying degree of success in local delivery of drugs to retinal circulation.Expert opinion: The intraocular devices have got very good success in providing sustained release of drugs in patients. The development of NDDS and their application through the ocular route has certainly provided an edge to treat DR over existing therapies such as anti-VEGF administration but their success rate is quite low. Moreover, most of them have proved to be effective only in animal models. In addition, the extent of targeting the drug to the retina still remains variable and unpredictable. The toxicity aspect of the NDDS has generally been neglected. In order to have successful commercialization of nanotechnology-based innovations well-designed clinical research studies need to be conducted to evaluate their clinical superiority over that of the existing formulations.
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Affiliation(s)
- Deep Shikha Sharma
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sheetu Wadhwa
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Monica Gulati
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | | | - Ankit Awasthi
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Rubiya Khursheed
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Leander Corrie
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Nitin Chitranshi
- Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Australia
| | - Vivek Kumar Gupta
- Faculty of Medicine, Health and Human Sciences, Macquarie University, North Ryde, Australia
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
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Protective Effects of Fucoxanthin on High Glucose- and 4-Hydroxynonenal (4-HNE)-Induced Injury in Human Retinal Pigment Epithelial Cells. Antioxidants (Basel) 2020; 9:antiox9121176. [PMID: 33255669 PMCID: PMC7760030 DOI: 10.3390/antiox9121176] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/18/2020] [Accepted: 11/23/2020] [Indexed: 12/11/2022] Open
Abstract
The incidence of diabetes mellitus is increasing due to the eating and living habits of modern people. As the disease progresses, the long-term effects of diabetes can cause microvascular disease, causing dysfunction in different parts of the body, which, in turn, leads to different complications, such as diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy (DR). DR is the main cause of vision loss and blindness in diabetic patients. Persistent hyperglycemia may cause damage to the retina, induce the accumulation of inflammatory factors, and destroy the blood–retinal barrier function. Fucoxanthin (Fx) is a marine carotenoid extracted from seaweed. It accounts for more than 10% of the total carotenoids in nature. Fx is mainly found in brown algae and has strong antioxidant properties, due to its unique biologically active structure. This carotenoid also has the effects of reducing lipid peroxidation, reducing DNA damage, and preventing cardiovascular diseases as well as anti-inflammatory and anti-tumor effects. However, there is no relevant research on the protective effect of Fx in DR. Therefore, in this study, we explore the protective effect of Fx on the retina. Human retinal epithelial cells (ARPE-19) are used to investigate the protective effect of Fx on high glucose stress- (glucose 75 mM) and high lipid peroxidation stress (4-hydroxynonenal, 4-HNE (30 μM))-induced DR. The cell viability test shows that Fx recovered the cell damage, and Western blotting shows that Fx reduced the inflammation response and maintained the integrity of the blood–retinal barrier by reducing its apoptosis and cell adhesion factor protein expression. Using an antioxidant enzyme assay kit, we find that the protective effect of Fx may be related to the strong antioxidant properties of Fx, which increases catalase and reduces oxidative stress to produce a protective effect on the retina.
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11
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Forrester JV, Kuffova L, Delibegovic M. The Role of Inflammation in Diabetic Retinopathy. Front Immunol 2020; 11:583687. [PMID: 33240272 PMCID: PMC7677305 DOI: 10.3389/fimmu.2020.583687] [Citation(s) in RCA: 230] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/21/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammation is central to pathogenic processes in diabetes mellitus and the metabolic syndrome and particularly implicates innate immunity in the development of complications. Inflammation is a primary event in Type 1 diabetes where infectious (viral) and/or autoimmune processes initiate disease; in contrast, chronic inflammation is typical in Type 2 diabetes and is considered a sequel to increasing insulin resistance and disturbed glucose metabolism. Diabetic retinopathy (DR) is perceived as a vascular and neurodegenerative disease which occurs after some years of poorly controlled diabetes. However, many of the clinical features of DR are late events and reflect the nature of the retinal architecture and its cellular composition. Retinal microvascular disease is, in fact, an early event pathogenetically, induced by low grade, persistent leukocyte activation which causes repeated episodes of capillary occlusion and, progressive, attritional retinal ischemia. The later, overt clinical signs of DR are a consequence of the retinal ischemia. Metabolic dysregulation involving both lipid and glucose metabolism may lead to leukocyte activation. On a molecular level, we have shown that macrophage-restricted protein tyrosine phosphatase 1B (PTP1B) is a key regulator of inflammation in the metabolic syndrome involving insulin resistance and it is possible that PTP1B dysregulation may underlie retinal microvascular disease. We have also shown that adherent CCR5+CD11b+ monocyte macrophages appear to be selectively involved in retinal microvascular occlusion. In this review, we discuss the relationship between early leukocyte activation and the later features of DR, common pathogenetic processes between diabetic microvascular disease and other vascular retinopathies, the mechanisms whereby leukocyte activation is induced in hyperglycemia and dyslipidemia, the signaling mechanisms involved in diabetic microvascular disease, and possible interventions which may prevent these retinopathies. We also address a possible role for adaptive immunity in DR. Although significant improvements in treatment of DR have been made with intravitreal anti-VEGF therapy, a sizeable proportion of patients, particularly with sight-threatening macular edema, fail to respond. Alternative therapies targeting inflammatory processes may offer an advantage.
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Affiliation(s)
- John V Forrester
- Institute of Medical Sciences, University of Aberdeen, Scotland, United Kingdom
| | - Lucia Kuffova
- Institute of Medical Sciences, University of Aberdeen, Scotland, United Kingdom.,Eye Clinic, Aberdeen Royal Infirmary, Aberdeen, United Kingdom
| | - Mirela Delibegovic
- Institute of Medical Sciences, University of Aberdeen, Scotland, United Kingdom
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12
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Dolinko AH, Chwa M, Atilano SR, Kenney MC. African and Asian Mitochondrial DNA Haplogroups Confer Resistance Against Diabetic Stresses on Retinal Pigment Epithelial Cybrid Cells In Vitro. Mol Neurobiol 2020; 57:1636-1655. [PMID: 31811564 PMCID: PMC7123578 DOI: 10.1007/s12035-019-01834-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 11/12/2019] [Indexed: 01/09/2023]
Abstract
Diabetic retinopathy (DR) is the most common cause of blindness for individuals under the age of 65. This loss of vision can be due to ischemia, neovascularization, and/or diabetic macular edema, which are caused by breakdown of the blood-retina barrier at the level of the retinal pigment epithelium (RPE) and inner retinal vasculature. The prevalence of diabetes and its complications differ between Caucasian-Americans and certain minority populations, such as African-Americans and Asian-Americans. Individuals can be classified by their mitochondrial haplogroups, which are collections of single nucleotide polymorphisms (SNPs) in mitochondrial DNA (mtDNA) representing ancient geographic origins of populations. In this study, we compared the responses of diabetic human RPE cybrids, cell lines containing identical nuclei but mitochondria from either European (maternal European) or maternal African or Asian individuals, to hypoxia and high glucose levels. The African and Asian diabetic ([Afr+Asi]/DM) cybrids showed (1) resistance to both hyperglycemic and hypoxic stresses; (2) downregulation of pro-apoptotic indicator BAX; (3) upregulation of DNA methylation genes, such as DNMT3A and DNMT3B; and (4) resistance to DNA demethylation by the methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-dC) compared to European diabetic (Euro/DM) cybrids. Our findings suggest that mitochondria from African and Asian diabetic subjects possess a "metabolic memory" that confers resistance against hyperglycemia, hypoxia, and demethylation, and that this "metabolic memory" can be transferred into the RPE cybrid cell lines in vitro.
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Affiliation(s)
- Andrew H Dolinko
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA
- Department of Ophthalmology Research, Gavin Herbert Eye Institute, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Road, Irvine, CA, 92697, USA
| | - Marilyn Chwa
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA
| | - Shari R Atilano
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA
| | - M Cristina Kenney
- Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, 92697, USA.
- Department of Ophthalmology Research, Gavin Herbert Eye Institute, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Road, Irvine, CA, 92697, USA.
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13
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Zhang Y, Wang YT, Koka S, Zhang Y, Hussain T, Li X. Simvastatin improves lysosome function via enhancing lysosome biogenesis in endothelial cells. Front Biosci (Landmark Ed) 2020; 25:283-298. [PMID: 31585890 DOI: 10.2741/4807] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Nlrp3 inflammasomes were shown to play a critical role in triggering obesity-associated early onsets of cardiovascular complications such as endothelial barrier dysfunction with endothelial hyperpermeability. Statins prevent endothelial dysfunction and decrease cardiovascular risk in patients with obesity and diabetes. However, it remains unclear whether statin treatment for obesity-induced endothelial barrier dysfunction is in part due to the blockade of Nlrp3 inflammasome signaling axis. The results showed that simvastatin, a clinically and widely used statin, prevented free fatty acid-induced endothelial hyperpermeability and disruption of ZO-1 and VE-cadherin junctions in mouse microvascular endothelial cells (MVECs). This protective effect of simvastatin was largely due to improved lysosome function that attenuated lysosome injury-mediated Nlrp3 inflammasome activation and subsequent release of high mobility group box protein-1 (HMGB1). Mechanistically, simvastatin induces autophagy that promotes removal of damaged lysosomes and also promotes lysosome regeneration that preserves lysosome function. Collectively, simvastatin treatment improves lysosome function via enhancing lysosome biogenesis and its autophagic turnover, which may be an important mechanism to suppress Nlrp3 inflammasome activation and prevents endothelial hyperpermeability in obesity.
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Affiliation(s)
- Youzhi Zhang
- School of Pharmacy, Hubei University of Science and Technology, Xianning, China
| | - Yun-Ting Wang
- Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
| | - Saisudha Koka
- Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
| | - Yang Zhang
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298
| | - Tahir Hussain
- Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204
| | - Xiang Li
- Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204,
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14
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Sha W, Wen S, Chen L, Xu B, Lei T, Zhou L. The Role of SGLT2 Inhibitor on the Treatment of Diabetic Retinopathy. J Diabetes Res 2020; 2020:8867875. [PMID: 33274239 PMCID: PMC7676957 DOI: 10.1155/2020/8867875] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy (DR) is one of the most serious complications of diabetic microangiopathy. DR has an early onset and is not easy to detect. When visual impairment occurs, the optimal period for therapy is often missed. Therefore, the prevention and treatment of DR should start from the early stage of diabetes. Sodium-dependent glucose transporter 2 inhibitor (SGLT2i) is a new antidiabetic drug which is mainly used in clinical practice to control blood glucose of patients with type 2 diabetes prone to develop chronic heart failure. Recent studies have found that SGLT2 is also expressed in the human retina. Now, the prevention and treatment of diabetic retinopathy with SGLT2i while reducing blood sugar has become a new research field. Hence, this article reviewed the recent therapeutic and research progress of SGLT2 in the treatment of diabetic retinopathy.
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Affiliation(s)
- Wenjun Sha
- Department of Endocrinology and Metabolism, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China
| | - Lin Chen
- Department of Endocrinology and Metabolism, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Bilin Xu
- Department of Endocrinology and Metabolism, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Tao Lei
- Department of Endocrinology and Metabolism, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai 201399, China
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15
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Zhou Z, Zhang B, Yang X, Shang W, Ma Q, Strappe P. Regulation of hyperglycemia in diabetic mice by autolysates from β-mannanase-treated brewer's yeast. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2019; 99:6981-6988. [PMID: 31414473 DOI: 10.1002/jsfa.9987] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 06/24/2019] [Accepted: 08/02/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Diabetes mellitus is a serious chronic disease, characterized by hyperglycemia. This study administered either β-mannanase-treated yeast cell autolysis supernatant (YCS) or yeast cell-wall residues after autolysis (YCR) to investigate their influence on the alleviation of diabetes in a diabetic mouse model. RESULTS Application of either YCS or YCR led to body weight gain, blood glucose reduction, and an improvement in lipid composition in the diabetic mice. Administration of YCS was more effective in inhibiting oxidative stress than YCR. The expression of PPARα and CPT1α was enhanced, improving lipid biosynthesis, and Trx1 and HIF-1-α genes were downregulated due to the activation of thioredoxin following the interventions, indicating that the processes of lipid metabolism and oxidative stress were heavily involved in the reduction of diabetic characteristics following the interventions. The current study revealed that consumption of YCR also led to a reduction in hyperglycemia, this being associated with its richness in mineral elements, such as chromium and selenium. CONCLUSION This study may highlight the potential of both YCS and YCR as functional ingredients in dietary formula for improving diabetic syndromes. © 2019 Society of Chemical Industry.
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Affiliation(s)
- Zhongkai Zhou
- Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China
- ARC Industrial Transformation Training Centre for Functional Grains, Charles Sturt University, Wagga Wagga, Australia
| | - Boxi Zhang
- Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China
| | - Xingyue Yang
- Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China
| | - Wenting Shang
- Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China
| | - Qiuchen Ma
- Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China
| | - Padraig Strappe
- School of Medical and Applied Sciences, Central Queensland University, Rockhampton, Australia
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16
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Ooi KGJ, Khoo P, Vaclavik V, Watson SL. Statins in ophthalmology. Surv Ophthalmol 2019; 64:401-432. [PMID: 30703407 DOI: 10.1016/j.survophthal.2019.01.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 01/14/2019] [Accepted: 01/17/2019] [Indexed: 01/07/2023]
Abstract
Statins, 3-hydroxy-3-methyl-gutaryl coenzyme A reductase inhibitors, are a class of lipid-lowering drugs with anti-inflammatory, immunomodulatory, and vascular effects. Statins are increasingly being used in the treatment of a variety of medical conditions. We examine the actions of statins on the eye and its associated ophthalmic disorders. Statins can be synthetic or nonsynthetic, and their differentiating derivations may contribute to their varying cholesterol-lowering and pleiotropic effects. There is conflicting evidence on the ocular therapeutic and adverse effects of the statins. Statins may play a role in reducing the burden of dry eye, corneal ulcer scarring, thyroid-associated orbitopathy, glaucoma, uveitis and other associated ocular inflammatory states, cataract, proliferative vitreoretinopathy, diabetic retinopathy, macular degeneration, and choroidal melanoma. Topical preparations of statins can be formulated, thereby extending the range of ocular diseases that may be amenable to treatment. Statins have a relatively safe side effect profile, but rare and serious adverse reactions have been reported with their usage in ophthalmology, including myopathies and rhabdomyolysis with acute renal failure.
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Affiliation(s)
- Kenneth G-J Ooi
- Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia.
| | - Pauline Khoo
- Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Veronika Vaclavik
- Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland
| | - Stephanie L Watson
- Save Sight Institute, University of Sydney, Sydney, New South Wales, Australia
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17
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Kong DQ, Li L, Liu Y, Zheng GY. Association between endoplasmic reticulum stress and risk factors of diabetic retinopathy. Int J Ophthalmol 2018; 11:1704-1710. [PMID: 30364130 DOI: 10.18240/ijo.2018.10.20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 07/12/2018] [Indexed: 12/13/2022] Open
Abstract
Diabetic retinopathy (DR) is one of the most common and challenging ocular complications of diabetes mellitus. As a chronic, progressive ocular disease that poses a serious threat to vision, DR has gradually become a leading cause of blindness worldwide. Emerging evidence points to an important role of endoplasmic reticulum (ER) stress in not only maintaining the steady-state equilibrium in the body, but also in intracellular synthesis, protein folding, and other essential functions. Recent studies have demonstrated clear associations between ER stress-related physiological functions and the pathogenesis of DR. When cells are stimulated by external stimuli, UPR pathway is activated firstly to protect it. However, long-term harmful factors can induce ER stress. which interferes with the physiological metabolism of retinal cells and participates in the occurrence of DR via the ATF6 pathway, PERK pathway and IRE1 pathway. At present, ER stress blocker is expected to become a new anti-DR therapy. Thus, understanding the relationship between ER stress and DR will help to develop new effective preventative treatments. In this review, we summarize the risk factors of DR pathogenesis induced by ER stress toward revealing potentially new therapeutic targets.
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Affiliation(s)
- De-Qian Kong
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Li Li
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yue Liu
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Guang-Ying Zheng
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
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18
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Safety and efficacy of Melissa officinalis (lemon balm) on ApoA-I, Apo B, lipid ratio and ICAM-1 in type 2 diabetes patients: A randomized, double-blinded clinical trial. Complement Ther Med 2018; 40:83-88. [DOI: 10.1016/j.ctim.2018.07.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 07/11/2018] [Accepted: 07/30/2018] [Indexed: 01/26/2023] Open
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Shi R, Zhao L, Wang F, Liu F, Chen Z, Li R, Liu Y, Lin R. Effects of lipid-lowering agents on diabetic retinopathy: a Meta-analysis and systematic review. Int J Ophthalmol 2018; 11:287-295. [PMID: 29487821 PMCID: PMC5824086 DOI: 10.18240/ijo.2018.02.18] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 11/17/2017] [Indexed: 12/15/2022] Open
Abstract
AIM To clarify this controversy and to provide evidence for application of lipid lowering agents in treatment of diabetic retinopathy (DR). METHODS We searched the databases of PubMed, Embase and Cochrane Library Central Register of Controlled Trials (CENTRAL) and abstracts from main annual meetings up to January 1, 2017. Google scholar and ClinicalTrials.gov were also searched for unpublished relevant studies. We included randomized controlled trials (RCTs) that studied lipid-lowering agents in type 1 or type 2 diabetes in this Meta-analysis. The primary endpoint was the progression of DR, and the secondary endpoints included vision loss, development of diabetic macular edema (DME) and aggravation of hard exudates. The pooled odds ratios (OR) with corresponding 95% confidence intervals (95%CIs) were calculated. RESULTS After systemic and manual literature search by two independent investigators, we included 8 RCTs from 7 published articles with 13 454 participants in this Meta-analysis. The results revealed that lipid-lowering drugs were associated with reduced risk in DR progression [OR=0.77 (95%CI: 0.62, 0.96), P=0.02]. Lipid-lowering agents might have protective effect on DME compared to placebo, although the difference was not statistically significant [OR=0.60 (95%CI: 0.34, 1.08), P=0.09]. However, no significant differences in the worsening of vision acuity [OR=0.96 (95%CI: 0.81,1.14), P=0.64] and hard exudates [OR=0.50 (95%CI:0.15, 1.74), P=0.28] were found between the lipid-lowering drugs and the placebo groups. CONCLUSION In DR patients, lipid-lowering agents show a protective effect on DR progression and might be associated with reduced risk in the development of DME. However, lipid-lowering agents have no effects on vision loss and hard exudates aggravation. Further clinical trials in larger scale are required to confirm the conclusion of this study and thus justify the use of intensive control lipids with anti-lipid agents at the early stages of DR.
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Affiliation(s)
- Rui Shi
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China
| | - Lei Zhao
- Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City 52242, IA, USA
| | - Feng Wang
- Department of Ophthalmology, the Second Affiliated Hospital of Xi'an Jiaotong University (Xibei Hospital), Xi'an 710004, Shaanxi Province, China
| | - Fen Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing 100069, China
| | - Zhuo Chen
- School of Pharmacy, Xi'an Medical University, Xi'an 710021, Shaanxi Province, China
| | - Rong Li
- Department of Ophthalmology, the First Affiliated Hospital, Xi'an Medical University, Xi'an 710077, Shaanxi Province, China
| | - Yang Liu
- Central Laboratory, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi Province, China
| | - Rong Lin
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi Province, China
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20
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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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21
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Arroba AI, Mazzeo A, Cazzoni D, Beltramo E, Hernández C, Porta M, Simó R, Valverde ÁM. Somatostatin protects photoreceptor cells against high glucose-induced apoptosis. Mol Vis 2016; 22:1522-1531. [PMID: 28050125 PMCID: PMC5204461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 12/28/2016] [Indexed: 11/28/2022] Open
Abstract
PURPOSE Many cellular and molecular studies in experimental animals and early retinal function tests in patients with diabetic retinopathy (DR) have shown that retinal neurodegeneration is an early event in the pathogenesis of the disease. Somatostatin (SST) is one of the most important neuroprotective factors synthesized by the retina: SST levels are decreased in parallel to retinal neurodegeneration in early stages of DR. In this study, we characterized the induction of apoptosis (programmed cell death) in a 661W photoreceptor-like cell line cultured under high glucose (HG) conditions and the effect of SST. METHODS A 661W photoreceptor-like cell line and retinal explants from 10-week-old male C57BL/6 mice were cultured under HG conditions and treated with SST. RESULTS Hyperglycemia significantly reduced the cellular viability by increasing the percentage of apoptotic cells, and this effect was ameliorated by SST (p˂0.05). Activation of caspase-8 by hyperglycemia was found in the 661W cells and retinal explants and decreased in the presence of SST (p˂0.05). Moreover, we detected activation of calpain-2 associated with hyperglycemia-induced cell death, as well as increased protein tyrosine phosphatase 1B (PTP1B) protein levels; both had a pattern of cleavage that was absent in the presence of SST (p˂0.05). Treatment of the 661W cells and retinal explants with SST for 24 h increased the phosphorylation of type 1 insulin-like growth factor receptor (IGF-IR; tyrosine 1165/1166) and protein kinase B (Akt; serine 473), suggesting this survival signaling is activated in the neuroretina by SST (p˂0.05). CONCLUSIONS This study has provided new mechanistic insights first into the involvement of calpain-2 and PTP1B in the loss of cell survival and increased caspase-8-dependent apoptosis induced by hyperglycemia in photoreceptor cells and second, on the protective effect of SST against apoptosis by the enhancement of IGF-IR-mediated Akt phosphorylation.
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Affiliation(s)
- Ana I. Arroba
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), 28029 Madrid, Spain,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Madrid, Spain
| | | | - Daniele Cazzoni
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), 28029 Madrid, Spain
| | | | - Cristina Hernández
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Madrid, Spain
| | | | - Rafael Simó
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Madrid, Spain
| | - Ángela M. Valverde
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), 28029 Madrid, Spain,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Madrid, Spain
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Lajko M, Cardona HJ, Taylor JM, Shah RS, Farrow KN, Fawzi AA. Hyperoxia-Induced Proliferative Retinopathy: Early Interruption of Retinal Vascular Development with Severe and Irreversible Neurovascular Disruption. PLoS One 2016; 11:e0166886. [PMID: 27861592 PMCID: PMC5115836 DOI: 10.1371/journal.pone.0166886] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 11/05/2016] [Indexed: 11/26/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a major cause of neonatal morbidity in premature infants, occurring as a result of arrested lung development combined with multiple postnatal insults. Infants with BPD exposed to supplemental oxygen are at risk of retinopathy of prematurity as well. Thus, we studied the effects of hyperoxia on the retinal vasculature in a murine model of BPD. The retinal phenotype of this model, which we termed hyperoxia-induced proliferative retinopathy (HIPR), shows severe disruption of retinal vasculature and loss of vascular patterning, disorganized intra-retinal angiogenesis, inflammation and retinal detachment. Neonatal mice were subjected to 75% oxygen exposure from postnatal day (P)0 to P14 to model BPD, then allowed to recover in room air for 1 (P15), 7 (P21), or 14 days (P28). We quantified retinal thickness, protein levels of HIF-1α, NOX2, and VEGF, and examined the cellular locations of these proteins by immunohistochemistry. We examined the retinal blood vessel integrity and inflammatory markers, including macrophages (F4/80) and lymphocytes (CD45R). Compared to controls, normal retinal vascular development was severely disrupted and replaced by a disorganized sheet of intra-retinal angiogenesis in the HIPR mice. At all time-points, HIPR showed persistent hyaloidal vasculature and a significantly thinner central retina compared to controls. HIF-1α protein levels were increased at P15, while VEGF levels continued to increase until P21. Intra-retinal fibrinogen was observed at P21 followed by sub-retinal deposition in at P28. Inflammatory lymphocytes and macrophages were observed at P21 and P28, respectively. This model presents a severe phenotype of disrupted retinal vascular development, intra-retinal angiogenesis inflammation and retinal detachment.
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Affiliation(s)
- Michelle Lajko
- Department of Ophthalmology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
| | - Herminio J. Cardona
- Department of Pediatrics, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
| | - Joann M. Taylor
- Department of Pediatrics, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
| | - Ronil S. Shah
- Department of Ophthalmology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
| | - Kathryn N. Farrow
- Department of Pediatrics, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
| | - Amani A. Fawzi
- Department of Ophthalmology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, United States
- * E-mail:
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Bahrami B, Zhu M, Hong T, Chang A. Diabetic macular oedema: pathophysiology, management challenges and treatment resistance. Diabetologia 2016; 59:1594-608. [PMID: 27179659 DOI: 10.1007/s00125-016-3974-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 04/11/2016] [Indexed: 02/07/2023]
Abstract
Diabetic macular oedema (DMO) is the leading cause of vision loss in patients living with diabetes. DMO results from hyperglycaemia-induced activation of pathways that lead to oxidative stress and release of cytokines, impairing the inner and outer blood-retinal barriers. Improved understanding of the pathophysiological mechanisms leading to DMO have led to the development of effective therapies, including vitreoretinal surgery, laser photocoagulation, intravitreal anti-vascular endothelial growth factor drugs and corticosteroids. Advances in imaging, including fluorescein angiography and optical coherence tomography, have also enhanced diagnosis and management of the condition. Despite these advances, there remain patients who do not respond completely to therapy, reflecting the complex pathophysiology of DMO. These patients may be considered treatment-resistant. In this review, we summarise the pathophysiology of DMO, as well as the available treatments and their mechanism of action. Additionally, we focus on treatment-resistant disease and review the literature on potential options for managing this complication of diabetes.
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Affiliation(s)
- Bobak Bahrami
- Sydney Institute of Vision Science, 13/187 Macquarie Street, Sydney, 2000, NSW, Australia
- Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Meidong Zhu
- Sydney Institute of Vision Science, 13/187 Macquarie Street, Sydney, 2000, NSW, Australia
- Save Sight Institute, University of Sydney, Sydney, NSW, Australia
| | - Thomas Hong
- Sydney Institute of Vision Science, 13/187 Macquarie Street, Sydney, 2000, NSW, Australia
| | - Andrew Chang
- Sydney Institute of Vision Science, 13/187 Macquarie Street, Sydney, 2000, NSW, Australia.
- Save Sight Institute, University of Sydney, Sydney, NSW, Australia.
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24
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Arroba AI, Alcalde-Estevez E, García-Ramírez M, Cazzoni D, de la Villa P, Sánchez-Fernández EM, Mellet CO, García Fernández JM, Hernández C, Simó R, Valverde ÁM. Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice. Biochim Biophys Acta Mol Basis Dis 2016; 1862:1663-74. [PMID: 27267343 DOI: 10.1016/j.bbadis.2016.05.024] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/10/2016] [Accepted: 05/26/2016] [Indexed: 12/20/2022]
Affiliation(s)
- Ana I Arroba
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), 28029 Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Spain; Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain.
| | | | - Marta García-Ramírez
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Spain; Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Daniele Cazzoni
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), 28029 Madrid, Spain
| | | | | | - Carmen Ortiz Mellet
- Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Sevilla, Spain
| | - José M García Fernández
- Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, Avda. Américo Vespucio 49, 41092 Sevilla, Spain
| | - Cristina Hernández
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Spain; Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Rafael Simó
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Spain; Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute (VHIR), 08035 Barcelona, Spain
| | - Ángela M Valverde
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), 28029 Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERdem), ISCIII, Spain.
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Abstract
The relationship between lipids and the development and/or severity of diabetic retinopathy (DR) is complex. Large epidemiologic studies suggest an inconsistent and overall modest association between serum triglycerides or major cholesterol species and the severity of DR; however, certain specific lipoprotein species may have stronger associations with DR severity, suggesting a pathophysiological role for lipoproteins analogous to that seen in atherosclerosis. In this lipoprotein-mediated DR pathogenesis model, damage to the blood-retinal barrier allows extravasation of lipoprotein species, which are modified in the intraretinal environment, creating substantial local damage. Additionally, hypolipidemic therapy with statins and fibrates--particularly the latter--have been shown to modulate DR in large-scale studies. Since serum lipid profile changes do not necessarily correlate with DR modulation, the efficacy of these agents may be due to their tissue-specific changes in lipoproteins and/or their anti-inflammatory, antioxidative, antiangiogenic, and antiapoptotic functions.
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Affiliation(s)
- Bobeck S Modjtahedi
- a Retina Service, Department of Ophthalmology , Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA
| | - Namrata Bose
- b Department of Endocrinology , Keck School of Medicine, University of Southern California , Los Angeles , California , USA
| | - Thanos D Papakostas
- a Retina Service, Department of Ophthalmology , Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA
| | - Lawrence Morse
- c Department of Ophthalmology and Vision Science , School of Medicine, University of California , Davis , Davis , California , USA , and
| | - Demetrios G Vavvas
- a Retina Service, Department of Ophthalmology , Massachusetts Eye and Ear Infirmary , Boston , Massachusetts , USA
| | - Amar U Kishan
- d Harvard Medical School , Boston , Massachusetts , USA
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Monickaraj F, McGuire PG, Nitta CF, Ghosh K, Das A. Cathepsin D: an Mϕ-derived factor mediating increased endothelial cell permeability with implications for alteration of the blood-retinal barrier in diabetic retinopathy. FASEB J 2015; 30:1670-82. [PMID: 26718887 DOI: 10.1096/fj.15-279802] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 12/17/2015] [Indexed: 01/08/2023]
Abstract
Inflammation plays an important role in the pathogenesis of diabetic retinopathy (DR). We have previously reported increased monocyte (Mono) trafficking into the retinas of diabetic animals. In this study, we have examined the effect of activated Monos on retinal endothelial cells (ECs). The U937 Mϕ-conditioned medium (CM) significantly decreased the transendothelial resistance of EC monolayers as measured by electric cell-substrate impedance sensing (P= 0.007). The CM was fractioned, and the effective fraction (30-100 kDa) was analyzed by liquid chromatography-mass spectrometry, and cathepsin D (CD) was identified as a major secreted product. Immunoprecipitated CD resulted in decreased resistance in ECs (P= 0.006). The specificity of CD in mediating alterations of the EC barrier was confirmed using small interfering RNA. The decreased resistance correlated with a significantly increased gap between ECs. CD altered the Ras homolog gene family, member A/Rho-associated kinase pathway with increased stress actin filament formation in the EC layer. Increased CD levels were found in the retinas of diabetic mice (3-fold) and serum samples of patients with diabetic macular edema (1.6-fold) measured by Western blot and ELISA. These findings suggest an important role for Mϕ-derived CD in altering the blood-retinal barrier and reveal a potential therapeutic target in the treatment of DR.-Monickaraj, F., McGuire, P. G., Nitta, C. F., Ghosh, K., Das, A. Cathepsin D: an Mϕ-derived factor mediating increased endothelial cell permeability with implications for alteration of the blood-retinal barrier in diabetic retinopathy.
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Affiliation(s)
- Finny Monickaraj
- *Department of Surgery and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA; New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA; and Department of Bioengineering, University of California, Riverside, Riverside, California, USA
| | - Paul G McGuire
- *Department of Surgery and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA; New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA; and Department of Bioengineering, University of California, Riverside, Riverside, California, USA
| | - Carolina Franco Nitta
- *Department of Surgery and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA; New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA; and Department of Bioengineering, University of California, Riverside, Riverside, California, USA
| | - Kaustabh Ghosh
- *Department of Surgery and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA; New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA; and Department of Bioengineering, University of California, Riverside, Riverside, California, USA
| | - Arup Das
- *Department of Surgery and Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA; New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA; and Department of Bioengineering, University of California, Riverside, Riverside, California, USA
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27
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Veenstra A, Liu H, Lee CA, Du Y, Tang J, Kern TS. Diabetic Retinopathy: Retina-Specific Methods for Maintenance of Diabetic Rodents and Evaluation of Vascular Histopathology and Molecular Abnormalities. ACTA ACUST UNITED AC 2015; 5:247-270. [PMID: 26331759 DOI: 10.1002/9780470942390.mo140190] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Diabetic retinopathy is a major cause of visual impairment, which continues to increase in prevalence as more and more people develop diabetes. Despite the importance of vision, the retina is one of the smallest tissues in the body, and specialized techniques have been developed to study retinopathy. This article summarizes several methods used to (i) induce diabetes in mice, (ii) maintain the diabetic animals throughout the months required for development of typical vascular histopathology, (iii) evaluate vascular histopathology of diabetic retinopathy, and (iv) quantitate abnormalities implicated in the development of the retinopathy.
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Affiliation(s)
- Alexander Veenstra
- Case Western Reserve University and Case Medical Center, Cleveland, Ohio.,Veterans Administration Medical Center Research Service 151, Cleveland, Ohio.,These authors contributed equally to this work
| | - Haitao Liu
- Case Western Reserve University and Case Medical Center, Cleveland, Ohio.,These authors contributed equally to this work
| | - Chieh Allen Lee
- Case Western Reserve University and Case Medical Center, Cleveland, Ohio
| | - Yunpeng Du
- Case Western Reserve University and Case Medical Center, Cleveland, Ohio
| | - Jie Tang
- Case Western Reserve University and Case Medical Center, Cleveland, Ohio.,Veterans Administration Medical Center Research Service 151, Cleveland, Ohio
| | - Timothy S Kern
- Case Western Reserve University and Case Medical Center, Cleveland, Ohio.,Veterans Administration Medical Center Research Service 151, Cleveland, Ohio
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28
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Abu El-Asrar AM, Mohammad G, Nawaz MI, Abdelsaid M, Siddiquei MM, Alam K, Van den Eynde K, De Hertogh G, Opdenakker G, Al-Shabrawey M, Van Damme J, Struyf S. The Chemokine Platelet Factor-4 Variant (PF-4var)/CXCL4L1 Inhibits Diabetes-Induced Blood-Retinal Barrier Breakdown. Invest Ophthalmol Vis Sci 2015; 56:1956-64. [PMID: 25711636 DOI: 10.1167/iovs.14-16144] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
PURPOSE To investigate the expression of platelet factor-4 variant (PF-4var/CXCL4L1) in epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) and the role of PF-4var/CXCL4L1 in the regulation of blood-retinal barrier (BRB) breakdown in diabetic rat retinas and human retinal microvascular endothelial cells (HRMEC). METHODS Rats were treated intravitreally with PF-4var/CXCL4L1 or the anti-vascular endothelial growth factor (VEGF) agent bevacizumab on the first day after diabetes induction. Blood-retinal barrier breakdown was assessed in vivo with fluorescein isothiocyanate (FITC)-conjugated dextran and in vitro in HRMEC by transendothelial electrical resistance and FITC-conjugated dextran cell permeability assay. Occludin, vascular endothelial (VE)-cadherin, hypoxia-inducible factor (HIF)-1α, VEGF, tumor necrosis factor (TNF)-α, receptor for advanced glycation end products (RAGE), caspase-3 levels, and generation of reactive oxygen species (ROS) were assessed by Western blot, enzyme-linked immunosorbent assays, or spectrophotometry. RESULTS In epiretinal membranes, vascular endothelial cells and stromal cells expressed PF-4var/CXCL4L1. In vitro, HRMEC produced PF-4var/CXCL4L1 after stimulation with a combination of interleukin (IL)-1β and TNF-α, and PF-4var/CXCL4L1 inhibited VEGF-mediated hyperpermeability in HRMEC. In rats, PF-4var/CXCL4L1 was as potent as bevacizumab in attenuating diabetes-induced BRB breakdown. This effect was associated with upregulation of occludin and VE-cadherin and downregulation of HIF-1α, VEGF, TNF-α, RAGE, and caspase-3, whereas ROS generation was not altered. CONCLUSIONS Our findings suggest that increasing the intraocular PF-4var/CXCL4L1 levels early after the onset of diabetes protects against diabetes-induced BRB breakdown.
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Affiliation(s)
- Ahmed M Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia Dr Nasser Al-Rashid Research Chair in Ophthalmology, King Saud University, Riyadh, Saudi Arabia
| | - Ghulam Mohammad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Abdelsaid
- Department of Oral Biology, Cellular Biology and Anatomy, Culver Vision Discovery Institute and Department of Ophthalmology, Georgia Regents University, Augusta, Georgia, United States
| | | | - Kaiser Alam
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Kathleen Van den Eynde
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Laboratory of Histochemistry and Cytochemistry, University of Leuven, KU Leuven, Leuven, Belgium
| | - Ghislain Opdenakker
- Laboratory of Immunobiology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium
| | - Mohamed Al-Shabrawey
- Department of Oral Biology, Cellular Biology and Anatomy, Culver Vision Discovery Institute and Department of Ophthalmology, Georgia Regents University, Augusta, Georgia, United States
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Rega Institute for Medical Research, Department of Microbiology and Immunology, University of Leuven, KU Leuven, Leuven, Belgium
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29
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Ding Y, Yuan S, Liu X, Mao P, Zhao C, Huang Q, Zhang R, Fang Y, Song Q, Yuan D, Xie P, Liu Y, Liu Q. Protective effects of astragaloside IV on db/db mice with diabetic retinopathy. PLoS One 2014; 9:e112207. [PMID: 25411784 PMCID: PMC4239035 DOI: 10.1371/journal.pone.0112207] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 10/10/2014] [Indexed: 10/31/2022] Open
Abstract
OBJECTIVES Diabetic retinopathy (DR) is a common diabetic eye disease which is well-known as the result of microvascular retinal changes. Although the potential biological functions of astragaloside IV (AS IV) have long been described in traditional system of medicine, its protective effect on DR remains unclear. This study aims to investigate the function and mechanism of AS IV on type 2 diabetic db/db mice. METHODS Db/db mice were treated with AS IV (4.5 mg/kg or 9 mg/kg) or physiological saline by oral gavage for 20 weeks along with db/m mice. In each group, retinal ganglion cell (RGC) function was measured by pattern electroretinogram (ERG) and apoptosis was determined by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Blood and retina aldose reductase (AR) activity were quantified by chemiluminescence analysis. The expressions of phosporylated-ERK1/2, NF-κB were determined by Western blot analysis. Furthermore, the expression of related downstream proteins were quantified by Label-based Mouse Antibody Array. RESULTS Administration of AS IV significantly improved the amplitude in pattern ERG and reduced the apoptosis of RGCs.in db/db mice. Furthermore, downregulation of AR activity, ERK1/2 phosphorylation, NF-κB and related cytokine were observed in AS IV treatment group. CONCLUSIONS Our study indicated that AS IV, as an inhibitor of AR, could prevent the activation of ERK1/2 phosporylation and NF-kB and further relieve the RGCs disfunction in db/db mice with DR. It has provided a basis for investigating the clinical efficacy of AR inhibitors in preventing DR.
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Affiliation(s)
- Yuzhi Ding
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Songtao Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaoyi Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pingan Mao
- Department of Ophthalmology, No. 2 People's Hospital of Changzhou, Changzhou, China
| | - Chen Zhao
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qiong Huang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Rihua Zhang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan Fang
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qinglu Song
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dongqing Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ping Xie
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Liu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qinghuai Liu
- Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Prasath GS, Subramanian SP. Antihyperlipidemic effect of fisetin, a bioflavonoid of strawberries, studied in streptozotocin-induced diabetic rats. J Biochem Mol Toxicol 2014; 28:442-9. [PMID: 24939606 DOI: 10.1002/jbt.21583] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 05/08/2014] [Accepted: 05/13/2014] [Indexed: 12/20/2022]
Abstract
Chronic hyperglycemia in diabetes is associated with profound changes in lipid and lipoprotein metabolism, with resultant alterations in particle distribution within lipoprotein classes. In the present study, an attempt has been made to explore the antihyperlipidemic effect of fisetin in streptozotocin-induced experimental diabetes in rats. Upon fisetin treatment to diabetic rats, the levels of blood glucose were significantly reduced with an improvement in plasma insulin. The increased levels of lipid contents in serum, hepatic, and renal tissues observed in diabetic rats were normalized upon fisetin administration. Also, the decreased levels of high-density lipoprotein cholesterol, and increased levels of low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol in serum of diabetic rats were normalized. Oil Red O staining established a large number of intracellular lipid droplets accumulation in the diabetic rats. Fisetin treatment exacerbated the degree of lipid accumulation. The results of the present study exemplify the antihyperlipidemic property of the fisetin.
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Affiliation(s)
- Gopalan Sriram Prasath
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, India
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The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration. PLoS One 2014; 9:e97302. [PMID: 24837086 PMCID: PMC4023966 DOI: 10.1371/journal.pone.0097302] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 04/17/2014] [Indexed: 01/20/2023] Open
Abstract
Background To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks). The retinas were evaluated in terms of morphological and functional abnormalities [electroretinography (ERG)]. Histological markers of neurodegeneration (glial activation and apoptosis) were evaluated by immunohistochemistry. In addition glutamate levels and glutamate/aspartate transporter (GLAST) expression were assessed. Furthermore, to define gene expression changes associated with early diabetic retinopathy a transcriptome analyses was performed at 8 week. Furthermore, an additional interventional study to lower blood glucose levels was performed. Results Glial activation was higher in diabetic than in non diabetic mice in all the stages (p<0.01). In addition, a progressive loss of ganglion cells and a significant reduction of neuroretinal thickness were also observed in diabetic mice. All these histological hallmarks of neurodegeneration were less pronounced at week 8 than at week 16 and 24. Significant ERG abnormalities were present in diabetic mice at weeks 16 and 24 but not at week 8. Moreover, we observed a progressive accumulation of glutamate in diabetic mice associated with an early downregulation of GLAST. Morphological and ERG abnormalities were abrogated by lowering blood glucose levels. Finally, a dysregulation of several genes related to neurotransmission and oxidative stress such as UCP2 were found at week 8. Conclusions Our results suggest that db/db mouse reproduce the features of the neurodegenerative process that occurs in the human diabetic eye. Therefore, it seems an appropriate model for investigating the underlying mechanisms of diabetes-induced retinal neurodegeneration and for testing neuroprotective drugs.
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Pillai SI, Subramanian SP, Kandaswamy M. Antidyslipidemic effect of a novel vanadium-3-hydroxy flavone complex in streptozotocin-induced experimental diabetes in rats. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.bionut.2013.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Ezquer F, Ezquer M, Arango-Rodriguez M, Conget P. Could donor multipotent mesenchymal stromal cells prevent or delay the onset of diabetic retinopathy? Acta Ophthalmol 2014; 92:e86-95. [PMID: 23773776 DOI: 10.1111/aos.12113] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus is a complex metabolic disease that has become a global epidemic with more than 285 million cases worldwide. Major medical advances over the past decades have substantially improved its management, extending patients' survival. The latter is accompanied by an increased risk of developing chronic macro- and microvascular complications. Amongst them, diabetic retinopathy (DR) is the most common and frightening. Furthermore, during the past two decades, it has become the leading cause of visual loss. Irrespective of the type of diabetes, DR follows a well-known clinical and temporal course characterized by pericytes and neuronal cell loss, formation of acellular-occluded capillaries, occasional microaneurysms, increased leucostasis and thickening of the vascular basement membrane. These alterations progressively affect the integrity of retinal microvessels, leading to the breakdown of the blood-retinal barrier, widespread haemorrhage and neovascularization. Finally, tractional retinal detachment occurs leading to blindness. Nowadays, there is growing evidence that local inflammation and oxidative stress play pivotal roles in the pathogenesis of DR. Both processes have been associated with pericytes and neuronal degeneration observed early during DR progression. They may also be linked to sustained retinal vasculature damage that results in abnormal neovascularization. Currently, DR therapeutic options depend on highly invasive surgical procedures performed only at advanced stages of the disease, and which have proved to be ineffective to restore visual acuity. Therefore, the availability of less invasive and more effective strategies aimed to prevent or delay the onset of DR is highly desirable. Multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), are promising healing agents as they contribute to tissue regeneration by pleiotropic mechanisms, with no evidence of significant adverse events. Here, we revise the pathophysiology of DR to identify therapeutic targets for donor MSCs. Also, we discuss whether an MSC-based therapy could prevent or delay the onset of DR.
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Affiliation(s)
- Fernando Ezquer
- Institute of Science, Faculty of Medicine Clinica Alemana Universidad del Desarrollo, Lo Barnechea, Santiago, Chile
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El-Azab MF, Mysona BA, El-Remessy AB. Statins for prevention of diabetic-related blindness: a new treatment option? EXPERT REVIEW OF OPHTHALMOLOGY 2014; 6:269-272. [PMID: 21938261 DOI: 10.1586/eop.11.36] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Mona F El-Azab
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, USA and Vision Discovery Institute, Georgia Health Science University, Augusta, GA, USA and Faculty of Pharmacy, Suez Canal University, Egypt
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Crespo MJ, Cruz N, Quidgley J, Torres H, Hernandez C, Casiano H, Rivera K. Daily Administration of Atorvastatin and Simvastatin for One Week Improves Cardiac Function in Type 1 Diabetic Rats. Pharmacology 2014; 93:84-91. [DOI: 10.1159/000358256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 12/24/2013] [Indexed: 12/15/2022]
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Szabadfi K, Pinter E, Reglodi D, Gabriel R. Neuropeptides, trophic factors, and other substances providing morphofunctional and metabolic protection in experimental models of diabetic retinopathy. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2014; 311:1-121. [PMID: 24952915 DOI: 10.1016/b978-0-12-800179-0.00001-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Vision is the most important sensory modality for many species, including humans. Damage to the retina results in vision loss or even blindness. One of the most serious complications of diabetes, a disease that has seen a worldwide increase in prevalence, is diabetic retinopathy. This condition stems from consequences of pathological metabolism and develops in 75% of patients with type 1 and 50% with type 2 diabetes. The development of novel protective drugs is essential. In this review we provide a description of the disease and conclude that type 1 diabetes and type 2 diabetes lead to the same retinopathy. We evaluate existing experimental models and recent developments in finding effective compounds against this disorder. In our opinion, the best models are the long-term streptozotocin-induced diabetes and Otsuka Long-Evans Tokushima Fatty and spontaneously diabetic Torii rats, while the most promising substances are topically administered somatostatin and pigment epithelium-derived factor analogs, antivasculogenic substances, and systemic antioxidants. Future drug development should focus on these.
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Affiliation(s)
- Krisztina Szabadfi
- Department of Experimental Zoology and Neurobiology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary.
| | - Erika Pinter
- Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary; Department of Pharmacology and Pharmacotherapy, University of Pecs, Pecs, Hungary
| | - Dora Reglodi
- Department of Anatomy, PTE MTA Lendulet-PACAP Research Team, University of Pecs, Pecs, Hungary
| | - Robert Gabriel
- Department of Experimental Zoology and Neurobiology, University of Pecs, Pecs, Hungary; Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary
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Peng H, Luo P, Li Y, Wang C, Liu X, Ye Z, Li C, Lou T. Simvastatin alleviates hyperpermeability of glomerular endothelial cells in early-stage diabetic nephropathy by inhibition of RhoA/ROCK1. PLoS One 2013; 8:e80009. [PMID: 24244596 PMCID: PMC3828237 DOI: 10.1371/journal.pone.0080009] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 10/04/2013] [Indexed: 02/03/2023] Open
Abstract
Background Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy (DN). There is increasing evidence that dysfunction of the endothelial tight junction is a crucial step in the development of endothelial hyperpermeability, but it is unknown whether this occurs in glomerular endothelial cells (GEnCs) during the progression of DN. We examined tight junction dysfunction of GEnCs during early-stage DN and the potential underlying mechanisms. We also examined the effect of simvastatin (3-Hydroxy-3-methylglutaryl CoA reductase inhibitor) on dysfunction of the tight junctions of cultured GEnCs and in db/db mice with early-stage DN. Methods We assessed the expression of occludin and ZO-1, two major components of the tight junction complex, in cultured rat GEnCs treated with high glucose and in 12 week-old db/db mice with early-stage DN. We also investigated activation of RhoA/ROCK1 signaling, GEnC permeability, and renal function of the mice. Results High glucose suppresses occludin expression and disrupts occludin/ZO-1 translocation in GEnCs. These changes were associated with increased permeability to albumin and activation of RhoA/ROCK1 signaling. Occludin and ZO-1 dysregulation also occurred in the glomeruli of mice with early-stage DN, and these abnormalities were accompanied by albuminuria and activation of RhoA/ROCK1 in isolated glomeruli. Simvastatin prevented high glucose or hyperglycemia-induced dysregulation of occludin and ZO-1 by inhibition of RhoA/ROCK1 signaling in cultured GEnCs and in db/db mice with early-stage DN. Conclusion Our results indicate that activation of RhoA/ROCK1 by high glucose disrupts the expression and translocation of occludin/ZO-1 and that simvastatin alleviates occludin/ZO-1 dysregulation and albuminuria by suppressing RhoA/ROCK1 signaling during early-stage DN. These results suggest a potential therapeutic strategy for preventing the onset of albuminuria in early-stage DN.
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Affiliation(s)
- Hui Peng
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Pengli Luo
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Yuanqing Li
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Cheng Wang
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Xun Liu
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Zengchun Ye
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Canming Li
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
| | - Tanqi Lou
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P. R. China
- * E-mail:
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Yu H, Wark L, Ji H, Willard L, Jaing Y, Han J, He H, Ortiz E, Zhang Y, Medeiros DM, Lin D. Dietary wolfberry upregulates carotenoid metabolic genes and enhances mitochondrial biogenesis in the retina of db/db diabetic mice. Mol Nutr Food Res 2013; 57:1158-69. [PMID: 23505020 DOI: 10.1002/mnfr.201200642] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 01/16/2013] [Accepted: 01/16/2013] [Indexed: 12/25/2022]
Abstract
SCOPE Our aim was to investigate whether dietary wolfberry altered carotenoid metabolic gene expression and enhanced mitochondrial biogenesis in the retina of diabetic mice. METHODS AND RESULTS Six-week-old male db/db and wild-type mice were fed the control or wolfberry diets for 8 weeks. At study termination, liver and retinal tissues were collected for analysis by transmission electron microscopy, real-time PCR, immunoprecipitation, Western blot, and HPLC. Wolfberry elevated zeaxanthin and lutein levels in the liver and retinal tissues and stimulated expression of retinal scavenger receptor class B type I, glutathione S-transferase Pi 1, and β,β-carotene 9',10'-oxygenase 2, and induced activation and nuclear enrichment of retinal AMP-activated protein kinase α2 (AMPK-α2). Furthermore, wolfberry attenuated hypoxia and mitochondrial stress as demonstrated by declined expression of hypoxia-inducible factor-1-α, vascular endothelial growth factor, and heat shock protein 60. Wolfberry enhanced retinal mitochondrial biogenesis in diabetic retinas as demonstrated by reversed mitochondrial dispersion in the retinal pigment epithelium, increased mitochondrial copy number, elevated citrate synthase activity, and upregulated expression of peroxisome proliferator-activated receptor γ co-activator 1α, nuclear respiratory factor 1, and mitochondrial transcription factor A. CONCLUSION Consumption of dietary wolfberry could be beneficial to retinoprotection through reversal of mitochondrial function in diabetic mice.
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Affiliation(s)
- Huifeng Yu
- Department of Human Nutrition, Kansas State University, Manhattan, KS, USA
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CHEN YESHAN, ZHANG SHENG, PENG GANG, YU JING, LIU TAO, MENG RUI, LI ZHENYU, ZHAO YANXIA, WU GANG. Endothelial NO synthase and reactive oxygen species mediated effect of simvastatin on vessel structure and function: Pleiotropic and dose-dependent effect on tumor vascular stabilization. Int J Oncol 2013; 42:1325-36. [DOI: 10.3892/ijo.2013.1833] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2012] [Accepted: 01/18/2013] [Indexed: 11/06/2022] Open
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Shi Y, Gong B, Chen L, Zuo X, Liu X, Tam POS, Zhou X, Zhao P, Lu F, Qu J, Sun L, Zhao F, Chen H, Zhang Y, Zhang D, Lin Y, Lin H, Ma S, Cheng J, Yang J, Huang L, Zhang M, Zhang X, Pang CP, Yang Z. A genome-wide meta-analysis identifies two novel loci associated with high myopia in the Han Chinese population. Hum Mol Genet 2013; 22:2325-33. [PMID: 23406873 DOI: 10.1093/hmg/ddt066] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
High myopia, highly prevalent in the Chinese population, is a leading cause of visual impairment worldwide. Genetic factors play a critical role in the development of this visual disorder. Genome-wide association studies in recent years have revealed several chromosomal regions that contribute to its progression. To identify additional genetic variants for high myopia susceptibility, we used a genome-wide meta-analysis to examine the associations between the disease and 286 031 single-nucleotide polymorphisms (SNPs) in a combined cohort of 665 cases and 960 controls. The most significant SNPs (n = 61) were genotyped in a replication cohort (850 cases and 1197 controls), and 14 SNPs were further tested through genotyping in two additional validation cohorts (combined 1278 cases and 2486 controls). As a result of this analysis, four SNPs reached genome-wide significance (P < 2.0 × 10(-7)). The most significantly associated SNP, rs2730260 [overall P = 8.95 × 10(-14); odds ratio (95% CI) =1.33 (1.23-1.44)], is located in the VIPR2 gene, which is located in the MYP4 locus. The other three SNPs (rs7839488, rs4395927 and rs4455882) in the same linkage disequilibrium block are located in the SNTB1 gene, with -P values ranging from 1.13 × 10(-8) to 2.13 × 10(-11). The VIPR2 and SNTB1 genes are expressed in the retina and the retinal pigment epithelium and have been previously reported to have potential functions for the pathogenesis of myopia. Our results suggest that variants of the VIPR2 and SNTB1 genes increase susceptibility to high myopia in Han Chinese.
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Affiliation(s)
- Yi Shi
- The Sichuan Provincial Key Laboratory for Human Disease Gene Study, The Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan 610072, China
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Li J, Wang JJ, Peng Q, Chen C, Humphrey MB, Heinecke J, Zhang SX. Macrophage metalloelastase (MMP-12) deficiency mitigates retinal inflammation and pathological angiogenesis in ischemic retinopathy. PLoS One 2012; 7:e52699. [PMID: 23285156 PMCID: PMC3527600 DOI: 10.1371/journal.pone.0052699] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2012] [Accepted: 11/19/2012] [Indexed: 11/21/2022] Open
Abstract
Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme’s contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis.
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Affiliation(s)
- Jingming Li
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Harold Hamm Oklahoma Diabetes, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Joshua J. Wang
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Harold Hamm Oklahoma Diabetes, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States of America
| | - Qisheng Peng
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
| | - Chen Chen
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Harold Hamm Oklahoma Diabetes, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
| | - Mary Beth Humphrey
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Department of Veterans Affairs, Oklahoma City, Oklahoma, United States of America
| | - Jay Heinecke
- Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - Sarah X. Zhang
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
- Harold Hamm Oklahoma Diabetes, University of Oklahoma, Oklahoma City, Oklahoma, United States of America
- Department of Ophthalmology, University at Buffalo, State University of New York, Buffalo, New York, United States of America
- * E-mail:
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Rangasamy S, McGuire PG, Das A. Diabetic retinopathy and inflammation: novel therapeutic targets. Middle East Afr J Ophthalmol 2012; 19:52-9. [PMID: 22346115 PMCID: PMC3277025 DOI: 10.4103/0974-9233.92116] [Citation(s) in RCA: 150] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Most anti-vascular endothelial growth factor (VEGF) therapies in diabetic macular edema are not as robust as in proliferative diabetic retinopathy. Although the VEGF appears to be a good target in diabetic macular edema, the anti-VEGF therapies appear to be of transient benefit as the edema recurs within a few weeks, and repeated injections are necessary. There is new evidence that indicates 'retinal inflammation' as an important player in the pathogenesis of diabetic retinopathy. There are common sets of inflammatory cytokines that are upregulated in both the serum and vitreous and aqueous samples, in subjects with diabetic retinopathy, and these cytokines can have multiple interactions to impact the pathogenesis of the disease. The key inflammatory events involved in the blood retinal barrier (BRB) alteration appear to be: (1) Increased expression of endothelial adhesion molecules such as ICAM1, VCAM1, PECAM-1, and P-selectin, (2) adhesion of leukocytes to the endothelium, (3) release of inflammatory chemokines, cytokines, and vascular permeability factors, (4) alteration of adherens and tight junctional proteins between the endothelial cells, and (5) infiltration of leukocytes into the neuro-retina, resulting in the alteration of the blood retinal barrier (diapedesis). VEGF inhibition itself may not achieve neutralization of other inflammatory molecules involved in the inflammatory cascade of the breakdown of the BRB. It is possible that the novel selective inhibitors of the inflammatory cascade (like angiopoietin-2, TNFα, and chemokines) may be useful therapeutic agents in the treatment of diabetic macular edema (DME), either alone or in combination with the anti-VEGF drugs.
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Affiliation(s)
- Sampathkumar Rangasamy
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131
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Chen Y, Wang J, Li J, Hosoya K, Ratan R, Townes T, Zhang S. Activating transcription factor 4 mediates hyperglycaemia-induced endothelial inflammation and retinal vascular leakage through activation of STAT3 in a mouse model of type 1 diabetes. Diabetologia 2012; 55:2533-45. [PMID: 22660795 PMCID: PMC3412945 DOI: 10.1007/s00125-012-2594-1] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 04/25/2012] [Indexed: 10/28/2022]
Abstract
AIMS/HYPOTHESIS There is convincing evidence that endoplasmic reticulum (ER) stress is implicated in the pathogenesis of diabetes and its complications; however, the mechanisms are not fully understood. This study aimed to dissect the role and signalling pathways of activating transcription factor 4 (ATF4) in ER-stress-associated endothelial inflammation and diabetic retinopathy. METHODS ER stress and ATF4 activity were manipulated by complementary pharmacological and genetic approaches in cultured retinal endothelial (TR-iBRB) cells. Diabetes was induced by streptozotocin in heterozygous Atf4 knockout and wild-type mice. ER stress markers, inflammatory cytokines and adhesion molecules, activation of the signal transducer and activator of transcription 3 (STAT3) pathway, and retinal vascular permeability were measured. RESULTS High-glucose treatment resulted in rapid induction of ER stress, activation of ATF4, and increased production of inflammatory factors in TR-iBRB cells. Suppressing ER stress or inhibiting ATF4 activity markedly attenuated high-glucose-induced production of intercellular adhesion molecule 1, TNF-α and vascular endothelial growth factor. Conversely, enhancing ER stress or overexpressing Atf4 was sufficient to induce endothelial inflammation, which was, at least in part, through activation of the STAT3 pathway. Furthermore, knockdown of the Stat3 gene or inhibiting STAT3 activity restored ER homeostasis in cells exposed to high glucose and prevented ATF4 activation, suggesting that STAT3 is required for high-glucose-induced ER stress. Finally, we showed that downregulation of Atf4 significantly ameliorated retinal inflammation, STAT3 activation and vascular leakage in a mouse model of type 1 diabetes. CONCLUSIONS/INTERPRETATION Taken together, our data reveal a pivotal role of ER stress and the ATF4/STAT3 pathway in retinal endothelial inflammation in diabetic retinopathy.
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Affiliation(s)
- Y. Chen
- Department of Medicine, Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Medicine, Endocrinology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - J.J. Wang
- Department of Medicine, Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - J. Li
- Department of Medicine, Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - K.I. Hosoya
- Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - R. Ratan
- Department of Neurology and Neuroscience, Weill Medical College of Cornell University, The Burke Medical Research Institute, White Plains, NY, USA
| | - T. Townes
- Department of Biochemistry & Molecular Genetics, the University of Alabama at Birmingham, Birmingham, AL, USA
| | - S.X. Zhang
- Department of Medicine, Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, 941 Stanton L Young Blvd, Oklahoma City, OK 73104, USA
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Adachi T, Teramachi M, Yasuda H, Kamiya T, Hara H. Contribution of p38 MAPK, NF-κB and glucocorticoid signaling pathways to ER stress-induced increase in retinal endothelial permeability. Arch Biochem Biophys 2012; 520:30-5. [DOI: 10.1016/j.abb.2012.01.014] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 01/07/2012] [Accepted: 01/20/2012] [Indexed: 02/07/2023]
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Zhong Y, Li J, Chen Y, Wang JJ, Ratan R, Zhang SX. Activation of endoplasmic reticulum stress by hyperglycemia is essential for Müller cell-derived inflammatory cytokine production in diabetes. Diabetes 2012; 61:492-504. [PMID: 22228718 PMCID: PMC3266398 DOI: 10.2337/db11-0315] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress-induced activating transcription factor 4 (ATF4) in the regulation of Müller cell-derived inflammatory mediators in diabetic retinopathy. In diabetic animals, elevated ER stress markers, ATF4, and vascular endothelial growth factor (VEGF) expression were partially localized to Müller cells in the retina. In cultured Müller cells, high glucose induced a time-dependent increase of ER stress, ATF4 expression, and inflammatory factor production. Inducing ER stress or overexpressing ATF4 resulted in elevated intracellular adhesion molecule 1 and VEGF proteins in Müller cells. In contrast, alleviation of ER stress or blockade of ATF4 activity attenuated inflammatory gene expression induced by high glucose or hypoxia. Furthermore, we found that ATF4 regulated the c-Jun NH2-terminal kinase pathway resulting in VEGF upregulation. ATF4 was also required for ER stress-induced and hypoxia-inducible factor-1α activation. Finally, we showed that administration of chemical chaperone 4-phenylbutyrate or genetic inhibition of ATF4 successfully attenuated retinal VEGF expression and reduced vascular leakage in mice with STZ-induced diabetes. Taken together, our data indicate that ER stress and ATF4 play a critical role in retinal inflammatory signaling and Müller cell-derived inflammatory cytokine production in diabetes.
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Affiliation(s)
- Yimin Zhong
- Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jingming Li
- Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yanming Chen
- Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Department of Medicine, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Joshua J. Wang
- Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Rajiv Ratan
- Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, New York
| | - Sarah X. Zhang
- Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- Corresponding author: Sarah X. Zhang,
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Marcus MW, Müskens RPHM, Ramdas WD, Wolfs RCW, De Jong PTVM, Vingerling JR, Hofman A, Stricker BH, Jansonius NM. Cholesterol-lowering drugs and incident open-angle glaucoma: a population-based cohort study. PLoS One 2012; 7:e29724. [PMID: 22238644 PMCID: PMC3251600 DOI: 10.1371/journal.pone.0029724] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Accepted: 12/03/2011] [Indexed: 12/05/2022] Open
Abstract
Background Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG. Methodology/Principal Findings Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31–0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81–5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.89 [0.41–1.94; P = 0.77] for use two years or less; 0.46 [0.23–0.94; P = 0.033] for use more than two years; P-value for trend 0.10). The analyzes were adjusted for age and gender, baseline IOP and IOP-lowering treatment, the family history of glaucoma, and myopia. There was no effect of statins on the IOP. Conclusions/Significance Long-term use of statins appears to be associated with a reduced risk of OAG. The observed effect was independent of the IOP. These findings are in line with the idea that statins have neuroprotective properties and may open a way to a new OAG treatment modality.
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Affiliation(s)
- Michael W. Marcus
- Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Rogier P. H. M. Müskens
- Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Wishal D. Ramdas
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Roger C. W. Wolfs
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Paulus T. V. M. De Jong
- Department of Ophthalmogenetics, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
- Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands
| | - Johannes R. Vingerling
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Albert Hofman
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Bruno H. Stricker
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands
- * E-mail:
| | - Nomdo M. Jansonius
- Department of Ophthalmology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
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Zhong Y, Wang JJ, Zhang SX. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 723:285-92. [PMID: 22183344 PMCID: PMC3243941 DOI: 10.1007/978-1-4614-0631-0_37] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Diabetic retinopathy is a chronic inflammatory disease characterized by vascular damage and neuronal degeneration. Previously we reported that activated retinal pericytes secret high levels of pro-inflammatory cytokines, such as macrophage chemoattractant protein 1 (MCP-1), and may play a pivotal role in macrophage recruitment and inflammatory retinal damage. However, the mechanism underlying diabetes-induced pericyte inflammation remains poorly understood. In the present study, we evaluated the effects of constant and intermittent high glucose on inflammatory cytokine production in human retinal pericytes (HRP) and explored the role of endoplasmic reticulum (ER) stress in pericyte inflammation. We found that intermittent high glucose, but not constant high glucose, increases MCP-1 secretion and expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key mediators of ER stress-associated inflammation and cell death. Inhibition of ER stress by chemical chaperones successfully prevented glucose fluctuation-induced ATF4/CHOP activation and inflammatory cytokine production. Our results suggest that activation of ER stress by glucose fluctuation may play a causal role in pericyte injury and inflammation in diabetic retinopathy.
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Affiliation(s)
- Yimin Zhong
- Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Joshua J. Wang
- Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Sarah X. Zhang
- Department of Medicine, Endocrinology and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res 2011; 30:343-58. [PMID: 21635964 PMCID: PMC3433044 DOI: 10.1016/j.preteyeres.2011.05.002] [Citation(s) in RCA: 834] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Revised: 05/14/2011] [Accepted: 05/16/2011] [Indexed: 12/14/2022]
Abstract
Diabetes causes a number of metabolic and physiologic abnormalities in the retina, but which of these abnormalities contribute to recognized features of diabetic retinopathy (DR) is less clear. Many of the molecular and physiologic abnormalities that have been found to develop in the retina in diabetes are consistent with inflammation. Moreover, a number of anti-inflammatory therapies have been found to significantly inhibit development of different aspects of DR in animal models. Herein, we review the inflammatory mediators and their relationship to early and late DR, and discuss the potential of anti-inflammatory approaches to inhibit development of different stages of the retinopathy. We focus primarily on information derived from in vivo studies, supplementing with information from in vitro studies were important.
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Affiliation(s)
- Johnny Tang
- Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, OH, USA
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Tang L, Zhang Y, Jiang Y, Willard L, Ortiz E, Wark L, Medeiros D, Lin D. Dietary wolfberry ameliorates retinal structure abnormalities in db/db mice at the early stage of diabetes. Exp Biol Med (Maywood) 2011; 236:1051-63. [PMID: 21750018 DOI: 10.1258/ebm.2011.010400] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Hyperglycemia-linked oxidative stress and/or consequent endoplasmic reticulum (ER) stress are the causative factors of pathogenesis of diabetic retinopathy. Dietary bioactive components which mitigate oxidative stress may serve as potential chemopreventive agents to prevent or slow down the disease progression. Wolfberry is a traditional Asian fruit consumed for years to prevent aging eye diseases in Asian countries. Here we report that dietary wolfberry ameliorated mouse retinal abnormality at the early stage of type 2 diabetes in db/db mice. Male mice at six weeks of age were fed the control diet with or without 1% (kcal) wolfberry for eight weeks. Dietary wolfberry restored the thickness of the whole retina, in particular the inner nuclear layer and photoreceptor layer, and the integrity of the retinal pigment epithelia (RPE), and the ganglion cell number in db/db mice. Western blotting of whole retinal cell lysates revealed that addition of wolfberry lowered expression of ER stress biomarkers binding immunoglobulin protein (BiP), protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and caspase-12, and restored AMP-activated protein kinase (AMPK), thioredoxin, Mn superoxide dismutase (Mn SOD) and forkhead O transcription factor 3 α (FOXO3α) activities. To determine if our observations were due to the high contents of zeaxanthin and lutein in wolfberry, additional studies using these carotenoids were conducted. Using the human adult diploid RPE cell line ARPE-19, we demonstrated that both zeaxanthin and lutein could mimic the wolfberry preventive effect on activation of AMPK, thioredoxin, Mn SOD, FOXO3α activities, normalize cellular reactive oxygen species and attenuate ER stress in ARPE-19 cells exposed to a high glucose challenge. The zeaxanthin preventive effect was abolished by small interfering RNA knockdown of AMPKα. These results suggested that AMPK activation appeared to play a key role in upregulated expression of thioredoxin and Mn SOD, and mitigation of cellular oxidative stress and/or ER stress by wolfberry and zeaxanthin and/or lutein. Taken together, dietary wolfberry on retinal protection in diabetic mice is, at least partially, due to zeaxanthin and/or lutein.
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Affiliation(s)
- Ling Tang
- Department of Human Nutrition, Kansas State University, Manhattan, KS 66506, USA
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Adachi T, Yasuda H, Nakamura S, Kamiya T, Hara H, Hara H, Ikeda T. Endoplasmic reticulum stress induces retinal endothelial permeability of extracellular-superoxide dismutase. Free Radic Res 2011; 45:1083-92. [DOI: 10.3109/10715762.2011.595408] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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