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Safwat A, Abdullah M, Abdelhalim AS, Hassanien R, Mourad K, Moustafa MT. Dual Application of Methotrexate Improves Functional and Anatomical Outcomes in Diabetic Tractional Retinal Detachment. Ophthalmic Surg Lasers Imaging Retina 2025:1-8. [PMID: 39998616 DOI: 10.3928/23258160-20250127-03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2025]
Abstract
BACKGROUND AND OBJECTIVE This study evaluated the use of a dual-delivery methotrexate (MTX) strategy for diabetic tractional retinal detachment (TRD). Diabetic retinopathy (DR) is a leading cause of blindness. Inflammation plays a key role in TRD, and MTX has anti-inflammatory properties. PATIENTS AND METHODS This is a pilot study that included 60 patients with TRD. They were block randomized to either MTX with pars plana vitrectomy (PPV) (n = 30) or PPV alone (control, n = 30). MTX was added to the irrigation fluid during surgery and an intra-silicone injection at the end. One month after silicone oil removal, visual acuity (VA), multifocal electroretinography (mfERG), and spectral-domain optical coherence tomography (SD-OCT) were assessed. RESULTS One month after silicone oil removal, VA and mfERG were significantly better with a lower prevalence of epiretinal membranes, disorganization of retinal inner layers, and cystic macular changes by SD-OCT in the MTX group. CONCLUSION This study found that dual-delivery MTX during PPV is a promising strategy to improve functional and anatomical results in diabetic TRD. [Ophthalmic Surg Lasers Imaging Retina 2025;56:XX-XX.].
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Sato T, Takenaka Y, Nishio Y, Ito M, Takeuchi M. Anterior Chamber Flare as a Non-Invasive Assessment of Intraocular Immune Status and Ocular Complications in Proliferative Diabetic Retinopathy. Int J Mol Sci 2024; 25:9158. [PMID: 39273105 PMCID: PMC11394674 DOI: 10.3390/ijms25179158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/12/2024] [Accepted: 08/21/2024] [Indexed: 09/15/2024] Open
Abstract
Proliferative diabetic retinopathy (PDR) is a vision-threatening complication of diabetes mellitus (DM). Anterior chamber (AC) flare and intraocular cytokines are potent biomarkers reflecting the intraocular immune status in PDR. This study aimed to elucidate the complex interrelationship between AC flare and intraocular cytokines in PDR eyes. A retrospective observational study was conducted on 19 PDR eyes of 19 patients with type 2 DM, and on 19 eyes of 19 patients with idiopathic macular hole or epiretinal membrane as controls. AC flare was measured before pars plana vitrectomy (PPV). Aqueous humor (AH) and vitreous fluid (VF) samples were collected at the time of PPV, and the quantities of 27 cytokines in both intraocular fluids were analyzed. In the PDR and control groups, Spearman's rank correlation analysis revealed a positive correlation between AC flare and IL-8 level in both AH and VF. Additionally, IL-8 levels in AH correlated positively with IL-8 levels in VF. In the PDR group, receiver operating characteristic curve analysis identified IL-8 level in AH as a significant predictor for both diabetic macular edema (DME) and vitreous hemorrhage (VH) complications. The cut-off values of IL-8 were established at ≥26.6 pg/mL for DME and ≥7.96 pg/mL for VH. Given the positive correlation between AC flare and AH IL-8 level, the present findings suggest that AC flare value may potentially be a non-invasive biomarker for predicting DME.
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Affiliation(s)
- Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan; (T.S.); (Y.T.); (Y.N.)
| | - Yuki Takenaka
- Department of Ophthalmology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan; (T.S.); (Y.T.); (Y.N.)
| | - Yoshiaki Nishio
- Department of Ophthalmology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan; (T.S.); (Y.T.); (Y.N.)
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan;
| | - Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, Tokorozawa 359-8513, Saitama, Japan; (T.S.); (Y.T.); (Y.N.)
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Boix-Lemonche G, Hildebrand T, Haugen HJ, Petrovski G, Nogueira LP. Contrast-enhanced Micro-CT 3D visualization of cell distribution in hydrated human cornea. Heliyon 2024; 10:e25828. [PMID: 38356495 PMCID: PMC10865036 DOI: 10.1016/j.heliyon.2024.e25828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/27/2024] [Accepted: 02/02/2024] [Indexed: 02/16/2024] Open
Abstract
Background The cornea, a vital component of the human eye, plays a crucial role in maintaining visual clarity. Understanding its ultrastructural organization and cell distribution is fundamental for elucidating corneal physiology and pathology. This study comprehensively examines the microarchitecture of the hydrated human cornea using contrast-enhanced micro-computed tomography (micro-CT). Method Fresh human corneal specimens were carefully prepared and hydrated to mimic their in vivo state. Contrast enhancement with Lugol's iodine-enabled high-resolution Micro-CT imaging. The cells' three-dimensional (3D) distribution within the cornea was reconstructed and analyzed. Results The micro-CT imaging revealed exquisite details of the corneal ultrastructure, including the spatial arrangement of cells throughout its depth. This novel approach allowed for the visualization of cells' density and distribution in different corneal layers. Notably, our findings highlighted variations in cell distribution between non-hydrated and hydrated corneas. Conclusions This study demonstrates the potential of contrast-enhanced micro-CT as a valuable tool for non-destructive, 3D visualization and quantitative analysis of cell distribution in hydrated human corneas. These insights contribute to a better understanding of corneal physiology and may have implications for research in corneal diseases and tissue engineering.
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Affiliation(s)
- Gerard Boix-Lemonche
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | | | | | - Goran Petrovski
- Center for Eye Research and Innovative Diagnostics, Department of Ophthalmology, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
- Department of Ophthalmology, and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway
- Department of Ophthalmology, University of Split School of Medicine and University Hospital Centre, Split, Croatia
- UKLO Network, University St. Kliment Ohridski – Bitola, Bitola, Macedonia
| | - Liebert Parreiras Nogueira
- Oral Research Laboratory, Institute of Clinical Dentistry, Faculty of Dentistry, University of Oslo, Oslo, Norway
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Sadikan MZ, Abdul Nasir NA, Bakar NS, Iezhitsa I, Agarwal R. Tocotrienol-rich fraction reduces retinal inflammation and angiogenesis in rats with streptozotocin-induced diabetes. BMC Complement Med Ther 2023; 23:179. [PMID: 37268913 DOI: 10.1186/s12906-023-04005-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 05/20/2023] [Indexed: 06/04/2023] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is the second commonest microvascular complication of diabetes mellitus. It is characterized by chronic inflammation and angiogenesis. Palm oil-derived tocotrienol-rich fraction (TRF), a substance with anti-inflammatory and anti-angiogenic properties, may provide protection against DR development. Therefore, in this study, we investigated the effect of TRF on retinal vascular and morphological changes in diabetic rats. The effects of TRF on the retinal expression of inflammatory and angiogenic markers were also studied in the streptozotocin (STZ)-induced diabetic rats. METHODS Male Sprague Dawley rats weighing 200-250 g were grouped into normal rats (N) and diabetic rats. Diabetes was induced by intraperitoneal injection of streptozotocin (55 mg/kg body weight) whereas N similarly received citrate buffer. STZ-injected rats with blood glucose of more than 20 mmol/L were considered diabetic and were divided into vehicle-treated (DV) and TRF-treated (DT) groups. N and DV received vehicle, whereas DT received TRF (100 mg/kg body weight) via oral gavage once daily for 12 weeks. Fundus images were captured at week 0 (baseline), week 6 and week 12 post-STZ induction to estimate vascular diameters. At the end of experimental period, rats were euthanized, and retinal tissues were collected for morphometric analysis and measurement of NFκB, phospho-NFκB (Ser536), HIF-1α using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Retinal inflammatory and angiogenic cytokines expression were measured by ELISA and real-time quantitative PCR. RESULTS TRF preserved the retinal layer thickness (GCL, IPL, INL and OR; p < 0.05) and retinal venous diameter (p < 0.001). TRF also lowered the retinal NFκB activation (p < 0.05) as well as expressions of IL-1β, IL-6, TNF-α, IFN-γ, iNOS and MCP-1 (p < 0.05) compared to vehicle-treated diabetic rats. Moreover, TRF also reduced retinal expression of VEGF (p < 0.001), IGF-1 (p < 0.001) and HIF-1α (p < 0.05) compared to vehicle-treated rats with diabetes. CONCLUSION Oral TRF provided protection against retinal inflammation and angiogenesis in rats with STZ-induced diabetes by suppressing the expression of the markers of retinal inflammation and angiogenesis.
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Affiliation(s)
- Muhammad Zulfiqah Sadikan
- Department of Pharmacology, Faculty of Medicine, Manipal University College Malaysia (MUCM), Bukit Baru, 75150, Melaka, Malaysia
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000, Sungai Buloh, Selangor, Malaysia
| | - Nurul Alimah Abdul Nasir
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000, Sungai Buloh, Selangor, Malaysia.
| | - Nor Salmah Bakar
- Department of Pathology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000, Sungai Buloh, Selangor, Malaysia
| | - Igor Iezhitsa
- School of Medicine, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov sq. 1, Volgograd, 400131, Russia
| | - Renu Agarwal
- School of Medicine, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
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Sato T, Okazawa R, Nagura K, Someya H, Nishio Y, Enoki T, Ito M, Takeuchi M. Association between Systemic Factors and Vitreous Fluid Cytokines in Proliferative Diabetic Retinopathy. J Clin Med 2023; 12:jcm12062354. [PMID: 36983353 PMCID: PMC10059790 DOI: 10.3390/jcm12062354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 03/10/2023] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
Proliferative diabetic retinopathy (PDR) is a vision-threatening complication of diabetes mellitus (DM). Systemic and intraocular factors are intricately related to PDR, and vitreous fluid (VF) cytokines are representative intraocular biomarkers. However, the associations between systemic factors and VF cytokines and their influence on PDR pathology are unclear. This study aimed to examine the correlation between systemic factors and VF cytokines and analyze their contributions to the pathology of PDR using multivariate analyses. We conducted a retrospective observational study on 26 PDR eyes of 25 patients with type 2 DM, and 30 eyes of 30 patients with idiopathic macular hole or epiretinal membrane as controls. Fifteen systemic and laboratory tests including blood pressure (BP) and body mass index (BMI), and 27 cytokines in VF were analyzed. BP and BMI correlated positively with VF levels of IL-6 and IP-10 in PDR patients, while no significant correlation was found between systemic factors and VF cytokines in controls. MCP-1 and VEGF-A in VF separately clustered with different systemic factors in controls, but these cytokines lost the property similarity with systemic factors and acquired property similarity with each other in PDR. Systemic factors contributed to only 10.4%, whereas VF cytokines contributed to 42.3% out of 52.7% variance of the whole PDR dataset. Our results suggest that intraocular factors play a major role in the pathology of PDR, whereas systemic factors may have limited effects, and that BP and BMI control in PDR could be useful interventions to improve intraocular immune condition.
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Affiliation(s)
- Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
| | - Rina Okazawa
- Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
| | - Koichi Nagura
- Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
| | - Hideaki Someya
- Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
| | - Yoshiaki Nishio
- Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
| | | | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Tokorozawa 359-8513, Japan
| | - Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa 359-8513, Japan
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Cheng Y, Fan H, Liu K, Liu J, Zou H, You Z. TFEB attenuates hyperglycemia-induced retinal capillary endothelial cells injury via autophagy regulation. Cell Biol Int 2023; 47:1092-1105. [PMID: 36807611 DOI: 10.1002/cbin.12002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 01/06/2023] [Accepted: 02/05/2023] [Indexed: 02/20/2023]
Abstract
Diabetic retinopathy is a common microvascular complication of diabetes mellitus. The maintenance of retinal capillary endothelial cell homeostasis requires a complete and unobtrusive flow of autophagy because it may help combat the inflammatory response, apoptosis, and oxidative stress damage of cells in diabetes mellitus. The transcription factor EB is a master regulator of autophagy and lysosomal biogenesis, but its role in diabetic retinopathy remains unknown. This study aimed to confirm the involvement of transcription factor EB in diabetic retinopathy and explore the role of transcription factor EB in hyperglycemia-linked endothelial injury in vitro. First, the expression levels, including the nuclear location of transcription factor EB and autophagy, were reduced in diabetic retinal tissues and high glucose-treated human retinal capillary endothelial cells. Subsequently, autophagy was mediated by transcription factor EB in vitro. Moreover, transcription factor EB overexpression reversed high glucose-induced autophagy inhibition and lysosomal dysfunction and protected human retinal capillary endothelial cells from inflammation, apoptosis, and oxidative stress damage caused by high glucose treatment. Additionally, under high-glucose stimulation, the autophagy inhibitor chloroquine attenuated transcription factor EB overexpression-mediated protection, and the autophagy agonist Torin1 rescued transcription factor EB knockdown-induced damage effects. Taken together, these results suggest that transcription factor EB is involved in the development of diabetic retinopathy. In addition, transcription factor EB protects human retinal capillary endothelial cells from high glucose-induced endothelial damage via autophagy.
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Affiliation(s)
- Yanhua Cheng
- Jiangxi Province Division of National Clinical Research Center for Ocular Diseases, Jiangxi Clinical Research Center for Ophthalmic Disease, Jiangxi Research Institute of Ophthalmology and Visual Science, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Huimin Fan
- Jiangxi Province Division of National Clinical Research Center for Ocular Diseases, Jiangxi Clinical Research Center for Ophthalmic Disease, Jiangxi Research Institute of Ophthalmology and Visual Science, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Kangcheng Liu
- Jiangxi Province Division of National Clinical Research Center for Ocular Diseases, Jiangxi Clinical Research Center for Ophthalmic Disease, Jiangxi Research Institute of Ophthalmology and Visual Science, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jingying Liu
- Jiangxi Province Division of National Clinical Research Center for Ocular Diseases, Jiangxi Clinical Research Center for Ophthalmic Disease, Jiangxi Research Institute of Ophthalmology and Visual Science, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hua Zou
- Jiangxi Province Division of National Clinical Research Center for Ocular Diseases, Jiangxi Clinical Research Center for Ophthalmic Disease, Jiangxi Research Institute of Ophthalmology and Visual Science, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhipeng You
- Jiangxi Province Division of National Clinical Research Center for Ocular Diseases, Jiangxi Clinical Research Center for Ophthalmic Disease, Jiangxi Research Institute of Ophthalmology and Visual Science, Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China
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Batsos G, Christodoulou E, Christou EE, Galanis P, Katsanos A, Limberis L, Stefaniotou M. Vitreous inflammatory and angiogenic factors on patients with proliferative diabetic retinopathy or diabetic macular edema: the role of Lipocalin2. BMC Ophthalmol 2022; 22:496. [PMID: 36536319 PMCID: PMC9761947 DOI: 10.1186/s12886-022-02733-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Quantitative analysis of vitreous inflammatory and angiogenic factors from patients with proliferative diabetic retinopathy (PDR) or diabetic macular edema (DME). MATERIALS AND METHODS Collection of undiluted vitreous samples from 20 diabetic patients: 13 with proliferative diabetic retinopathy (PDR) and 7 with diabetic macular edema (DME). DME patients had suboptimal response to anti-VEGF treatment. Samples from 11 control patients, with vitreomacular interface pathology such as idiopathic epiretinal membrane (iERM) (n = 4), vitreomacular traction syndrome (VMT) (n = 3) and full thickness macular hole (FTMH) (n = 3), were also collected. The levels of IL1b, IL6, IL8, IL27, TNFα, ICAM-1, VCAM, MCP-1, VEGFA and LCN2 were measured using cytometry flow analysis. Median values were compared with Mann-Whitney test since the distributions were skewed. Statistical analysis was performed with the Statistical Package for Social Sciences software (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.). RESULTS The median concentration of LCN2, IL6, IL8, IL1b, IL27, ICAM, VCAM-1, MCP-1, TNFa and VEGFA was higher in PDR patients than in controls. Similarly, the median concentration of LCN2, IL6, IL8, IL27, ICAM, VCAM-1, TNFa and VEGFA was higher in DME patients than in controls. In particular, median LCN2 concentration in diabetic patients was 5,711 pg/ml (interquartile range [IR] = 2,534), while in controls was 2,586 pg/ml (IR = 2,345). Moreover, median LCN2 was 6,534 pg/ml in the DME group (IR = 6,850) and 4,785 pg/ml in the PDR group (IR = 2,608), (p = 0.025). CONCLUSION Various inflammatory and angiogenic factors are involved in the pathophysiology of PDR and DME. Elevated vitreous levels of LCN2 in PDR and especially in DME patients reveal a potential pathogenic association. More extended studies could verify LCN2 as an alternative therapeutic target.
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Affiliation(s)
- Georgios Batsos
- grid.9594.10000 0001 2108 7481Faculty of Medicine, Department of Ophthalmology, University of Ioannina, 45110 Ioannina, Greece
| | - Eleni Christodoulou
- grid.9594.10000 0001 2108 7481Faculty of Medicine, Department of Ophthalmology, University of Ioannina, 45110 Ioannina, Greece
| | - Evita Evangelia Christou
- grid.9594.10000 0001 2108 7481Faculty of Medicine, Department of Ophthalmology, University of Ioannina, 45110 Ioannina, Greece
| | - Petros Galanis
- grid.5216.00000 0001 2155 0800Clinical Epidemiology Laboratory, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Katsanos
- grid.9594.10000 0001 2108 7481Faculty of Medicine, Department of Ophthalmology, University of Ioannina, 45110 Ioannina, Greece
| | - Loren Limberis
- grid.255364.30000 0001 2191 0423Department of Engineering, East Carolina University, Greenville, NC USA
| | - Maria Stefaniotou
- grid.9594.10000 0001 2108 7481Faculty of Medicine, Department of Ophthalmology, University of Ioannina, 45110 Ioannina, Greece
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Lu A, Duan P, Xie J, Gao H, Chen M, Gong Y, Li J, Xu H. Recent progress and research trend of anti-cataract pharmacology therapy: A bibliometric analysis and literature review. Eur J Pharmacol 2022; 934:175299. [PMID: 36181780 DOI: 10.1016/j.ejphar.2022.175299] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 11/30/2022]
Abstract
Cataract is the leading cause of blindness worldwide. Cataract phacoemulsification combined with intraocular lens implantation causes great burden to global healthcare, especially for low- and middle-income countries. Such burden would be significantly relieved if cataracts can effectively be treated or delayed by non-surgical means. Excitingly, novel drugs have been developed to treat cataracts in recent decades. For example, oxysterols are found to be able to innovatively reverse lens clouding, novel nanotechnology-loaded drugs improve anti-cataract pharmacological effect, and traditional Chinese medicine demonstrates promising therapeutic effects against cataracts. In the present review, we performed bibliometric analysis to provide an overview perspective regarding the research status, hot topics, and academic trends in the field of anti-cataract pharmacology therapy. We further reviewed the curative effects and molecular mechanisms of anti-cataract drugs such as lanosterol, metformin, resveratrol and curcumin, and prospected the possibility of their clinical application in future.
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Affiliation(s)
- Ao Lu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China; The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China
| | - Ping Duan
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Jing Xie
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Hui Gao
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Mengmeng Chen
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Yu Gong
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China
| | - Jiawen Li
- Department of Ophthalmology, University-Town Hospital of Chongqing Medical University, China.
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing, China.
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Pereira-da-Mota AF, Vivero-Lopez M, Serramito M, Diaz-Gomez L, Serro AP, Carracedo G, Huete-Toral F, Concheiro A, Alvarez-Lorenzo C. Contact lenses for pravastatin delivery to eye segments: Design and in vitro-in vivo correlations. J Control Release 2022; 348:431-443. [PMID: 35688348 DOI: 10.1016/j.jconrel.2022.06.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/12/2022] [Accepted: 06/01/2022] [Indexed: 10/18/2022]
Abstract
Oral administration of cholesterol-lowering statins, HMG-CoA reductase inhibitors, is associated with beneficial effects on eye conditions. This work aims to design contact lenses (CLs) that can sustainedly deliver pravastatin and thus improve the ocular efficacy while avoiding systemic side effects of statins. Bioinspired hydrogels were prepared with monomers that resemble hydrophobic (ethylene glycol phenyl ether methacrylate) and amino (2-aminoethyl methacrylamide hydrochloride) functionalities of the active site of HMG-CoA. Best performing CLs loaded >6 mg/g, in vitro fulfilled the release demands for daily wearing, and showed anti-inflammatory activity (lowering TNF-α). High hydrostatic pressure sterilization preserved the stability of both the drug and the hydrogel network. Ex vivo tests revealed the ability of pravastatin to accumulate in cornea and sclera and to penetrate through transscleral route. In vivo tests (rabbits) confirmed that, compared to eye drops and for the same dose, CLs provided significantly higher pravastatin levels in tear fluid within 1 to 7 h of wearing. Moreover, after 8 h wearing pravastatin was present in cornea, sclera, aqueous humour and vitreous humour. Strong correlations between percentages of drug released in vitro and in vivo were found. Effects of volume and proteins on release rate and Levy plots were identified.
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Affiliation(s)
- Ana F Pereira-da-Mota
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Maria Vivero-Lopez
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Maria Serramito
- Ocupharm Research Group, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain
| | - Luis Diaz-Gomez
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Ana Paula Serro
- Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Gonzalo Carracedo
- Ocupharm Research Group, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain
| | - Fernando Huete-Toral
- Ocupharm Research Group, Faculty of Optic and Optometry, University Complutense of Madrid, C/Arcos del Jalon 118, 28037 Madrid, Spain
| | - Angel Concheiro
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Carmen Alvarez-Lorenzo
- Departamento de Farmacología, Farmacia y Tecnología Farmacéutica, I+D Farma Group (GI-1645), Facultad de Farmacia, Instituto de Materiales (iMATUS) and Health Research Institute of Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
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Xu Z, Tian N, Li S, Li K, Guo H, Zhang H, Jin H, An M, Yu X. Extracellular vesicles secreted from mesenchymal stem cells exert anti-apoptotic and anti-inflammatory effects via transmitting microRNA-18b in rats with diabetic retinopathy. Int Immunopharmacol 2021; 101:108234. [PMID: 34655847 DOI: 10.1016/j.intimp.2021.108234] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/14/2021] [Accepted: 10/04/2021] [Indexed: 12/28/2022]
Abstract
Diabetic retinopathy (DR) is a major cause of visual deficits and blindness in the working-age population and inflammatory response is a key event during DR. In this study, we investigated the anti-inflammatory properties of small extracellular vesicles (sEVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in a diabetic rat model and human retinal microvascular endothelial cells. After development of DR in rats subjected to diabetes induction with streptozotocin (STZ), the DR rats were treated with different concentrations of hUCMSC-sEVs. Our results showed that the treatment of the retinas of DR rats with hUCMSC-sEVs not only reduced the level of vascular leakage in the retinas of rats but also decreased the retinal thickness as well as the associated inflammation. Further, our in vitro evidences suggest that hUCMSC-sEVs repress high glucose (HG)-induced cell inflammation and apoptosis. Subsequently, we analyzed the differentially expressed microRNAs (miRNAs) in the hUCMSC-sEVs by microarray and performed in silico studies to predict the target mRNA of miR-18b. Our findings also revealed that the expression of miR-18b was significantly elevated in the retina of diabetic rats after sEV treatment. In addition, miR-18b was found to target mitogen-activated protein kinase kinase kinase 1 (MAP3K1), thereby inhibiting NF-κB p65 phosphorylation to alleviate DR. Overall, this study highlights the potential of hUCMSCs-sEVs as biomaterials for anti-inflammatory and anti-apoptotic effects in DR by transferring miR-18b.
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Affiliation(s)
- Zepeng Xu
- Department of Ophthalmology, Jiangmen Wuyi Hospital of TCM, Jiangmen 529000, Guangdong, China; The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
| | - Ni Tian
- Department of Ophthalmology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China.
| | - Songtao Li
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
| | - Kunmeng Li
- The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
| | - Haike Guo
- Department of Ophthalmology, Shanghai Heping Eye Hospital, Shanghai 200437, China
| | - Hongyang Zhang
- Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangzhou 510120, Guangdong, China
| | - Haiying Jin
- Department of Ophthalmology, Shanghai No. 10 People's Hospital, Shanghai 200040, China
| | - Meixia An
- Department of Ophthalmology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, Guangdong, China
| | - Xiaoyi Yu
- Department of Ophthalmology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510504, Guangdong, China
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11
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Rodríguez ML, Millán I, Ortega ÁL. Cellular targets in diabetic retinopathy therapy. World J Diabetes 2021; 12:1442-1462. [PMID: 34630899 PMCID: PMC8472497 DOI: 10.4239/wjd.v12.i9.1442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/08/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.
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Affiliation(s)
- María Lucía Rodríguez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
| | - Iván Millán
- Neonatal Research Group, Health Research Institute La Fe, Valencia 46026, Valencia, Spain
| | - Ángel Luis Ortega
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
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12
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Dysregulation of circulating follicular helper T cells in type 2 diabetic patients with diabetic retinopathy. Immunol Res 2021; 69:153-161. [PMID: 33625683 DOI: 10.1007/s12026-021-09182-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 02/14/2021] [Indexed: 12/23/2022]
Abstract
Inflammation is known to be involved in the progression of diabetic retinopathy. Follicular helper T cells (Tfh) play critical roles in the differentiation of long-live plasma cells and production of antibodies, whereas circulating CD4+CXCR5+ T cells may act as a counterpart to measure Tfh cell disorders. In this study, we investigated whether Tfh could be involved in the development of diabetic retinopathy (DR) by assessing circulating Tfh cells in peripheral blood. Data showed that serum levels of total IgG and IgA were both significantly increased in type 2 diabetes mellitus (T2DM) patients with proliferative diabetic retinopathy (PDR) than with non-PDR. Also, B cell activation and differentiation were both enhanced in T2DM patients with PDR. Little changes were detected in levels of Th1, Th2, and Th17 cells. As indicated by elevated serum levels and supernatant from cultured PBMC of IL-21, we found increased circulating Tfh cells in PDR patients with dysregulated subsets. This study suggests the involvement of circulating Tfh cells in DR and, in particular, the pathogenesis of PDR.
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13
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Filippelli M, Campagna G, Vito P, Zotti T, Ventre L, Rinaldi M, Bartollino S, dell'Omo R, Costagliola C. Anti-inflammatory Effect of Curcumin, Homotaurine, and Vitamin D3 on Human Vitreous in Patients With Diabetic Retinopathy. Front Neurol 2021; 11:592274. [PMID: 33633656 PMCID: PMC7901953 DOI: 10.3389/fneur.2020.592274] [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: 08/06/2020] [Accepted: 12/03/2020] [Indexed: 01/01/2023] Open
Abstract
Purpose: To determine the levels of pro-inflammatory cytokines and soluble mediators (TNF-α, IL6, IL2, and PDGF-AB) in 28 vitreous biopsies taken from patients with proliferative diabetic retinopathy (PDR) and treated with increasing doses of curcumin (0. 5 and 1 μM), with or without homotaurine (100 μM) and vitamin D3 (50 nM). Materials and Methods: ELISA tests were performed on the supernatants from 28 vitreous biopsies that were incubated with bioactive molecules at 37°C for 20 h. The concentration of the soluble mediators was calculated from a calibration curve and expressed in pg/mL. Shapiro-Wilk test was used to verify the normality of distribution of the residuals. Continuous variables among groups were compared using the General Linear Model (GLM). Homoscedasticity was verified using Levene and Brown-Forsythe tests. Post-hoc analysis was also performed with the Tukey test. A p ≤ 0.05 was considered statistically significant. Results: The post-hoc analysis revealed statistically detectable changes in the concentrations of TNF-α, IL2, and PDGF-AB in response to the treatment with curcumin, homotaurine, and vitamin D3. Specifically, the p-values for between group comparisons are as follows: TNF-α: (untreated vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.008, (curcumin 0.5 μM vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.0004, (curcumin 0.5 μM vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.02, (curcumin 1 μM vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.025, and (homotaurine 100 μM + vitamin D3 50 nM vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.009; IL2: (untreated vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.0023, and (curcumin 0.5 μM vs. curcumin 0.5 μM+ homotaurine 100 μM + vitamin D3 50 nM) p = 0.0028; PDGF-AB: (untreated vs. curcumin 0.5 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.04, (untreated vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.0006, (curcumin 0.5 μM vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.006, and (homotaurine 100 μM + vitamin D3 50 nM vs. curcumin 1 μM + homotaurine 100 μM + vitamin D3 50 nM) p = 0.022. IL6 levels were not significantly affected by any treatment. Conclusions: Pro-inflammatory cytokines are associated with inflammation and angiogenesis, although there is a discrete variability in the doses of the mediators investigated among the different vitreous samples. Curcumin, homotaurine, and vitamin D3 individually have a slightly appreciable anti-inflammatory effect. However, when used in combination, these substances are able to modify the average levels of the soluble mediators of inflammation and retinal damage. Multi-target treatment may provide a therapeutic strategy for diabetic retinopathy in the future. Clinical Trial Registration : The trial was registered at clinical trials.gov as NCT04378972 on 06 May 2020 ("retrospectively registered") https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid = S0009UI8&selectaction = Edit&uid = U0003RKC&ts = 2&cx = dstm4o.
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Affiliation(s)
- Mariaelena Filippelli
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Giuseppe Campagna
- Department of Medical-Surgical Sciences and Translational Medicine, University of Rome "La Sapienza", Rome, Italy
| | - Pasquale Vito
- Sannio Tech Consortium, Apollosa, Italy.,Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Tiziana Zotti
- Sannio Tech Consortium, Apollosa, Italy.,Department of Science and Technology, University of Sannio, Benevento, Italy
| | - Luca Ventre
- Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, University Eye Clinic, Turin, Italy
| | - Michele Rinaldi
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Silvia Bartollino
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Roberto dell'Omo
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Ciro Costagliola
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy.,Sannio Tech Consortium, Apollosa, Italy
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14
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Laddha UD, Kshirsagar SJ. Formulation of PPAR-gamma agonist as surface modified PLGA nanoparticles for non-invasive treatment of diabetic retinopathy: in vitro and in vivo evidences. Heliyon 2020; 6:e04589. [PMID: 32832706 PMCID: PMC7432955 DOI: 10.1016/j.heliyon.2020.e04589] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/10/2020] [Accepted: 07/27/2020] [Indexed: 12/19/2022] Open
Abstract
Diabetic retinopathy is one of the worst complications of diabetes and it is treated by invasive method. We prepared a surface modified poly (D, L-lactide-co-glycolide) i.e. PLGA nanoparticles for delivery of pioglitazone-a peroxisome proliferator-activated receptor-gamma agonist to posterior segment of the eye by topical administration. The present study investigated two grades of PLGA viz. 75:25 and 50:50. Surface modification was performed using polysorbate 80. Nanoparticles were prepared by single emulsion solvent evaporation method and optimized by using 3-factor 3-level Box-Behnken statistical design. Mean particle size, PDI and entrapment efficiency for optimized batch of PLGA 75:25 was found to be 163.23 nm, 0.286 and 91%, whereas; for PLGA 50:50 it was 171.7 nm, 0.280 and 93% respectively. DSC confirms the molecular dispersion of drug in polymer. In vitro release study showed biphasic drug release pattern with 58.48 ± 1.38% and 74.17 ± 1.38% cumulative drug release by PLGA 75:25 and 50:50 nanoparticles at the end of 10h. The release profile of pioglitazone from nanoparticles appeared to fit best with Higuchi model. In vivo study on rat showed dose dependent reduction in vascular endothelial growth factor concentration in vitreous fluid. The study reveals significance of peroxisome proliferator-activated receptor-gamma in management of diabetic retinopathy.
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Affiliation(s)
- Umesh D Laddha
- MET's Institute of Pharmacy, Bhujbal Knowledge City, Affiliated to Savitribai Phule Pune University, Nashik, 422003, MS, India
| | - Sanjay J Kshirsagar
- MET's Institute of Pharmacy, Bhujbal Knowledge City, Affiliated to Savitribai Phule Pune University, Nashik, 422003, MS, India
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15
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Taguchi M, Someya H, Inada M, Nishio Y, Takayama K, Harimoto K, Karasawa Y, Ito M, Takeuchi M. Retinal changes in mice spontaneously developing diabetes by Th17-cell deviation. Exp Eye Res 2020; 198:108155. [PMID: 32717339 DOI: 10.1016/j.exer.2020.108155] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/30/2020] [Accepted: 07/16/2020] [Indexed: 10/23/2022]
Abstract
Elevated level of interleukin (IL)-17, predominantly produced by T helper (Th) 17 cells, has been implicated in diabetic retinopathy (DR), but it remains unclear whether IL-17 is involved in the pathogenesis of DR. Ins2Akita (Akita) mice spontaneously develop diabetes, and show early pathophysiological changes in diabetic complications. On the other hand, interferon-γ knock out (GKO) mice exhibit high differentiation and activation of Th2 and Th17 cells as a result of Th1 cell inhibition. In this study, Ins2Akita IFN-γ-deficient (Akita-GKO) mice were established by crossbreeding Akita mice with GKO mice, and Th17-mediated immune responses on DR were investigated. Blood glucose levels (BGL) of Akita mice and Akita-GKO mice were significantly higher than those of age-matched wild type (WT) or GKO mice, and there was no significant difference in BGL between Akita and Akita-GKO mice. Relative mRNA expression of ROR-γt that is a transcriptional factor of Th17 cells but not GATA-3 that is for Th2 cells was significantly upregulated only in Akita-GKO mice compared with WT mice, and the proportions of IL-17 and IL-22-producing splenic CD4+ cells were significantly higher in Akita-GKO mice than in wild type (WT), Akita, or GKO mice. In the retina, mRNA expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) were increased in Akita-GKO mice more than in Akita or GKO mice, and statistically significant differences were observed between Akita-GKO mice and WT mice. Leukostasis in retinal vessels and ocular level of VEGF protein increased significantly in Akita-GKO mice compared with the other groups. Edematous change in the retinal surface layer, retinal exudative lesions depicted as areas of hyperfluorescence in fluorescein angiography (FA), and vascular basement membrane thickening in all layers of the retina were also observed in Akita-GKO mice at 9-week-old but not in age-matched Akita or GKO mice. These results suggested that Th17 cell-mediated immune responses might be involved in promotion of functional and morphological changes in the retina of mice spontaneously developing diabetes.
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Affiliation(s)
- Manzo Taguchi
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Hideaki Someya
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Makoto Inada
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Yoshiaki Nishio
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Kei Takayama
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Kozo Harimoto
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Yoko Karasawa
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Masataka Ito
- Department of Developmental Anatomy, NDMC, Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan
| | - Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College (NDMC), Namiki 3-2, Tokorozawa, Saitama, 359-0042, Japan.
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16
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Wang H, Lou H, Li Y, Ji F, Chen W, Lu Q, Xu G. Elevated vitreous Lipocalin-2 levels of patients with proliferative diabetic retinopathy. BMC Ophthalmol 2020; 20:260. [PMID: 32605546 PMCID: PMC7329527 DOI: 10.1186/s12886-020-01462-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 05/01/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Lipocalin-2 (LCN2) is a novel adipokine with potential roles in obesity, insulin resistance, and inflammation. This study aims to assess the concentrations of LCN2 and vascular endothelial growth factor (VEGF) expressed in the vitreous humors of patients with proliferative diabetic retinopathy (PDR). METHODS The concentrations of LCN2 and VEGF were measured from the vitreous of 67 patients undergoing vitrectomy (20 controls and 47 PDR) via enzyme-linked immunosorbent assay (ELISA). Patients with non-ocular pathology that could elevate the LCN2 level in the vitreous were excluded. PDR activity and a history of panretinal photocoagulation were used for further grouping analysis. RESULTS The vitreous concentration of LCN2 was statistically significantly higher in the PDR group compared to the control group (63,522 (30,009) pg/ml versus 1663 (1191) pg/ml, respectively; P < 0.001). VEGF level was also significantly higher in the PDR group than in the control group (1038 (1326) pg/ml versus 9 pg/ml, respectively; P < 0.001). The mean vitreous LCN2 and VEGF levels in active PDR patients were significantly higher than that of the inactive PDR patients. The mean LCN2 concentration in vitreous humor was significantly lower in the 28 PDR patients with a history of complete PRP (37,304 (16,651) pg/mL) in comparison with 19 PDR patients without preperformed panretinal photocoagulation or with preperformed incomplete panretinal photocoagulation (79,796 (24,391) pg/mL). A significant correlation between the vitreous LCN2 level and VEGF level was found in patients with PDR (R = 0.34; P = 0.019). CONCLUSIONS This report shows a significant increase of LCN2 in the vitreous fluid of patients with PDR and present a significant correlation between LCN2 and VEGF, suggesting LCN2 might be involved in the pathogenesis of PDR.
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Affiliation(s)
- Hui Wang
- Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China
- Department of Ophthalmology, The Second People's Hospital of Hefei, Hefei, 230011, China
| | - Hui Lou
- Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China
| | - Yongrong Li
- Department of Ophthalmology, The Second People's Hospital of Hefei, Hefei, 230011, China
| | - Fengtao Ji
- Department of Ophthalmology, The Second People's Hospital of Hefei, Hefei, 230011, China
| | - Wei Chen
- Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Qianyi Lu
- Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - Guoxu Xu
- Department of Ophthalmology, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China.
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17
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Shen Y, Cao H, Chen F, Suo Y, Wang N, Xu X. A cross-sectional study of vitreous and serum high mobility group box-1 levels in proliferative diabetic retinopathy. Acta Ophthalmol 2020; 98:e212-e216. [PMID: 31421026 PMCID: PMC7078975 DOI: 10.1111/aos.14228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 07/23/2019] [Indexed: 01/14/2023]
Abstract
PURPOSE We determined vitreous and serum levels of high mobility group box-1 (HMGB-1) in patients with proliferative diabetic retinopathy (PDR) and elucidate their relationship with receptor for advanced glycation end products (RAGE), vascular endothelial growth factor (VEGF) and interleukin-1β (IL-1β). METHODS In this cross-sectional study, patients with PDR who underwent vitrectomy were enrolled, and the control group included non-diabetic eyes. Vitreous and serum samples were analysed for HMGB-1, RAGE, VEGF and IL-1β by ELISA. We investigated the correlation between serum and vitreous levels of each cytokine, and we analysed the influence of intravitreal anti-VEGF treatment prior to vitrectomy on the cytokine levels in PDR. RESULTS Of 78 eyes of 78 patients enrolled consecutively, there were 32 PDR eyes and 46 control eyes. The serum levels were higher in diabetic than in non-diabetic subjects for HMGB-1, RAGE, VEGF and IL-1β (all p < 0.001), respectively. Similarly, the vitreous levels were higher in diabetic than in non-diabetic subjects for HMGB-1 (p < 0.001), RAGE (p = 0.001), VEGF (p < 0.001) and IL-1β (p < 0.001), respectively. We found a positive correlation between serum and vitreous levels of HMGB-1 in patient with PDR (p = 0.047, R = 0.353). There was a negative correlation between serum and vitreous levels of VEGF in patient with PDR (p = 0.001, R = -0.546). For the subgroup analysis, we detected that the vitreous levels of RAGE were significantly lower in patients who underwent anti-VEGF injection prior to vitrectomy than those who did not (p < 0.001). CONCLUSIONS Our findings suggest that HMGB-1 is involved in PDR disorders, and it may be a novel therapeutic target to inhibit progression of PDR.
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Affiliation(s)
- Yinchen Shen
- Department of OphthalmologyShanghai General HospitalSchool of medicineShanghai Jiaotong UniversityShanghaiChina
| | - Hui Cao
- Department of OphthalmologyShanghai General HospitalSchool of medicineShanghai Jiaotong UniversityShanghaiChina
| | - Feng'e Chen
- Department of OphthalmologyShanghai General HospitalSchool of medicineShanghai Jiaotong UniversityShanghaiChina
| | - Yan Suo
- Department of OphthalmologyShanghai General HospitalSchool of medicineShanghai Jiaotong UniversityShanghaiChina
| | - Ning Wang
- Department of OphthalmologyShanghai General HospitalSchool of medicineShanghai Jiaotong UniversityShanghaiChina
| | - Xun Xu
- Department of OphthalmologyShanghai General HospitalSchool of medicineShanghai Jiaotong UniversityShanghaiChina
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18
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Xing X, Jiang Y, Wang H, Zhang Y, Niu T, Qu Y, Wang C, Wang H, Liu K. Identification of novel differentially expressed genes in retinas of STZ-induced long-term diabetic rats through RNA sequencing. Mol Genet Genomic Med 2020; 8:e1115. [PMID: 31958216 PMCID: PMC7057111 DOI: 10.1002/mgg3.1115] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/08/2019] [Accepted: 12/20/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The aim of this research was to investigate the retinal transcriptome changes in long-term streptozotocin (STZ)-induced rats' retinas using RNA sequencing (RNA-seq), to explore the molecular mechanisms of diabetic retinopathy (DR), and to identify novel targets for the treatment of DR by comparing the gene expression profile we obtained. METHODS In this study, 6 healthy male SD rats were randomly divided into wild-type (WT) group and streptozotocin (STZ)-induced group, 3 rats each group. After 6 months, 3 normal retina samples and 3 DM retina samples (2 retinas from the same rat were considered as 1 sample) were tested and differentially expressed genes (DEGs) were measured by RNA-seq technology. Then, we did Gene Ontology (GO) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and validated the results of RNA-seq through qRT-PCR. RESULTS A total of 118 DEGs were identified, of which 72 were up-regulated and 46 were down-regulated. The enriched GO terms showed that 3 most significant enrichment terms were binding (molecular function), cell part (cellular component), and biological regulation (biological process). The results of the KEGG pathway analysis revealed a significant enrichment in cell adhesion molecules, PI3K-Akt signaling pathway, and allograft rejection, etc. CONCLUSION: Our research has identified specific DEGs and also speculated their potential functions, which will provide novel targets to explore the molecular mechanisms of DR.
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Affiliation(s)
- Xindan Xing
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yan Jiang
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hanying Wang
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuan Zhang
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Tian Niu
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yuan Qu
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Chingyi Wang
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Haiyan Wang
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Kun Liu
- Department of OphthalmologyShanghai General HospitalNational Clinical Research Center for Eye DiseasesShanghai Key Laboratory of Ocular Fundus DiseasesShanghai Engineering Center for Visual Science and PhotomedicineShanghai Engineering Center for Precise Diagnosis and Treatment of Eye DiseasesShanghai Jiao Tong University School of MedicineShanghaiChina
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Yu C, Yang K, Meng X, Cao B, Wang F. Downregulation of Long Noncoding RNA MIAT in the Retina of Diabetic Rats with Tail-vein Injection of Human Umbilical-cord Mesenchymal Stem Cells. Int J Med Sci 2020; 17:591-598. [PMID: 32210708 PMCID: PMC7085208 DOI: 10.7150/ijms.38078] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 01/15/2020] [Indexed: 12/28/2022] Open
Abstract
Diabetic retinopathy (DR) is the common and important cause for visual impairment and blindness in working-aged people. Microangiopathy and inflammatory reactions are the key components of DR. Recently, long non-coding RNA myocardial infarction-associated transcript (MIAT) has emerged as a vital player in regulation for inflammatory processes and microvascular dysfunction. Additionally, cell-based therapy provides a potential option for the treatment of DR. The anti-inflammatory effects and repair therapy of mesenchymal stem cells (MSCs) have been paid more attention. This study investigated the effects of human umbilical-cord mesenchymal stem cells (HUMSCs) injection on diabetic rat model. The results show that the level of MIAT is significantly decreased in the diabetic retina after the injection of HUMSCs. Moreover, HUMSCs can significantly decrease the expression of IL-1β and IL-6 mRNA; alleviate microvascular permeability, and upregulate Occludin expression. Studies have shown that MIAT knockdown could alleviate diabetes-induced inflammation responses and vascular leakage. Furthermore, our findings also showed that the expression of MIAT was positively correlated with the expression of IL-1β and IL-6. These results suggest that MIAT might play important regulatory roles in alleviating inflammatory reactions and microangiopathy inducing by DR after transplantation of HUMSCs.
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Affiliation(s)
- Chuan Yu
- Ophthalmology, Affiliated Hospital of Qingdao University, Qingdao 266500, Shandong Province, China
| | - Kun Yang
- Central Laboratory, Affiliated Hospital of Qingdao University, Qingdao 266500, Shandong Province, China
| | - Xuxia Meng
- Ophthalmology, Affiliated Hospital of Qingdao University, Qingdao 266500, Shandong Province, China
| | - Bowen Cao
- Center for Ophthalmology, Institute for Ophthalmic Research, University of Tuebingen, 72076, Tuebingen, Germany
| | - Fenglei Wang
- Ophthalmology, Affiliated Hospital of Qingdao University, Qingdao 266500, Shandong Province, China
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Liu J, Bhuvanagiri S, Qu X. The protective effects of lycopus lucidus turcz in diabetic retinopathy and its possible mechanisms. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:2900-2908. [PMID: 31307239 DOI: 10.1080/21691401.2019.1640230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The aim of the present study was to investigate the effect of Lycopus lucidus Turcz (LT) on diabetic retinopathy (DR) and its underlying mechanisms. SD rats and human retinal microvascular endothelial cells (HRECs) were applied for establishment DR model. HE and TUNEL staining were used to evaluate the pathological changes and apoptosis of retinal ganglion cells. Additionally, retinal vessels were detected by immunofluorescence staining with CD31 and VEGF. The function of BRB was observed using Evans blue. Moreover, the oxidative stress, inflammation and angiogenesis associated factors were measured respectively. The expression of p38-MAPK/NF-κB signalling proteins were detected by Western blot. The results demonstrated that pathological changes and retinal optic disc cells apoptosis in retinas of diabetic rats, both of which were reduced in the LT-treated group. And LT treatment attenuated the levels of oxidative stress, inflammation and angiogenesis factors. Importantly, the expression levels of p-p38, p-ERK, p-JNK and NF-κB were decreased. After treatment with TNF-α combined with LT, the levels of inflammatory factors were decreased but higher than the negative control. Taken together, the results suggested that LT treatment is of therapeutic benefit by ameliorating oxidative stress, inflammation and angiogenesis of DR via p38-MAPK/NF-κB signaling pathway.
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Affiliation(s)
- Jinlu Liu
- a Department of Ophthalmology, The Fourth Affiliated Hospital of China Medical University , Shenyang , China
| | - Sai Bhuvanagiri
- b Queens Hospital Center, Mt. Sinai, Icahn School of Medicine , Jamaica , NY , USA
| | - Xiaohan Qu
- c Department of Thoracic Surgery, The First Hospital of China Medical University , Shenyang , China
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Anti-Inflammatory and Anticancer Properties of Bioactive Compounds from Sesamum indicum L.-A Review. Molecules 2019; 24:molecules24244426. [PMID: 31817084 PMCID: PMC6943436 DOI: 10.3390/molecules24244426] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Revised: 11/28/2019] [Accepted: 12/03/2019] [Indexed: 12/24/2022] Open
Abstract
The use of foodstuff as natural medicines has already been established through studies demonstrating the pharmacological activities that they exhibit. Knowing the nutritional and pharmacological significance of foods enables the understanding of their role against several diseases. Among the foods that can potentially be considered as medicine, is sesame or Sesamum indicum L., which is part of the Pedaliaceae family and is composed of its lignans such as sesamin, sesamol, sesaminol and sesamolin. Its lignans have been widely studied and are known to possess antiaging, anticancer, antidiabetes, anti-inflammatory and antioxidant properties. Modern chronic diseases, which can transform into clinical diseases, are potential targets of these lignans. The prime example of chronic diseases is rheumatic inflammatory diseases, which affect the support structures and the organs of the body and can also develop into malignancies. In line with this, studies emphasizing the anti-inflammatory and anticancer activities of sesame have been discussed in this review.
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Wang J, Gao X, Liu J, Wang J, Zhang Y, Zhang T, Zhang H. Effect of intravitreal conbercept treatment on the expression of Long Noncoding RNAs and mRNAs in Proliferative Diabetic Retinopathy Patients. Acta Ophthalmol 2019; 97:e902-e912. [PMID: 30900812 DOI: 10.1111/aos.14083] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Accepted: 02/16/2019] [Indexed: 01/03/2023]
Abstract
PURPOSE To evaluate the effect of conbercept on the expression of long noncoding RNAs (lncRNAs) and mRNAs in the fibrovascular membranes of proliferative diabetic retinopathy (PDR) patients. METHODS Twenty patients, diagnosed with PDR, who underwent pars plana vitrectomy (PPV), were recruited for this study. Ten patients were treated for PPV alone (Control Group), and the others received conbercept injections before PPV (Treated Group). The fibrovascular membranes were harvested during surgery. Expression of lncRNAs and mRNAs in the membranes was tested using lncRNA Arrays. Bioinformatics analyses were performed to identify the related biological modules and pathways of the differentially expressed genes. A lncRNA/mRNA coexpression network was built to identify the correlations between lncRNAs and mRNAs. Real-time PCR was conducted to verify the microarray results. RESULTS We identified 427 differentially expressed lncRNAs, of which 263 were upregulated and 164 were downregulated. Gene ontology (GO) analysis indicated that these lncRNAs-coexpressed mRNAs targeted various metabolic processes, especially the gluconeogenesis. Kyoto Encyclopaedia of Genes and Genomes (KEGG) results indicated that 16 pathways had significant differences in gene expression, including gluconeogenesis, HIF-1 signalling pathway, NOD-like receptor pathway, etc. The lncRNA/mRNA coexpression network revealed that many differentially expressed lncRNAs were enriched in the HIF-1, TNF-α and NOD-like receptor pathways. LincRNAs were the largest category and further bioinformatics analysis implied that these lincRNAs-coexpressed mRNAs were mainly involved in PDR-related biological processes and pathological pathways. CONCLUSION Conbercept treatment can change the expression profiles of lncRNAs and mRNAs in the fibrovascular membranes of PDR patients. A complete understanding of the relationship between lncRNAs and anti-VEGF drugs may contribute to new therapeutic regimen for PDR.
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Affiliation(s)
- Jiawei Wang
- Eye Center of Shandong University The Second Hospital of Shandong University Jinan People's Republic of China
| | - Xue Gao
- Eye Center of Shandong University The Second Hospital of Shandong University Jinan People's Republic of China
| | - Jing Liu
- Eye Center of Shandong University The Second Hospital of Shandong University Jinan People's Republic of China
| | - Jing Wang
- Eye Center of Shandong University The Second Hospital of Shandong University Jinan People's Republic of China
| | - Yue Zhang
- Department of surgery The Second Hospital of Shandong University Jinan People's Republic of China
| | - Tonghe Zhang
- Department of ophthalmology The second people's Hospital of Jinan 148# Jingyi Road Jinan People's Republic of China
| | - Han Zhang
- Eye Center of Shandong University The Second Hospital of Shandong University Jinan People's Republic of China
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Gonzalez VH, Wang PW, Ruiz CQ. Panretinal Photocoagulation for Diabetic Retinopathy in the RIDE and RISE Trials: Not "1 and Done". Ophthalmology 2019; 128:1448-1457. [PMID: 31668888 DOI: 10.1016/j.ophtha.2019.08.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 08/09/2019] [Accepted: 08/10/2019] [Indexed: 11/28/2022] Open
Abstract
PURPOSE To evaluate panretinal photocoagulation (PRP) treatment and re-treatment patterns in patients with diabetic retinopathy (DR) and diabetic macular edema (DME). DESIGN Post hoc analysis of the phase 3 RIDE (clinicaltrials.gov identifier, NCT00473382) and RISE (clinicaltrials.gov identifier, NCT00473330) clinical trials of ranibizumab for the treatment of DME. PARTICIPANTS Seven hundred fifty-nine patients were randomized for treatment. METHODS Panretinal photocoagulation treatment patterns and clinical experiences were assessed by baseline PRP treatment status. MAIN OUTCOME MEASURES Number and timing of on-study PRP treatment sessions undergone through month 24. Time to new proliferative event (composite end point) was also assessed. RESULTS At baseline, approximately 25% of patients in RIDE and RISE had undergone PRP treatment before enrollment (22.2%, 24.4%, and 25.4% of patients in the sham, ranibizumab 0.3 mg, and ranibizumab 0.5 mg arms, respectively). In patients without prior PRP at baseline (n = 577), 9.5% of sham-treated patients underwent 1 or more PRP treatments through month 24, compared with 1.1% and 1.6% of patients receiving ranibizumab 0.3 mg and ranibizumab 0.5 mg, respectively (P < 0.001 for both ranibizumab arms vs. sham). In patients with prior PRP at baseline (n = 182), 19.3% of sham-treated patients underwent 1 or more PRP treatments through month 24. No ranibizumab-treated patients with prior PRP at baseline required additional on-study PRP through month 24 (P < 0.001 for both ranibizumab arms vs. sham). Ranibizumab treatment also significantly reduced clinical DR progression among patients who underwent prior PRP. By month 24 in patients with prior PRP at baseline, the probability of experiencing a new proliferative event was 10.3% and 9.9% in patients receiving ranibizumab 0.3 mg and ranibizumab 0.5 mg treatment, respectively, compared with 39.4% in sham-treated patients (P < 0.0001). Overall, sham-treated patients, including those patients who were PRP naïve at baseline who went on to require PRP, experienced more clinical events than ranibizumab-treated patients. CONCLUSIONS In RIDE and RISE, PRP treatment was not a "1 and done" procedure, with on-study PRP re-treatment occurring in patients both with and without prior PRP treatment at baseline. Ranibizumab treatment reduced on-study PRP treatment and DR progression regardless of prior PRP treatment status at baseline.
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Affiliation(s)
| | - Pin-Wen Wang
- Genentech, Inc., South San Francisco, California
| | - Carlos Quezada Ruiz
- Genentech, Inc., South San Francisco, California; Clinica de Ojos Garza Viejo, San Pedro Garza Garcia, NL, Mexico
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24
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Wubben TJ, Johnson MW. Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Retinopathy: Consequences of Inadvertent Treatment Interruptions. Am J Ophthalmol 2019; 204:13-18. [PMID: 30878488 DOI: 10.1016/j.ajo.2019.03.005] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 02/03/2019] [Accepted: 03/06/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE To illustrate that patients with diabetic retinopathy who are treated exclusively with anti-vascular endothelial growth factor (VEGF) therapy and have an interruption in treatment may experience marked progression of disease with potentially devastating visual consequences. DESIGN Retrospective, multicenter, case series. METHODS Retrospective review of patients treated exclusively with anti-VEGF therapy for proliferative diabetic retinopathy (PDR) or nonproliferative diabetic retinopathy (NPDR), with or without diabetic macular edema (DME), and temporarily lost to follow-up. Baseline disease characteristics, cause and duration of the treatment interruption, and resulting disease progression, complications, and outcomes were assessed. RESULTS Thirteen eyes of 12 patients with type 2 diabetes were identified. The mean age was 57 ± 10 years, and 50% were women. Anti-VEGF therapy was indicated for PDR with DME in 7 (54%) eyes, PDR without DME in 3 (23%) eyes, and moderate to severe NPDR with DME in 3 (23%) eyes. Eight eyes had visual acuity (VA) of 20/80 or better before treatment interruption. The median duration of treatment hiatus was 12 months. Reasons for treatment interruption included intercurrent illness (31%), noncompliance (31%), and financial issues (15%). Complications upon follow-up included vitreous hemorrhage (9 eyes), neovascular glaucoma (5 eyes), and traction retinal detachment (4 eyes). Despite treatment of these complications, 77% of eyes lost ≥3 lines of VA, with 46% of eyes having a final VA of hand motion or worse. CONCLUSIONS Diabetic patients are subject to significant lapses in follow-up because of illness, financial hardship, or noncompliance. In patients with diabetic retinopathy, especially PDR, who are managed with anti-VEGF therapy alone, unintentional treatment interruptions can result in irreversible blindness.
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Affiliation(s)
- Thomas J Wubben
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Mark W Johnson
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.
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Zhang T, Ouyang H, Mei X, Lu B, Yu Z, Chen K, Wang Z, Ji L. Erianin alleviates diabetic retinopathy by reducing retinal inflammation initiated by microglial cells via inhibiting hyperglycemia-mediated ERK1/2-NF-κB signaling pathway. FASEB J 2019; 33:11776-11790. [PMID: 31365278 DOI: 10.1096/fj.201802614rrr] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Blood-retinal barrier (BRB) breakdown is a typical event in the early stage of diabetic retinopathy (DR). This study aims to elucidate the protection of erianin, a natural compound isolated from Dendrobium chrysotoxum Lindl, against DR development. Erianin alleviated BRB breakdown and rescued the reduced claudin1 and occludin expression in retinas from streptozotocin-induced diabetic mice. Erianin reduced microglial activation, ERK1/2 phosphorylation, NF-κB transcriptional activation, and the elevated TNF-α expression both in vitro and in vivo. ERK1/2 inhibitor U0126 abrogated NF-κB activation in d-glucose-treated BV2 cells. Erianin reduced cellular glucose uptake, and molecular docking analysis indicated the potential interaction of erianin with glucose transporter (GLUT)1. GLUT1 inhibitor (STF31) reduced the activation of the ERK1/2-NF-κB signaling pathway. Coculture with d-glucose-stimulated microglial BV2 cells and with TNF-α stimulation both induced inner BRB and outer BRB damage in human retinal endothelial cells and APRE19 cells, but erianin improved all these damages. In summary, erianin attenuated BRB breakdown during DR development by inhibiting microglia-triggered retinal inflammation via reducing cellular glucose uptake and abrogating the subsequent activation of the downstream ERK1/2-NF-κB pathway. Moreover, erianin also alleviated BRB damage induced by TNF-α released from the activated microglia.-Zhang, T., Ouyang, H., Mei, X., Lu, B., Yu, Z., Chen, K., Wang, Z., Ji, L. Erianin alleviates diabetic retinopathy by reducing retinal inflammation initiated by microglial cells via inhibiting hyperglycemia-mediated ERK1/2-NF-κB signaling pathway.
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Affiliation(s)
- Tianyu Zhang
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hao Ouyang
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiyu Mei
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Bin Lu
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zengyang Yu
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kaixian Chen
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengtao Wang
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Ji
- The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines-The State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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26
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Zhang D, Li M. Puerarin prevents cataract development and progression in diabetic rats through Nrf2/HO‑1 signaling. Mol Med Rep 2019; 20:1017-1024. [PMID: 31173182 PMCID: PMC6625395 DOI: 10.3892/mmr.2019.10320] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Accepted: 04/17/2019] [Indexed: 12/30/2022] Open
Abstract
Puerarin is the major bioactive ingredient isolated from the dry root of Pueraria lobata, a plant used in traditional Chinese medicine. Puerarin has been used to treat diabetes and cataracts in China; however, its underlying mechanism of action remains unclear. The aim of the present study was to investigate the effectiveness and mechanism of puerarin in preventing cataracts in diabetic rats. Diabetes was induced by streptozocin (STZ) administration and rats were intraperitoneally injected with puerarin (25, 50 and 100 mg/kg). Blood glucose levels and cataract development were examined in the different experimental groups. In addition, the expression levels of markers associated with oxidative stress, including nuclear factor erythroid 2 like 2 (Nrf2) and heme oxygenase‑1 (HO‑1), were analyzed. The present results suggested that treatment with puerarin at 25, 50 and 100 mg/kg significantly reduced blood glucose levels and the incidence of cataract in STZ‑induced diabetic rats. Additionally, puerarin treatment reduced oxidative stress, restoring the levels of malondialdehyde and glutathione, and the activity of glutathione peroxidase. Furthermore, puerarin administration decreased the expression levels of retinal vascular endothelial growth factor and interleukin‑1β and increased the mRNA expression levels of Nrf2 and HO‑1, thus inhibiting oxidative stress. The present findings suggested that puerarin had hypoglycemic effects and that it prevented cataract development and progression in diabetic rats by reducing oxidative stress through the Nrf2/HO‑1 signaling pathway.
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Affiliation(s)
- Duzhen Zhang
- Department of Ophthalmology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
| | - Man Li
- Department of Ophthalmology, Linyi Central Hospital, Linyi, Shandong 276400, P.R. China
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Frith E, Loprinzi PD. Physical Activity, Muscle-Strengthening Activities, and Systemic Inflammation Among Retinopathy Patients. Diabetes Spectr 2019; 32:16-20. [PMID: 30853760 PMCID: PMC6380237 DOI: 10.2337/ds18-0002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE We evaluated the specific association between muscle-strengthening activity (MSA) and accelerometer-assessed physical activity on systemic inflammation among retinopathy patients in the United States. METHODS Data from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) were used to identify 157 retinopathy patients between 40 and 85 years of age with complete data on select study variables. MSA was assessed via self-report. Participation in moderate-to-vigorous physical activity (MVPA) was determined from objective accelerometer data. Systemic inflammation was assessed using C-reactive protein (CRP), which was quantified using latex-enhanced nephelometry. Nonproliferative retinopathy was determined using Early Treatment Diabetic Retinopathy Study grading criteria, as well as objective retinal imaging assessments using the Canon Non-Mydriatic Retinal Camera CR6-45NM. Individuals were excluded if they had been diagnosed with coronary artery disease, congestive heart failure, heart attack, or stroke. RESULTS MVPA (β = -0.004, 95% CI -0.007 to -0.001, P = 0.006) but not MSA (β = -0.0001, 95% CI -0.002 to 0.001, P = 0.86) was associated with lower CRP levels. Additionally, for a more substantive 30 minutes/day increase in MVPA, there was a corresponding 0.12 mg/dL decrease in CRP. CONCLUSION In this nationally representative sample of adults, only individuals who engaged in higher levels of MVPA had lower CRP levels, which is indicative of reduced systemic inflammation. MSA was not associated with systemic inflammation among this cohort. Our findings suggest that MVPA is inversely associated with systemic inflammation among retinopathy patients, which is noteworthy because increased systemic inflammation may facilitate retinopathic severity.
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Affiliation(s)
- Emily Frith
- Physical Activity Epidemiology and Exercise Psychology Laboratories, Department of Health, Exercise Science and Recreation Management, University of Mississippi, University, MS
| | - Paul D Loprinzi
- Physical Activity Epidemiology and Exercise Psychology Laboratories, Department of Health, Exercise Science and Recreation Management, University of Mississippi, University, MS
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Baicalin protects human retinal pigment epithelial cell lines against high glucose-induced cell injury by up-regulation of microRNA-145. Exp Mol Pathol 2019; 106:123-130. [PMID: 30625293 DOI: 10.1016/j.yexmp.2019.01.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 01/03/2019] [Accepted: 01/04/2019] [Indexed: 12/28/2022]
Abstract
BACKGROUND Diabetic retinopathy (DR) is a common complication of diabetes mellitus, which is a major reason of blindness. Baicalin (BAI) is a flavonoid extracted from Scutellaria baicalensis, whose pharmacological characterizes have been widely reported in various diseases. However, it remains unclear the effect of BAI on DR. The study aimed to confirm the protective effect of BAI on DR. METHODS ARPE-19 cells and HRMECs were exposed to the high glucose (HG) environment to construct a cell injury model. After treatment with HG and BAI, cell viability, apoptosis, inflammatory cytokines and ROS generations were determined in ARPE-19 cells and HRMECs. Subsequently, microRNA-145 (miR-145) inhibitor and its negative control were transfected into ARPE-19 cells, and the regulatory effects on HG-and BAI-co-treated cells were detected. NF-κB and p38MAPK signaling pathways were finally examined to state the underling mechanisms. RESULTS HG treatment significantly induced ARPE-19 cells and HRMECs injury in vitro. BAI significantly promoted cell proliferation, reduced apoptosis, as well as inhibited the release of IL-1β, IL-6, IL-8 and ROS level in HG-injured ARPE-19 cells and HRMECs. Additionally, the expression level of miR-145 was up-regulated in HG-and BAI-co-treated cells. More importantly, miR-145 inhibition reversed the protective effect of BAI on HG-injured ARPE-19 cells. Besides, we observed that BAI inhibited the activations of NF-κB and p38MAPK pathways by up-regulating miR-145. CONCLUSIONS Results demonstrated that BAI exhibited the protective effect against HG-induced cell injury by up-regulation of miR-145.
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Zhang T, Mei X, Ouyang H, Lu B, Yu Z, Wang Z, Ji L. Natural flavonoid galangin alleviates microglia-trigged blood-retinal barrier dysfunction during the development of diabetic retinopathy. J Nutr Biochem 2018; 65:1-14. [PMID: 30597356 DOI: 10.1016/j.jnutbio.2018.11.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 10/12/2018] [Accepted: 11/27/2018] [Indexed: 12/15/2022]
Abstract
Hyperglycemia-induced blood-retinal barrier (BRB) breakdown is an early and typical event of diabetic retinopathy (DR). Although chronic inflammation plays an important role in DR development, the concrete mechanism remains unclear. This study aims to investigate the role of microglia cells-triggered inflammatory response in hyperglycemia-induced BRB breakdown and the amelioration of galangin, a natural flavonoid. Galangin alleviated BRB breakdown in streptozotocin-induced diabetic mice. D-glucose (25 mM)-stimulated microglia BV2 cells induced BRB damage in vitro, but galangin reversed this injury. Galangin decreased the activation of microglia cells, ROS formation, the phosphorylation of extracellular-signal-regulated protein kinase (ERK)1/2, the transcriptional activation of nuclear factor κB (NFκB) and early growth response (Egr1) protein, and the elevated expression of tumor necrosis factor (TNF)-α both in vitro and in vivo. ERK1/2 inhibitor U0126 reduced ROS formation, the activation of NFκB and Egr1, and the elevated TNFα expression in D-glucose-stimulated BV2 cells. N-acetylcysteine, a well-known antioxidant, abrogated D-glucose-induced NFκB and Egr1 activation in BV2 cells. Galangin also reversed the decreased expression of claudin1 and occludin, and the increased BRB injury and ROS formation in TNFα-treated human retinal endothelial cells (HRECs) and ARPE19 cells. Galangin induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in both HRECs and ARPE19 cells. Moreover, the galangin-provided attenuation on BRB breakdown was diminished in Nrf2 knockout diabetic mice. In conclusion, galangin alleviated DR by attenuating BRB damage via inhibiting microglia-triggered inflammation and further reversing TNFα-induced BRB dysfunction by abrogating oxidative stress injury via activating Nrf2.
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Affiliation(s)
- Tianyu Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiyu Mei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hao Ouyang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zengyang Yu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengtao Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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30
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Sodi A, Passerini I, Bacherini D, Boni L, Palchetti S, Murro V, Caporossi O, Mucciolo DP, Franco F, Vannozzi L, Torricelli F, Pelo E, Rizzo S, Virgili G. CFH Y402H polymorphism in Italian patients with age-related macular degeneration, retinitis pigmentosa, and Stargardt disease. Ophthalmic Genet 2018; 39:699-705. [PMID: 30285522 DOI: 10.1080/13816810.2018.1525753] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
BACKGROUND The complement system has been implicated in the pathogenesis of age-related macular degeneration (AMD) and the CFH Y402H polymorphism has been suggested as a major risk factor for AMD. Recent evidences supported the role of inflammation in the pathogenesis of some retinal dystrophies. Aim of this study was to evaluate the prevalence of CFHY402H polymorphism in a group of Italian patients affected by atrophic AMD, Stargardt disease (STGD), or retinitis pigmentosa(RP). MATERIALS AND METHODS Our case-control association study included 116 patients with atrophic AMD, 77 with RP, 86 with STGD, and 100 healthy controls. All the patients were evaluated by a standard ophthalmologic examination and OCT. ERG was performed on STGD and RP patients. All the subjects underwent a blood drawing for genetic testing and the CFHY402H polymorphism was genotyped with the TaqMan real-time polymerase chain reaction single nucleotide polymorphism assay. RESULTS The prevalence of the risk genotype C/C was higher in the AMD group than in controls (p < 0.001). The risk allele C was more frequent in the AMD group than in controls (p < 0.001). The prevalence of the risk genotype was higher in the RP patients than in controls (p < 0.001) and similarly the risk allele C was more frequent in the RP group (p = 0.008). The CFHY402H genotype distribution was not different between patients with STGD and the controls, for the biallelic (p = 0.531) and for the monoallelic (p = 0.318) evaluation. CONCLUSIONS In our series of Italian patients, the CFHY402H genotype is associated with atrophic AMD and RP, but not with STGD. This result may support the hypothesis of a complement system dysregulation in the pathogenesis of AMD and RP.
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Affiliation(s)
- Andrea Sodi
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Ilaria Passerini
- b Department of Genetic Diagnosis , Careggi Teaching Hospital , Florence , Italy
| | - Daniela Bacherini
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Luca Boni
- c Clinical Trials Coordinating Center , Careggi Teaching Hospital , Florence , Italy
| | - Simona Palchetti
- b Department of Genetic Diagnosis , Careggi Teaching Hospital , Florence , Italy
| | - Vittoria Murro
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Orsola Caporossi
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Dario Pasquale Mucciolo
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Fabrizio Franco
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Lorenzo Vannozzi
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Francesca Torricelli
- b Department of Genetic Diagnosis , Careggi Teaching Hospital , Florence , Italy
| | - Elisabetta Pelo
- b Department of Genetic Diagnosis , Careggi Teaching Hospital , Florence , Italy
| | - Stanislao Rizzo
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
| | - Gianni Virgili
- a Department of Surgery and Translational Medicine, Eye Clinic , Careggi Teaching Hospital, University of Florence , Florence , Italy
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31
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Lee DH, Lee J, Jeon J, Kim KJ, Yun JH, Jeong HS, Lee EH, Koh YJ, Cho CH. Oleanolic Acids Inhibit Vascular Endothelial Growth Factor Receptor 2 Signaling in Endothelial Cells: Implication for Anti-Angiogenic Therapy. Mol Cells 2018; 41:771-780. [PMID: 30037214 PMCID: PMC6125422 DOI: 10.14348/molcells.2018.0207] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/14/2018] [Accepted: 06/20/2018] [Indexed: 12/21/2022] Open
Abstract
Angiogenesis must be precisely controlled because uncontrolled angiogenesis is involved in aggravation of disease symptoms. Vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR-2) signaling is a key pathway leading to angiogenic responses in vascular endothelial cells (ECs). Therefore, targeting VEGF/VEGFR-2 signaling may be effective at modulating angiogenesis to alleviate various disease symptoms. Oleanolic acid was verified as a VEGFR-2 binding chemical from anticancer herbs with similar binding affinity as a reference drug in the Protein Data Bank (PDB) entry 3CJG of model A coordination. Oleanolic acid effectively inhibited VEGF-induced VEGFR-2 activation and angiogenesis in HU-VECs without cytotoxicity. We also verified that oleanolic acid inhibits in vivo angiogenesis during the development and the course of the retinopathy of prematurity (ROP) model in the mouse retina. Taken together, our results suggest a potential therapeutic benefit of oleanolic acid for inhibiting angiogenesis in proangiogenic diseases, including retinopathy.
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Affiliation(s)
- Da-Hye Lee
- Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080,
Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080,
Korea
| | - Jungsul Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141,
Korea
- Cellex Life Science Inc., Daejeon 34051,
Korea
| | - Jongwook Jeon
- The Korean Research Institute of Science, Technology and Civilization, Chonbuk National University, Jeonju 54896,
Korea
| | - Kyung-Jin Kim
- Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080,
Korea
| | - Jang-Hyuk Yun
- Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080,
Korea
| | - Han-Seok Jeong
- Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080,
Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080,
Korea
| | - Eun Hui Lee
- Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 06591,
Korea
| | - Young Jun Koh
- Department of Pathology, College of Korean Medicine, Dongguk University, Goyang 10326,
Korea
| | - Chung-Hyun Cho
- Vascular Microenvironment Laboratory, Department of Pharmacology and Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 03080,
Korea
- Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080,
Korea
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32
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Akbari M, Ostadmohammadi V, Tabrizi R, Mobini M, Lankarani KB, Moosazadeh M, Heydari ST, Chamani M, Kolahdooz F, Asemi Z. The effects of alpha-lipoic acid supplementation on inflammatory markers among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. Nutr Metab (Lond) 2018; 15:39. [PMID: 29930690 PMCID: PMC5989440 DOI: 10.1186/s12986-018-0274-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/01/2018] [Indexed: 02/08/2023] Open
Abstract
Objective This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of alpha-lipoic acid (ALA) supplementation on the inflammatory markers among patients with metabolic syndrome (MetS) and related disorders. Methods We searched the following databases until November 2017: PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. Three reviewers independently assessed study eligibility, extracted data, and evaluated risk of bias of included primary studies. Statistical heterogeneity was assessed using Cochran's Q test and I-square (I2) statistic. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as the summary effect size. Results Eighteen trials out of 912 potential citations were found to be eligible for our meta-analysis. The findings indicated that ALA supplementation significantly decreased C-reactive protein (CRP) (SMD = - 1.52; 95% CI, - 2.25, - 0.80; P < 0.001), interlokin-6 (IL-6) (SMD = - 1.96; 95% CI, - 2.60, - 1.32; P < 0.001), and tumor necrosis factor alpha levels (TNF-α) (SMD = - 2.62; 95% CI, - 3.70, - 1.55; P < 0.001) in patients diagnosed with metabolic diseases. Conclusion In summary, the current meta-analysis demonstrated the promising impact of ALA administration on decreasing inflammatory markers such as CRP, IL-6 and TNF-α among patients with MetS and related disorders.
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Affiliation(s)
- Maryam Akbari
- 1Health Policy Research Center, Institute of Health, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahidreza Ostadmohammadi
- 2Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R Iran
| | - Reza Tabrizi
- 1Health Policy Research Center, Institute of Health, Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Moein Mobini
- 3Kinesiology Department, University of Calgary, Calgary, AB Canada
| | - Kamran B Lankarani
- 4Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahmood Moosazadeh
- 5Health Science Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed Taghi Heydari
- 4Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Chamani
- 6Department of Gynecology and Obstetrics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fariba Kolahdooz
- 7Indigenous and Global Health Research, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Zatollah Asemi
- 2Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, I.R Iran
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Farnoodian M, Sorenson CM, Sheibani N. Negative Regulators of Angiogenesis, Ocular Vascular Homeostasis, and Pathogenesis and Treatment of Exudative AMD. J Ophthalmic Vis Res 2018; 13:470-486. [PMID: 30479719 PMCID: PMC6210860 DOI: 10.4103/jovr.jovr_67_18] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels from pre-existing capillaries, is very tightly regulated and normally does not occur except during developmental and reparative processes. This tight regulation is maintained by a balanced production of positive and negative regulators, and alterations under pathological conditions such as retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration can lead to growth of new and abnormal blood vessels. Although the role of proangiogenic factors such as vascular endothelial growth factor has been extensively studied, little is known about the roles of negative regulators of angiogenesis in the pathogenesis of these diseases. Here, we will discuss the role of thrombospondin-1 (TSP1), one of the first known endogenous inhibitors of angiogenesis, in ocular vascular homeostasis, and how its alterations may contribute to the pathogenesis of age-related macular degeneration and choroidal neovascularization. We will also discuss its potential utility as a therapeutic target for treatment of ocular diseases with a neovascular component.
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Affiliation(s)
- Mitra Farnoodian
- Department of Ophthalmology and Visual Sciences, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA
| | - Christine M Sorenson
- Department of Pediatrics, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA.,McPherson Eye Research Institute, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA
| | - Nader Sheibani
- Department of Ophthalmology and Visual Sciences, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA.,McPherson Eye Research Institute, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA.,Department of Biomedical Engineering, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA.,Department of Cell and Regenerative Biology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA
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34
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Feng S, Yu H, Yu Y, Geng Y, Li D, Yang C, Lv Q, Lu L, Liu T, Li G, Yuan L. Levels of Inflammatory Cytokines IL-1 β, IL-6, IL-8, IL-17A, and TNF- α in Aqueous Humour of Patients with Diabetic Retinopathy. J Diabetes Res 2018; 2018:8546423. [PMID: 29850610 PMCID: PMC5904804 DOI: 10.1155/2018/8546423] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 12/29/2017] [Accepted: 01/24/2018] [Indexed: 02/01/2023] Open
Abstract
Diabetic retinopathy is the leading cause of blindness in working age individuals in developed countries. However, the role of inflammation in the pathogenesis of DR is not completely understood. This is an observational clinical research enrolling 80 type II diabetic patients who had undergone cataract surgeries either with DR or without DR. All cases were further categorized by the proliferative stages of retinal neovascularization and by the lengths of diabetic history. The levels of inflammatory cytokines including IL-1β, IL-6, IL-8, IL-17, and TNF-α in aqueous humour were tested. Results in this study indicated that these cytokine levels were increased in DR patients and might have a synergistic effect on the pathogenesis of this disease. They were also elevated along with the progression of neovascularization, reflecting the severity of DR. The results also suggested that for diabetic patients, the higher these levels are, the sooner retinal complications might appear. In conclusion, the levels of inflammatory cytokines IL-1β, IL-6, IL-8, IL-17A, and TNF-α in aqueous humour may be associated with the pathogenesis, severity, and prognosis of DR.
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Affiliation(s)
- Songfu Feng
- Department of Ophthalmology, ZhuJiang Hospital of Southern Medical University, Guangzhou 510280, China
| | - Honghua Yu
- Department of Ophthalmology, Guangdong Eye Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Ying Yu
- Department of Ophthalmology, ZhuJiang Hospital of Southern Medical University, Guangzhou 510280, China
| | - Yu Geng
- Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical College, Kunming 650031, China
| | - Dongli Li
- Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical College, Kunming 650031, China
| | - Chun Yang
- Gejiu People's Hospital, Gejiu 661000, China
| | - Qingjun Lv
- Gejiu People's Hospital, Gejiu 661000, China
| | - Li Lu
- Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical College, Kunming 650031, China
| | - Ting Liu
- Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical College, Kunming 650031, China
| | - Guodong Li
- The Second People's Hospital of Jiangxi, Nanchang 330000, China
| | - Ling Yuan
- Department of Ophthalmology, The First Affiliated Hospital of Kunming Medical College, Kunming 650031, China
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35
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Negative regulators of angiogenesis: important targets for treatment of exudative AMD. Clin Sci (Lond) 2017; 131:1763-1780. [PMID: 28679845 DOI: 10.1042/cs20170066] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 03/17/2017] [Accepted: 04/03/2017] [Indexed: 12/12/2022]
Abstract
Angiogenesis contributes to the pathogenesis of many diseases including exudative age-related macular degeneration (AMD). It is normally kept in check by a tightly balanced production of pro- and anti-angiogenic factors. The up-regulation of the pro-angiogenic factor, vascular endothelial growth factor (VEGF), is intimately linked to the pathogenesis of exudative AMD, and its antagonism has been effectively targeted for treatment. However, very little is known about potential changes in expression of anti-angiogenic factors and the role they play in choroidal vascular homeostasis and neovascularization associated with AMD. Here, we will discuss the important role of thrombospondins and pigment epithelium-derived factor, two major endogenous inhibitors of angiogenesis, in retinal and choroidal vascular homeostasis and their potential alterations during AMD and choroidal neovascularization (CNV). We will review the cell autonomous function of these proteins in retinal and choroidal vascular cells. We will also discuss the potential targeting of these molecules and use of their mimetic peptides for therapeutic development for exudative AMD.
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36
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Mei XY, Zhou LY, Zhang TY, Lu B, Ji LL. Scutellaria barbata attenuates diabetic retinopathy by preventing retinal inflammation and the decreased expression of tight junction protein. Int J Ophthalmol 2017; 10:870-877. [PMID: 28730076 DOI: 10.18240/ijo.2017.06.07] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 03/13/2017] [Indexed: 01/25/2023] Open
Abstract
AIM To observe the attenuation of ethanol extract of Herba Scutellaria barbata (SE) against diabetic retinopathy (DR) and its engaged mechanism. METHODS C57BL/6J mice were intraperitoneally injected with streptozotocin (STZ, 55 mg/kg) for 5 consecutive days to induce diabetes. The diabetic mice were orally given with SE (100, 200 mg/kg) for 1mo at 1mo after STZ injection. Blood-retinal barrier (BRB) breakdown was detected by using Evans blue permeation assay. Real-time polymerase chain reaction (RT-PCR), Western blot and immunofluorescence staining were used to detect mRNA and protein expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum contents of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. RESULTS SE (100, 200 mg/kg) reversed the breakdown of BRB in STZ-induced diabetic mice. The decreased expression of retinal claudin-1 and claudin-19, which are both tight junction (TJ) proteins, was reversed by SE. SE decreased the increased serum contents and retinal mRNA expression of TNF-α and IL-1β. SE also decreased the increased retinal expression of intercellular cell adhesion molecule-1 (ICAM-1). SE reduced the increased phosphorylation of nuclear factor kappa B (NFκB) p65 and its subsequent nuclear translocation in retinas from STZ-induced diabetic mice. Results of Western blot and retinal immunofluorescence staining of ionized calcium-binding adapter molecule 1 (Iba1) demonstrated that SE abrogated the activation of microglia cells in STZ-induced diabetic mice. CONCLUSION SE attenuates the development of DR by inhibiting retinal inflammation and restoring the decreased expression of TJ proteins including claudin-1 and claudin-19.
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Affiliation(s)
- Xi-Yu Mei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ling-Yu Zhou
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tian-Yu Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li-Li Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Complex Prescription, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Takeuchi M, Sato T, Sakurai Y, Taguchi M, Harimoto K, Karasawa Y, Ito M. Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy. PLoS One 2017; 12:e0178230. [PMID: 28558009 PMCID: PMC5448770 DOI: 10.1371/journal.pone.0178230] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 04/20/2017] [Indexed: 12/13/2022] Open
Abstract
Inflammation is known to be involved in the progression of diabetic retinopathy. We have recently reported that vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα are higher than the respective serum levels in proliferative diabetic retinopathy (PDR) patients, and that vitreous levels of these cytokines are higher in PDR than in other non-inflammatory vitreoretinal diseases or uveitis associated with sarcoidosis. In the present study, we investigated inflammatory cytokines including Th17 cell-related cytokines in aqueous humor samples obtained from eyes with PDR, and analyzed the association between the aqueous humor and vitreous fluid levels of individual cytokines. The study group consisted of 31 consecutive type 2 diabetic patients with PDR who underwent cataract surgery and vitrectomy for vitreous hemorrhage and/or tractional retinal detachment. Undiluted aqueous humor was collected during cataract surgery, and then vitreous fluid was obtained using a 25G vitreous cutter inserted into the mid-vitreous cavity at the beginning of vitrectomy. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα levels in the aqueous humor and vitreous fluid were measured using a beads-array system. Although IL-17A was detected in the aqueous humor of eyes with PDR and the level correlated with IL-17A level in the vitreous fluid, both percent detectable and level of IL-17A in the aqueous humor were significantly lower than those in the vitreous fluid. Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFα levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFα level. The present study demonstrated that IL-17A level and detectable rate in the aqueous humor of patients with PDR are markedly lower than those in the vitreous fluid and aqueous IL-17A does not correlate with vitreous levels of other cytokines, and hence should not be used as a surrogate for IL-17A in the vitreous fluid.
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Affiliation(s)
- Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
- * E-mail:
| | - Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Yutaka Sakurai
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Manzo Taguchi
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Kozo Harimoto
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Yoko Karasawa
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Saitama, Japan
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Zhang LQ, Cui H, Wang L, Fang X, Su S. Role of microRNA-29a in the development of diabetic retinopathy by targeting AGT gene in a rat model. Exp Mol Pathol 2017; 102:296-302. [PMID: 28189547 DOI: 10.1016/j.yexmp.2017.02.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/05/2017] [Accepted: 02/08/2017] [Indexed: 12/31/2022]
Abstract
OBJECTIVES This study intends to explore the role of microRNA-29a (miRNA-29a) in the development of diabetic retinopathy by targeting AGT gene in a rat model. METHODS Fifty-six DR rat models were established and divided into 7 groups (with 8 rats in each group): the model group, the miRNA-29a group, the miRNA-29a knockdown group, the negative control (NC) group, the AGT group, the miRNA-29a+AGT group, and the miRNA-29a knockdown+AGT group respectively, while 8 normal rats were selected as the normal group. The qRT-PCR was used to detect the expression of miRNA-29a and AGT mRNA. The AGT protein expression was measured using Western blotting. The ADPase histochemical staining was applied to detect retinal neo-vascular morphology. The number of retinal vascular endothelial cells was counted by H&E staining. RESULTS MiRNA-29a and AGT mRNA expressions were negatively correlated. Compared with rats in the normal group, the miRNA-29a expression in DR rats of each group decreased, but the AGT mRNA and protein expression increased; the vascular distribution was in disorder, and the new retinal vessels, vascular density, and endothelial nuclei all increased. Compared with the model group, miRNA-29a increased, and the AGT mRNA and protein expression decreased in the miRNA-29a group; additionally, the vascular density, tortuosity, and endothelial cell nuclei significantly decreased. The opposite trend was found in the miRNA-29a knockdown group, the miRNA-29a knockdown+AGT group, and the AGT group, particularly in the miRNA-29a knockdown+AGT group. CONCLUSION Overexpression of miRNA-29a could down-regulate AGT expression, thereby preventing the development of DR in a rat model.
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Affiliation(s)
- Li-Qiong Zhang
- Department of Ophthalmology, First Affiliated Hospital, Harbin Medical University, Harbin 150001, PR China.
| | - Hao Cui
- Department of Ophthalmology, First Affiliated Hospital, Harbin Medical University, Harbin 150001, PR China
| | - Lin Wang
- Department of Ophthalmology, First Affiliated Hospital, Harbin Medical University, Harbin 150001, PR China
| | - Xu Fang
- Department of Ophthalmology, First Affiliated Hospital, Harbin Medical University, Harbin 150001, PR China
| | - Sheng Su
- Department of Ophthalmology, First Affiliated Hospital, Harbin Medical University, Harbin 150001, PR China
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Yun JH, Park SW, Kim KJ, Bae JS, Lee EH, Paek SH, Kim SU, Ye S, Kim JH, Cho CH. Endothelial STAT3 Activation Increases Vascular Leakage Through Downregulating Tight Junction Proteins: Implications for Diabetic Retinopathy. J Cell Physiol 2016; 232:1123-1134. [PMID: 27580405 DOI: 10.1002/jcp.25575] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023]
Abstract
Vascular inflammation is characteristic feature of diabetic retinopathy. In diabetic retina, a variety of the pro-inflammatory cytokines are elevated and involved in endothelial dysfunction. STAT3 transcription factor has been implicated in mediating cytokine signaling during vascular inflammation. However, whether and how STAT3 is involved in the direct regulation of the endothelial permeability is currently undefined. Our studies revealed that IL-6-induced STAT3 activation increases retinal endothelial permeability and vascular leakage in retinas of mice through the reduced expression of the tight junction proteins ZO-1 and occludin. In a co-culture model with microglia and endothelial cells under a high glucose condition, the microglia-derived IL-6 induced STAT3 activation in the retinal endothelial cells, leading to increasing endothelial permeability. In addition, IL-6-induced STAT3 activation was independent of ROS generation in the retinal endothelial cells. Moreover, we demonstrated that STAT3 activation downregulates the ZO-1 and occludin levels and increases the endothelial permeability through the induction of VEGF production in retinal endothelial cells. These results suggest the potential importance of IL-6/STAT3 signaling in regulating endothelial permeability and provide a therapeutic target to prevent the pathology of diabetic retinopathy. J. Cell. Physiol. 232: 1123-1134, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Jang-Hyuk Yun
- Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sung Wook Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyung-Jin Kim
- Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong-Sup Bae
- College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Eun Hui Lee
- Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sun Ha Paek
- Department of Neurosurgery, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seung U Kim
- Medical Research Institute, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Sangkyu Ye
- Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jeong-Hun Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Fight Against Angiogenesis-Related Blindness Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.,Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chung-Hyun Cho
- Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.,Department of Biomedical Sciences, Seoul National University College of Medicine, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
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The significance of the increased expression of phosphorylated MeCP2 in the membranes from patients with proliferative diabetic retinopathy. Sci Rep 2016; 6:32850. [PMID: 27616658 PMCID: PMC5018725 DOI: 10.1038/srep32850] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 08/16/2016] [Indexed: 01/13/2023] Open
Abstract
The purpose of this study was to evaluate the correlation of expression of phosphorylated methyl-CpG binding protein 2-Ser421 (MeCP2-S421) and VEGF in the membranes of patients with PDR. We examined the expression of phospho-MeCP2-S80, S421, VEGF and PEDF in surgically excised PDR membranes from 33 patients with diabetes, and idiopathic epiretinal membranes from 11 patients without diabetes, using immunohistochemistry and western blot. The colocalization of MeCP2-S421 with VEGF, PEDF, CD31, GFAP and αSMA was revealed by fluorescent double labeling. The effect of CoCl2 and knock down MeCP2 using specific siRNA on the expression of MeCP2 and VEGF were analyzed in HUCAC cells by Western blot. We found that phospho-MeCP2-S421 was significantly increased in the membranes from the patients with PDR compared with the specimens from patients without diabetes (P < 0.01). The expression of phospho-MeCP2-S421 was much stronger than that of phospho-MeCP2-S80 in the PDR membranes. Double labeling showed that the high phospho-MeCP2-S421 expression was associated with strong expression of VEGF, but not PEDF. Further, phospho-MeCP2-S421 and VEGF were increased by the stimulation of CoCl2 and knock down MeCP2 inhibited the expression of VEGF. Our result suggests that phospho-MeCP2-S421 might involve in the pathogenesis of PDR.
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Li J, Hu WC, Song H, Lin JN, Tang X. Increased Vitreous Chemerin Levels Are Associated with Proliferative Diabetic Retinopathy. Ophthalmologica 2016; 236:61-6. [PMID: 27548269 DOI: 10.1159/000447752] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 04/14/2016] [Indexed: 11/19/2022]
Abstract
PURPOSE To investigate chemerin in the vitreous bodies of patients with proliferative diabetic retinopathy (PDR) and determine the correlation between the levels of vitreous chemerin and vascular endothelial growth factor (VEGF). METHODS This study included 17 patients suffering from PDR and vitreous hemorrhage (VH) (group A), 21 patients with PDR and tractional retinal detachment (TRD) (group B) and 25 patients with idiopathic macular holes or preretinal membranes (control group). All vitreous samples were obtained through pars plana vitrectomy. Enzyme-linked immunosorbent assay and Western blot analysis were performed to evaluate the levels of vitreous chemerin and VEGF. RESULTS Vitreous concentrations of chemerin were significantly higher in PDR patients with VH and TRD than those in the controls [4.82 ng/ml (3.91-6.13) vs. 5.03 ng/ml (4.01-6.15) vs. 2.53 ng/ml (1.53-5.66), p = 0.025]. The ratio of vitreous chemerin to plasma chemerin concentration significantly differed between groups A and B and the control group [4.93% (4.69-5.34) vs. 4.98% (4.63-5.19) vs. 2.58% (1.78-4.58), p < 0.001]. Western blot results indicated that the levels of vitreous chemerin protein in PDR patients significantly increased compared with those in the controls. Spearman correlation analysis further showed that vitreous chemerin levels in patients with PDR were positively correlated with vitreous VEGF levels (r = -0.542, p < 0.001). CONCLUSIONS Increased vitreous chemerin levels are associated with the development of PDR.
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Affiliation(s)
- Jun Li
- Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science, Clinical College of Ophthalmology, Tianjin, PR China
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Sorrentino FS, Allkabes M, Salsini G, Bonifazzi C, Perri P. The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy. Life Sci 2016; 162:54-9. [PMID: 27497914 DOI: 10.1016/j.lfs.2016.08.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 07/24/2016] [Accepted: 08/02/2016] [Indexed: 01/18/2023]
Abstract
Diabetic retinopathy (DR) is a remarkable microvascular complication of diabetes and it has been considered the leading cause of legal blindness in working-age adults in the world. Several overlapping and interrelated molecular pathways are involved in the development of this disease. DR is staged into different levels of severity, from the nonproliferative to the advanced proliferative form. Over the years the progression of DR evolves through a series of changes involving distinct types of specialized cells: neural, vascular and glial. Prior to the clinically observable vascular complications, hyperglycemia and inflammation affect retinal glial cells which undergo a wide range of structural and functional alterations. In this review, we provide an overview of the status of macroglia and microglia in the course of DR, trying to briefly take into account the complex biochemical mechanisms that affect the intimate relationship among neuroretina, vessels and glial cells.
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Affiliation(s)
| | - Michael Allkabes
- Department of Biomedical and Surgical Sciences, Division of Ophthalmology, University of Ferrara, Ferrara, Italy
| | - Giulia Salsini
- Department of Biomedical and Surgical Sciences, Division of Ophthalmology, University of Ferrara, Ferrara, Italy
| | - Claudio Bonifazzi
- Department of Biomedical and Surgical Sciences, Section of Human Physiology, University of Ferrara, Ferrara, Italy
| | - Paolo Perri
- Department of Biomedical and Surgical Sciences, Division of Ophthalmology, University of Ferrara, Ferrara, Italy
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Capitão M, Soares R. Angiogenesis and Inflammation Crosstalk in Diabetic Retinopathy. J Cell Biochem 2016; 117:2443-53. [PMID: 27128219 DOI: 10.1002/jcb.25575] [Citation(s) in RCA: 216] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 12/11/2022]
Abstract
Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes and one of the most frequent causes of blindness in active age. Etiopathogenesis behind this important complication is related to several biochemical, hemodynamic and endocrine mechanisms with a preponderant initial role assumed by polyol pathways, increment of growth factors, accumulation of advanced glycation end products (AGE), activation of protein kinase C (PKC), activation of the renin-angiotensin-aldosterone system (RAAS), and leukostasis. Chronic and sustained hyperglycemia works as a trigger to the early alterations that culminate in vascular dysfunction. Hypoxia also plays an essential role in disease progression with promotion of neovascularization and vascular dystrophies with vitreous hemorrhages induction. Thus, the accumulation of fluids and protein exudates in ocular cavities leads to an opacity augmentation of the cornea that associated to neurodegeneration results in vision loss, being this a devastating characteristic of the disease final stage. During disease progression, inflammatory molecules are produced and angiogenesis occur. Furthermore, VEGF is overexpressed by the maintained hyperglycemic environment and up-regulated by tissue hypoxia. Also pro-inflammatory mediators regulated by cytokines, such as tumor necrosis factor (TNF-α) and interleukin-1 beta (IL-1β), and growth factors leads to the progression of these processes, culminating in vasopermeability (diabetes macular edema) and/or pathological angiogenesis (proliferative diabetic retinopathy). It was found a mutual contribution between inflammation and angiogenesis along the process. J. Cell. Biochem. 117: 2443-2453, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Margarida Capitão
- Department of Biochemistry, Faculty of Medicine, University of Porto, Portugal
| | - Raquel Soares
- Department of Biochemistry, Faculty of Medicine, University of Porto, Portugal. .,i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal.
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Yan Y, Zhu L, Hong L, Deng J, Song Y, Chen X. The impact of ranibizumab on the level of intercellular adhesion molecule type 1 in the vitreous of eyes with proliferative diabetic retinopathy. Acta Ophthalmol 2016; 94:358-64. [PMID: 26285163 DOI: 10.1111/aos.12806] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 06/15/2015] [Indexed: 01/07/2023]
Abstract
PURPOSE This study was to investigate the impact of ranibizumab on the level of intercellular adhesion molecule type 1 (ICAM-1) in the vitreous of eyes with PDR. METHODS This is an interventional case-control study. A total of 82 eyes from 82 patients who had undergone vitreous surgery for the treatment of retinal disorders were included. Twenty-two eyes with PDR received an intravitreal ranibizumab injection (IVR) 3-7 days before vitrectomy and were grouped as 'PDR with recent IVR' or Group 1. Sixteen eyes with PDR received IVR more than 7 days before vitrectomy and were grouped as 'PDR with remote IVR' or Group 2. Twenty-two matched PDR eyes did not receive IVR before vitrectomy and were grouped as 'PDR without IVR' or Group 3. Finally, 22 eyes from 22 patients with idiopathic macular pucker (IMP) served as the 'non-diabetic control' group, or Group 4. Vitreous samples were obtained at the time of vitrectomy from all eyes, and the levels of vascular endothelium growth factor (VEGF) and ICAM-1 were analysed using ELISA. RESULTS PDR without IVR (Group 3) had the highest vitreous VEGF concentration; the difference was significant compared with those in the PDR with recent IVR (Group 1), PDR with remote IVR (Group 2) and the non-diabetic control group (Group 4) (p < 0.001). Group 2 had a lower vitreous VEGF level than Group 1 (p = 0.041). Group 1 had the highest vitreous ICAM-1 levels (p < 0.001 versus. Groups 2, 3 and 4); Group 2 had a lower vitreous ICAM-1 level than Group 3 (p = 0.028). CONCLUSION The vitreous fluid level of ICAM-1 was significantly increased within 1 week of IVR administration, but markedly decreased after a week of administration in eyes with PDR. This suggests that leucostasis, vascular leakage and endothelial dysfunction may be amplified in the early days after IVR, but that a therapeutic effect of IVR in these processes may appear after 1 week of ranibizumab administration in eyes with PDR.
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Affiliation(s)
- Ying Yan
- Department of Ophthalmology; Wuhan General Hospital of Guangzhou Command; Wuhan Hubei China
| | - Li Zhu
- Department of Ophthalmology; Wuhan General Hospital of Guangzhou Command; Wuhan Hubei China
| | - Ling Hong
- Department of Ophthalmology; Wuhan General Hospital of Guangzhou Command; Wuhan Hubei China
| | - Jun Deng
- Department of Ophthalmology; Wuhan General Hospital of Guangzhou Command; Wuhan Hubei China
| | - Yanpin Song
- Department of Ophthalmology; Wuhan General Hospital of Guangzhou Command; Wuhan Hubei China
| | - Xiao Chen
- Department of Ophthalmology; Wuhan General Hospital of Guangzhou Command; Wuhan Hubei China
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Ahmad S, ElSherbiny NM, Jamal MS, Alzahrani FA, Haque R, Khan R, Zaidi SK, AlQahtani MH, Liou GI, Bhatia K. Anti-inflammatory role of sesamin in STZ induced mice model of diabetic retinopathy. J Neuroimmunol 2016; 295-296:47-53. [DOI: 10.1016/j.jneuroim.2016.04.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Revised: 03/30/2016] [Accepted: 04/01/2016] [Indexed: 12/24/2022]
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Liu YJ, Lian ZY, Liu G, Zhou HY, Yang HJ. RNA sequencing reveals retinal transcriptome changes in STZ-induced diabetic rats. Mol Med Rep 2016; 13:2101-9. [PMID: 26781437 PMCID: PMC4768987 DOI: 10.3892/mmr.2016.4793] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 12/11/2015] [Indexed: 02/05/2023] Open
Abstract
The present study aimed to investigate changes in retinal gene expression in streptozotocin (STZ)‑induced diabetic rats using next‑generation sequencing, utilize transcriptome signatures to investigate the molecular mechanisms of diabetic retinopathy (DR), and identify novel strategies for the treatment of DR. Diabetes was chemically induced in 10‑week‑old male Sprague‑Dawley rats using STZ. Flash‑electroretinography (F‑ERG) was performed to evaluate the visual function of the rats. The retinas of the rats were removed to perform high throughput RNA sequence (RNA‑seq) analysis. The a‑wave, b‑wave, oscillatory potential 1 (OP1), OP2 and ∑OP amplitudes were significantly reduced in the diabetic group, compared with those of the control group (P<0.05). Furthermore, the implicit b‑wave duration 16 weeks post‑STZ induction were significantly longer in the diabetic rats, compared with the control rats (P<0.001). A total of 868 genes were identified, of which 565 were upregulated and 303 were downregulated. Among the differentially expressed genes (DEGs), 94 apoptotic genes and apoptosis regulatory genes, and 19 inflammatory genes were detected. The results of the KEGG pathway significant enrichment analysis revealed enrichment in cell adhesion molecules, complement and coagulation cascades, and antigen processing and presentation. Diabetes alters several transcripts in the retina, and RNA‑seq provides novel insights into the molecular mechanisms underlying DR.
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Affiliation(s)
- Yuan-Jie Liu
- Department of Human Anatomy, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Zhi-Yun Lian
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Geng Liu
- Department of Human Anatomy, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong-Ying Zhou
- Department of Human Anatomy, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hui-Jun Yang
- Department of Human Anatomy, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Ocular Complications of Diabetes and Therapeutic Approaches. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3801570. [PMID: 27119078 PMCID: PMC4826913 DOI: 10.1155/2016/3801570] [Citation(s) in RCA: 93] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 03/02/2016] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disease defined by elevated blood glucose (BG). DM is a global epidemic and the prevalence is anticipated to continue to increase. The ocular complications of DM negatively impact the quality of life and carry an extremely high economic burden. While systemic control of BG can slow the ocular complications they cannot stop them, especially if clinical symptoms are already present. With the advances in biodegradable polymers, implantable ocular devices can slowly release medication to stop, and in some cases reverse, diabetic complications in the eye. In this review we discuss the ocular complications associated with DM, the treatments available with a focus on localized treatments, and what promising treatments are on the horizon.
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Takeuchi M, Sato T, Tanaka A, Muraoka T, Taguchi M, Sakurai Y, Karasawa Y, Ito M. Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients. PLoS One 2015; 10:e0137358. [PMID: 26352837 PMCID: PMC4564282 DOI: 10.1371/journal.pone.0137358] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 08/14/2015] [Indexed: 02/06/2023] Open
Abstract
Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR) by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th) cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes) with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM), 26 patients with idiopathic macular hole (MH), and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR.
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Affiliation(s)
- Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
- * E-mail:
| | - Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Atsushi Tanaka
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Tadashi Muraoka
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Manzo Taguchi
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Yutaka Sakurai
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Yoko Karasawa
- Department of Ophthalmology, National Defense Medical College, Saitama, Japan
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Saitama, Japan
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The ethanol extract of Zingiber zerumbet rhizomes mitigates vascular lesions in the diabetic retina. Vascul Pharmacol 2015; 76:18-27. [PMID: 26319672 DOI: 10.1016/j.vph.2015.08.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Revised: 07/29/2015] [Accepted: 08/23/2015] [Indexed: 11/19/2022]
Abstract
Diabetic retinopathy (DR) is a common diabetic eye disease which is well-known as the result of microvascular retinal changes. Although the ethanol extract from Zingiber zerumbet (L.) Smith rhizome (EEZZR) has been indicated to ameliorate hyperglycemia in diabetes, its protective effect on DR remains unclear. The aim of this study was to determine the effects of EEZZR on DR in streptozotocin (STZ) diabetic rats. Diabetic rats were treated orally with EEZZR (200, 300 mg/kg per day) or calcium dobesilate (CD; 500 mg/kg per day) for 12 weeks. EEZZR displayed similar characteristics to CD in reducing blood-retinal barrier permeability in diabetic rats. Retinal histopathological observation showed that retinal vessels were decreased in EEZZR-treated diabetic rats. EEZZR decreased the increased retinal expression of vascular endothelial growth factor (VEGF) and upregulate the expressions of renal pigment epithelium-derived factor (PEDF) in diabetic rats. Retinal mRNA expression of tumor necrosis factor-α, interleukin (IL)-1, IL-6, monocyte chemotactic proteins-1, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were all decreased in EEZZR-treated diabetic rats. Moreover, EEZZR could attenuate phosphorylation of nuclear factor Kappa B (NF-κB) p65 and extracellular signal-regulated kinase (ERK)1/2 as well as inhibit the nuclear translocation of pNF-κB p65 induced by diabetes. In conclusion, restoring the balance between stimulators and inhibitors of angiogenesis may be associated with the protective effect of EEZZR on DR. In addition, EEZZR can ameliorate retinal inflammation via transrepression of NF-κB and inhibition of ERK1/2 signaling pathway.
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Elevated Serum Levels of Soluble TNF Receptors and Adhesion Molecules Are Associated with Diabetic Retinopathy in Patients with Type-1 Diabetes. Mediators Inflamm 2015; 2015:279393. [PMID: 26339132 PMCID: PMC4539119 DOI: 10.1155/2015/279393] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/10/2014] [Accepted: 09/11/2014] [Indexed: 12/24/2022] Open
Abstract
Aims. To examine the association of the serum levels of TNF receptors, adhesion molecules, and inflammatory mediators with diabetic retinopathy (DR) in T1D patients. Methods. Using the multiplex immunoassay, we measured serum levels of eight proteins in 678 T1D subjects aged 20–75 years. Comparisons were made between 482 T1D patients with no complications and 196 T1D patients with DR. Results. The levels of sTNFR-I, sTNFR-II, CRP, SAA, sgp130, sIL6R, sVCAM1, and sICAM1 were significantly higher in the T1D patients with DR as compared to T1D patients with no complications. Multivariate logistic regression analysis revealed significant association for five proteins after adjustment for age, sex, and disease duration (sTNFR-I: OR = 1.57, sgp130: OR = 1.43, sVCAM1: OR = 1.27, sICAM1: OR = 1.42, and CRP: OR = 1.15). Conditional logistic regression on matched paired data revealed that subjects in the top quartile for sTNFR-I (OR = 2.13), sTNFR-II (OR = 1.66), sgp130 (OR = 1.82), sIL6R (OR = 1.75), sVCAM1 (OR = 1.98), sICAM1 (OR = 2.23), CRP (OR = 2.40) and SAA (OR = 2.03), had the highest odds of having DR. Conclusions. The circulating markers of inflammation, endothelial injury, and TNF signaling are significantly associated with DR in patients with T1D. TNFR-I and TNFR-II receptors are highly correlated, but DR associated more strongly with TNFR-I in these patients.
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