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1
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Akotoye C, Perkins SW, Sharma N, Singh RP. Long-term visual outcomes and fluid compartment changes in limited-early versus early response to anti-VEGF treatment for diabetic macular edema. CANADIAN JOURNAL OF OPHTHALMOLOGY 2025; 60:113-119. [PMID: 39097291 DOI: 10.1016/j.jcjo.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/17/2024] [Accepted: 06/11/2024] [Indexed: 08/05/2024]
Abstract
OBJECTIVE This study assessed best visual acuity (BVA) and central subfield thickness (CST) outcomes for LER (limited early responder) and ER (early responder) patients at 24 and 36 months. DESIGN Retrospective chart review PARTICIPANTS: One-hundred and twelve patients characterized at 3 months after their first anti-VEGF injections as either LER if they met the anatomic criteria (aLER = CST reductions ≤ 10%), visual criteria (vLER = ETDRS letter gains < 5 letter), or both (cLER). All other patients were classified as ER (aER/vER/cER). METHODS Variables collected include CST and ETDRS letters at baseline, 3, 24, and 36 months following injections, comorbidities, smoking status, demographics, baseline systemic factors, and the type and quantity of anti-VEGF injections. Analyses were performed using Welch's t-test, multivariable linear and multivariable logistic regression. RESULTS BVA changes from 3 months were significant between cLER versus cER and vLER versus vER groups (p < 0.05). There was a greater decrease in mean BVA from 3 months to 36 months in the cER group compared to the cLER group. Alternatively, mean BVA decreased in the vER cohort, while the vLER cohort slightly increased. CST changes from 3 months were statistically significant (p < 0.01) between all LER and ER groups with LER groups showing greater reductions compared to ER counterparts. BVA and CST changes from baseline to 24 and 36 months were not significant after controlling for baseline differences between LER and ER groups. CONCLUSION Results highlight the value of long-term anti-VEGF treatment and the need to further explore options that may lead to continued BVA improvements beyond 3 months.
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Affiliation(s)
| | | | - Neha Sharma
- Case Western Reserve University School of Medicine, Cleveland, OH; Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH
| | - Rishi P Singh
- Cleveland Clinic Lerner College of Medicine, Cleveland, OH; Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH; Cleveland Clinic Cole Eye Institute, Cleveland, OH; Cleveland Clinic Martin Hospitals, Cleveland Clinic FL..
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2
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Arora A, Morya AK, Gupta PC, Menia NK, Nishant P, Gupta V. Intravitreal therapy for the management of diabetic retinopathy: A concise review. World J Exp Med 2024; 14:99235. [PMID: 39713073 PMCID: PMC11551706 DOI: 10.5493/wjem.v14.i4.99235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/08/2024] [Accepted: 09/20/2024] [Indexed: 10/31/2024] Open
Abstract
Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus and may result in irreversible visual loss. Laser treatment has been the gold standard treatment for diabetic macular edema and proliferative diabetic retinopathy for many years. Of late, intravitreal therapy has emerged as a cornerstone in the management of DR. Among the diverse pharmacotherapeutic options, anti-vascular endothelial growth factor agents have demonstrated remarkable efficacy by attenuating neovascularization and reducing macular edema, thus preserving visual acuity in DR patients.
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Affiliation(s)
- Atul Arora
- Teleophthalmology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, Punjab, India
| | - Arvind K Morya
- Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Parul C Gupta
- Department of Ophthalmology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, Punjab, India
| | - Nitin K Menia
- Department of Ophthalmology, All India Institute of Medical Sciences, Vijaypur 180001, Jammu and Kashmīr, India
| | - Prateek Nishant
- Department of Ophthalmology, ESIC Medical College, Patna 801103, Bihār, India
| | - Vishali Gupta
- Department of Ophthalmology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, Punjab, India
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3
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Chen PC, Chang YC, Tsai KL, Shen CH, Lee SD. Vitexin Suppresses High-Glucose-upregulated Adhesion Molecule Expression in Endothelial Cells through Inhibiting NF-κB Signaling Pathway. ACS OMEGA 2024; 9:32727-32734. [PMID: 39100339 PMCID: PMC11292651 DOI: 10.1021/acsomega.4c02545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/24/2024] [Accepted: 07/05/2024] [Indexed: 08/06/2024]
Abstract
Vascular damage is one of the significant complications of diabetes mellitus (DM). Central to this damage is endothelial damage, especially under high-glucose conditions, which promotes inflammation via the NF-κB signaling pathway. Inflammatory processes in endothelial cells directly contribute to endothelial dysfunction, such as promoting inflammatory cytokine release and activation of adhesion molecules. Vitexin, a compound found in many medicinal plants, shows promise in countering oxidative stress in diabetic contexts and modulating blood glucose. However, its effect on high-glucose-induced endothelial cell activation has not yet been studied. This research explores vitexin's potential role in this process, focusing on its influence on the NF-κB pathway in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were stimulated with 30 mM glucose (high glucose, HG) with or without vitexin treatment for 24 h. Western blotting assay was conducted for the NF-κB pathway and p-p38. Adhesion molecules (ICAM-1, VCAM-1, E-selectin, and MCP-1) were studied using flow cytometry, while pro-inflammatory cytokines were investigated using ELISA. Monocyte adhesion and vascular permeability tests were conducted to confirm the protective effect of vitexin under HG exposure. This study confirms vitexin's capacity to suppress p38 MAPK and NF-κB activation under HG conditions, reducing HG-elevated adhesion molecules and pro-inflammatory cytokine secretion. Additionally, vitexin mitigates HG-stimulated vascular permeability and monocyte adhesion. In conclusion, this study shows the therapeutic potential of vitexin against hyperglycemia-related vascular complications via p38 MAPK/NF-κB inhibition.
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Affiliation(s)
- Pie-Che Chen
- Department
of Urology, Ditmanson Medical Foundation
Chiayi Christian Hospital, Chia-Yi 60002, Taiwan
- Chung
Jen Junior College of Nursing, Health Science
and Management, Chia-Yi 60002, Taiwan
| | - Yun-Ching Chang
- School
of Medicine, College of Medicine, I-Shou
University, Kaohsiung 84001, Taiwan
| | - Kun-Ling Tsai
- Department
of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
- Institute
of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
| | - Cheng Huang Shen
- Department
of Urology, Ditmanson Medical Foundation
Chiayi Christian Hospital, Chia-Yi 60002, Taiwan
- Department
of Biomedical Sciences, National Chung Cheng
University, Min Hsiung, Chia-Yi 60002Taiwan
| | - Shin-Da Lee
- Department
of Physical Therapy, PhD program in Healthcare Science, China Medical University, Taichung 40202, Taiwan
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Gouliopoulos N, Siasos G, Oikonomou E, Sapounas S, Rouvas A, Ziogas AC, Moschos MM, Tousoulis D. The Association of Systemic Endothelial Dysfunction With Diffuse Diabetic Macular Edema. Angiology 2024:33197241263384. [PMID: 38889729 DOI: 10.1177/00033197241263384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
Our aim was to assess whether systemic endothelial dysfunction, evaluated non-invasively by flow mediated dilation (FMD), is associated with diabetic macular edema (DME) and to determine if it is further impaired in patients with diffuse-DME. Consecutive patients (n = 84) with type-2 diabetes mellitus (T2DM) and diabetic retinopathy were enrolled. DME was not present in 38 (non-DME) and present in 46 patients; 25 with focal and 21 with diffuse-DME. No differences were detected between DME and non-DME groups regarding the clinical and demographic characteristics, except for the age of T2DM initiation (lower in non-DME). FMD values were significantly impaired in DME compared with non-DME patients, even after adjustment for multiple covariates (3.56 ± 1.03 vs 4.57 ± 1.25%, P = .003). Among DME patients, no differences were found concerning the clinical and demographic data, while FMD levels were significantly lower in diffuse-DME patients, compared with the focal-DME ones, regardless of the impact several confounders (2.88 ± 0.65 vs 4.08 ± 0.95%, P = .002). It is noteworthy that FMD values of non-DME and focal-DME patients did not differ significantly (4.52 ± 1.24 vs 4.21 ± 1.06%, P = .307). Moreover, among DME patients, impaired FMD was an independent predictor of diffuse-DME (odds ratio: 0.06, 95% CI 0.01-0.47, P = .007).
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Affiliation(s)
- Nikolaos Gouliopoulos
- 2nd Department of Ophthalmology, Medical School of National and Kapodistrian University of Athens, 'Attikon' University General Hospital, Athens, Greece
| | - Gerasimos Siasos
- Department of Cardiology, Medical School of National and Kapodistrian University of Athens, Sotiria Thoracic Diseases General Hospital, Athens, Greece
| | - Evangelos Oikonomou
- Department of Cardiology, Medical School of National and Kapodistrian University of Athens, Sotiria Thoracic Diseases General Hospital, Athens, Greece
| | - Spyros Sapounas
- Endocrine Unit and Diabetes Centre, Department of Clinical Therapeutics, Medical School of National and Kapodistrian University of Athens, 'Alexandra' Hospital, Athens, Greece
| | - Alexandros Rouvas
- 2nd Department of Ophthalmology, Medical School of National and Kapodistrian University of Athens, 'Attikon' University General Hospital, Athens, Greece
| | - Apostolos C Ziogas
- Department of Obstetrics and Gynecology, Medical School of University of Thessaly, University Hospital of Larissa, Larissa, Greece
| | - Marilita M Moschos
- 1st Department of Ophthalmology, Medical School of National and Kapodistrian University of Athens, 'G. Gennimatas' General Hospital, Athens, Greece
| | - Dimitris Tousoulis
- Department of Cardiology, Medical School of National and Kapodistrian University of Athens, 'Hippokration' General Hospital, Athens, Greece
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Alvarez IA, Lee M, Eshaq RS, Leskova W, Harris NR. High Glucose Induces Oxidative Stress That Alters Glycocalyx Proteoglycan Levels in Primary Rat Retinal Microvascular Endothelial Cells and in Isolated Ophthalmic Arteries. PATHOPHYSIOLOGY 2024; 31:89-99. [PMID: 38390944 PMCID: PMC10885024 DOI: 10.3390/pathophysiology31010007] [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: 11/21/2023] [Revised: 12/28/2023] [Accepted: 02/02/2024] [Indexed: 02/24/2024] Open
Abstract
Our purpose in this study was to identify the role played by oxidative stress in the changes to proteoglycans that occur under hyperglycemic conditions, using primary rat retinal microvascular endothelial cells (RRMEC) and cultured ophthalmic arteries. The cells and blood vessels obtained from rats were cultured in normal glucose (5.6 mM) and high glucose (25 mM) with or without N-acetylcysteine (NAC), an antioxidant. Intracellular oxidative stress was determined by measuring dihydroethidium (DHE) fluorescence and malondialdehyde (MDA)-modified protein levels. mRNA and protein levels were evaluated using quantitative real-time polymerase chain reaction and immunoblot, respectively. High glucose increased levels of glypican-1 mRNA and protein. The level of syndecan-1 mRNA also was increased, but its protein level was decreased, by high glucose. Evaluation of DHE and MDA showed that high glucose increased oxidative stress. These changes caused by high glucose were significantly reversed by NAC treatment. Matrix metalloproteinase-9 (MMP-9) levels, which increased under high glucose conditions, were suppressed by NAC treatment. Oxidative stress caused by hyperglycemia may be responsible for significant changes to the ocular endothelial glycocalyx.
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Affiliation(s)
- Ivan A Alvarez
- School of Medicine, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA
| | - Minsup Lee
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA
| | - Randa S Eshaq
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA
| | - Wendy Leskova
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA
| | - Norman R Harris
- Department of Molecular and Cellular Physiology, Louisiana State University Health Shreveport, 1501 Kings Hwy, Shreveport, LA 71103, USA
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Kwak J, Lee YH, Kang KT, Kim YC. Comparison of the Effectiveness of Intravitreal Bevacizumab Injections with and without Simultaneous Cataract Surgery in Diabetic Patients with Macular Edema. J Clin Med 2023; 12:4060. [PMID: 37373753 DOI: 10.3390/jcm12124060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/08/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Intravitreal bevacizumab (IVB), often injected during cataract surgery, is currently the main treatment for diabetic macular edema. This retrospective study aimed to compare the effectiveness of IVB injections alone and during cataract surgery in patients with diabetic macular edema. We examined 43 eyes in 40 patients who underwent cataract surgery with simultaneous IVB injections 3-12 months after IVB injections alone. Best-corrected visual acuity and central subfield macular thickness (CMT) were measured 1-month post-injection. The CMTs of the same eyes with IVB-only first and combined-treatment procedures later were 384 ± 149 vs. 315 ± 109 μm pretreatment (p = 0.0002), and after 1 month, they were 319 ± 102 vs. 419 ± 183 μm (p < 0.0001). In the IVB-only procedure, 56.1% of eyes had CMT < 300 μm 1 month after the injection compared to 32.5% after the combined treatment. Therefore, on average, when IVB was administered during cataract surgery, CMT increased, whereas after IVB injection alone, it effectively decreased. More prospective trials with large sample sizes are needed to evaluate the effectiveness of IVB injection performed simultaneously with cataract surgery.
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Affiliation(s)
- Jeeyoung Kwak
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
| | - You Hyun Lee
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
| | - Kyung Tae Kang
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
| | - Yu Cheol Kim
- Department of Ophthalmology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea
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Sabeti F, Rai BB, van Kleef JP, Rohan EMF, Carle CF, Barry RC, Essex RW, Nolan CJ, Maddess T. Objective perimetry identifies regional functional progression and recovery in mild Diabetic Macular Oedema. PLoS One 2023; 18:e0287319. [PMID: 37319294 PMCID: PMC10270604 DOI: 10.1371/journal.pone.0287319] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 06/02/2023] [Indexed: 06/17/2023] Open
Abstract
PURPOSE Retinal function beyond foveal vision is not routinely examined in the clinical screening and management of diabetic retinopathy although growing evidence suggests it may precede structural changes. In this study we compare optical coherence tomography (OCT) based macular structure with function measured objectively with the ObjectiveFIELD Analyzer (OFA), and with Matrix perimetry. We did that longitudinally in Type 2 diabetes (T2D) patients with mild Diabetic Macular Oedema (DMO) with good vision and a similar number of T2D patients without DMO, to evaluate changes in retinal function more peripherally over the natural course of retinopathy. METHODS Both eyes of 16 T2D patients (65.0 ± 10.1, 10 females), 10 with baseline DMO, were followed for up longitudinally for 27 months providing 94 data sets. Vasculopathy was assessed by fundus photography. Retinopathy was graded using to Early Treatment of Diabetic Retinopathy Study (ETDRS) guidelines. Posterior-pole OCT quantified a 64-region/eye thickness grid. Retinal function was measured with 10-2 Matrix perimetry, and the FDA-cleared OFA. Two multifocal pupillographic objective perimetry (mfPOP) variants presented 44 stimuli/eye within either the central 30° or 60° of the visual field, providing sensitivities and delays for each test-region. OCT, Matrix and 30° OFA data were mapped to a common 44 region/eye grid allowing change over time to be compared at the same retinal regions. RESULTS In eyes that presented with DMO at baseline, mean retinal thickness reduced from 237 ± 25 μm to 234.2 ± 26.7 μm, while the initially non-DMO eyes significantly increased their mean thickness from 250.7 ± 24.4 μm to 255.7 ± 20.6 μm (both p<0.05). Eyes that reduced in retinal thickness over time recovered to more normal OFA sensitivities and delays (all p<0.021). Matrix perimetry quantified fewer regions that changed significantly over the 27 months, mostly presenting in the central 8 degrees. CONCLUSIONS Changes in retinal function measured by OFA possibly offer greater power to monitor DMO over time than Matrix perimetry data.
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Affiliation(s)
- Faran Sabeti
- The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
- Faculty of Health, School of Optometry, University of Canberra, Bruce, Canberra, Australia
| | - Bhim B. Rai
- The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Josh P. van Kleef
- The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Emilie M. F. Rohan
- The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Corinne F. Carle
- The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Richard C. Barry
- The Canberra Hospital, ACT Health, Garran, Canberra, ACT, Australia
- Blink Eye Clinic, Canberra, ACT, Australia
| | - Rohan W. Essex
- The Canberra Hospital, ACT Health, Garran, Canberra, ACT, Australia
- ANU Medical School, Australian National University, Canberra, ACT, Australia
| | - Christopher J. Nolan
- The Canberra Hospital, ACT Health, Garran, Canberra, ACT, Australia
- ANU Medical School, Australian National University, Canberra, ACT, Australia
| | - Ted Maddess
- The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
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Thomas L, Low S, Hansen G, Bakker RA, Zippel N. BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies. J Pharmacol Exp Ther 2023; 385:214-221. [PMID: 36997325 DOI: 10.1124/jpet.122.001473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 04/01/2023] Open
Abstract
Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Despite an established standard of care for advanced forms of DR, some patients continue to lose vision after treatment. This may be due to the development of diabetic macular ischemia (DMI), which has no approved treatment. Neuropilin-1 (Nrp-1) is a coreceptor with two ligand-binding domains, with semaphorin-3A (Sema3A) binding to the A-domain and vascular endothelial growth factor-A (VEGF-A) binding to the B-domain. Sema3A directs a subset of neuronal growth cones as well as blood vessel growth by repulsion; when bound to Nrp-1, VEGF-A mediates vascular permeability and angiogenesis. Modulating Nrp-1 could therefore address multiple complications arising from DR, such as diabetic macular edema (DME) and DMI. BI-Y is a monoclonal antibody that binds to the Nrp-1 A-domain, antagonizing the effects of the ligand Sema3A and inhibiting VEGF-A-induced vascular permeability. This series of in vitro and in vivo studies examined the binding kinetics of BI-Y to Nrp-1 with and without VEGF-A165, the effect of BI-Y on Sema3A-induced cytoskeletal collapse, the effect of BI-Y on VEGF- A165-induced angiogenesis, neovascularization, cell integrity loss and permeability, and retinal revascularization. The data show that BI-Y binds to Nrp-1 and inhibits Sema3A-induced cytoskeletal collapse in vitro, may enhance revascularization of ischemic areas in an oxygen-induced retinopathy mouse model, and prevents VEGF-A-induced retinal hyperpermeability in rats. However, BI-Y does not interfere with VEGF-A-dependent choroidal neovascularization. These results support further investigation of BI-Y as a potential treatment for DMI and DME. SIGNIFICANCE STATEMENT: Diabetic macular ischemia (DMI) is a complication of diabetic retinopathy (DR) with no approved pharmacological treatment. Diabetic macular edema (DME) commonly co-occurs with DMI in patients with DR. This series of preclinical studies in mouse and rat models shows that neuropilin-1 antagonist BI-Y may enhance the revascularization of ischemic areas and prevents vascular endothelial growth factor-A (VEGF-A)-induced retinal hyperpermeability without affecting VEGF-A-dependent choroidal neovascularization; thus, BI-Y may be of interest as a potential treatment for patients with DR.
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Affiliation(s)
- Leo Thomas
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.)
| | - Sarah Low
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.)
| | - Gale Hansen
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.)
| | - Remko A Bakker
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.)
| | - Nina Zippel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (L.T., R.A.B., N.Z.) and Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut (S.L., G.H.)
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Ramos H, Hernández C, Simó R, Simó-Servat O. Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications. Int J Mol Sci 2023; 24:ijms24108796. [PMID: 37240138 DOI: 10.3390/ijms24108796] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/25/2023] [Accepted: 05/12/2023] [Indexed: 05/28/2023] Open
Abstract
The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development.
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Affiliation(s)
- Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
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10
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Gnanasekaran R, Aickareth J, Hawwar M, Sanchez N, Croft J, Zhang J. CmPn/CmP Signaling Networks in the Maintenance of the Blood Vessel Barrier. J Pers Med 2023; 13:jpm13050751. [PMID: 37240921 DOI: 10.3390/jpm13050751] [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: 03/23/2023] [Revised: 04/19/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood-brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood-brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood-brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs).
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Affiliation(s)
- Revathi Gnanasekaran
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Justin Aickareth
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Majd Hawwar
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Nickolas Sanchez
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Jacob Croft
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
| | - Jun Zhang
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, TX 79905, USA
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Mugisho OO, Aryal J, Shome A, Lyon H, Acosta ML, Green CR, Rupenthal ID. Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy. Int J Mol Sci 2023; 24:3876. [PMID: 36835288 PMCID: PMC9961562 DOI: 10.3390/ijms24043876] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with pronounced inflammation arising from the activation of a nucleotide-binding and oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome. Cell culture models have shown that a connexin43 hemichannel blocker can prevent inflammasome activation in DR. The aim of this study was to evaluate the ocular safety and efficacy of tonabersat, an orally bioavailable connexin43 hemichannel blocker, to protect against DR signs in an inflammatory non-obese diabetic (NOD) DR mouse model. For retina safety studies, tonabersat was applied to retinal pigment epithelial (ARPE-19) cells or given orally to control NOD mice in the absence of any other stimuli. For efficacy studies, either tonabersat or a vehicle was given orally to the inflammatory NOD mouse model two hours before an intravitreal injection of pro-inflammatory cytokines, interleukin-1 beta, and tumour necrosis factor-alpha. Fundus and optical coherence tomography images were acquired at the baseline as well as at 2- and 7-day timepoints to assess microvascular abnormalities and sub-retinal fluid accumulation. Retinal inflammation and inflammasome activation were also assessed using immunohistochemistry. Tonabersat did not have any effect on ARPE-19 cells or control NOD mouse retinas in the absence of other stimuli. However, the tonabersat treatment in the inflammatory NOD mice significantly reduced macrovascular abnormalities, hyperreflective foci, sub-retinal fluid accumulation, vascular leak, inflammation, and inflammasome activation. These findings suggest that tonabersat may be a safe and effective treatment for DR.
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Affiliation(s)
- Odunayo O. Mugisho
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand; (O.O.M.); (J.A.); (A.S.); (H.L.); (I.D.R.)
| | - Jyoti Aryal
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand; (O.O.M.); (J.A.); (A.S.); (H.L.); (I.D.R.)
| | - Avik Shome
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand; (O.O.M.); (J.A.); (A.S.); (H.L.); (I.D.R.)
| | - Heather Lyon
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand; (O.O.M.); (J.A.); (A.S.); (H.L.); (I.D.R.)
| | - Monica L. Acosta
- School of Optometry and Vision Science, University of Auckland, Auckland 1023, New Zealand;
| | - Colin R. Green
- Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand
| | - Ilva D. Rupenthal
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, University of Auckland, Auckland 1023, New Zealand; (O.O.M.); (J.A.); (A.S.); (H.L.); (I.D.R.)
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12
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Peng H, Han W, Ma B, Dai S, Long J, Zhou S, Li H, Chen B. Autophagy and senescence of rat retinal precursor cells under high glucose. Front Endocrinol (Lausanne) 2023; 13:1047642. [PMID: 36686430 PMCID: PMC9846177 DOI: 10.3389/fendo.2022.1047642] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 12/05/2022] [Indexed: 01/05/2023] Open
Abstract
Backgrounds Diabetic retinopathy (DR) is a common diabetic ocular disease characterized by retinal ganglion cell (RGC) changes. An abnormal environment, hyperglycemia, may progressively alter the structure and function of RGCs, which is a primary pathological feature of retinal neurodegeneration in DR. Accumulated studies confirmed autophagy and senescence play a vital role in DR; however, the underlying mechanisms need to be clarified. Methods This study included the microarray expression profiling dataset GSE60436 from Gene Expression Omnibus (GEO) to conduct the bioinformatics analysis. The R software was used to identify autophagy-related genes (ARGs) that were differentially expressed in fibrovascular membranes (FVMs) and normal retinas. Co-expression and tissue-specific expression were elicited for the filtered genes. The genes were then analyzed by ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and Gene Set Enrichment Analysis (GSEA). R28 cells were cultured with high glucose, detected by reverse transcription-quantitative (RT-qPCR) and stained by apoptosis kit. Results In the retina, 31 differentially expressed ARGs (24 up-regulated genes) were discovered and enriched. The enrichment results revealed that differentially expressed ARGs were significantly enriched in autophagy, apoptosis, aging, and neural function. Four hub genes (i.e., TP53, CASP1, CCL2, and CASP1) were significantly up-regulated. Upregulation of cellular autophagy and apoptosis level was detected in the hyperglycemia model in vitro. Conclusions Our results provide evidence for the autophagy and cellular senescence mechanisms involved in retinal hyperglycemia injury, and the protective function of autophagy is limited. Further study may favour understanding the disease progression and neuroprotection of DR.
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Affiliation(s)
- Hanhan Peng
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Wentao Han
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Benteng Ma
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Shirui Dai
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Jianfeng Long
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Shu Zhou
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Haoyu Li
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
| | - Baihua Chen
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Clinical Research Centre of Ophthalmic Disease, Changsha, China
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13
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Kim AH, Kolesnikova M, Ngo WK, Tsang SH. Effects of medications on hypoxia-inducible factor in the retina: A review. Clin Exp Ophthalmol 2023; 51:205-216. [PMID: 36594241 DOI: 10.1111/ceo.14161] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/22/2022] [Accepted: 08/26/2022] [Indexed: 01/04/2023]
Abstract
Hypoxia-inducible factor (HIF) plays a critical role in the mechanisms that allow cells to adapt to various oxygen levels in the environment. Specifically, HIF-1⍺ has shown to be widely involved in cellular repair, survival, and energy metabolism. HIF-1⍺ has also been found in increased levels in cancer cells, highlighting the importance of balance in the hypoxic response. Promoting HIF-1⍺ activity as a potential therapy for degenerative diseases and inhibiting HIF-1⍺ as a therapy for pathologies with overactive cell proliferation are actively being explored. Digoxin and metformin, HIF-1⍺ inhibitors, and deferoxamine and ⍺-ketoglutarate analogues, HIF-1⍺ activators, are being studied for application in age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. However, these same medications have retinal toxicities that must be assessed before implementation of therapeutic care. Herein, we highlight the duality of therapeutic and toxic potential of HIF-1⍺ that must be carefully assessed prior to its clinical application in retinal disorders.
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Affiliation(s)
- Angela H Kim
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, USA.,Edward S. Harkness Eye Institute, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, New York, USA.,SUNY Downstate Medical School, Brooklyn, New York, USA
| | - Masha Kolesnikova
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, USA.,Edward S. Harkness Eye Institute, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, New York, USA.,SUNY Downstate Medical School, Brooklyn, New York, USA
| | - Wei Kiong Ngo
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, USA.,Edward S. Harkness Eye Institute, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, New York, USA.,National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore, Singapore
| | - Stephen H Tsang
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, USA.,Edward S. Harkness Eye Institute, Columbia University Irving Medical Center/New York-Presbyterian Hospital, New York, New York, USA.,Departments of Pathology & Cell Biology, Columbia Stem Cell Initiative, New York, New York, USA.,Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
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14
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Hanna J, David LA, Touahri Y, Fleming T, Screaton RA, Schuurmans C. Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair. Front Cell Dev Biol 2022; 10:887764. [PMID: 35663397 PMCID: PMC9157592 DOI: 10.3389/fcell.2022.887764] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/19/2022] [Indexed: 12/11/2022] Open
Abstract
Vision commences in the retina with rod and cone photoreceptors that detect and convert light to electrical signals. The irreversible loss of photoreceptors due to neurodegenerative disease leads to visual impairment and blindness. Interventions now in development include transplanting photoreceptors, committed photoreceptor precursors, or retinal pigment epithelial (RPE) cells, with the latter protecting photoreceptors from dying. However, introducing exogenous human cells in a clinical setting faces both regulatory and supply chain hurdles. Recent work has shown that abnormalities in central cell metabolism pathways are an underlying feature of most neurodegenerative disorders, including those in the retina. Reversal of key metabolic alterations to drive retinal repair thus represents a novel strategy to treat vision loss based on cell regeneration. Here, we review the connection between photoreceptor degeneration and alterations in cell metabolism, along with new insights into how metabolic reprogramming drives both retinal development and repair following damage. The potential impact of metabolic reprogramming on retinal regeneration is also discussed, specifically in the context of how metabolic switches drive both retinal development and the activation of retinal glial cells known as Müller glia. Müller glia display latent regenerative properties in teleost fish, however, their capacity to regenerate new photoreceptors has been lost in mammals. Thus, re-activating the regenerative properties of Müller glia in mammals represents an exciting new area that integrates research into developmental cues, central metabolism, disease mechanisms, and glial cell biology. In addition, we discuss this work in relation to the latest insights gleaned from other tissues (brain, muscle) and regenerative species (zebrafish).
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Affiliation(s)
- Joseph Hanna
- Sunnybrook Research Institute, Biological Sciences, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
| | - Luke Ajay David
- Sunnybrook Research Institute, Biological Sciences, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
| | - Yacine Touahri
- Sunnybrook Research Institute, Biological Sciences, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Taylor Fleming
- Sunnybrook Research Institute, Biological Sciences, Toronto, ON, Canada
| | - Robert A. Screaton
- Sunnybrook Research Institute, Biological Sciences, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Carol Schuurmans
- Sunnybrook Research Institute, Biological Sciences, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
- *Correspondence: Carol Schuurmans,
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15
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Karimi S, Arabi A, Shahraki T, Safi S. Association of WBC Counts, Leukocyte Ratios, and Serum Uric Acid with Clinical Outcome of Intravitreal Bevacizumab in Diabetic Macular Edema. KOREAN JOURNAL OF OPHTHALMOLOGY 2022; 36:244-252. [PMID: 35527530 PMCID: PMC9194729 DOI: 10.3341/kjo.2021.0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 02/18/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose To investigate the role of serum uric acid and leukocyte counts and ratios as predictors of clinical outcomes of intravitreal bevacizumab in diabetic macular edema. Method In this prospective study, the patients were treated with three monthly intravitreal bevacizumab. The correlation of serum uric acid and immune cell indices with the changes of best corrected visual acuity and central macular thickness at the end of month 3 were evaluated through univariate and multivariate linear regression analysis. Result A total of 80 eyes from 80 diabetic patients were included in the study. The difference of uric acid level and immune indices between groups with different retinopathy severity was no statistically significant(P>0.05). Lower duration of diabetes (P=0.0451), monocyte count (P=0.021), and uric acid level (P<0.001) were correlated with larger improvement in visual acuity at 3-month visit. Higher logMAR of baseline visual acuity (P=0.007), lymphocyte count (P=0.008), lymphocyte-to-neutrophil ratio (LNR) (P<0.001) and lymphocyte-to-platelet ratio (LPR) (P<0.001) were correlated with larger improvement in visual acuity at 3-month visits. According to multivariate analysis, baseline logMAR (coefficient=0.125, P=0.009), duration of diabetes (coefficient=-0.216, P=0.047), LNR (coefficient=0.712, P<0.001), LPR (coefficient=0.238, P<0.001), and uric acid level (coefficient=-0.397, P<0.001) were the significant predictors of changes in visual acuity in our subset of patients. Conclusion Serum uric acid and leukocyte counts and ratios may predict the response of diabetic macular edema to intravitreal injection.
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Affiliation(s)
- Saeed Karimi
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Arabi
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Toktam Shahraki
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sare Safi
- Ophthalmic Epidemiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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16
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Someya H, Ito M, Nishio Y, Sato T, Harimoto K, Takeuchi M. Osteopontin-induced vascular hyperpermeability through tight junction disruption in diabetic retina. Exp Eye Res 2022; 220:109094. [PMID: 35490836 DOI: 10.1016/j.exer.2022.109094] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/17/2022] [Accepted: 04/25/2022] [Indexed: 11/29/2022]
Abstract
Diabetic retinopathy is a major cause of blindness in developed countries, and is characterized by deterioration of barrier function causing vascular hyperpermeability and retinal edema. Vascular endothelial growth factor (VEGF) is a major mediator of diabetic macular edema. Although anti-VEGF drugs are the first-line treatment for diabetic macular edema, some cases are refractory to anti-VEGF therapy. Osteopontin (OPN) is a phosphoglycoprotein with diverse functions and expressed in various cells and tissues. Elevated OPN level has been implicated in diabetic retinopathy, but whether OPN is involved in hyperpermeability remains unclear. Using streptozotocin-induced diabetic mice (STZ mice) and human retinal endothelial cells (HRECs), we tested the hypothesis that up-regulated OPN causes tight junction disruption, leading to vascular hyperpermeability. The serum and retinal OPN concentrations were elevated in STZ mice compared to controls. Intravitreal injection of anti-OPN neutralizing antibody (anti-OPN Ab) suppressed vascular hyperpermeability and prevented decreases in claudin-5 and ZO-1 gene expression levels in the retina of STZ mice. Immunohistochemical staining of retinal vessels in STZ mice revealed claudin-5 immunoreactivity with punctate distribution and attenuated ZO-1 immunoreactivity, and these changes were prevented by anti-OPN Ab. Intravitreal injection of anti-OPN Ab did not change VEGF gene expression or protein concentration in retina of STZ mice. In an in vitro study, HRECs were exposed to normal glucose or high glucose with or without OPN for 48 h, and barrier function was evaluated by transendothelial electrical resistance and Evans blue permeation. Barrier function deteriorated under high glucose condition, and was further exacerbated by the addition of OPN. Immunofluorescence localization of claudin-5 and ZO-1 demonstrated punctate appearance with discontinuous junction in HRECs exposed to high glucose and OPN. There were no changes in VEGF and VEGF receptor-2 expression levels in HRECs by exposure to OPN. Our results suggest that OPN induces tight junction disruption and vascular hyperpermeability under diabetic conditions. Targeting OPN may be an effective approach to manage diabetic retinopathy.
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Affiliation(s)
- Hideaki Someya
- Department of Ophthalmology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Yoshiaki Nishio
- Department of Ophthalmology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Kozo Harimoto
- Department of Ophthalmology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan
| | - Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, Namiki 3-2, Tokorozawa, Saitama, 359-8513, Japan.
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17
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Discovery of Therapeutic Candidates for Diabetic Retinopathy Based on Molecular Switch Analysis: Application of a Systematic Process. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3412032. [PMID: 35035658 PMCID: PMC8758313 DOI: 10.1155/2022/3412032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/13/2021] [Accepted: 11/16/2021] [Indexed: 12/29/2022]
Abstract
The pathogenesis of diabetic retinopathy (DR) is complicated, and there is no effective drug. Oxidative stress-induced human retinal microvascular endothelial cells (HRMECs) injury is one of the pathogenic factors for DR. Molecular switches are considered high-risk targets in disease progression. Identification of molecular switch is crucial to interpret the pathogenesis of disease and screen effective ingredients. In this study, a systematic process was executed to discover therapeutic candidates for DR based on HRMECs injury. First of all, the molecular mechanism of HRMECs oxidative stress injury was revealed by transcriptomics and network pharmacology. We found that oxidative stress was one of the pivotal pathogenic factors, which interfered with vascular system development, inflammation, cell adhesion, and cytoskeleton damaged HRMECs through crosstalk. Then, network topology analysis was used to recognize molecular switches. The results indicated that the Keap1-Nrf2-ARE signaling pathway was the molecular switch in HRMECs oxidative stress injury. On this basis, the HEK293-ARE overexpression cell line was applied to obtain 18 active traditional Chinese medicine (TCM) ingredients. Furthermore, andrographolide, one of the 18 candidates, was applied in the HRMECs oxidative stress model to evaluate the accuracy of the systematic process. The efficacy evaluation results showed that andrographolide could regulate oxidative stress, vascular system development, inflammation, adhesion, and skeleton tissue to inhibit HRMECs injury cooperatively. And its mechanism was related to the Nrf2 signaling pathway. Overall, our data suggest that the Nrf2 signaling pathway is the molecular switch in the HRMECs oxidative stress injury. 18 potential Nrf2 agonists are likely to be promising DR candidates.
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18
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Ikeda T, Nakamura K, Kida T, Oku H. Possible roles of anti-type II collagen antibody and innate immunity in the development and progression of diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2022; 260:387-403. [PMID: 34379187 PMCID: PMC8786754 DOI: 10.1007/s00417-021-05342-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 11/08/2022] Open
Abstract
The pathogenesis of both diabetic retinopathy (DR) and rheumatoid arthritis (RA) has recently been considered to involve autoimmunity. Serum and synovial fluid levels of anti-type II collagen antibodies increase early after the onset of RA, thus inducing immune responses and subsequent hydrarthrosis and angiogenesis, which resemble diabetic macular edema and proliferative DR (PDR), respectively. We previously reported that DR is also associated with increased serum levels of anti-type II collagen antibodies. Retinal hypoxia in DR may induce pericytes to express type II collagen, resulting in autoantibody production against type II collagen. As the result of blood-retinal barrier disruption, anti-type II collagen antibodies in the serum come into contact with type II collagen around the retinal vessels. A continued loss of pericytes and type II collagen around the retinal vessels may result in a shift of the immune reaction site from the retina to the vitreous. It has been reported that anti-inflammatory M2 macrophages increased in the vitreous of PDR patients, accompanied by the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of innate immunity. M2 macrophages promote angiogenesis and fibrosis, which might be exacerbated and prolonged by dysregulated innate immunity.
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Affiliation(s)
- Tsunehiko Ikeda
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki City, Osaka, Japan.
- Department of Ophthalmology, Osaka Kaisei Hospital, 1-6-10 Miyahara Yodogawa-ku, Osaka City, Osaka, Japan.
| | | | - Teruyo Kida
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki City, Osaka, Japan
| | - Hidehiro Oku
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Takatsuki City, Osaka, Japan
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Li J, Lu X, Wei L, Ye D, Lin J, Tang X, Cui K, Yu S, Xu Y, Liang X. PHD2 attenuates high-glucose-induced blood retinal barrier breakdown in human retinal microvascular endothelial cells by regulating the Hif-1α/VEGF pathway. Inflamm Res 2021; 71:69-79. [PMID: 34773469 DOI: 10.1007/s00011-021-01518-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 10/20/2021] [Accepted: 10/25/2021] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE Diabetic macular edema (DME) is one of the most frequent causes of severe vision loss. The pathogenesis of DME is still not fully understood; however, it is hypothesized to result from breakdown of the blood-retinal barrier (BRB) due to retinal inflammation by vascular endothelial growth factor (VEGF) secretion under hyperglycemic conditions. In this investigation, we discovered that Prolyl-4-hydroxylase 2 (PHD2), an upstream regulator of hypoxia-inducible factor 1 (HIF-1) modulates VEGF expression and thus preserves BRB function in the mouse retina. MATERIALS AND METHODS Primary human retinal microvascular endothelial cells (hRMECs) were cultured in human endothelial serum-free growth medium and exposed to hyperglycemia. Changes in cell viability were investigated by an MTT assay. BRB function in each group was revealed by a paracellular permeability assay and trans-endothelial electrical resistance (TEER). Morphological changes in the BRB were investigated by immunofluorescence staining of occludin and zonula occludens-1 (ZO-1). The mRNA and protein levels of the tight junction proteins, PHD2, HIF-1α, and VEGF were measured by reverse transcription-quantitative PCR (RT-qPCR), western blot analysis and ELISA. RESULTS Under hyperglycemic conditions, the viability of hRMECs was decreased, and PHD2 expression was downregulated, accompanied by increased paracellular permeability and decreased trans-endothelial electrical resistance. Additionally, HIF-1α and VEGF expression levels were increased, whereas the expression levels of tight junction proteins, including occludin and ZO-1, were decreased and BRB function was compromised. The PHD2 activator R59949 (diacylglycerol kinase inhibitor II), altered these pathological changes, and the PHD2 inhibitor dimethyloxalylglycine (DMOG) resulted in the opposite effects. CONCLUSION These results demonstrated that PHD2 inhibited HIF-1 activity by inhibiting HIF-1α expression in hRMECs under hyperglycemic conditions, which led to the downregulation of the expression of the angiogenic factor VEGF, and thus helped to maintain the functions of hRMECs. Therefore, it is reasonable to propose that PHD2 could be a potential novel target for the treatment of DME or other diseases with a similar pathogenesis.
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Affiliation(s)
- Jia Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Xi Lu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Liqing Wei
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
- Eye Hospital of Wenzhou Medical University, Hangzhou Xihu Zhijiang Eye Hospital, No.7 Jinsui Rd, Hangzhou, Zhejiang, People's Republic of China, 310024
| | - Dan Ye
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Jianqiang Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Xiaoyu Tang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Kaixuan Cui
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Shanshan Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030
| | - Yue Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030.
| | - Xiaoling Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.7 Jinsui Rd, Tianhe District, Guangzhou, Guangdong, People's Republic of China, 510030.
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Sheemar A, Soni D, Takkar B, Basu S, Venkatesh P. Inflammatory mediators in diabetic retinopathy: Deriving clinicopathological correlations for potential targeted therapy. Indian J Ophthalmol 2021; 69:3035-3049. [PMID: 34708739 PMCID: PMC8725076 DOI: 10.4103/ijo.ijo_1326_21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/10/2021] [Accepted: 09/27/2021] [Indexed: 11/22/2022] Open
Abstract
The role of inflammation in diabetic retinopathy (DR) is well-established and dysregulation of a large number of inflammatory mediators is known. These include cytokines, chemokines, growth factors, mediators of proteogenesis, and pro-apoptotic molecules. This para-inflammation as a response is not directed to a particular pathogen or antigen but is rather directed toward the by-products of the diabetic milieu. The inflammatory mediators take part in cascades that result in cellular level responses like neurodegeneration, pericyte loss, leakage, capillary drop out, neovascularization, etc. There are multiple overlaps between the inflammatory pathways occurring within the diabetic retina due to a large number of mediators, their varied sources, and cross-interactions. This makes understanding the role of inflammation in clinical manifestations of DR difficult. Currently, mediator-based therapy for DR is being evaluated for interventions that target a specific step of the inflammatory cascade. We reviewed the role of inflammation in DR and derived a simplified clinicopathological correlation between the sources and stimuli of inflammation, the inflammatory mediators and pathways, and the clinical manifestations of DR. By doing so, we deliberate mediator-specific therapy for DR. The cross-interactions between inflammatory mediators and the molecular cycles influencing the inflammatory cascades are crucial challenges to such an approach. Future research should be directed to assess the feasibility of the pathology-based therapy for DR.
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Affiliation(s)
- Abhishek Sheemar
- Department of Ophthalmology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Deepak Soni
- Department of Ophthalmology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Brijesh Takkar
- Smt. Kanuri Santhamma Center for Vitreoretinal Diseases, L V Prasad Eye Institute, Hyderabad, India
- Indian Health Outcomes, Public Health and Economics Research (IHOPE) Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Soumyava Basu
- Uveitis Service, L V Prasad Eye Institute, Hyderabad, Telangana, India
| | - Pradeep Venkatesh
- Dr.R.P.Centre for Ophthalmic Sciences, All India Institute of Medical Science, New Delhi, India
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21
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Huang H, Kuang X, Zhu X, Cheng H, Zou Y, Du H, Tang H, Zhou L, Zeng J, Liu H, Yan J, Long C, Shen H. Maintaining blood retinal barrier homeostasis to attenuate retinal ischemia-reperfusion injury by targeting the KEAP1/NRF2/ARE pathway with lycopene. Cell Signal 2021; 88:110153. [PMID: 34571190 DOI: 10.1016/j.cellsig.2021.110153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 09/13/2021] [Accepted: 09/16/2021] [Indexed: 12/15/2022]
Abstract
Retinal ischemia-reperfusion (I/R) often results in intractable visual impairments, where blood retinal barrier (BRB) homeostasis mediated by retinal pigment epithelium (RPE) and retinal microvascular endothelium (RME) is crucial. However, strategies targeting the BRB are limited. Thus, we investigated the inconclusive effect of lycopene (LYC) in retinal protection under I/R. LYC elevated cellular viability and reversed oxidative stress in aRPE-19 cells/hRME cells under I/R conditions based on oxygen-glucose deprivation (OGD) in vitro. Molecular analysis showed that LYC promoted NRF2 expression and enhanced the downstream factors of the KEAP1/NRF2/ARE pathway: LYC increased the activities of antioxidants, including SOD and CAT, whereas it enhanced the mRNA expression of HO-1 (ho-1) and NQO-1 (nqo-1). The activation resulted in restrained ROS and MDA. On the other hand, LYC ameliorated the damage to retinal function and morphology in a mouse I/R model, which was established by unilateral ligation of the left pterygopalatine artery/external carotid artery and reperfusion. LYC promoted the expression of NRF2 in both the neural retina and the RPE choroid in vivo. This evidence revealed the potential of LYC in retinal protection under I/R, uncovering the pharmacological effect of the KEAP1/NRF2/ARE pathway in BRB targeting. The study generates new insights into scientific practices in retinal research.
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Affiliation(s)
- Hao Huang
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Department of Ophthalmology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Xielan Kuang
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Xiaobo Zhu
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Hao Cheng
- Department of Ophthalmology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Yuxiu Zou
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Han Du
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Han Tang
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Linbin Zhou
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Jingshu Zeng
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Huijun Liu
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Jianhua Yan
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
| | - Chongde Long
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
| | - Huangxuan Shen
- State Key laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Biobank of Eye, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
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22
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Schmidt-Erfurth U, Reiter GS, Riedl S, Seeböck P, Vogl WD, Blodi BA, Domalpally A, Fawzi A, Jia Y, Sarraf D, Bogunović H. AI-based monitoring of retinal fluid in disease activity and under therapy. Prog Retin Eye Res 2021; 86:100972. [PMID: 34166808 DOI: 10.1016/j.preteyeres.2021.100972] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/11/2021] [Accepted: 05/13/2021] [Indexed: 12/21/2022]
Abstract
Retinal fluid as the major biomarker in exudative macular disease is accurately visualized by high-resolution three-dimensional optical coherence tomography (OCT), which is used world-wide as a diagnostic gold standard largely replacing clinical examination. Artificial intelligence (AI) with its capability to objectively identify, localize and quantify fluid introduces fully automated tools into OCT imaging for personalized disease management. Deep learning performance has already proven superior to human experts, including physicians and certified readers, in terms of accuracy and speed. Reproducible measurement of retinal fluid relies on precise AI-based segmentation methods that assign a label to each OCT voxel denoting its fluid type such as intraretinal fluid (IRF) and subretinal fluid (SRF) or pigment epithelial detachment (PED) and its location within the central 1-, 3- and 6-mm macular area. Such reliable analysis is most relevant to reflect differences in pathophysiological mechanisms and impacts on retinal function, and the dynamics of fluid resolution during therapy with different regimens and substances. Yet, an in-depth understanding of the mode of action of supervised and unsupervised learning, the functionality of a convolutional neural net (CNN) and various network architectures is needed. Greater insight regarding adequate methods for performance, validation assessment, and device- and scanning-pattern-dependent variations is necessary to empower ophthalmologists to become qualified AI users. Fluid/function correlation can lead to a better definition of valid fluid variables relevant for optimal outcomes on an individual and a population level. AI-based fluid analysis opens the way for precision medicine in real-world practice of the leading retinal diseases of modern times.
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Affiliation(s)
- Ursula Schmidt-Erfurth
- Department of Ophthalmology Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| | - Gregor S Reiter
- Department of Ophthalmology Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| | - Sophie Riedl
- Department of Ophthalmology Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| | - Philipp Seeböck
- Department of Ophthalmology Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| | - Wolf-Dieter Vogl
- Department of Ophthalmology Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| | - Barbara A Blodi
- Fundus Photograph Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
| | - Amitha Domalpally
- Fundus Photograph Reading Center, Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
| | - Amani Fawzi
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
| | - Yali Jia
- Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, OR, USA.
| | - David Sarraf
- Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA.
| | - Hrvoje Bogunović
- Department of Ophthalmology Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
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Simó-Servat O, Ramos H, Bogdanov P, García-Ramírez M, Huerta J, Hernández C, Simó R. ERM Complex, a Therapeutic Target for Vascular Leakage Induced by Diabetes. Curr Med Chem 2021; 29:2189-2199. [PMID: 34042029 DOI: 10.2174/0929867328666210526114417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Ezrin, radixin, and moesin (the ERM complex) interact directly with membrane proteins regulating their attachment to actin filaments. ERM protein activation modifies cytoskeleton organization and alters the endothelial barrier function, thus favoring vascular leakage. However, little is known regarding the role of ERM proteins in diabetic retinopathy (DR). OBJECTIVE This study aimed to examine whether overexpression of the ERM complex exists in db/db mice and its main regulating factors. METHOD 9 male db/db mice and 9 male db/+ aged 14 weeks were analyzed. ERM proteins were assessed by western blot and by immunohistochemistry. Vascular leakage was determined by the Evans blue method. To assess ERM regulation, HRECs were cultured in a medium containing 5.5 mM D-glucose (mimicking physiological conditions) and 25 mM D-glucose (mimicking hyperglycemia that occurs in diabetic patients). Moreover, treatment with TNF-α, IL-1β, or VEGF was added to a high glucose condition. The expression of ERM proteins was quantified by RT-PCR. Cell permeability was evaluated by measuring movements of FITC-dextran. RESULTS A significant increase of ERM in diabetic mice in comparison with non-diabetic mice was observed. A high glucose condition alone did not have any effect on ERM expression. However, TNF-α and IL-1β induced a significant increase in ERM proteins. CONCLUSIONS The increase of ERM proteins induced by diabetes could be one of the mechanisms involved in vascular leakage and could be considered as a therapeutic target. Moreover, the upregulation of the ERM complex by diabetes is induced by inflammatory mediators rather than by high glucose itself.
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Affiliation(s)
- Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Marta García-Ramírez
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Jordi Huerta
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
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24
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Eshaq RS, Harris NR. The role of tumor necrosis factor-α and interferon-γ in the hyperglycemia-induced ubiquitination and loss of platelet endothelial cell adhesion molecule-1 in rat retinal endothelial cells. Microcirculation 2021; 28:e12717. [PMID: 34008903 PMCID: PMC10078990 DOI: 10.1111/micc.12717] [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: 10/26/2020] [Revised: 05/03/2021] [Accepted: 05/11/2021] [Indexed: 11/25/2022]
Abstract
OBJECTIVE This study aimed to investigate the role of the hyperglycemia-induced increase in tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in the ubiquitination and degradation of platelet endothelial cell adhesion molecule-1 (PECAM-1) in the diabetic retina. METHODS Type I diabetes was induced in rats by the injection of streptozotocin, with age-matched non-diabetic rats as controls. Primary rat retinal microvascular endothelial cells were grown in normal or high glucose media for 6 days or in normal glucose media for 24 h with addition of TNF-α and/or IFN-γ. PECAM-1, TNF-α, IFN-γ, and ubiquitin levels were assessed using Western blotting, immunofluorescence, and immunoprecipitation assays. Additionally, proteasome activity was assessed both in vivo and in vitro. RESULTS Under hyperglycemic conditions, total ubiquitination levels in the retina and RRMECs, and PECAM-1 ubiquitination levels in RRMECs, were significantly increased. Additionally, TNF-α and IFN-γ levels were significantly increased under hyperglycemic conditions. PECAM-1 levels in RRMECs treated with TNF-α and/or IFN-γ were significantly decreased. Moreover, there was a significant decrease in proteasome activity in the diabetic retina, hyperglycemic RRMECs, and RRMECs treated with TNF-α or IFN-γ. CONCLUSION Tumor necrosis factor-α and IFN-γ may contribute to the hyperglycemia-induced loss of PECAM-1 in retinal endothelial cells, possibly by upregulating PECAM-1 ubiquitination.
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Affiliation(s)
- Randa S Eshaq
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Norman R Harris
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
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25
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Sharma S. Interleukin-6 Trans-signaling: A Pathway With Therapeutic Potential for Diabetic Retinopathy. Front Physiol 2021; 12:689429. [PMID: 34093244 PMCID: PMC8170152 DOI: 10.3389/fphys.2021.689429] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 04/12/2021] [Indexed: 12/29/2022] Open
Affiliation(s)
- Shruti Sharma
- Center for Biotechnology & Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, United States.,Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
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26
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Diabetic retinal neurodegeneration as a form of diabetic retinopathy. Int Ophthalmol 2021; 41:3223-3248. [PMID: 33954860 DOI: 10.1007/s10792-021-01864-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/08/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE To review the evidence supporting diabetic retinal neurodegeneration (DRN) as a form of diabetic retinopathy. METHOD Review of literature. RESULTS DRN is recognized to be a part of retinopathy in patients with diabetes mellitus (DM), in addition to the well-established diabetic retinal vasculopathy (DRV). DRN has been noted in the early stages of DM, before the onset of clinically evident diabetic retinopathy. The occurrence of DRN has been confirmed in animal models of DM, histopathological examination of donor's eyes from diabetic individuals and assessment of neural structure and function in humans. DRN involves alterations in retinal ganglion cells, photoreceptors, amacrine cells and bipolar cells, and is thought to be driven by glutamate, oxidative stress and dysregulation of neuroprotective factors in the retina. Potential therapeutic options for DRN are under evaluation. CONCLUSIONS Literature is divided on the temporal relation between DRN and DRV, with evidence of both precedence and simultaneous occurrence. The relationship between DRN and multi-system neuropathy in DM is yet to be evaluated critically.
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27
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Oddone F, Rossetti L, Parravano M, Sbardella D, Coletta M, Ziccardi L, Roberti G, Carnevale C, Romano D, Manni G, Parisi V. Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review. Pharmaceuticals (Basel) 2021; 14:281. [PMID: 33804675 PMCID: PMC8003774 DOI: 10.3390/ph14030281] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 12/12/2022] Open
Abstract
Cytidine 5'-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer's disease, Parkinson's disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials).
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Affiliation(s)
- Francesco Oddone
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
| | - Luca Rossetti
- Eye Clinic, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Via Antonio di Rudinì, 8, 20142 Milan, Italy; (L.R.); (D.R.)
| | - Mariacristina Parravano
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
| | - Diego Sbardella
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
| | - Massimo Coletta
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (M.C.); (G.M.)
| | - Lucia Ziccardi
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
| | - Gloria Roberti
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
| | - Carmela Carnevale
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
| | - Dario Romano
- Eye Clinic, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Via Antonio di Rudinì, 8, 20142 Milan, Italy; (L.R.); (D.R.)
| | - Gianluca Manni
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; (M.C.); (G.M.)
| | - Vincenzo Parisi
- IRCCS-Fondazione Bietti, Via Livenza, 3, 00198 Rome, Italy; (F.O.); (D.S.); (L.Z.); (G.R.); (C.C.); (V.P.)
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Kodjikian L, Baillif S, Creuzot-Garcher C, Delyfer MN, Matonti F, Weber M, Mathis T. Real-World Efficacy and Safety of Fluocinolone Acetonide Implant for Diabetic Macular Edema: A Systematic Review. Pharmaceutics 2021; 13:pharmaceutics13010072. [PMID: 33430389 PMCID: PMC7827527 DOI: 10.3390/pharmaceutics13010072] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/24/2020] [Accepted: 01/04/2021] [Indexed: 12/18/2022] Open
Abstract
To assess real-world outcomes of fluocinolone acetonide (FAc) implant in treating diabetic macular edema (DME), a systematic literature review was conducted on PubMed in order to identify publications assessing the efficacy and safety of the FAc implant in DME in daily practice. Case reports and randomized controlled trials were excluded. Twenty-two observational real-world studies analyzing a total of 1880 eyes were included. Mean peak visual gain was +8.7 letters (11.3 months post-FAc injection) and was greater for lower baseline best corrected visual acuity (BCVA) and for more recent DME. Mean central retinal thickness (CRT) decreased 34.3% from baseline. 77.0% of the analyzed studies reported both BCVA improvement of at least five letters and a CRT decrease by 20% or more. Rescue therapy was needed more frequently when FAc was administered for chronic DME. FAc-induced ocular hypertension was reported in 20.1% of patients but only 0.6% needed surgery. Cataract extraction was performed in 43.2% of phakic patients. Adequate patient selection is essential for optimal FAc response and better safety profile. Currently positioned as second- or third-line treatment in the management algorithm, FAc implant decreases treatment burden and provides better letter gain when administered for more recent DME.
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Affiliation(s)
- Laurent Kodjikian
- Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon 1, 69004 Lyon, France;
- CNRS-UMR 5510 Mateis, University of Lyon 1, 69100 Villeurbane, France
- Correspondence: ; Tel.: +33-(0)4-26-10-94-31
| | - Stephanie Baillif
- Department of Ophthalmology, Pasteur 2 University Hospital, 06000 Nice, France;
| | - Catherine Creuzot-Garcher
- Department of Ophthalmology, Dijon-Bourgogne University Hospital, 21000 Dijon, France;
- Eye and Nutrition Research Group, CSGA, UMR1324 INRA, 6265 CNRS, Burgundy, 21000 Dijon, France
| | - Marie-Noëlle Delyfer
- Department of Ophthalmology, Bordeaux 2 University Hospital, 33000 Bordeaux, France;
- Bordeaux Population Health Research Center, Team LEHA, 33000 Bordeaux, France
| | - Frédéric Matonti
- Monticelli Paradis Center, 13000 Marseille, France;
- Institut de Neurosciences de la Timone-UMR 7289, University of Aix-Marseille, 13000 Marseille, France
| | - Michel Weber
- Department of Ophthalmology, Nantes University Hospital, 44000 Nantes, France;
- Clinical Investigation Centre CIC1413, INSERM and Nantes University Hospital, 44000 Nantes, France
| | - Thibaud Mathis
- Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon 1, 69004 Lyon, France;
- CNRS-UMR 5510 Mateis, University of Lyon 1, 69100 Villeurbane, France
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29
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Chang X, Zhu G, Cai Z, Wang Y, Lian R, Tang X, Ma C, Fu S. miRNA, lncRNA and circRNA: Targeted Molecules Full of Therapeutic Prospects in the Development of Diabetic Retinopathy. Front Endocrinol (Lausanne) 2021; 12:771552. [PMID: 34858342 PMCID: PMC8631471 DOI: 10.3389/fendo.2021.771552] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/25/2021] [Indexed: 12/20/2022] Open
Abstract
Diabetic retinopathy (DR) is a common diabetic complication and the main cause of blindness worldwide, which seriously affects the quality of life of patients. Studies have shown that noncoding RNA (ncRNA) has distinct differentiated expression in DR and plays an important role in the occurrence and development of DR. ncRNAs represented by microRNAs (miRNAs), lncRNAs (lncRNAs), and circRNAs (circRNAs) have been shown to be widely involved in the regulation of gene expression and affect multiple biological processes of retinopathy. This article will review three RNAs related to the occurrence and development of DR on the basis of previous studies (especially their effects on retinal microangiopathy, retinal pigment epithelial cells, and retinal nerve cells) and discuss their underlying mechanisms and connections. Overall, this review will help us better understand the role of ncRNAs in the occurrence and development of DR and provide ideas for exploring potential therapeutic directions and targets.
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Affiliation(s)
- Xingyu Chang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Guomao Zhu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Zongyan Cai
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yaqi Wang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Rongna Lian
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xulei Tang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Endocrine Disease, Lanzhou, China
| | - Chengxu Ma
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Songbo Fu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Endocrine Disease, Lanzhou, China
- *Correspondence: Songbo Fu,
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30
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Rudraraju M, Narayanan SP, Somanath PR. Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy. Pharmacol Res 2020; 161:105115. [PMID: 32750417 PMCID: PMC7755666 DOI: 10.1016/j.phrs.2020.105115] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 12/15/2022]
Abstract
Loss of the blood-retinal barrier (BRB) integrity and subsequent damage to the neurovascular unit in the retina are the underlying reasons for diabetic retinopathy (DR). Damage to BRB eventually leads to severe visual impairment in the absence of prompt intervention. Diabetic macular edema and proliferative DR are the advanced stages of the disease where BRB integrity is altered. Primary mechanisms contributing to BRB dysfunction include loss of cell-cell barrier junctions, vascular endothelial growth factor, advanced glycation end products-induced damage, and oxidative stress. Although much is known about the involvement of adherens and tight-junction proteins in the regulation of vascular permeability in various diseases, there is a significant gap in our knowledge on the junctional proteins expressed in the BRB and how BRB function is modulated in the diabetic retina. In this review article, we present our current understanding of the molecular composition of BRB, the changes in the BRB junctional protein turnover in DR, and how BRB functional modulation affects vascular permeability and macular edema in the diabetic retina.
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Affiliation(s)
- Madhuri Rudraraju
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, United States
| | - S Priya Narayanan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; Vascular Biology Center, Augusta University, Augusta, GA 30912, United States; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912, United States
| | - Payaningal R Somanath
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; Vascular Biology Center, Augusta University, Augusta, GA 30912, United States; Department of Medicine, Augusta University, Augusta, GA 30912, United States.
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Simó-Servat O, Hernández C, Simó R. The ERM Complex: A New Player Involved in Diabetes-induced Vascular Leakage. Curr Med Chem 2020; 27:3012-3022. [PMID: 30332939 DOI: 10.2174/0929867325666181016162327] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 09/27/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Microvascular complications remain an important cause of morbidity in diabetic patients, and they are associated with a significant economic burden for healthcare systems. Vascular leakage is one of the earlier hallmarks in diabetic microvascular complications. Ezrin, Radixin and Moesin (ERM) proteins have recently been involved in vascular dysfunction under the effect of molecular mediators of diabetes complications. In this review, we will present the available evidence regarding the role of these proteins in vascular leakage and their putative implication in diabetic microvascular complications. METHODS AND RESULTS A comprehensive literature search of the electronic MEDLINE database was performed between November 2017 and January 2018. As a result, 36 articles have been reviewed and discussed. DISCUSSION ERM proteins are cytoskeleton-membrane linkers, and when activated in endothelial cells are able to induce cytoskeleton reorganization in stress fibers leading to the disassembly of focal adhesions and the formation of paracellular gaps which result in an increase of vascular permeability. The activation of these proteins is induced by mediators involved in diabetic complications such as PKC activation, TNF-α, AGEs and oxidative stress. In conclusion, ERMs play an essential role in endothelium homeostasis and can be envisaged as a new therapeutic molecular target for preventing or arresting diabetes-induced vascular leakage.
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Affiliation(s)
- Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Barcelona, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Barcelona, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), Madrid, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Barcelona, Spain.,Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), Madrid, Spain
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Mazzoli V, Zhong LH, Dang VT, Shi Y, Werstuck GH. Characterization of Retinal Microvascular Complications and the Effects of Endoplasmic Reticulum Stress in Mouse Models of Diabetic Atherosclerosis. Invest Ophthalmol Vis Sci 2020; 61:49. [PMID: 32852545 PMCID: PMC7452854 DOI: 10.1167/iovs.61.10.49] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/27/2020] [Indexed: 11/24/2022] Open
Abstract
Purpose Recent evidence suggests that there is a correlation between the micro- and macrovascular complications of diabetes mellitus. The aim of this study is to investigate the molecular mechanisms by which diabetes promotes the development of microvascular disease (diabetic retinopathy [DR]) through characterization of the effects of hyperglycemia in the retina of mouse models of diabetic atherosclerosis. Methods Hyperglycemia was induced in apolipoprotein E-deficient (ApoE-/-) mice, a model of accelerated atherosclerosis, either through streptozotocin (STZ) injection or introduction of the Ins2Akita mutation (ApoE-/-Ins2+/Akita). Another subset of ApoE-/- mice was supplemented with glucosamine (GlcN). To attenuate atherosclerosis, subsets of mice from each experimental group were treated with the chemical chaperone, 4-phenylbutyric acid (4PBA). Eyes from 15-week-old mice were either trypsin digested and stained with periodic acid-Schiff (PAS) or frozen for cryostat sectioning and immunostained for endoplasmic reticulum (ER) stress markers, including C/EBP homologous protein (CHOP) and 78-kDa glucose-regulated protein (GRP78). PAS-stained retinal flatmounts were analyzed for microvessel density, acellular capillaries, and pericyte ghosts. Results Features of DR, including pericyte ghosts and reduced microvessel density, were observed in hyperglycemic and GlcN-supplemented mice. Treatment with 4PBA reduced ER stress in the retinal periphery and attenuated DR in the experimental groups. Conclusions Mouse models of diabetic atherosclerosis show characteristic pathologies of DR that correlate with atherosclerosis. The increased magnitude of these changes and responses to 4PBA in the peripheral retina suggest that future studies should be aimed at assessing regional differences in mechanisms of ER stress-related pathways in these mouse models.
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Affiliation(s)
- Vienna Mazzoli
- Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Lexy H. Zhong
- Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Vi T. Dang
- Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada
| | - Yuanyuan Shi
- Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Geoff H. Werstuck
- Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada
- Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
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Torres-Costa S, Alves Valente MC, Falcão-Reis F, Falcão M. Cytokines and Growth Factors as Predictors of Response to Medical Treatment in Diabetic Macular Edema. J Pharmacol Exp Ther 2020; 373:445-452. [PMID: 32245883 DOI: 10.1124/jpet.119.262956] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 03/30/2020] [Indexed: 03/08/2025] Open
Abstract
Diabetic macular edema (DME) is the most common cause of visual loss in patients with diabetes. Antivascular endothelial growth factors (anti-VEGF) agents are first-line therapy for DME. Nevertheless, up to 60% of patients (depending on the anti-VEGF drug used) have an inadequate response to anti-VEGF treatment. Several cytokines are increased in aqueous humor of patients with DME. Differences in response to treatment may be related to baseline cytokine levels. Intravitreal corticosteroids may be used as an alternative to anti-VEGF agents. Steroids have a different pharmacological profile and act on different pathophysiologic mechanisms. Their effect on aqueous humor cytokines is different from the effect of anti-VEGF therapy. This review highlights the major cytokines involved in DME and evaluates whether baseline cytokine levels could be predictors of response to treatment in DME. SIGNIFICANCE STATEMENT: Antivascular endothelial growth factor (anti-VEGF) agents are efficient as diabetic macular edema (DME) treatment. However, in some cases, DME fails to respond to anti-VEGF intravitreal injections. Changes in cytokine levels after treatment supported the idea that other cytokines than VEGF are implicated in DME pathogenesis and could be predictors of response to anti-VEGF treatment or corticosteroids allowing targeted and individualized therapy guided by cytokine levels.
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Affiliation(s)
- Sónia Torres-Costa
- Department of Ophthalmology, Centro Hospitalar Universitário de São João, Porto, Portugal (S.T.-C., F.F.-R., M.F.); Faculty of Medicine, University of Porto, Porto, Portugal (M.C.A.V.); and Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal (F.F.-R., M.F.)
| | - Maria Carolina Alves Valente
- Department of Ophthalmology, Centro Hospitalar Universitário de São João, Porto, Portugal (S.T.-C., F.F.-R., M.F.); Faculty of Medicine, University of Porto, Porto, Portugal (M.C.A.V.); and Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal (F.F.-R., M.F.)
| | - Fernando Falcão-Reis
- Department of Ophthalmology, Centro Hospitalar Universitário de São João, Porto, Portugal (S.T.-C., F.F.-R., M.F.); Faculty of Medicine, University of Porto, Porto, Portugal (M.C.A.V.); and Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal (F.F.-R., M.F.)
| | - Manuel Falcão
- Department of Ophthalmology, Centro Hospitalar Universitário de São João, Porto, Portugal (S.T.-C., F.F.-R., M.F.); Faculty of Medicine, University of Porto, Porto, Portugal (M.C.A.V.); and Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal (F.F.-R., M.F.)
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Parravano M, Scarinci F, Parisi V, Giorno P, Giannini D, Oddone F, Varano M. Citicoline and Vitamin B 12 Eye Drops in Type 1 Diabetes: Results of a 3-year Pilot Study Evaluating Morpho-Functional Retinal Changes. Adv Ther 2020; 37:1646-1663. [PMID: 32180131 PMCID: PMC7140741 DOI: 10.1007/s12325-020-01284-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION This study aimed to evaluate the effect of treatment with eye drops containing citicoline and vitamin B12 on changes in function of the inner retina, morphology of the inner and outer retina, and microvascular condition in patients with type 1 diabetes (DM1) with mild signs of non-proliferative diabetic retinopathy (NPDR) during 3 years of follow-up. METHODS A pilot study with prospective, randomized, and double-masked design was conducted to address the aims. Twenty patients with DM1 were enrolled and randomly divided into two groups: the DC group comprising patients treated with citicoline and vitamin B12 eye drops (10 patients; mean age ± standard deviation, 46.86 ± 8.78 years) and the DP group comprising those treated with placebo (10 patients; mean age ± standard deviation, 47.89 ± 7.74 years). In the DC group, one eye of each patient was treated with citicoline and vitamin B12 eye drops (OMK2®, Omikron Italia srl, Italy, 3 drops/day), while in the DP group, it was treated with placebo (eye drops containing hypromellose 0.3%, 3 drops/day) for a 3-year period. In both groups, Humphrey Matrix frequency doubling technology (FDT), spectral domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA), and adaptive optics (AO) were applied at baseline and 12, 24, and 36 months of the follow-up period. RESULTS In the results of follow-up evaluation, the DC and DP groups were significantly different: Significant reduction in function in terms of 10-2 FDT mean sensitivity and in morphology reflected by an increase in inner nuclear layer thickness and decrease in other plexiform layer thickness and foveal vessel density were observed in the DP group, while no such significant changes were observed in the DC group in the long term. CONCLUSIONS This pilot study indicated that patients with DM1 with mild signs of diabetic retinopathy (DR) who underwent treatment with citicoline and vitamin B12 eye drops for a 3-year duration achieved stabilization or decreased rate of functional impairment, neuroretinal degeneration, and microvascular damage. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT04009980.
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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: 22] [Impact Index Per Article: 4.4] [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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Shi Y, Qian J, Zhang F, Jia B, Liu X, Hu Y, Zhang Q, Yang Y, Sun D, Jiang L. Low molecular weight heparin (nadroparin) improves placental permeability in rats with gestational diabetes mellitus via reduction of tight junction factors. Mol Med Rep 2019; 21:623-630. [PMID: 31974593 PMCID: PMC6947895 DOI: 10.3892/mmr.2019.10868] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 10/15/2019] [Indexed: 12/26/2022] Open
Abstract
Placental structural abnormalities and dysfunction in those with gestational diabetes mellitus (GDM) can lead to increased placental permeability, which is in turn related to a poorer maternal and fetal prognosis. The present study sought to assess whether increased placental permeability in rats with GDM was accompanied by alterations in tight junction (TJ) factors and to evaluate the impact of low molecular weight heparin (LMWH) on these factors. The present study was conducted using pregnant female rats that were randomized into control, GDM and GDM + LMWH groups. Diabetes was induced via intraperitoneal administration of streptozotocin to rats in the GDM and GDM + LMWH groups, whereas rats in the GDM + LMWH group received daily subcutaneous LMWH starting on day 5 of pregnancy. On gestational day 16, all rats were sacrificed and Evans Blue (EB) assay was used to gauge vascular permeability based on EB dye leakage. Transmission electron microscopy was further used to assess TJ structures, and the TJ proteins zonular occludens-1 (ZO-1) and occludin (OCLN) were assessed using immunohistochemistry and western blotting. Blood samples were obtained from the abdominal aorta for ELISA measurements of advanced glycation end products (AGEs) concentrations, and placental receptor for AGEs (RAGE) and vascular endothelial growth factor (VEGF) expression was assessed using reverse transcription-quantitative PCR. In addition, western blotting was used to measure placental NF-κB. Compared with in the control group, EB leakage was markedly increased in GDM group rats; this was associated with reduced ZO-1 and OCLN expression. Conversely, LMWH attenuated this increase in placental permeability in rats with GDM and also mediated a partial recovery of ZO-1 and OCLN expression. Blood glucose and serum AGEs concentrations did not differ between the GDM and GDM + LMWH groups. Furthermore, LMWH treatment resulted in decreases in RAGE and VEGF mRNA expression levels, which were upregulated in the GDM group, whereas it had the opposite effect on the expression of NF-κB. In conclusion, GDM was associated with increased placental permeability and this may be linked with changes in TJs. LMWH intervention mediated protection against this GDM-associated shift in placental permeability via the RAGE/NF-κB pathway.
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Affiliation(s)
- Yuehua Shi
- Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Jie Qian
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Feng Zhang
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Beibei Jia
- Department of Pediatrics, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, Jiangsu 214002, P.R. China
| | - Xiaoyan Liu
- Maternal and Child Health Care Center, Nanjing, Jiangsu 211100, P.R. China
| | - Yan Hu
- Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Qinfen Zhang
- Department of Obstetrics and Gynecology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
| | - Ye Yang
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumors, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Dongdong Sun
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumors, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Li Jiang
- Department of Pediatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China
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George AK, Homme RP, Majumder A, Tyagi SC, Singh M. Effect of MMP-9 gene knockout on retinal vascular form and function. Physiol Genomics 2019; 51:613-622. [PMID: 31709889 DOI: 10.1152/physiolgenomics.00041.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Retinal degeneration from inherited gene mutation(s) is a common cause of blindness because of structural and functional alterations in photoreceptors. Accordingly, various approaches are being tested to ameliorate or even cure neuroretinal blinding conditions in susceptible patients by employing neuroprotective agents, gene therapeutics, optogenetics, regenerative therapies, and retinal prostheses. The FVB/NJ mouse strain inherently has a common Pde6b rd1 homozygous allele that renders its progeny blind by the time pups reach weaning age. To study the role matrix metalloproteinase-9 (MMP-9) in retinal structure and function, we examined a global MMP-9 knockout (KO) mouse model that has been engineered on the same FVB/NJ background to test the hypothesis whether lack of MMP-9 activity diminishes neuroretinal degenerative changes and thus helps improve the vision. We compared side-by-side various aspects of the ocular physiology in the wild-type (WT) C57BL/6J, FVB/NJ, and MMP-9 KO strains of mice. The results suggest that MMP-9 KO mice display subdued changes in their retinae as reflected by both structural and functional enhancement in the overall ocular neurophysiological parameters. Altogether, the findings appear to have clinical relevance for targeting conditions wherein MMPs and their overactivities are suspected to play dominant pathophysiological roles in advancing neurodegenerative retinal diseases.
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Affiliation(s)
- Akash K George
- Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Rubens P Homme
- Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Avisek Majumder
- Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California
| | - Suresh C Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky
| | - Mahavir Singh
- Eye and Vision Science Laboratory, Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky
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Eshaq RS, Harris NR. Hyperglycemia-induced ubiquitination and degradation of β-catenin with the loss of platelet endothelial cell adhesion molecule-1 in retinal endothelial cells. Microcirculation 2019; 27:e12596. [PMID: 31628816 DOI: 10.1111/micc.12596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 09/13/2019] [Accepted: 10/16/2019] [Indexed: 10/25/2022]
Abstract
OBJECTIVE Increased retinal vascular permeability is one of the earliest manifestations of diabetic retinopathy. The aim of this study was to investigate the role of hyperglycemia-induced platelet endothelial cell adhesion molecule-1 loss on retinal vascular permeability via the β-catenin pathway. METHODS Type I diabetes was induced in male Wistar rats using streptozotocin injections, with age-matched non-diabetic rats as controls. Rat retinal microvascular endothelial cells were grown under normal or high glucose conditions for 6 days. Small interfering Ribonucleic Acid was used to knock down platelet endothelial cell adhesion molecule-1 in rat retinal microvascular endothelial cells for loss-of-function studies. Retinas and rat retinal microvascular endothelial cells were subjected to Western blot, immunofluorescence labeling, and co-immunoprecipitation analyses to assess protein levels and interactions. A biotinylated gelatin and fluorescein isothiocyanate-avidin assay was used for retinal endothelial cell permeability studies. RESULTS β-catenin, β-catenin/platelet endothelial cell adhesion molecule-1 interaction, active Src homology 2 domain-containing protein tyrosine phosphatase were significantly decreased, while β-catenin ubiquitination levels and endothelial permeability were significantly increased, in hyperglycemic retinal endothelial cells. Similar results were observed with platelet endothelial cell adhesion molecule-1 partial knockdown, where β-catenin and active Src homology 2 domain-containing protein tyrosine phosphatase levels were decreased, while phospho-β-catenin and retinal endothelial cell permeability were increased. CONCLUSION Platelet endothelial cell adhesion molecule-1 loss may contribute to increased retinal endothelial cell permeability by attenuating β-catenin levels under hyperglycemic conditions.
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Affiliation(s)
- Randa S Eshaq
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
| | - Norman R Harris
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
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DECREASED RETINAL CAPILLARY DENSITY IS ASSOCIATED WITH A HIGHER RISK OF DIABETIC RETINOPATHY IN PATIENTS WITH DIABETES. Retina 2019; 39:1710-1719. [DOI: 10.1097/iae.0000000000002232] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Akla N, Viallard C, Popovic N, Lora Gil C, Sapieha P, Larrivée B. BMP9 (Bone Morphogenetic Protein-9)/Alk1 (Activin-Like Kinase Receptor Type I) Signaling Prevents Hyperglycemia-Induced Vascular Permeability. Arterioscler Thromb Vasc Biol 2019; 38:1821-1836. [PMID: 29880487 DOI: 10.1161/atvbaha.118.310733] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Objective- Diabetic macular edema is a major cause of visual impairment. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. However, long-term intravitreal use of anti-VEGFs is associated with potential safety issues, and the identification of alternative regulators of vascular permeability may provide safer therapeutic options. The vascular specific BMP (bone morphogenetic protein) receptor ALK1 (activin-like kinase receptor type I) and its circulating ligand BMP9 have been shown to be potent vascular quiescence factors, but their role in the context of microvascular permeability associated with hyperglycemia has not been evaluated. Approach and Results- We investigated Alk1 signaling in hyperglycemic endothelial cells and assessed whether BMP9/Alk1 signaling could modulate vascular permeability. We show that high glucose concentrations impair Alk1 signaling, both in cultured endothelial cells and in a streptozotocin model of mouse diabetes mellitus. We observed that Alk1 signaling participates in the maintenance of vascular barrier function, as Alk1 haploinsufficiency worsens the vascular leakage observed in diabetic mice. Conversely, sustained delivery of BMP9 by adenoviral vectors significantly decreased the loss of retinal barrier function in diabetic mice. Mechanistically, we demonstrate that Alk1 signaling prevents VEGF-induced phosphorylation of VE-cadherin and induces the expression of occludin, thus strengthening vascular barrier functions. Conclusions- From these data, we suggest that by preventing retinal vascular permeability, BMP9 could serve as a novel therapeutic agent for diabetic macular edema.
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Affiliation(s)
- Naoufal Akla
- From the Department of Biochemistry (N.A., P.S.).,University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.)
| | - Claire Viallard
- Department of Molecular Biology (C.V., B.L.).,University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.)
| | - Natalija Popovic
- Department of Biomedical Sciences (N.P., C.L.G., B.L.).,University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.)
| | - Cindy Lora Gil
- Department of Biomedical Sciences (N.P., C.L.G., B.L.).,University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.)
| | - Przemyslaw Sapieha
- From the Department of Biochemistry (N.A., P.S.).,Department of Ophthalmology (P.S., B.L.).,University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.)
| | - Bruno Larrivée
- Department of Molecular Biology (C.V., B.L.).,Department of Biomedical Sciences (N.P., C.L.G., B.L.).,Department of Ophthalmology (P.S., B.L.).,University of Montreal, Quebec, Canada; and Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada (N.A., C.V., N.P., C.L.G., P.S., B.L.)
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George AK, Homme RP, Majumder A, Laha A, Metreveli N, Sandhu HS, Tyagi SC, Singh M. Hydrogen sulfide intervention in cystathionine-β-synthase mutant mouse helps restore ocular homeostasis. Int J Ophthalmol 2019; 12:754-764. [PMID: 31131233 DOI: 10.18240/ijo.2019.05.09] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 02/24/2019] [Indexed: 02/03/2023] Open
Abstract
AIM To investigate the applications of hydrogen sulfide (H2S) in eye-specific ailments in mice. METHODS Heterozygous cystathionine-β-synthase (CBS+/-) and wild-type C57BL/6J (WT) mice fed with or without high methionine diet (HMD) were administered either phosphate buffered saline (PBS) or the slow-release H2S donor: GYY4137. Several analyses were performed to study GYY4137 effects by examining retinal lysates for key protein expressions along with plasma glutamate and glutathione estimations. Intraocular pressure (IOP) was monitored during GYY4137 treatment; barium sulfate and bovine serum albumin conjugated fluorescein isothiocyanate (BSA-FITC) angiographies were performed for examining vasculature and its permeability post-treatment. Vision-guided behavior was also tested employing novel object recognition test (NORT) and light-dark box test (LDBT) recordings. RESULTS CBS deficiency (CBS+/-) coupled with HMD led disruption of methionine/homocysteine (Hcy) metabolism leading to hyperhomocysteinemia (HHcy) in CBS+/- mice as reflected by increased Hcy, and s-adenosylhomocysteine hydrolase (SAHH) levels. Unlike CBS, cystathionine-γ lyase (CSE), methylenetetrahydrofolate reductase (MTHFR) levels which were reduced but compensated by GYY4137 intervention. Heightened oxidative and endoplasmic reticulum (ER) stress responses were mitigated by GYY4137 effects along with enhanced glutathione (GSH) levels. Increased glutamate levels in CBS+/- strain were prominent than WT mice and these mice also exhibited higher IOP that was lowered by GYY4137 treatment. CBS deficiency also resulted in vision-guided behavioral impairment as revealed by NORT and LDBT findings. Interestingly, GYY4137 was able to improve CBS+/- mice behavior together with lowering their glutamate levels. Blood-retinal barrier (BRB) appeared compromised in CBS+/- with vessels' leakage that was mitigated in GYY4137 treated group. This corroborated the results for occludin (an integral plasma membrane protein of the cellular tight junctions) stabilization. CONCLUSION Findings reveal that HHcy-induced glutamate excitotoxicity, oxidative damage, ER-stress and vascular permeability alone or together can compromise ocular health and that GYY4137 could serve as a potential therapeutic agent for treating HHcy induced ocular disorders.
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Affiliation(s)
- Akash K George
- Eye and Vision Science Laboratory, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
| | - Rubens P Homme
- Eye and Vision Science Laboratory, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
| | - Avisek Majumder
- Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA
| | - Anwesha Laha
- Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
| | - Naira Metreveli
- Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
| | - Harpal S Sandhu
- Department of Ophthalmology and Visual Sciences; Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
| | - Suresh C Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
| | - Mahavir Singh
- Eye and Vision Science Laboratory, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.,Department of Physiology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
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Wang B, Li PK, Ma JX, Chen D. Therapeutic Effects of a Novel Phenylphthalimide Analog for Corneal Neovascularization and Retinal Vascular Leakage. Invest Ophthalmol Vis Sci 2019; 59:3630-3642. [PMID: 30029250 PMCID: PMC6054429 DOI: 10.1167/iovs.18-24015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Purpose Neovascularization (NV) and retinal vascular leakage are major causes of impaired vision in ocular diseases. The purpose of this study was to identify novel phenylphthalimide analogs with therapeutic effects on NV and vascular leakage and to explore the mechanism of action. Methods Antiangiogenic activities of novel phenylphthalimide analogs were assessed in vitro by using VEGF ELISA and endothelial cell proliferation assay. Their efficacies on retinal vascular leakage were evaluated using rat models of oxygen-induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetes. The in vivo antiangiogenic activity was evaluated using topical administration in the alkali burn-induced corneal NV model. The expression of VEGF and intercellular adhesion molecule-1 (ICAM-1) were measured using ELISA. Results Thalidomide and three novel analogs all showed inhibitory effects on endothelial cell proliferation and VEGF expression in vitro. Through intravitreal injection, all of the compounds reduced retinal vascular leakage in the OIR and STZ-induced diabetic models. Among these compounds, (2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione (DAID) displayed the most potent efficacy and reduced retinal vascular leakage in a dose-dependent manner in both the OIR and STZ-diabetes models. Topical administration of DAID also inhibited alkali burn-induced corneal NV. Furthermore, DAID attenuated the overexpression of VEGF and ICAM-1 in the retina of the OIR model. Intravitreal injection of DAID did not result in any detectable side effects, as shown by electroretinogram and retinal histological analysis. Conclusions DAID is a novel phenylphthalimide analog with potent effects on NV and retinal vascular leakage through downregulation of VEGF and inflammatory factors and has therapeutic potential.
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Affiliation(s)
- Bing Wang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.,Department of Ophthalmology, Fujian Medical University Union Hospital, Fujian Province, China
| | - Pui-Kai Li
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, Ohio, United States
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Danyang Chen
- Charlesson, LLC, Oklahoma City, Oklahoma, United States
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NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy. Proc Natl Acad Sci U S A 2019; 116:4538-4547. [PMID: 30787185 DOI: 10.1073/pnas.1814711116] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
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Sarao V, Veritti D, Maurutto E, Rassu N, Borrelli E, Loewenstein A, Sadda S, Lanzetta P. Pharmacotherapeutic management of macular edema in diabetic subjects undergoing cataract surgery. Expert Opin Pharmacother 2018; 19:1551-1563. [PMID: 30185069 DOI: 10.1080/14656566.2018.1516206] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Cataracts and diabetes are widespread pathologies that are of growing concern to the global population. In diabetic patients who have had cataract surgery, the worsening of preexisting diabetic macular edema or occurrence of pseudophakic cystoid macular edema are common causes of visual impairment even with the most advanced surgical techniques available today for phacoemulsification. AREAS COVERED In this review, the authors assess the available literature to evaluate and compare different drugs, with the aim of establishing the best pharmacological strategies for the prevention and treatment of macular edema in diabetic patients undergoing cataract surgery. EXPERT OPINION Guidelines for the optimal management of diabetic macular edema in conjunction with cataract surgery or treatment of pseudophakic cystoid macular edema in diabetic patients are still lacking. To treat these conditions, clinicians need to understand the pharmacokinetics, posology, and efficacy of available drugs: topical non-steroidal anti-inflammatory drugs (NSAIDs), intravitreal anti-vascular endothelial growth factors (VEGFs), and both topical and intravitreal steroids. Diabetic patients undergoing cataract surgery should receive topical NSAIDs to prevent pseudophakic cystoid macular edema. Intravitreal anti-VEGFs and steroids, in association with cataract surgery, are indicated for patients with preexisting diabetic macular edema or those at high risk of macular edema after surgery.
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Affiliation(s)
- Valentina Sarao
- a Department of Medicine - Ophthalmology , University of Udine , Udine , Italy.,b Istituto Europeo di Microchirurgia Oculare (IEMO) , Udine , Italy
| | - Daniele Veritti
- a Department of Medicine - Ophthalmology , University of Udine , Udine , Italy.,b Istituto Europeo di Microchirurgia Oculare (IEMO) , Udine , Italy
| | - Erica Maurutto
- b Istituto Europeo di Microchirurgia Oculare (IEMO) , Udine , Italy
| | - Nicolò Rassu
- b Istituto Europeo di Microchirurgia Oculare (IEMO) , Udine , Italy
| | - Enrico Borrelli
- c Ophthalmology Clinic, Department of Medicine and Science of Ageing , University G. D'Annunzio Chieti-Pescara , Chieti , Italy
| | | | - Srinivas Sadda
- e Doheny Eye Institute , Los Angeles , CA , USA.,f Department of Ophthalmology, David Geffen School of Medicine , University of California , Los Angeles , CA , USA
| | - Paolo Lanzetta
- a Department of Medicine - Ophthalmology , University of Udine , Udine , Italy.,b Istituto Europeo di Microchirurgia Oculare (IEMO) , Udine , Italy
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Horváth H, Kovács I, Sándor GL, Czakó C, Mallár K, Récsán Z, Somogyi A, Nagy ZZ, Ecsedy M. Choroidal thickness changes in non-treated eyes of patients with diabetes: swept-source optical coherence tomography study. Acta Diabetol 2018; 55:927-934. [PMID: 29876669 DOI: 10.1007/s00592-018-1169-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 05/27/2018] [Indexed: 11/26/2022]
Abstract
AIMS To measure choroidal thickness (CT) in diabetic eyes and its correlation with metabolic status and the severity of diabetic retinopathy (DR). MATERIALS AND METHODS Prospective cross-sectional study using swept-source optical coherence tomography. CT maps of 96 treatment naïve eyes of 48 patients with diabetes were compared to 46 eyes of 23 healthy controls. CT changes and their relation to diabetes, age, gender, disease duration, hypertension (HT), hemoglobin A1c level, type and severity of DR were evaluated. RESULTS A significantly thinner choroid was measured in patients with diabetes compared to controls (p < 0.009). In the diabetic group age, gender, disease duration and HT were significantly correlated with CT in univariable regression models (p < 0.05). In multivariable analysis, the duration of diabetes significantly negatively correlated with CT (p = 0.02). According to analysis of variance, there was a significant difference among means of CT in different stages of DR (p = 0.002), with thinner CT in cases with more advanced DR. In a multivariable predictive model, thinner CT was associated with an increased risk for the presence of DR (p = 0.02). CONCLUSIONS Diabetes mellitus itself and the severity of DR affect CT significantly, even after adjusting for the effects of confounding systemic factors. Disease duration seems to be associated with a reduction of choroidal thickness. Decreased CT proved to be correlated with the severity of DR.
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Affiliation(s)
- Hajnalka Horváth
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary.
| | - Illés Kovács
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
| | - Gábor László Sándor
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
| | - Cecília Czakó
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
| | - Klaudia Mallár
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
| | - Zsuzsanna Récsán
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
| | - Anikó Somogyi
- 2nd Department of Internal Medicine, Semmelweis University, Szentkirályi 46, Budapest, 1088, Hungary
| | - Zoltán Zsolt Nagy
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
| | - Mónika Ecsedy
- Department of Ophthalmology, Semmelweis University, Mária 39, Budapest, 1085, Hungary
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46
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Mugisho OO, Green CR, Kho DT, Zhang J, Graham ES, Acosta ML, Rupenthal ID. The inflammasome pathway is amplified and perpetuated in an autocrine manner through connexin43 hemichannel mediated ATP release. Biochim Biophys Acta Gen Subj 2018; 1862:385-393. [DOI: 10.1016/j.bbagen.2017.11.015] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/30/2017] [Accepted: 11/16/2017] [Indexed: 12/20/2022]
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The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. Int J Mol Sci 2018; 19:ijms19010110. [PMID: 29301251 PMCID: PMC5796059 DOI: 10.3390/ijms19010110] [Citation(s) in RCA: 267] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 12/15/2022] Open
Abstract
Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be part of diabetic retinopathy. Microglia, the resident monocytes of the retina, are activated due to a complex interplay between the different cell types of the retina and diverse pathological pathways. The trigger for developing diabetic retinopathy is diabetes-induced hyperglycemia, accompanied by leukostasis and vascular leakages. Transcriptional changes in activated microglia, mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and extracellular signal–regulated kinase (ERK) signaling pathways, results in release of various pro-inflammatory mediators, including cytokines, chemokines, caspases and glutamate. Activated microglia additionally increased proliferation and migration. Among other consequences, these changes in microglia severely affected retinal neurons, causing increased apoptosis and subsequent thinning of the nerve fiber layer, resulting in visual loss. New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients.
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Hooper P, Boucher MC, Cruess A, Dawson KG, Delpero W, Greve M, Kozousek V, Lam WC, Maberley DAL. Excerpt from the Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy. Can J Ophthalmol 2017; 52 Suppl 1:S45-S74. [PMID: 29074014 DOI: 10.1016/j.jcjo.2017.09.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Affiliation(s)
- Philip Hooper
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)..
| | - Marie Carole Boucher
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Alan Cruess
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Keith G Dawson
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Walter Delpero
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Mark Greve
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Vladimir Kozousek
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - Wai-Ching Lam
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
| | - David A L Maberley
- Philip Hooper, London, ON (Chair) (retina and uveitis); Marie Carole Boucher, Montreal, QC (retina and teleophthalmology); Alan Cruess, Halifax, NS (retina); Keith G. Dawson, Vancouver, BC (endocrinology); Walter Delpero, Ottawa, ON (cataract and strabismus); Mark Greve, Edmonton, AB (retina and teleophthalmology); Vladimir Kozousek, Halifax, NS (medical retina); Wai-Ching Lam, Toronto, ON (retina and research); David A.L. Maberley, Vancouver, BC (retina)
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Mugisho OO, Green CR, Zhang J, Binz N, Acosta ML, Rakoczy E, Rupenthal ID. Immunohistochemical Characterization of Connexin43 Expression in a Mouse Model of Diabetic Retinopathy and in Human Donor Retinas. Int J Mol Sci 2017; 18:ijms18122567. [PMID: 29186067 PMCID: PMC5751170 DOI: 10.3390/ijms18122567] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 11/21/2017] [Accepted: 11/24/2017] [Indexed: 12/25/2022] Open
Abstract
Diabetic retinopathy (DR) develops due to hyperglycemia and inflammation-induced vascular disruptions in the retina with connexin43 expression patterns in the disease still debated. Here, the effects of hyperglycemia and inflammation on connexin43 expression in vitro in a mouse model of DR and in human donor tissues were evaluated. Primary human retinal microvascular endothelial cells (hRMECs) were exposed to high glucose (HG; 25 mM) or pro-inflammatory cytokines IL-1β and TNF-α (10 ng/mL each) or both before assessing connexin43 expression. Additionally, connexin43, glial fibrillary acidic protein (GFAP), and plasmalemma vesicular associated protein (PLVAP) were labeled in wild-type (C57BL/6), Akita (diabetic), and Akimba (DR) mouse retinas. Finally, connexin43 and GFAP expression in donor retinas with confirmed DR was compared to age-matched controls. Co-application of HG and cytokines increased connexin43 expression in hRMECs in line with results seen in mice, with no significant difference in connexin43 or GFAP expression in Akita but higher expression in Akimba compared to wild-type mice. On PLVAP-positive vessels, connexin43 was higher in Akimba but unchanged in Akita compared to wild-type mice. Connexin43 expression appeared higher in donor retinas with confirmed DR compared to age-matched controls, similar to the distribution seen in Akimba mice and correlating with the in vitro results. Although connexin43 expression seems reduced in diabetes, hyperglycemia and inflammation present in the pathology of DR seem to increase connexin43 expression, suggesting a causal role of connexin43 channels in the disease progression.
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Affiliation(s)
- Odunayo O Mugisho
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland 1142, New Zealand.
- School of Optometry and Vision Science, New Zealand National Eye Centre, University of Auckland, Auckland 1142, New Zealand.
| | - Colin R Green
- Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland 1142, New Zealand.
| | - Jie Zhang
- Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland 1142, New Zealand.
| | - Nicolette Binz
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth 6009, Western Australia, Australia.
| | - Monica L Acosta
- School of Optometry and Vision Science, New Zealand National Eye Centre, University of Auckland, Auckland 1142, New Zealand.
| | - Elizabeth Rakoczy
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth 6009, Western Australia, Australia.
| | - Ilva D Rupenthal
- Buchanan Ocular Therapeutics Unit, Department of Ophthalmology, New Zealand National Eye Centre, University of Auckland, Auckland 1142, New Zealand.
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50
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Deng G, Moran EP, Cheng R, Matlock G, Zhou K, Moran D, Chen D, Yu Q, Ma JX. Therapeutic Effects of a Novel Agonist of Peroxisome Proliferator-Activated Receptor Alpha for the Treatment of Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2017; 58:5030-5042. [PMID: 28979999 PMCID: PMC5633008 DOI: 10.1167/iovs.16-21402] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Purpose Clinical studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) agonist fenofibrate has therapeutic effects on diabetic retinopathy (DR). The purpose of this study was to identify a novel PPARα agonist and to evaluate its beneficial effects on DR. Methods The transcriptional activity of PPARα was measured by a luciferase-based promoter assay. TUNEL was used to evaluate apoptosis in retinal precursor cells (R28). Diabetes was induced in rats by injection of streptozotocin. Retinal inflammation was examined using leukostasis assay, and retinal vascular leakage was measured using permeability assay. Retinal function was measured using electroretinogram (ERG) recording, and retinal apoptosis was quantified using the cell death ELISA. The anti-angiogenic effect was evaluated in the oxygen-induced retinopathy (OIR) model. Results A compound, 7-chloro-8-methyl-2-phenylquinoline-4-carboxylic acid (Y-0452), with a chemical structure distinct from existing PPARα agonists, activated PPARα transcriptional activity and upregulated PPARα expression. Y-0452 significantly inhibited human retinal capillary endothelial cell migration and tube formation. The compound also protected R28 cells against apoptosis and inhibited NF-κB signaling in R28 cells exposed to palmitate. In diabetic rats, Y-0452 ameliorated leukostasis and vascular leakage in the retina. In addition, Y-0452 preserved the retinal function and reduced retinal cell death in diabetic rats. Y-0452 also alleviated retinal neovascularization in the OIR model. Conclusions Y-0452 is a novel PPARα agonist and has therapeutic potential for DR.
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Affiliation(s)
- Guotao Deng
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.,Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Elizabeth P Moran
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Rui Cheng
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Greg Matlock
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Kelu Zhou
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - David Moran
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Danyang Chen
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
| | - Qiang Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jian-Xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
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