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Wang H, Xue J, Song Y, Li D, Wei C, Wan L. Deciphering the Transformed bacterial ocular surface microbiome in diabetic mice and its Consequential influence on corneal wound healing restoration. Exp Eye Res 2025; 255:110350. [PMID: 40122365 DOI: 10.1016/j.exer.2025.110350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/13/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Abstract
To obtain a profound understanding of microbiome variations and their associations with diabetic cornea wound healing, a type 1 diabetic mouse model and a corneal epithelial wound healing model were established. Corneal tissues from diabetic mice and healthy controls were collected. The 2bRAD sequencing for microbiome (2bRAD-M)technique was used to analyze the ocular microbiome profiles. Fifty-five distinct bacterial species were identified through alignment against the 2bRAD-M database. Among all the species identified on the corneal wound, 17 (30.91 %) unique species were discovered on the diabetic epithelium side, 13 (23.64 %) on the non-diabetic epithelium side, and 25 (45.45 %) species were common to both. The top five most abundant bacterial species on the non-diabetic side were Exiguobacterium sibiricum (26.50 %), Enterobacter hormaechei (13.37 %), Brevibacillus agri (6.24 %), Ralstonia sp. UNC404CL21Col (6.11 %), and Cupriavidus pauculus (5.71 %). On the diabetic side, the predominant five species were Methylobacterium sp. MB200 (38.73 %), Exiguobacterium sibiricum (11.58 %), Acinetobacter johnsonii (9.80 %), Corynebacterium glutamicum (6.46 %), and Corynebacterium stationis (5.71 %). Increased levels of gram-negative bacilli, such as Methylobacterium, in the diabetic ocular surface microbiota may be involved in the delayed healing of corneal wounds. Gatifloxacin eye drops with antibacterial activity against gram-negative bacteria were applied to the ocular surface. The corneal epithelium of diabetic mice healed more rapidly after the application of gatifloxacin eye drops. The changes in the ocular surface microbiota of diabetic corneal wounds may be related to delayed healing of the corneal epithelium in diabetic mice, providing a new research target for the investigation of this pathology.
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Affiliation(s)
- Huifeng Wang
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, China; State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, China; School of Ophthalmology, Shandong First Medical University, China
| | - Junfa Xue
- Shanghai Fosun Pharmaceutical (Group) Co., Ltd., 9th Floor, No. 510, Caoyang Road, Shanghai, China
| | - Yi Song
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, China; State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, China; School of Ophthalmology, Shandong First Medical University, China
| | - Dewei Li
- Eye Institute of Shandong First Medical University, China
| | - Chao Wei
- State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, China; School of Ophthalmology, Shandong First Medical University, China; Eye Institute of Shandong First Medical University, China
| | - Luqin Wan
- Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, China; State Key Laboratory Cultivation Base, Shandong Key Laboratory of Eye Diseases, China; School of Ophthalmology, Shandong First Medical University, China.
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Sandoval-Castellanos AM, Qin S, Ma L, Ferreira F, Reid B, Zhao M. Oxygen uptake at the ocular surface in diabetic animals is impaired in response to central corneal injury. Exp Eye Res 2025; 255:110384. [PMID: 40204226 DOI: 10.1016/j.exer.2025.110384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 03/13/2025] [Accepted: 04/07/2025] [Indexed: 04/11/2025]
Abstract
Poor wound healing is one of the most devastating complications in late-stage diabetic patients. The avascular cornea does not rely on circulation for its oxygen consumption, uptaking it mainly from the atmosphere. Previous studies demonstrated that oxygen uptake (O2U) in diabetic experimental animals and patients is significantly lower than in the non-diabetic condition. Our recent experiments show that upon wounding of the central cornea the O2U decreased across the ocular surface, followed by two increases at 6-24 h, and at 72 h, which appeared to be important for proper wound healing. It is however not known whether the two distinct O2U increases are maintained in diabetic ocular surface in response to corneal injury. In this study, we used an optic-fiber oxygen micro-sensor to measure O2U across the ocular surface of streptozotocin (STZ)- induced diabetic mice and age-matched control mice following injury to the central cornea. We found that the injury causes an immediate and substantial reduction of O2U across the ocular surface. O2U in non-diabetic corneas increases at 2-6 h post wounding (hpw), decreasing again before the second rise to peak at 72 hpw, especially at the limbus. O2U in the diabetic cornea decreases more markedly than that of non-diabetic control. This defective diabetic O2U persisted, precluding the two dynamic rises in O2U, leading to a failure in recovery. Altogether, our results suggest a previously unknown mechanism of a defective O2U response to injury in the diabetic ocular surface, which warrants further research and may lead to new therapeutic paths.
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Affiliation(s)
- Ana M Sandoval-Castellanos
- Department of Ophthalmology & Vision Science, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA
| | - Sun Qin
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA; School of Life Science, Yunnan Normal University, Yunnan, China
| | - Li Ma
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA; Skin and Cosmetic Research Department, Shanghai Skin Disease Hospital, Shanghai, China
| | - Fernando Ferreira
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA; Departamento de Biologia, Centro de Biologia Molecular e Ambiental (CBMA), Universidade do Minho, Braga, Portugal
| | - Brian Reid
- Department of Ophthalmology & Vision Science, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA; Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA
| | - Min Zhao
- Department of Ophthalmology & Vision Science, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA; Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, Davis, California, USA.
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Maugeri G, D'Amico AG, Saccone S, Bruno F, Pricoco E, Scollo D, Avitabile T, Longo A, D'Agata V. Modeling diabetic epitheliopathy using 3D-Organotypic corneal epithelium. Transl Res 2025; 280:55-63. [PMID: 40389075 DOI: 10.1016/j.trsl.2025.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/27/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
Diabetic keratopathy (DK) is a degenerative corneal disease occurring in more than 50 % of diabetic patients. DK is correlated with the hyperglycemic state causing morphological and functional changes in corneal layers. Currently, most studies on the cornea are performed on two-dimensional (2D) cultures in vitro or animal models. Although 2D culture models can provide large amounts of data at low cost, they poorly represent the complex pathophysiology of the human cornea and hardly predict in vivo responses that can be achieved with animal model studies. However, the use of the latter presents ethical problems. Therefore, it is necessary to identify new strategies and models that can integrate the information validly and effectively, to reduce the number of animals used. Here, we used human corneal epithelial cells (hCECs) derived from donor cornea differentiated into three-dimensional (3D)-organotypic air-liquid interface (ALI), which resemble the features of the corneal epithelium. The 3D-organotypic ALI corneal epithelium was subjected to high-glucose conditions to generate a model of diabetic epitheliopathy. Our model showed well-established molecular and cellular characteristics of this pathology, such as epithelial defects and inflammation, with increased expression of IL-1β, TNF-α, p-NF-kB, COX-2, MMP-2 and MMP-9. The data provided highlight the utility of 3D-organotypic corneal epithelium in modeling diabetic epitheliopathy, offering new avenues in drug screening, as well as in precision and personalized medicine.
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Affiliation(s)
- Grazia Maugeri
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy.
| | | | - Salvatore Saccone
- Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, Catania 95123, Italy
| | - Francesca Bruno
- Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, Catania 95123, Italy
| | - Elisabetta Pricoco
- Anatomic Pathology, A.O.U. Policlinico "G. Rodolico-San Marco", Catania, Italy
| | - Davide Scollo
- Eye Clinic Catania University San Marco Hospital, Viale Carlo Azeglio Ciampi, 95121, Catania, Italy
| | - Teresio Avitabile
- Department of Ophthalmology, University of Catania, 95123, Catania, Italy
| | - Antonio Longo
- Department of Ophthalmology, University of Catania, 95123, Catania, Italy
| | - Velia D'Agata
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
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Ziafati M, Mirshahi R, Cicinelli MV, Nazari R. Persistent Corneal Epithelial Defect Following Pars Plana Vitrectomy: A Narrative Review. Semin Ophthalmol 2025:1-13. [PMID: 39989218 DOI: 10.1080/08820538.2025.2470253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 02/12/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
PURPOSE Persistent corneal epithelial defects (PCEDs) following pars plana vitrectomy (PPV) represent a significant clinical challenge, potentially leading to corneal scarring, vision loss, and other severe complications. This review aims to summarize the prevalence, associated risk factors, and management strategies for PCEDs in the context of PPV, providing evidence-based guidance for clinicians. METHODS A comprehensive systematic review was conducted using PubMed and Embase databases, identifying English-language studies addressing PCEDs after PPV. RESULTS The prevalence of PCEDs post-PPV varied widely, from 0% to 78.37%, influenced by intrinsic factors such as diabetes mellitus, which impairs corneal nerve function and healing, and extrinsic factors like intraoperative tamponade with C3F8. Management strategies ranged from conservative options like bandage contact lenses to advanced treatments like topical insulin. CONCLUSION PCEDs after PPV are multifactorial and demand individualized management. Advanced therapies, particularly serum-based treatments, and topical insulin, show promising outcomes. Further prospective research is warranted to refine these treatments.
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Affiliation(s)
- Makan Ziafati
- The Five Senses Institute, Rassoul Akram Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Mirshahi
- The Five Senses Institute, Rassoul Akram Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maria Vittoria Cicinelli
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
- Department of Ophthalmology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rezvaneh Nazari
- The Five Senses Institute, Rassoul Akram Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Ekin MA, Kahraman HG, Egrilmez ED, Arici S, Oruk GG. Association of peripheral neuropathy with dry eye disease and meibomian gland dysfunction in patients with type 1 diabetes. Int Ophthalmol 2025; 45:61. [PMID: 39920472 DOI: 10.1007/s10792-025-03420-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 01/19/2025] [Indexed: 02/09/2025]
Abstract
PURPOSE To explore the relationship between dry eye disease and type 1 diabetes mellitus (DM) and also to identify whether diabetic peripheral neuropathy (DPN) was a significant predictor for the development of dry eye disease. MATERIALS AND METHODS This prospective cross sectional study involved patients with type 1 DM and aged- and sex-matched healthy controls. All of the participants underwent dry eye tests including meibomian gland function. Based on neurologic examination and electromyography findings, diabetic patients were grouped as DPN + and DPN-. All findings were compared and predictive factors for dry eye disease were identified. RESULTS Of the 97 patients with type 1 DM, 42 (43.3%) were diagnosed as DPN. In patients with DM, there was a significant increase in the ocular surface disease index, corneal surface staining, eyelid margin abnormality and meibomian gland dysfunction and a significant decrease in tear break-up time and Schirmer's I test (p < 0.05). Measurements of dry eye tests were more severe with the presence of DPN (p < 0.05). Age of the patients, duration of DM and HbA1c level were significantly correlated with ocular surface and meibomian gland dysfunction parameters (p < 0.05). Age of the patients (p < 0.001), duration of DM (p = 0.001), HbA1c level (p = 0.036) and presence of DPN (p < 0.001) were found to be the independent and significant predictors of dry eye disease. CONCLUSION Type 1 DM was found to be significantly associated with ocular surface abnormalities including meibomian gland dysfunction. Furthermore, age of the patients, duration of DM, HbA1c level and presence of DPN were predictive factors of dry eye disease in type 1 DM.
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Affiliation(s)
- Meryem Altin Ekin
- Department of Ophthalmology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey.
| | - Hazan Gul Kahraman
- Department of Ophthalmology, Izmir Buca Seyfi Demirsoy Training and Research Hospital, Izmir, Turkey
| | - Emine Deniz Egrilmez
- Department of Ophthalmology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Sehnaz Arici
- Department of Neurology, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
| | - Guzide Gonca Oruk
- Department of Endocrinology and Metabolism, Izmir Katip Celebi University Ataturk Training and Research Hospital, Izmir, Turkey
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Peng H, Kaplan N, Liu M, Jiang H, Lavker RM. Keeping an Eye Out for Autophagy in the Cornea: Sample Preparation for Single-Cell RNA-Sequencing. Methods Mol Biol 2025; 2879:113-122. [PMID: 37930627 PMCID: PMC11162605 DOI: 10.1007/7651_2023_502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023]
Abstract
Single-cell RNA-sequencing (scRNA-seq) is a powerful technique that can barcode individual cells and thus used to obtain a gene expression profile for every individual cell within a tissue. This makes scRNA-seq an excellent method for characterizing rare cell populations such as stem cells. We describe how scRNA-seq can be utilized to examine limbal epithelial stem cell population as well as investigate the contribution of autophagy to the function of limbal epithelial stem cells. To accomplish this, we used the Beclin1 heterozygous (Beclin1 het) mouse, a well-established model of autophagy deficiency. We provide a protocol that we developed for the isolation of viable, single-cell suspensions of limbal/corneal tissues, as well as the analysis of scRNA-seq data.
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Affiliation(s)
- Han Peng
- Department of Dermatology, Northwestern University, Chicago, IL, USA
| | - Nihal Kaplan
- Department of Dermatology, Northwestern University, Chicago, IL, USA
| | - Min Liu
- Department of Dermatology, Northwestern University, Chicago, IL, USA
| | - Huimin Jiang
- Department of Dermatology, Northwestern University, Chicago, IL, USA
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Robert M Lavker
- Department of Dermatology, Northwestern University, Chicago, IL, USA.
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Akansha, Yadav RS. Comparative assessment of the corneal endothelium following phacoemulsification surgery in patients with type II diabetes and nondiabetes. Saudi J Ophthalmol 2025; 39:77-83. [PMID: 40182979 PMCID: PMC11964349 DOI: 10.4103/sjopt.sjopt_226_23] [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: 09/06/2023] [Revised: 10/11/2023] [Accepted: 11/13/2023] [Indexed: 04/05/2025] Open
Abstract
PURPOSE The purpose is to assess the corneal endothelial changes after phacoemulsification surgery in diabetic patients and compare with those of nondiabetic subjects. METHODS The study compared the corneal endothelial changes in diabetics and nondiabetics after phacoemulsification surgery. The study population included 40 patients with diabetes mellitus with good glycemic control and 40 nondiabetic patients who underwent uneventful phacoemulsification surgery. Central corneal endothelial cell density (ECD), central corneal thickness (CCT), and percentage of hexagonality percentage coefficient of variation (%CV) were measured preoperatively and postoperatively (at 4 and 12 weeks) using a specular microscope. RESULTS Mean ECD loss (%) was measured as 9.85% and 8.41% at 4 weeks and 12 weeks postoperatively in the diabetic group while ECD loss percentage was 7.09% and 5.74% in the control group at the same time intervals, respectively. Furthermore, a significant difference was noted on comparing mean ECD measurements between the two groups at the postsurgical visits (4 weeks and 12 weeks). While the CCT was found to be similar in both diabetic and nondiabetic patients, increase was observed in the values of (%CV in both the groups at postoperative 4 weeks' and 12 weeks' follow-up. The values of both %CV and percentage hexagonality showed statistically significant differences between the diabetic and nondiabetic group before surgery and at 4 weeks' and 12 weeks' postoperative examinations. CONCLUSION The patients with diabetes suffered greater endothelial damage despite good glycemic control as compared to nondiabetic patients which indicates the necessity of far more care to protect cornea endothelium in patients with diabetes.
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Affiliation(s)
- Akansha
- Department of Ophthalmology, BRD Medical College, Gorakhpur, Uttar Pradesh, India
| | - Ramyash S. Yadav
- Department of Ophthalmology, BRD Medical College, Gorakhpur, Uttar Pradesh, India
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Zarei-Ghanavati S, Hadi Y, Habibi A, Ashraf Khorasani M, Yoo SH. Cataract and diabetes: review of the literature. J Cataract Refract Surg 2024; 50:1275-1283. [PMID: 39254426 PMCID: PMC11556822 DOI: 10.1097/j.jcrs.0000000000001547] [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: 04/03/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/11/2024]
Abstract
Cataracts can cause visual impairment in diabetic patients. Diabetes mellitus affects different parts of the eye and causes many complications and problems before, during, and after intraocular surgeries. In this review, we will discuss the effects of diabetes on different aspects of cataract surgery and review the current management of diabetic cataracts. Careful preoperative examination of the patient's ocular surface, cornea, iris, and posterior segment, as well as the use of advanced phacoemulsification techniques, new intraocular lenses and the appropriate use of auxiliary medications such as nonsteroidal anti-inflammatory drugs and anti-vascular endothelial growth factors have improved the outcomes of cataract surgery in diabetic patients.
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Affiliation(s)
- Siamak Zarei-Ghanavati
- From the Department of Ophthalmology, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (Zarei-Ghanavati); Eye Research Center, Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Hadi, Habibi, Ashraf Khorasani); Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (Yoo)
| | - Yasaman Hadi
- From the Department of Ophthalmology, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (Zarei-Ghanavati); Eye Research Center, Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Hadi, Habibi, Ashraf Khorasani); Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (Yoo)
| | - Abbas Habibi
- From the Department of Ophthalmology, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (Zarei-Ghanavati); Eye Research Center, Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Hadi, Habibi, Ashraf Khorasani); Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (Yoo)
| | - Maryam Ashraf Khorasani
- From the Department of Ophthalmology, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (Zarei-Ghanavati); Eye Research Center, Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Hadi, Habibi, Ashraf Khorasani); Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (Yoo)
| | - Sonia H. Yoo
- From the Department of Ophthalmology, Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran (Zarei-Ghanavati); Eye Research Center, Five Senses Institute, Rassoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran (Hadi, Habibi, Ashraf Khorasani); Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida (Yoo)
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Barone V, Surico PL, Cutrupi F, Mori T, Gallo Afflitto G, Di Zazzo A, Coassin M. The Role of Immune Cells and Signaling Pathways in Diabetic Eye Disease: A Comprehensive Review. Biomedicines 2024; 12:2346. [PMID: 39457658 PMCID: PMC11505591 DOI: 10.3390/biomedicines12102346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/02/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Diabetic eye disease (DED) encompasses a range of ocular complications arising from diabetes mellitus, including diabetic retinopathy, diabetic macular edema, diabetic keratopathy, diabetic cataract, and glaucoma. These conditions are leading causes of visual impairments and blindness, especially among working-age adults. Despite advancements in our understanding of DED, its underlying pathophysiological mechanisms remain incompletely understood. Chronic hyperglycemia, oxidative stress, inflammation, and neurodegeneration play central roles in the development and progression of DED, with immune-mediated processes increasingly recognized as key contributors. This review provides a comprehensive examination of the complex interactions between immune cells, inflammatory mediators, and signaling pathways implicated in the pathogenesis of DED. By delving in current research, this review aims to identify potential therapeutic targets, suggesting directions of research for future studies to address the immunopathological aspects of DED.
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Affiliation(s)
- Vincenzo Barone
- Department of Ophthalmology, Campus Bio-Medico University, 00128 Rome, Italy; (V.B.); (F.C.); (T.M.); (A.D.Z.); (M.C.)
- Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, 00128 Rome, Italy
| | - Pier Luigi Surico
- Department of Ophthalmology, Campus Bio-Medico University, 00128 Rome, Italy; (V.B.); (F.C.); (T.M.); (A.D.Z.); (M.C.)
- Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, 00128 Rome, Italy
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Francesco Cutrupi
- Department of Ophthalmology, Campus Bio-Medico University, 00128 Rome, Italy; (V.B.); (F.C.); (T.M.); (A.D.Z.); (M.C.)
- Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, 00128 Rome, Italy
| | - Tommaso Mori
- Department of Ophthalmology, Campus Bio-Medico University, 00128 Rome, Italy; (V.B.); (F.C.); (T.M.); (A.D.Z.); (M.C.)
- Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, 00128 Rome, Italy
- Department of Ophthalmology, University of California San Diego, La Jolla, CA 92122, USA
| | - Gabriele Gallo Afflitto
- Ophthalmology Unit, Department of Experimental Medicine, University of Rome “Tor Vergata”, 00128 Rome, Italy;
- Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK
| | - Antonio Di Zazzo
- Department of Ophthalmology, Campus Bio-Medico University, 00128 Rome, Italy; (V.B.); (F.C.); (T.M.); (A.D.Z.); (M.C.)
- Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, 00128 Rome, Italy
| | - Marco Coassin
- Department of Ophthalmology, Campus Bio-Medico University, 00128 Rome, Italy; (V.B.); (F.C.); (T.M.); (A.D.Z.); (M.C.)
- Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, 00128 Rome, Italy
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10
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Segars KL, Azzari N, Cole M, Kushimi L, Rapaka S, Rich CB, Trinkaus-Randall V. Diverse calcium signaling profiles regulate migratory behavior in avascular wound healing and aberrant signal hierarchy occurs early in diabetes. Am J Physiol Cell Physiol 2024; 327:C1051-C1072. [PMID: 39129489 PMCID: PMC11482046 DOI: 10.1152/ajpcell.00249.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/06/2024] [Accepted: 08/06/2024] [Indexed: 08/13/2024]
Abstract
In avascular wound repair, calcium signaling events are the predominant mechanism cells use to transduce information about stressors in the environment into an effective and coordinated migratory response. Live cell imaging and computational analysis of corneal epithelial wound healing revealed that signal initiation and propagation at the wound edge are highly ordered, with groups of cells engaging in cyclical patterns of initiation and propagation. The cells in these groups exhibit a diverse range of signaling behavior, and dominant "conductor cells" drive activity in groups of lower-signaling neighbors. Ex vivo model systems reveal that conductor cells are present in wing cell layers of the corneal epithelium and that signaling propagates both within and between wing and basal layers. There are significant aberrations in conductor phenotype and interlayer propagation in type II diabetic murine models, indicating that signal hierarchy breakdown is an early indicator of disease. In vitro models reveal that signaling profile diversity and conductor cell phenotype is eliminated with P2X7 inhibition and is altered in Pannexin-1 or P2Y2 but not Connexin-43 inhibition. Conductor cells express significantly less P2X7 than their lower-signaling neighbors and exhibit significantly less migratory behavior after injury. Together, our results show that the postinjury calcium signaling cascade exhibits significantly more ordered and hierarchical behavior than previously thought, that proteins previously shown to be essential for regulating motility are also essential for determining signaling phenotype, and that loss of signal hierarchy integrity is an early indicator of disease state. NEW & NOTEWORTHY Calcium signaling in corneal epithelial cells after injury is highly ordered, with groups of cells engaged in cyclical patterns of event initiation and propagation driven by high-signaling cells. Signaling behavior is determined by P2X7, Pannexin-1, and P2Y2 and influences migratory behavior. Signal hierarchy is observed in healthy ex vivo models after injury and becomes aberrant in diabetes. This represents a paradigm shift, as signaling was thought to be random and determined by factors in the environment.
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Affiliation(s)
- Kristen L Segars
- Department of Pharmacology, Physiology, and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Nicholas Azzari
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Malia Cole
- STaRS Program, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Landon Kushimi
- Department of Computer Science, Boston University Center for Computing and Data Sciences, Boston, Massachusetts, United States
| | - Srikar Rapaka
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Celeste B Rich
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
| | - Vickery Trinkaus-Randall
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, United States
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Chen X, Li Y, Lu L, Wu J, Yan R, Xiang J, Fan Q, Liu J, Li S, Xue Y, Fu T, Liu J, Li Z. Activation of the SST-SSTR5 signaling pathway enhances corneal wound healing in diabetic mice. Mucosal Immunol 2024; 17:858-870. [PMID: 38866206 DOI: 10.1016/j.mucimm.2024.06.002] [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: 12/15/2023] [Revised: 04/23/2024] [Accepted: 06/04/2024] [Indexed: 06/14/2024]
Abstract
Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration, and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SST receptor type 5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.
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Affiliation(s)
- Xinwei Chen
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Yan Li
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liyuan Lu
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiaxin Wu
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ruyu Yan
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jiayan Xiang
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Qiwei Fan
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Jiangman Liu
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Senmao Li
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Yunxia Xue
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Ting Fu
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Jun Liu
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China; Guangdong-Hong Kong-Macau Great Bay Area Geroscience Joint Laboratory, School of Medicine, Jinan University, Guangzhou, China.
| | - Zhijie Li
- International Ocular Surface Research Center, Institute of Ophthalmology, and Key Laboratory for Regenerative Medicine, School of Medicine, Jinan University, Guangzhou, China; Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
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12
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Ouyang W, Yan D, Hu J, Liu Z. Multifaceted mitochondrial as a novel therapeutic target in dry eye: insights and interventions. Cell Death Discov 2024; 10:398. [PMID: 39242592 PMCID: PMC11379830 DOI: 10.1038/s41420-024-02159-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/09/2024] Open
Abstract
Dry eye, recognized as the most prevalent ocular surface disorder, has risen to prominence as a significant public health issue, adversely impacting the quality of life for individuals across the globe. Despite decades of extensive research into the chronic inflammation that characterizes dry eye, the intricate mechanisms fueling this persistent inflammatory state remain incompletely understood. Among the various cellular components under investigation, mitochondria-essential for cellular energy production and homeostasis-have attracted increasing attention for their role in dry eye pathogenesis. This involvement points to mechanisms such as oxidative stress, apoptosis, and sustained inflammation, which are central to the progression of the disease. This review aims to provide a thorough exploration of mitochondrial dysfunction in dry eye, shedding light on the critical roles played by mitochondrial oxidative stress, apoptosis, and mitochondrial DNA damage. It delves into the mechanisms through which diverse pathogenic factors may trigger mitochondrial dysfunction, thereby contributing to the onset and exacerbation of dry eye. Furthermore, it lays the groundwork for an overview of current therapeutic strategies that specifically target mitochondrial dysfunction, underscoring their potential in managing this complex condition. By spotlighting this burgeoning area of research, our review seeks to catalyze the development of innovative drug discovery and therapeutic approaches. The ultimate goal is to unlock promising avenues for the future management of dry eye, potentially revolutionizing treatment paradigms and improving patient outcomes. Through this comprehensive examination, we endeavor to enrich the scientific community's understanding of dry eye and inspire novel interventions that address the underlying mitochondrial dysfunctions contributing to this widespread disorder.
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Affiliation(s)
- Weijie Ouyang
- Xiamen University affiliated Xiamen Eye Center, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine of Xiamen University, Xiamen, Fujian, China; Department of Ophthalmology, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Dan Yan
- Xiamen University affiliated Xiamen Eye Center, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine of Xiamen University, Xiamen, Fujian, China
| | - Jiaoyue Hu
- Xiamen University affiliated Xiamen Eye Center, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine of Xiamen University, Department of Ophthalmology of Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China.
| | - Zuguo Liu
- Xiamen University affiliated Xiamen Eye Center, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Eye Institute of Xiamen University, School of Medicine of Xiamen University, Department of Ophthalmology of Xiang'an Hospital of Xiamen University, Xiamen, Fujian, China; Department of Ophthalmology, the First Affiliated Hospital of University of South China, University of South China, Hengyang, Hunan, China.
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Jiang H, Liu M, Yang W, Hong YK, Xu D, Nalbant EK, Clutter ED, Foroozandeh P, Kaplan N, Wysocki J, Batlle D, Miller SD, Lu K, Peng H. Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway. iScience 2024; 27:110534. [PMID: 39175771 PMCID: PMC11338997 DOI: 10.1016/j.isci.2024.110534] [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: 01/24/2024] [Revised: 05/19/2024] [Accepted: 07/15/2024] [Indexed: 08/24/2024] Open
Abstract
In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.
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Affiliation(s)
- Huimin Jiang
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Ophthalmology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Min Liu
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Wending Yang
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yi-Kai Hong
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Dan Xu
- Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Elif Kayaalp Nalbant
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Elwin D. Clutter
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Parisa Foroozandeh
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Nihal Kaplan
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jan Wysocki
- Medicine (Nephrology and Hypertension), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Daniel Batlle
- Medicine (Nephrology and Hypertension), Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Stephen D. Miller
- Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Kurt Lu
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Han Peng
- Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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14
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Yildiz P, Kebapci MN, Colak E, Mutlu F, Simsek T, Yildirim N. Relationship between hyperglycemia and intraocular pressure, corneal biomechanics, and corneal topography during the oral glucose tolerance test in nondiabetic patients. Int Ophthalmol 2024; 44:347. [PMID: 39138825 DOI: 10.1007/s10792-024-03264-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 07/29/2024] [Indexed: 08/15/2024]
Abstract
PURPOSE Altered corneal biomechanics in patients with diabetes may affect intraocular pressure (IOP) measurements. Although a relationship between IOP and glucose levels has been reported in diabetic and nondiabetic patients, the mechanism by which hyperglycemia influences IOP is unclear. The aim of this study was to determine the effects of hyperglycemia on IOP, corneal biomechanics, and anterior segment parameters during the oral glucose tolerance test (OGTT) in nondiabetic patients. METHODS Twenty-one patients without DM who underwent OGTT were included in this study. A complete ophthalmologic examination was performed before the test. Blood glucose, insulin level, IOP (iCare rebound tonometer), Ocular Response Analyzer, and corneal topography (Pentacam) measurements were obtained at 0, 1, and 2 h during the OGTT. Data from the patients' right eyes were included in the analysis. RESULTS The mean age of the patients was 46.9 ± 11.0 years. There was a statistically significant difference in IOP between 1 and 2 h (p = 0.03) and a clinically significant difference between 0 and 1 h (p = 0.06). Corneal resistance factor was lower at 2 h than 1 h (p = 0.03), while central cornea thickness was increased at 1 h (p = 0.01) and 2 h (p = 0.05) compared to 0 h. There was positive partial correlation between hyperglycemia and IOP at 1 h (p = 0.049, r = 0.67). CONCLUSION The positive partial correlation between IOP and glucose level suggests that acute hyperglycemia may lead to increased IOP. However, further research is needed to explain the mechanism of IOP elevation in the hyperglycemic phase during OGTT.
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Affiliation(s)
- Pinar Yildiz
- Department of Internal Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey.
| | - Medine Nur Kebapci
- Department of Internal Medicine, Eskişehir Osmangazi University, Eskişehir, Turkey
| | - Ertugrul Colak
- Department of Biostatistics, Eskişehir Osmangazi University, Eskisehir, Turkey
| | - Fezan Mutlu
- Department of Biostatistics, Eskişehir Osmangazi University, Eskisehir, Turkey
| | - Tulay Simsek
- Department of Ophthalmology, Eskişehir Osmangazi University, Eskisehir, Turkey
| | - Nilgun Yildirim
- Department of Ophthalmology, Eskişehir Osmangazi University, Eskisehir, Turkey
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15
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Moshirfar M, Melanson DG, Pandya S, Moin KA, Talbot CL, Hoopes PC. Implications of Celiac Disease in Prospective Corneal Refractive Surgery Patients: A Narrative Review. Cureus 2024; 16:e65761. [PMID: 39211645 PMCID: PMC11361327 DOI: 10.7759/cureus.65761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2024] [Indexed: 09/04/2024] Open
Abstract
Celiac disease (CeD) is a prevalent autoimmune disorder incited by gluten consumption, resulting in intestinal damage. Affecting approximately one in 133 people globally, CeD often remains undiagnosed due to its varied clinical presentations. The prevalence and diagnosis of CeD are influenced by several factors, including demographics and genetics, and it often coexists with other autoimmune diseases. Thus, the objective of this paper was to review the literature on ophthalmic manifestations of CeD and to create preliminary considerations for these patients wishing to undergo elective corneal refractive surgery (CRS). A literature review was conducted through July 2024, and relevant search terms were used to identify contributing papers. The review enabled the development of detailed considerations for the ocular manifestations of CeD and recommended management strategies for healthcare teams before and following CRS. The 24 papers included in this study illustrate that nutritional deficiencies and autoimmune concerns linked to CeD have distinctive ocular presentations. Based on these findings, patients with CeD may exhibit unconventional ocular manifestations beyond their typical gastrointestinal symptoms, such as decreased endothelial cell density (ECD), vitamin A deficiency leading to dryness, altered corneal nerve density, cataracts, uveitis, changes in choroidal thickness, papilledema, and neurological issues such as nystagmus. Patients with CeD may also experience synergistic impacts from concomitant autoimmune conditions such as Type 1 Diabetes Mellitus (T1DM) in addition to the coexistence of thyroid ophthalmopathy. Recognizing that CeD is an autoimmune disorder that can be exacerbated by other conditions, it is essential to conduct a thorough evaluation for elective CRS. Due to the variability in ocular manifestations among CeD patients, individualized evaluations are crucial for determining surgical candidacy and optimizing outcomes, especially for patients who may not be well controlled. Evaluations are likely to encompass a subjective assessment through a questionnaire exploring the patient's past medical history related to CeD. These questions can range from inquiring about general past medical history related to CeD regarding dietary gluten intake and weight loss to joint pain and cognitive impairments such as brain fog. Clinicians should also perform a comprehensive objective assessment utilizing slit-lamp biomicroscopy, Schirmer test, tear break-up time (TBUT), optical coherence tomography (OCT), Scheimpflug imaging, or fundoscopy. Although there is currently no specific information regarding CRS recommendations for patients with CeD, we believe the considerations outlined in this paper should serve as preliminary guidelines for clinicians. While our findings have formed considerations for future healthcare teams, further research is needed to fully understand the impact of CeD on CRS outcomes and refine these recommendations.
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Affiliation(s)
- Majid Moshirfar
- Ophthalmology, Hoopes Vision Research Center, Draper, USA
- Ophthalmology, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, USA
- Eye Banking and Corneal Transplantation, Utah Lions Eye Bank, Murray, USA
| | - David G Melanson
- Ophthalmology, Rocky Vista University College of Osteopathic Medicine, Ivins, USA
| | - Shreya Pandya
- Ophthalmology, University of Louisville School of Medicine, Louisville, USA
| | - Kayvon A Moin
- Ophthalmology, Hoopes Vision Research Center, Draper, USA
- School of Medicine, American University of the Caribbean, Cupecoy, SXM
| | - Chad L Talbot
- Ophthalmology, Rocky Vista University College of Osteopathic Medicine, Ivins, USA
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Ghenciu LA, Hațegan OA, Bolintineanu SL, Dănilă AI, Faur AC, Prodan-Bărbulescu C, Stoicescu ER, Iacob R, Șișu AM. Immune-Mediated Ocular Surface Disease in Diabetes Mellitus-Clinical Perspectives and Treatment: A Narrative Review. Biomedicines 2024; 12:1303. [PMID: 38927510 PMCID: PMC11201425 DOI: 10.3390/biomedicines12061303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic disorder marked by hyperglycemia due to defects in insulin secretion, action, or both, with a global prevalence that has tripled in recent decades. This condition poses significant public health challenges, affecting individuals, healthcare systems, and economies worldwide. Among its numerous complications, ocular surface disease (OSD) is a significant concern, yet understanding its pathophysiology, diagnosis, and management remains challenging. This review aims to explore the epidemiology, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies of diabetes-related OSD. The ocular surface, including the cornea, conjunctiva, and associated structures, is vital for maintaining eye health, with the lacrimal functional unit (LFU) playing a crucial role in tear film regulation. In DM, changes in glycosaminoglycan metabolism, collagen synthesis, oxygen consumption, and LFU dysfunction contribute to ocular complications. Persistent hyperglycemia leads to the expression of cytokines, chemokines, and cell adhesion molecules, resulting in neuropathy, tear film abnormalities, and epithelial lesions. Recent advances in molecular research and therapeutic modalities, such as gene and stem cell therapies, show promise for managing diabetic ocular complications. Future research should focus on pathogenetically oriented therapies for diabetic neuropathy and keratopathy, transitioning from animal models to clinical trials to improve patient outcomes.
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Affiliation(s)
- Laura Andreea Ghenciu
- Department of Functional Sciences, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania;
| | - Ovidiu Alin Hațegan
- Discipline of Anatomy and Embriology, Medicine Faculty, ‘Vasile Goldis’ Western University of Arad, Revolution Boulevard 94, 310025 Arad, Romania
| | - Sorin Lucian Bolintineanu
- Department of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (S.L.B.); (A.-I.D.); (A.C.F.); (C.P.-B.); (R.I.); (A.M.Ș.)
| | - Alexandra-Ioana Dănilă
- Department of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (S.L.B.); (A.-I.D.); (A.C.F.); (C.P.-B.); (R.I.); (A.M.Ș.)
| | - Alexandra Corina Faur
- Department of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (S.L.B.); (A.-I.D.); (A.C.F.); (C.P.-B.); (R.I.); (A.M.Ș.)
| | - Cătălin Prodan-Bărbulescu
- Department of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (S.L.B.); (A.-I.D.); (A.C.F.); (C.P.-B.); (R.I.); (A.M.Ș.)
- Doctoral School, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
- IInd Surgery Clinic, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
| | - Emil Robert Stoicescu
- Field of Applied Engineering Sciences, Specialization Statistical Methods and Techniques in Health and Clinical Research, Faculty of Mechanics, ‘Politehnica’ University Timisoara, Mihai Viteazul Boulevard No. 1, 300222 Timisoara, Romania;
- Department of Radiology and Medical Imaging, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
- Research Center for Pharmaco-Toxicological Evaluations, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
| | - Roxana Iacob
- Department of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (S.L.B.); (A.-I.D.); (A.C.F.); (C.P.-B.); (R.I.); (A.M.Ș.)
- Doctoral School, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
- Field of Applied Engineering Sciences, Specialization Statistical Methods and Techniques in Health and Clinical Research, Faculty of Mechanics, ‘Politehnica’ University Timisoara, Mihai Viteazul Boulevard No. 1, 300222 Timisoara, Romania;
| | - Alina Maria Șișu
- Department of Anatomy and Embriology, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (S.L.B.); (A.-I.D.); (A.C.F.); (C.P.-B.); (R.I.); (A.M.Ș.)
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Valdés-Arias D, Locatelli EVT, Sepulveda-Beltran PA, Mangwani-Mordani S, Navia JC, Galor A. Recent United States Developments in the Pharmacological Treatment of Dry Eye Disease. Drugs 2024; 84:549-563. [PMID: 38652355 PMCID: PMC11189955 DOI: 10.1007/s40265-024-02031-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2024] [Indexed: 04/25/2024]
Abstract
Dry eye disease (DED) can arise from a variety of factors, including inflammation, meibomian gland dysfunction (MGD), and neurosensory abnormalities. Individuals with DED may exhibit a range of clinical signs, including tear instability, reduced tear production, and epithelial disruption, that are driven by different pathophysiological contributors. Those affected often report a spectrum of pain and visual symptoms that can impact physical and mental aspects of health, placing an overall burden on an individual's well-being. This cumulative impact of DED on an individual's activities and on society underscores the importance of finding diverse and effective management strategies. Such management strategies necessitate an understanding of the underlying pathophysiological mechanisms that contribute to DED in the individual patient. Presently, the majority of approved therapies for DED address T cell-mediated inflammation, with their tolerability and effectiveness varying across different studies. However, there is an emergence of treatments that target additional aspects of the disease, including novel inflammatory pathways, abnormalities of the eyelid margin, and neuronal function. These developments may allow for a more nuanced and precise management strategy for DED. This review highlights the recent pharmacological advancements in DED therapy in the United States. It discusses the mechanisms of action of these new treatments, presents key findings from clinical trials, discusses their current stage of development, and explores their potential applicability to different sub-types of DED. By providing a comprehensive overview of products in development, this review aims to contribute valuable insights to the ongoing efforts in enhancing the therapeutic options available to individuals suffering from DED.
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Affiliation(s)
- David Valdés-Arias
- Bascom Palmer Eye Institute, University of Miami, 900 NW 17th St, Miami, FL, 33136, USA
| | - Elyana V T Locatelli
- Bascom Palmer Eye Institute, University of Miami, 900 NW 17th St, Miami, FL, 33136, USA
- Surgical Services, Miami Veterans Affairs Medical Center, 1201 Northwest 16th Street, Miami, FL, 33125, USA
| | | | | | - Juan Carlos Navia
- Bascom Palmer Eye Institute, University of Miami, 900 NW 17th St, Miami, FL, 33136, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami, 900 NW 17th St, Miami, FL, 33136, USA.
- Surgical Services, Miami Veterans Affairs Medical Center, 1201 Northwest 16th Street, Miami, FL, 33125, USA.
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Chen S, Barnstable CJ, Zhang X, Li X, Zhao S, Tombran-Tink J. A PEDF peptide mimetic effectively relieves dry eye in a diabetic murine model by restoring corneal nerve, barrier, and lacrimal gland function. Ocul Surf 2024; 32:1-12. [PMID: 38103731 DOI: 10.1016/j.jtos.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 10/27/2023] [Accepted: 12/09/2023] [Indexed: 12/19/2023]
Abstract
PURPOSE The study investigated effectiveness of a novel PEDF peptide mimetic to alleviate dry eye-like pathologies in a Type I diabetic mouse model established using streptozotocin. METHODS Mice were treated topically for 3-6 weeks with Ppx (a 17-mer PEDF mimetic) 2x/day or vehicle. Corneal sensitivity, tear film, epithelial and endothelial injury were measured using Cochet-Bonnet esthesiometer, phenol red cotton thread wetting, fluorescein sodium staining, and ZO1 expression, respectively. Inflammatory and parasympathetic nerve markers and activation of the MAPK/JNK pathways in the lacrimal glands were measured. RESULTS Diabetic mice exhibited features of dry eye including reduced corneal sensation and tear secretion and increased corneal epithelium injury, nerve degeneration, and edema. Ppx reversed these pathologies and restored ZO1 expression and morphological integrity of the endothelium. Upregulation of IL-1β and TNFα, increased activation of P-38, JNK, and ERK, and higher levels of M3ACHR in diabetic lacrimal glands were also reversed by the peptide treatment. CONCLUSION The study demonstrates that topical application of a synthetic PEDF mimetic effectively alleviates diabetes-induced dry eye by restoring corneal sensitivity, tear secretion, and endothelial barrier and lacrimal gland function. These findings have significant implications for the potential treatment of dry eye using a cost-effective and reproducible approach with minimal invasiveness and no obvious side effects.
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Affiliation(s)
- Shuangping Chen
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Colin James Barnstable
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China; Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033-0850, USA; Skyran Biologics Inc., Harrisburg, PA, USA, 17112
| | - Xiaomin Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China
| | - Shaozhen Zhao
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China.
| | - Joyce Tombran-Tink
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China; Department of Neural and Behavioral Sciences, Penn State College of Medicine, Hershey, PA, 17033-0850, USA; Skyran Biologics Inc., Harrisburg, PA, USA, 17112.
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Melnyk S, Bollag WB. Aquaporins in the Cornea. Int J Mol Sci 2024; 25:3748. [PMID: 38612559 PMCID: PMC11011575 DOI: 10.3390/ijms25073748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/18/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
The cornea is an avascular, transparent tissue that allows light to enter the visual system. Accurate vision requires proper maintenance of the cornea's integrity and structure. Due to its exposure to the external environment, the cornea is prone to injury and must undergo proper wound healing to restore vision. Aquaporins (AQPs) are a family of water channels important for passive water transport and, in some family members, the transport of other small molecules; AQPs are expressed in all layers of the cornea. Although their functions as water channels are well established, the direct function of AQPs in the cornea is still being determined and is the focus of this review. AQPs, primarily AQP1, AQP3, and AQP5, have been found to play an important role in maintaining water homeostasis, the corneal structure in relation to proper hydration, and stress responses, as well as wound healing in all layers of the cornea. Due to their many functions in the cornea, the identification of drug targets that modulate the expression of AQPs in the cornea could be beneficial to promote corneal wound healing and restore proper function of this tissue crucial for vision.
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Affiliation(s)
- Samuel Melnyk
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Wendy B. Bollag
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA;
- Charlie Norwood Department of Veterans Affairs Medical Center, Augusta, GA 30904, USA
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20
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Surico PL, Narimatsu A, Forouzanfar K, Singh RB, Shoushtari S, Dana R, Blanco T. Effects of Diabetes Mellitus on Corneal Immune Cell Activation and the Development of Keratopathy. Cells 2024; 13:532. [PMID: 38534376 PMCID: PMC10969384 DOI: 10.3390/cells13060532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/12/2024] [Accepted: 03/16/2024] [Indexed: 03/28/2024] Open
Abstract
Diabetes mellitus (DM) is one of the most prevalent diseases globally, and its prevalence is rapidly increasing. Most patients with a long-term history of DM present with some degree of keratopathy (DK). Despite its high incidence, the underlying inflammatory mechanism of DK has not been elucidated yet. For further insights into the underlying immunopathologic processes, we utilized streptozotocin-induced mice to model type 1 DM (T1D) and B6.Cg-Lepob/J mice to model type 2 DM (T2D). We evaluated the animals for the development of clinical manifestations of DK. Four weeks post-induction, the total frequencies of corneal CD45+CD11b+Ly-6G- myeloid cells, with enhanced gene and protein expression levels for the proinflammatory cytokines TNF-α and IL-1β, were higher in both T1D and T2D animals. Additionally, the frequencies of myeloid cells/mm2 in the sub-basal neural plexus (SBNP) were significantly higher in T1D and T2D compared to non-diabetic mice. DK clinical manifestations were observed four weeks post-induction, including significantly lower tear production, corneal sensitivity, and epitheliopathy. Nerve density in the SBNP and intraepithelial terminal endings per 40x field were lower in both models compared to the normal controls. The findings of this study indicate that DM alters the immune quiescent state of the cornea during disease onset, which may be associated with the progressive development of the clinical manifestations of DK.
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Affiliation(s)
| | | | | | | | | | | | - Tomas Blanco
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; (P.L.S.); (A.N.); (K.F.); (R.B.S.); (S.S.); (R.D.)
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21
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Qin S, Ma L, Ferreira F, Brown C, Navedo MF, Reid B, Zhao M. Diabetic Ocular Surface Has Defects in Oxygen Uptake Revealed by Optic Fiber Microsensor. Invest Ophthalmol Vis Sci 2024; 65:27. [PMID: 38506851 PMCID: PMC10959196 DOI: 10.1167/iovs.65.3.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/25/2024] [Indexed: 03/21/2024] Open
Abstract
Purpose Diabetes mellitus causes diabetic keratopathy (DK). This and other ocular surface disorders are underdiagnosed and problematic for affected patients as well as recipients of diabetic donor corneas. Thus, it is important to find noninvasive means to facilitate determination of the potentially vision-threatening DK. It has been reported that diabetic corneas uptake significantly less oxygen (O2) than healthy controls. However, an integral assessment of the ocular surface is missing. Methods Using an optic-fiber O2 micro-sensor (optrode) we demonstrated recently that the healthy ocular surface displays a unique spatiotemporal map of O2 consumption. We hypothesize that diabetes impairs the spatiotemporal profile of O2 uptake at the ocular surface. Results Using streptozotocin (STZ)-induced diabetic mice, we found diminished O2 uptake and loss of the unique pattern across the ocular surface. A diabetic cornea consumes significantly less O2 at the bulbar conjunctiva and limbus, but not the central and peripheral cornea, compared to controls. Further, we show that, contrary to the healthy cornea, the diabetic cornea does not increase the O2 consumption at the limbus in the evening as the normal control. Conclusions Altogether, our measurements reveal a previously unknown impairment in O2 uptake at the diabetic cornea, making it a potential tool to diagnose ocular surface abnormalities and suggesting a new etiology mechanism.
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Affiliation(s)
- Sun Qin
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
- School of Life Science, Yunnan Normal University, Yunnan, China
| | - Li Ma
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
| | - Fernando Ferreira
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
- Departamento de Biologia, Centro de Biologia Molecular e Ambiental (CBMA), Universidade do Minho, Braga, Portugal
| | - Chelsea Brown
- Department of Ophthalmology & Vision Science, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
| | - Manuel F. Navedo
- Department of Pharmacology, School of Medicine, University of California, Davis, California, United States
| | - Brian Reid
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
- Department of Ophthalmology & Vision Science, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
| | - Min Zhao
- Department of Dermatology, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
- Department of Ophthalmology & Vision Science, Institute for Regenerative Cures, School of Medicine, University of California, Davis, California, United States
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22
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Sharma P, Ma JX, Karamichos D. Effects of hypoxia in the diabetic corneal stroma microenvironment. Exp Eye Res 2024; 240:109790. [PMID: 38224848 DOI: 10.1016/j.exer.2024.109790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/15/2023] [Accepted: 01/12/2024] [Indexed: 01/17/2024]
Abstract
Corneal dysfunctions associated with Diabetes Mellitus (DM), termed diabetic keratopathy (DK), can cause impaired vision and/or blindness. Hypoxia affects both Type 1 (T1DM) and Type 2 (T2DM) surprisingly, the role of hypoxia in DK is unexplored. The aim of this study was to examine the impact of hypoxia in vitro on primary human corneal stromal cells derived from Healthy (HCFs), and diabetic (T1DMs and T2DMs) subjects, by exposing them to normoxic (21% O2) or hypoxic (2% O2) conditions through 2D and 3D in vitro models. Our data revealed that hypoxia affected T2DMs by slowing their wound healing capacity, leading to significant alterations in oxidative stress-related markers, mitochondrial health, cellular homeostasis, and endoplasmic reticulum health (ER) along with fibrotic development. In T1DMs, hypoxia significantly modulated markers related to membrane permeabilization, oxidative stress via apoptotic marker (BAX), and protein degradation. Hypoxic environment induced oxidative stress (NOQ1 mediated reduction of superoxide in T1DMs and Nrf2 mediated oxidative stress in T2DMs), modulation in mitochondrial health (Heat shock protein 27 (HSP27), and dysregulation of cellular homeostasis (HSP90) in both T1DMs and T2DMs. This data underscores the significant impact of hypoxia on the diabetic cornea. Further studies are warranted to delineate the complex interactions.
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Affiliation(s)
- Purnima Sharma
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3430 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
| | - Jian-Xing Ma
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3430 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3430 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3430 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
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23
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Erb C, Erb C, Kazakov A, Umetalieva M, Weisser B. Influence of Diabetes Mellitus on Glaucoma-Relevant Examination Results in Primary Open-Angle Glaucoma. Klin Monbl Augenheilkd 2024; 241:177-185. [PMID: 37643738 DOI: 10.1055/a-2105-0756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Primary open-angle glaucoma (POAG) is no longer considered an isolated eye pressure-dependent optic neuropathy, but a neurodegenerative disease in which oxidative stress and neuroinflammation are prominent. These processes may be exacerbated by additional systemic diseases. The most common are arterial hypertension, dyslipidemia, and diabetes mellitus. Using diabetes mellitus as an example, it will be shown how far-reaching the influence of such a systemic disease can be on both the functional and the structural diagnostic methods for POAG. This knowledge is essential, since these interferences can lead to misinterpretations of POAG, which can also affect therapeutic decisions.
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Affiliation(s)
- Carl Erb
- Augenklinik am Wittenbergplatz, Berlin, Deutschland
| | | | - Avaz Kazakov
- Department of External Relations and Development, Salymbekov University, Bishkek, Kyrgyzstan
| | - Maana Umetalieva
- Medical Faculty of Medicine, Salymbekov University, Bishkek, Kyrgyzstan
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24
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Buonfiglio F, Wasielica-Poslednik J, Pfeiffer N, Gericke A. Diabetic Keratopathy: Redox Signaling Pathways and Therapeutic Prospects. Antioxidants (Basel) 2024; 13:120. [PMID: 38247544 PMCID: PMC10812573 DOI: 10.3390/antiox13010120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 01/23/2024] Open
Abstract
Diabetes mellitus, the most prevalent endocrine disorder, not only impacts the retina but also significantly involves the ocular surface. Diabetes contributes to the development of dry eye disease and induces morphological and functional corneal alterations, particularly affecting nerves and epithelial cells. These changes manifest as epithelial defects, reduced sensitivity, and delayed wound healing, collectively encapsulated in the context of diabetic keratopathy. In advanced stages of this condition, the progression to corneal ulcers and scarring further unfolds, eventually leading to corneal opacities. This critical complication hampers vision and carries the potential for irreversible visual loss. The primary objective of this review article is to offer a comprehensive overview of the pathomechanisms underlying diabetic keratopathy. Emphasis is placed on exploring the redox molecular pathways responsible for the aberrant structural changes observed in the cornea and tear film during diabetes. Additionally, we provide insights into the latest experimental findings concerning potential treatments targeting oxidative stress. This endeavor aims to enhance our understanding of the intricate interplay between diabetes and ocular complications, offering valuable perspectives for future therapeutic interventions.
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Affiliation(s)
- Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (J.W.-P.); (N.P.)
| | | | | | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (J.W.-P.); (N.P.)
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25
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Wei S, Liao D, Hu J. Inhibition of miR-144-3p/FOXO1 Attenuates Diabetic Keratopathy Via Modulating Autophagy and Apoptosis. Invest Ophthalmol Vis Sci 2024; 65:1. [PMID: 38165707 PMCID: PMC10768711 DOI: 10.1167/iovs.65.1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 12/05/2023] [Indexed: 01/04/2024] Open
Abstract
Purpose Diabetic keratopathy (DK) is a vision-threatening disease that occurs in people with diabetes. Mounting evidence indicates that microRNAs (miRNAs) are indispensable in nerve regeneration within DK. Herein, the role of miRNAs associated with DK, especially focusing on autophagy and apoptosis regulation, was investigated. Methods To identify differentially expressed miRNAs, we performed miRNA sequencing on trigeminal ganglion (TG) tissues derived from streptozotocin-induced type 1 diabetic mellitus (T1DM) and normal mice. MiR-144-3p was chosen for the subsequent experiments. To explore the regulatory role of miR-144-3p in DK, miRNA antagomir was utilized to inhibit miR-144-3p expression. Bioinformatic tools were used to predict the target genes of miR-144-3p, and a dual-luciferase reporter assay was then applied for validation. Autophagy and apoptosis activities were measured utilizing TUNEL staining, immunofluorescence staining, and Western blotting. Results Overall, 56 differentially expressed miRNAs were detected in diabetic versus control mice. In the diabetic mouse TG tissue, miR-144-3p expression was aberrantly enhanced, whereas decreasing its expression contributed to improved diabetic corneal re-epithelialization and nerve regeneration. Fork-head Box O1 (FOXO1) was validated as a target gene of miR-144-3p. Overexpression of FOXO1 could prevent both inadequate autophagy and excessive apoptosis in DK. Consistently, a specific miR-144-3p inhibition enhanced autophagy and prevented apoptosis in DK. Conclusions In this study, our research confirmed the target binding relationship between miR-144-3p and FOXO1. Inhibiting miR-144-3p might modulate autophagy and apoptosis, which could generate positive outcomes for corneal nerves via targeting FOXO1 in DK.
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Affiliation(s)
- Shijia Wei
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Danling Liao
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jianzhang Hu
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fuzhou, China
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26
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Lin CJ, Mondal S, Lee SL, Kang JW, So PTC, Dong CY. Multiphoton imaging of the monosachharide induced formation of fluorescent advanced glycation end products in tissues. JOURNAL OF BIOPHOTONICS 2024; 17:e202300261. [PMID: 37679896 DOI: 10.1002/jbio.202300261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/05/2023] [Accepted: 09/05/2023] [Indexed: 09/09/2023]
Abstract
We studied the in vitro rate of fluorescent advanced glycation end products (fAGEs) formation with multiphoton microscopy in different porcine tissues (aorta, cornea, kidney, dermis, and tendon). These tissues were treated with d-glucose, d-galactose, and d-fructose, three primary monosaccharides found in human diets. We found that the use of d-fructose resulted in the highest glycation rate, followed by d-galactose and then d-glucose. Moreover, compared to non-collagen tissue constituents such as elastic fibers and cells, the rate of tissue glycation was consistently higher in collagen, suggesting that collagen is a more sensitive target for fAGE formation. However, we also found that collagen in different tissues exhibits different rates of fAGE formation, with slower rates observed in tightly packed tissues such as cornea and tendon. Our study suggests that for fAGE to be developed into a long-term glycemic biomarker, loosely organized collagen tissues located in the proximity of vasculature may be the best targets.
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Affiliation(s)
- Chih-Ju Lin
- Department of Physics, National Taiwan University, Taipei, Taiwan, ROC
| | - Sohidul Mondal
- Department of Physics, National Taiwan University, Taipei, Taiwan, ROC
| | - Sheng-Lin Lee
- Department of Physics, National Taiwan University, Taipei, Taiwan, ROC
| | - Jeon-Woong Kang
- Laser Biomedical Research Center, G. R. Harrison Spectroscopy Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Peter T C So
- Laser Biomedical Research Center, G. R. Harrison Spectroscopy Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Chen Yuan Dong
- Department of Physics, National Taiwan University, Taipei, Taiwan, ROC
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27
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Azzari NA, Segars KL, Rapaka S, Kushimi L, Rich CB, Trinkaus-Randall V. Aberrations in Cell Signaling Quantified in Diabetic Murine Globes after Injury. Cells 2023; 13:26. [PMID: 38201230 PMCID: PMC10778404 DOI: 10.3390/cells13010026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/12/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The corneal epithelium is an avascular structure that has a unique wound healing mechanism, which allows for rapid wound closure without compromising vision. This wound healing mechanism is attenuated in diabetic patients, resulting in poor clinical outcomes and recurrent non-healing erosion. We investigated changes in cellular calcium signaling activity during the wound response in murine diabetic tissue using live cell imaging from both ex vivo and in vitro models. The calcium signaling propagation in diabetic cells was significantly decreased and displayed altered patterns compared to non-diabetic controls. Diabetic cells and tissue display distinct expression of the purinergic receptor, P2X7, which mediates the wound healing response. We speculate that alterations in P2X7 expression, interactions with other proteins, and calcium signaling activity significantly impact the wound healing response. This may explain aberrations in the diabetic wound response.
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Affiliation(s)
- Nicholas A. Azzari
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA; (N.A.A.); (C.B.R.)
| | - Kristen L. Segars
- Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA;
| | - Srikar Rapaka
- Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA;
| | - Landon Kushimi
- Department of Computer Science, Center for Computing and Data Sciences, Boston University, 665 Commonwealth Ave, Boston, MA 02115, USA;
| | - Celeste B. Rich
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA; (N.A.A.); (C.B.R.)
| | - Vickery Trinkaus-Randall
- Department of Biochemistry and Cell Biology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA; (N.A.A.); (C.B.R.)
- Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA;
- Department of Ophthalmology, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord St., Boston, MA 02118, USA
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28
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Sidhu N, Vanathi M, Gupta N, Tandon R. COVID and COVID vaccine-related corneal morbidity: A review. Indian J Ophthalmol 2023; 71:3595-3599. [PMID: 37991289 PMCID: PMC10788745 DOI: 10.4103/ijo.ijo_765_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/24/2023] [Accepted: 07/30/2023] [Indexed: 11/23/2023] Open
Abstract
Systemic coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has had several ocular consequences. Many vaccines have been developed against the disease, with adverse events being reported as well. Various ocular adverse events secondary to coronavirus disease 2019 (COVID-19) vaccines have also featured in literature in recent times. This review features the reported corneal-related effects of COVID infection and vaccination. These include direct effects on corneal grafts and unilateral or bilateral corneal melts. The compilation of reported experiences from across the world in this systematic review will help clinicians recognize the possible presentations, pathogenesis, and management of the same.
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Affiliation(s)
- Navneet Sidhu
- Dr. R. P. Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Murugesan Vanathi
- Dr. R. P. Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Noopur Gupta
- Dr. R. P. Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Radhika Tandon
- Dr. R. P. Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
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29
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Priyadarsini S, McKay TB, Escandon P, Nicholas SE, Ma JX, Karamichos D. Cell sheet-based approach to study the diabetic corneal stroma. Exp Eye Res 2023; 237:109717. [PMID: 37944849 DOI: 10.1016/j.exer.2023.109717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/24/2023] [Accepted: 11/06/2023] [Indexed: 11/12/2023]
Abstract
Prolonged hyperglycemia during diabetes mellitus (DM) is associated with severe complications that may affect both the anterior and posterior ocular segments, leading to impaired vision or blindness. The cornea is a vital part of the eye that has a dual role as a protective transparent barrier and as a major refractive structure and is likewise negatively affected by hyperglycemia in DM. Understanding the cellular and molecular mechanisms underlying the phenotypic changes associated with DM is critical to developing targeted therapies to promote tissue integrity. In this proof-of-concept study, we applied a cell sheet-based approach to generate stacked constructs of physiological corneal thickness using primary human corneal fibroblasts isolated from cadaveric control (healthy), Type 1 DM and Type 2 DM corneal tissues. Self-assembled corneal stromal sheets were generated after 2 weeks in culture, isolated, and subsequently assembled to create stacked constructs, which were evaluated using transmission electron microscopy. Analysis of gene expression patterns revealed significant downregulation of fibrotic markers, α-smooth muscle actin, and collagen type 3, with stacking in Type 2 DM constructs when compared to controls. IGF1 expression was significantly upregulated in Type 2 DM constructs compared to controls with a significant reduction induced by stacking. This study describes the development of a thicker, self-assembled corneal stromal construct as a platform to evaluate phenotypic differences associated with DM-derived corneal fibroblasts and enable the development of targeted therapeutics to promote corneal integrity.
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Affiliation(s)
- Shrestha Priyadarsini
- Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Tina B McKay
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Paulina Escandon
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA
| | - Sarah E Nicholas
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA
| | - Jian-Xing Ma
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, 27101, USA
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA; Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
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30
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Tarvestad-Laise KE, Ceresa BP. Modulating Growth Factor Receptor Signaling to Promote Corneal Epithelial Homeostasis. Cells 2023; 12:2730. [PMID: 38067157 PMCID: PMC10706396 DOI: 10.3390/cells12232730] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 11/20/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
The corneal epithelium is the first anatomical barrier between the environment and the cornea; it is critical for proper light refraction onto the retina and prevents pathogens (e.g., bacteria, viruses) from entering the immune-privileged eye. Trauma to the highly innervated corneal epithelium is extremely painful and if not resolved quickly or properly, can lead to infection and ultimately blindness. The healthy eye produces its own growth factors and is continuously bathed in tear fluid that contains these proteins and other nutrients to maintain the rapid turnover and homeostasis of the ocular surface. In this article, we review the roles of growth factors in corneal epithelial homeostasis and regeneration and some of the limitations to their use therapeutically.
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Affiliation(s)
- Kate E. Tarvestad-Laise
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Brian P. Ceresa
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA
- Department of Ophthalmology and Vision Sciences, University of Louisville, Louisville, KY 40202, USA
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31
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Loiseau A, Raîche-Marcoux G, Maranda C, Bertrand N, Boisselier E. Animal Models in Eye Research: Focus on Corneal Pathologies. Int J Mol Sci 2023; 24:16661. [PMID: 38068983 PMCID: PMC10706114 DOI: 10.3390/ijms242316661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 09/27/2023] [Accepted: 11/19/2023] [Indexed: 12/18/2023] Open
Abstract
The eye is a complex sensory organ that enables visual perception of the world. The dysfunction of any of these tissues can impair vision. Conduction studies on laboratory animals are essential to ensure the safety of therapeutic products directly applied or injected into the eye to treat ocular diseases before eventually proceeding to clinical trials. Among these tissues, the cornea has unique homeostatic and regenerative mechanisms for maintaining transparency and refraction of external light, which are essential for vision. However, being the outermost tissue of the eye and directly exposed to the external environment, the cornea is particularly susceptible to injury and diseases. This review highlights the evidence for selecting appropriate animals to better understand and treat corneal diseases, which rank as the fifth leading cause of blindness worldwide. The development of reliable and human-relevant animal models is, therefore, a valuable research tool for understanding and translating fundamental mechanistic findings, as well as for assessing therapeutic potential in humans. First, this review emphasizes the unique characteristics of animal models used in ocular research. Subsequently, it discusses current animal models associated with human corneal pathologies, their utility in understanding ocular disease mechanisms, and their role as translational models for patients.
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Affiliation(s)
- Alexis Loiseau
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
| | - Gabrielle Raîche-Marcoux
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
| | - Cloé Maranda
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
| | - Nicolas Bertrand
- Faculty of Pharmacy, CHU de Quebec Research Center, Université Laval, Québec, QC G1V 4G2, Canada;
| | - Elodie Boisselier
- Faculty of Medicine, Department of Ophthalmology and Otolaryngology—Head and Neck Surgery, CHU de Québec Research Center, Université Laval, Québec, QC G1S 4L8, Canada; (G.R.-M.); (C.M.)
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Ebrahim AS, Carion TW, Ebrahim T, Win J, Kani H, Wang Y, Stambersky A, Ibrahim AS, Sosne G, Berger EA. A Novel Combination Therapy Tβ4/VIP Protects against Hyperglycemia-Induced Changes in Human Corneal Epithelial Cells. BIOSENSORS 2023; 13:974. [PMID: 37998149 PMCID: PMC10669755 DOI: 10.3390/bios13110974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/14/2023] [Accepted: 11/01/2023] [Indexed: 11/25/2023]
Abstract
Despite the prevalence of diabetic retinopathy, the majority of adult diabetic patients develop visually debilitating corneal complications, including impaired wound healing. Unfortunately, there is limited treatment for diabetes-induced corneal damage. The current project investigates a novel, peptide-based combination therapy, thymosin beta-4 and vasoactive intestinal peptide (Tβ4/VIP), against high-glucose-induced damage to the corneal epithelium. Electric cell-substrate impedance sensing (ECIS) was used for real-time monitoring of barrier function and wound healing of human corneal epithelial cells maintained in either normal glucose (5 mM) or high glucose (25 mM) ± Tβ4 (0.1%) and VIP (5 nM). Barrier integrity was assessed by resistance, impedance, and capacitance measurements. For the wound healing assay, cell migration was also monitored. Corneal epithelial tight junction proteins (ZO-1, ZO-2, occludin, and claudin-1) were assessed to confirm our findings. Barrier integrity and wound healing were significantly impaired under high-glucose conditions. However, barrier function and cell migration significantly improved with Tβ4/VIP treatment. These findings were supported by high-glucose-induced downregulation of tight junction proteins that were effectively maintained similar to normal levels when treated with Tβ4/VIP. These results strongly support the premise that Tβ4 and VIP work synergistically to protect corneal epithelial cells against hyperglycemia-induced damage. In addition, this work highlights the potential for significant translational impact regarding the treatment of diabetic patients and associated complications of the cornea.
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Affiliation(s)
- Abdul Shukkur Ebrahim
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Thomas W. Carion
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Thanzeela Ebrahim
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Jeff Win
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Hussein Kani
- Department of Health Sciences, University of Central Florida College of Health Professions and Sciences, Orlando, FL 32816, USA;
| | - Yuxin Wang
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Ashten Stambersky
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Ahmed S. Ibrahim
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Gabriel Sosne
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
| | - Elizabeth A. Berger
- Department of Ophthalmology, Visual & Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA; (A.S.E.); (T.W.C.); (T.E.); (J.W.); (Y.W.); (A.S.); (A.S.I.); (G.S.)
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Weng J, Ross C, Baker J, Alfuraih S, Shamloo K, Sharma A. Diabetes-Associated Hyperglycemia Causes Rapid-Onset Ocular Surface Damage. Invest Ophthalmol Vis Sci 2023; 64:11. [PMID: 37938936 PMCID: PMC10637200 DOI: 10.1167/iovs.64.14.11] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 10/16/2023] [Indexed: 11/10/2023] Open
Abstract
Purpose The metabolic alterations due to chronic hyperglycemia are well-known to cause diabetes-associated complications. Short-term hyperglycemia has also been shown to cause many acute changes, including hemodynamic alterations and osmotic, oxidative, and inflammatory stress. The present study was designed to investigate whether diabetes-associated hyperglycemia can cause rapid-onset detrimental effects on the tear film, goblet cells, and glycocalyx and can lead to activation of an inflammatory cascade or cellular stress response in the cornea. Methods Mouse models of type 1 and type 2 diabetes were used. Tear film volume, goblet cell number, and corneal glycocalyx area were measured on days 7, 14, and 28 after the onset of hyperglycemia. Transcriptome analysis was performed to quantify changes in 248 transcripts of genes involved in inflammatory, apoptotic, and stress response pathways. Results Our data demonstrate that type 1 and type 2 diabetes-associated hyperglycemia caused a significant decrease in the tear film volume, goblet cell number, and corneal glycocalyx area. The decrease in tear film and goblet cell number was noted as early as 7 days after onset of hyperglycemia. The severity of ocular surface injury was significantly more in type 1 compared to type 2 diabetes. Diabetes mellitus also caused an increase in transcripts of genes involved in the inflammatory, apoptotic, and cellular stress response pathways. Conclusions The results of the present study demonstrate that diabetes-associated hyperglycemia causes rapid-onset damage to the ocular surface. Thus, short-term hyperglycemia in patients with diabetes mellitus may also play an important role in causing ocular surface injury and dry eye.
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Affiliation(s)
- Judy Weng
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Christopher Ross
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Jacob Baker
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Saleh Alfuraih
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Kiumars Shamloo
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
| | - Ajay Sharma
- Chapman University School of Pharmacy, Chapman University, Irvine, California, United States
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Verma N, Khare D, Poe AJ, Amador C, Ghiam S, Fealy A, Ebrahimi S, Shadrokh O, Song XY, Santiskulvong C, Mastali M, Parker S, Stotland A, Van Eyk JE, Ljubimov AV, Saghizadeh M. MicroRNA and Protein Cargos of Human Limbal Epithelial Cell-Derived Exosomes and Their Regulatory Roles in Limbal Stromal Cells of Diabetic and Non-Diabetic Corneas. Cells 2023; 12:2524. [PMID: 37947602 PMCID: PMC10649916 DOI: 10.3390/cells12212524] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/08/2023] [Accepted: 10/18/2023] [Indexed: 11/12/2023] Open
Abstract
Epithelial and stromal/mesenchymal limbal stem cells contribute to corneal homeostasis and cell renewal. Extracellular vesicles (EVs), including exosomes (Exos), can be paracrine mediators of intercellular communication. Previously, we described cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos in non-diabetic (N) and diabetic (DM) limbal epithelial cells (LECs). Presently, we quantify the miRNA and proteome profiles of human LEC-derived Exos and their regulatory roles in N- and DM-LSC. We revealed some miRNA and protein differences in DM vs. N-LEC-derived Exos' cargos, including proteins involved in Exo biogenesis and packaging that may affect Exo production and ultimately cellular crosstalk and corneal function. Treatment by N-Exos, but not by DM-Exos, enhanced wound healing in cultured N-LSCs and increased proliferation rates in N and DM LSCs vs. corresponding untreated (control) cells. N-Exos-treated LSCs reduced the keratocyte markers ALDH3A1 and lumican and increased the MSC markers CD73, CD90, and CD105 vs. control LSCs. These being opposite to the changes quantified in wounded LSCs. Overall, N-LEC Exos have a more pronounced effect on LSC wound healing, proliferation, and stem cell marker expression than DM-LEC Exos. This suggests that regulatory miRNA and protein cargo differences in DM- vs. N-LEC-derived Exos could contribute to the disease state.
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Affiliation(s)
- Nagendra Verma
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Drirh Khare
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
- Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, USA
| | - Adam J. Poe
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Cynthia Amador
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Sean Ghiam
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
- Sackler School of Medicine, New York State/American Program of Tel Aviv University, Tel Aviv 6997801, Israel
| | - Andrew Fealy
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Shaghaiegh Ebrahimi
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Odelia Shadrokh
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Xue-Ying Song
- Genomics Core, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (X.-Y.S.); (C.S.)
| | - Chintda Santiskulvong
- Genomics Core, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (X.-Y.S.); (C.S.)
| | - Mitra Mastali
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (M.M.); (S.P.); (A.S.); (J.E.V.E.)
| | - Sarah Parker
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (M.M.); (S.P.); (A.S.); (J.E.V.E.)
| | - Aleksandr Stotland
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (M.M.); (S.P.); (A.S.); (J.E.V.E.)
| | - Jennifer E. Van Eyk
- Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; (M.M.); (S.P.); (A.S.); (J.E.V.E.)
| | - Alexander V. Ljubimov
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA
| | - Mehrnoosh Saghizadeh
- Eye Program, Board of Governors Regenerative Medicine Institute, Cedars Sinai Medical Center, 8700 Beverly Boulevard, AHSP-A8104, Los Angeles, CA 90048, USA; (N.V.); (D.K.); (C.A.); (A.F.); (S.E.); (O.S.); (A.V.L.)
- Departments of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA
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Nureen L, Di Girolamo N. Limbal Epithelial Stem Cells in the Diabetic Cornea. Cells 2023; 12:2458. [PMID: 37887302 PMCID: PMC10605319 DOI: 10.3390/cells12202458] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the limbus. In patients afflicted with diabetes, hyperglycemia-induced impairments in corneal epithelial regeneration results in persistent epithelial and other defects on the ocular surface, termed diabetic keratopathy (DK), which progressively diminish vision and quality of life. Reports of delayed corneal wound healing and the reduced expression of putative stem cell markers in diabetic relative to healthy eyes suggest that the pathogenesis of DK may be associated with the abnormal activity of LESCs. However, the precise role of these cells in diabetic corneal disease is poorly understood and yet to be comprehensively explored. Herein, we review existing literature highlighting aberrant LESC activity in diabetes, focusing on factors that influence their form and function, and emerging therapies to correct these defects. The consequences of malfunctioning or depleted LESC stocks in DK and limbal stem cell deficiency (LSCD) are also discussed. These insights could be exploited to identify novel targets for improving the management of ocular surface complications that manifest in patients with diabetes.
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Affiliation(s)
| | - Nick Di Girolamo
- School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia;
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Sobczak M, Asejczyk M, Wilczyński M. The effect of pupil size on the measurement of corneal birefringence properties: preliminary study. Sci Rep 2023; 13:17439. [PMID: 37838761 PMCID: PMC10576786 DOI: 10.1038/s41598-023-44706-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 10/11/2023] [Indexed: 10/16/2023] Open
Abstract
We used a partial Mueller matrix polarimeter to measure the corneal anisotropic properties at three pupil sizes (dilated, natural, and constricted). The geometrical parameters of first order isochromes were described by quadrilaterals. These parameters are statistically significantly different between the three pupil sizes. The pupillary size changes do not influence the azimuth angle distribution α. The retardation R and birefringence distributions show asymmetry in the nasal-temporal cross-section. There are differences between pupil sizes for both nasal and temporal parts of the cornea for these distributions. Iridial light scattering and diffraction might be the reason for these differences.
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Affiliation(s)
- Marcelina Sobczak
- Department of Optics and Photonics, Wrocław University of Science and Technology, Wybrzeże Stanisława Wyspiańskiego 27, 50-370, Wrocław, Poland.
- School of Optometry, Indiana University, 800 Atwater, Bloomington, IN, 47405, United States.
| | - Magdalena Asejczyk
- Department of Optics and Photonics, Wrocław University of Science and Technology, Wybrzeże Stanisława Wyspiańskiego 27, 50-370, Wrocław, Poland
| | - Maciej Wilczyński
- Faculty of Pure and Applied Mathematics, Wrocław University of Science and Technology, Wybrzeże Stanisława Wyspiańskiego 27, 50-370, Wrocław, Poland
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Nealon CL, Halladay CW, Gorman BR, Simpson P, Roncone DP, Canania RL, Anthony SA, Rogers LRS, Leber JN, Dougherty JM, Bailey JNC, Crawford DC, Sullivan JM, Galor A, Wu WC, Greenberg PB, Million Veteran Program, Lass JH, Iyengar SK, Peachey NS. Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity. Cornea 2023; 42:1140-1149. [PMID: 37170406 PMCID: PMC10523841 DOI: 10.1097/ico.0000000000003311] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 04/11/2023] [Indexed: 05/13/2023]
Abstract
PURPOSE The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). METHODS We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. RESULTS Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. CONCLUSIONS Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.
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Affiliation(s)
- Cari L. Nealon
- Eye Clinic, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | - Christopher W. Halladay
- Center of Innovation in Long Term Services and Supports, Providence VA Medical Center, Providence, Rhode Island, USA
| | - Bryan R. Gorman
- VA Cooperative Studies Program, VA Boston Healthcare System, Boston, Massachusetts
- Booz Allen Hamilton, McLean, Virginia, USA
| | - Piana Simpson
- Eye Clinic, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | - David P. Roncone
- Eye Clinic, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | | | - Scott A. Anthony
- Eye Clinic, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | | | - Jenna N. Leber
- Ophthalmology Section, VA Western NY Health Care System, Buffalo, New York, USA
| | | | - Jessica N. Cooke Bailey
- Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Research Service, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | - Dana C. Crawford
- Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Research Service, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | - Jack M. Sullivan
- Ophthalmology Section, VA Western NY Health Care System, Buffalo, New York, USA
- Research Service, VA Western NY Health Care System, Buffalo, New York, USA
- Department of Ophthalmology (Ross Eye Institute), University at Buffalo-SUNY, Buffalo, New York, USA
| | - Anat Galor
- Miami Veterans Affairs Medical Center, Miami, Florida, USA
- Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
| | - Wen-Chih Wu
- Cardiology Section, Medical Service, Providence VA Medical Center, Providence, Rhode Island, USA
| | - Paul B. Greenberg
- Ophthalmology Section, Providence VA Medical Center, Providence, Rhode Island, USA
- Division of Ophthalmology, Alpert Medical School, Brown University, Providence, Rhode Island, USA
| | | | - Jonathan H. Lass
- Department of Ophthalmology & Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA
- University Hospitals Eye Institute, Cleveland, Ohio, USA
| | - Sudha K. Iyengar
- Cleveland Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Department of Population & Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Research Service, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
| | - Neal S. Peachey
- Research Service, VA Northeast Ohio Healthcare System, Cleveland, Ohio, USA
- Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
- Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
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Blanco T, Musayeva A, Singh RB, Nakagawa H, Lee S, Alemi H, Gonzalez-Nolasco B, Ortiz G, Wang S, Kahale F, Dohlman TH, Chen Y, Dana R. The impact of donor diabetes on corneal transplant immunity. Am J Transplant 2023; 23:1345-1358. [PMID: 37245642 PMCID: PMC10527508 DOI: 10.1016/j.ajt.2023.05.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 05/12/2023] [Accepted: 05/24/2023] [Indexed: 05/30/2023]
Abstract
Corneal transplantation is the most common form of solid tissue grafting, with an approximately 80% to 90% success rate. However, success rates may decline when donor tissues are derived from patients with a history of diabetes mellitus (DM). To evaluate the underlying immunopathologic processes that cause graft rejection, we used streptozotocin-induced type 1 DM (DM1) and transgenic Lepob/ob type 2 DM (DM2) diabetic murine models as donors and nondiabetic BALB/c as recipients. DM resulted in an increased frequency of corneal antigen-presenting cells (APCs) with an acquired immunostimulatory phenotype. Following transplantation, recipients that received either type of diabetic graft showed increased APC migration and T helper type 1 alloreactive cells, impaired functional regulatory T cells, and graft survival. Insulin treatment in streptozotocin-induced diabetic mice led to an increased tolerogenic profile of graft APC, lower T helper type 1 sensitization, and a higher frequency of functional regulatory T cells with high suppressive capacity, reflected in increased graft survival. We conclude that both DM1 and DM2 in donors can impact corneal APC functional phenotype, rendering the tissue more immunogenic and thereby increasing the risk of graft failure.
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Affiliation(s)
- Tomás Blanco
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Aytan Musayeva
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Rohan Bir Singh
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Hayate Nakagawa
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Seokjoo Lee
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Hamid Alemi
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Bruno Gonzalez-Nolasco
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gustavo Ortiz
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Shudan Wang
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Francesca Kahale
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas H Dohlman
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Yihe Chen
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA
| | - Reza Dana
- Laboratory of Corneal Immunology, Transplantation, and Regeneration, Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
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Chao C, Lema C, Redfern R, Richdale K. Changes in tear glucose and insulin concentrations following an oral glucose tolerance test. Clin Exp Optom 2023; 106:752-758. [PMID: 35977531 PMCID: PMC11970258 DOI: 10.1080/08164622.2022.2111204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/15/2022] [Accepted: 08/03/2022] [Indexed: 10/15/2022] Open
Abstract
CLINICAL RELEVANCE Tear glucose and insulin are responsible for the health of the ocular surface; thus, it is important for clinicians to detect the tear glucose and insulin using point-of-care methods. AIM To determine if changes in blood glucose and insulin levels following an oral glucose tolerance test are reflected in the tears and to test the association between gene expression and tear insulin and glucose. METHODS Twenty healthy young adults were enrolled. Basal tears and peripheral blood samples were collected to assess glucose and insulin using a point-of-care glucometer and ELISA assays in fasted subjects, and 1.5 and 3 h after an oral glucose challenge. Conjunctival impression cytology was collected to determine gene expression of insulin receptor (INSR) and glucose transporters (GLUT1 and GLUT4). Changes were examined using non-parametric one-way ANOVA. Spearman tests were conducted to examine associations between variables. RESULTS Glucose and insulin levels increased 1.5 h after oral glucose in both blood (P < 0.001) and tears (P < 0.049) and returned to near baseline values after 3 h. There was a positive correlation between glucose levels in the blood and tears (rho = 0.57, P < 0.001), but not between blood and tear insulin levels (P = 0.18). Glucose and insulin levels in tears were correlated (rho = 0.32, P = 0.048). Tear glucose concentration at 1.5 h after oral glucose was associated with INSR expression (rho = 0.49, P = 0.03), and there was a trend with GLUT1 (P = 0.06) but not GLUT4. CONCLUSION Tear glucose reflected blood glucose levels but this correspondence was not observed for insulin. Further studies are required to determine the role of glucose and insulin on the ocular surface in both health and diabetes.
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Affiliation(s)
- Cecilia Chao
- College of Optometry, University of Houston, Houston, TX, USA
- School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
| | - Carolina Lema
- College of Optometry, University of Houston, Houston, TX, USA
| | - Rachel Redfern
- College of Optometry, University of Houston, Houston, TX, USA
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Reihanifar T, Şahin M, Stefek M, Ceylan AF, Karasu Ç. Cemtirestat, an aldose reductase inhibitor and antioxidant compound, induces ocular defense against oxidative and inflammatory stress in rat models for glycotoxicity. Cell Biochem Funct 2023; 41:622-632. [PMID: 37272424 DOI: 10.1002/cbf.3818] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/15/2023] [Accepted: 05/27/2023] [Indexed: 06/06/2023]
Abstract
Fructose, endogenously produced as a consequence of activation of the polyol pathway under hyperglycemic conditions, contribute to formation of advanced glycoxidation end products (AGEs) and carbonyl stress. Oxidative stress is increased in diabetes (DM) due to AGEs formation and the utilization of NADPH by aldo-keto reductase, AKR1B1(AR), the first enzyme in polyol pathway. Since inhibition of AR is an attractive approach for the management of diabetic eye diseases, we aimed to compare the effects of a novel AR inhibitor (ARI)/antioxidant (AO) compound cemtirestat on eye tissues with the effects of ARI drug epalrestat and AO agent stobadine in rat model for glycotoxicity. One group of rats was fed high fructose (10% drinking water; 14 weeks), while type-2 DM was induced in the other group of rats with fructose plus streptozotocin (40 mg/kg-bw/day). Diabetic (D) and nondiabetic fructose-fed rats (F) were either untreated or treated with two different doses of cemtirestat (2.5 and 7.5 mg/kg-bw/day), epalrestat (25 and 50 mg/kg-bw/day), or stobadine (25 and 50 mg/kg-bw/day) for 14 weeks. Cemtirestat, epalrestat, and stobadine elaviate the increase in TNF-α, IL-1β, NF-ƙB, and caspase-3 in retina, lens, cornea, and sclera of F and D rats. Both glycotoxicity models resulted in a decrease in GSH to GSSG ratio and a change in glutathione S-transferase activity in eye tissues, but these alterations were improved especially with cemtirestat and stobadine. Lens D-sorbitol of D rats increased more than that of F rats, this increase was only attenuated by cemtirestat and epalrestat. Epalrestat was more effective than cemtirestat and stobadine in inhibiting the increase of vascular endothelial growth factor (VEGF) in the retina of F and D rats. Cemtirestat and stobadine but not epalrestat decreased high level of Nε-(carboxymethyl)lysine in the lens and retina of F and D rats. Cemtirestat is a potential therapeutic in protecting the rat eye against glycotoxicity insults.
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Affiliation(s)
- Tala Reihanifar
- Cellular Stress Response and Signal Transduction Research Laboratory, Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Muzaffer Şahin
- Department of Ophthalmology, Ankara City Hospital General Hospital (MHC), Eye Section, Ankara, Turkey
| | - Milan Stefek
- Institute of Experimental Pharmacology and Toxicology, CEM, Slovak Academy of Sciences, Bratislava, Slovak Republic
| | - Aslı F Ceylan
- Department of Medical Pharmacology, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
| | - Çimen Karasu
- Cellular Stress Response and Signal Transduction Research Laboratory, Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey
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Li X, Su X, Xia F, Qiu J, Zhang J, Wu H, Xie X, Xu M. Bibliometric and visual analysis of diabetes mellitus and pyroptosis from 2011 to 2022. Eur J Med Res 2023; 28:235. [PMID: 37443131 DOI: 10.1186/s40001-023-01175-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023] Open
Abstract
OBJECTIVE To visualize and analyze the published literature on diabetes mellitus and pyroptosis based on a bibliometric approach, so as to provide a comprehensive picture of the hot research directions and dynamic progress in this field. METHODS This study was based on the web of science core collection database to conduct a comprehensive search of the published literature in the field of diabetes mellitus and Pyroptosis from January 1985 to August 2022, including the published research literature in this field, as well as a visual analysis of the number of citations, year of publication, journal, author, research institution, country, and research topic. RESULTS A total of 139 literature on research related to diabetes mellitus and cellular scorch from 2011 to 2022 were retrieved, with a total of 3009 citations and a maximum of 255 citations for a single article, which had a first author Schmid-Burgk, JL The first author of this article is from Germany; among 20 publishing countries, China leads with 100 articles; among 222 publishing institutions, Harbin Medical University leads with 18 articles and 184 citations; among 980 authors, Chen, X from China tops the list of high-impact authors with 5 articles and 29 citations. Among the 98 journals, "CELL DEATH DISEASE" ranked first in both volume and high-impact journals with 4 articles and 29 citations. Among 349 keywords, "pyroptosis" ranked first with a cumulative frequency of 65 times. The cluster analysis was divided into three categories, chronic complications of diabetes mellitus and pyroptosis (67 articles), diabetes mellitus and pyroptosis (60 articles), and diabetes mellitus combined with other diseases and pyroptosis (12 articles), and the number of articles related to diabetes mellitus and its chronic complications increased rapidly from 2019, among which, diabetic cardiomyopathy (27 articles) had the highest number of articles. CONCLUSIONS Based on a comprehensive analysis of published literature in the field of diabetes mellitus and pyroptosis from 2011 to 2022, this study achieved a visual analysis of studies with significant and outstanding contributions to the field, thus framing a picture showing the development and changes in the field. At the same time, this study provides research information and direction for clinicians and investigators to conduct diabetes mellitus and pyroptosis-related research in the future.
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Affiliation(s)
- Xiaodong Li
- The First Affiliated Hospital of Guizhou University of Chinese Medicine, Guiyang, 550000, China
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Xiaojuan Su
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Fenglin Xia
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jing Qiu
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Jiaqi Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Haiyan Wu
- Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China
| | - Xuejun Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Mingchao Xu
- Traditional Chinese Medicine Hospital of Meishan, Meishan, 620010, China.
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Sumioka T, Matsumoto KI, Reinach PS, Saika S. Tenascins and osteopontin in biological response in cornea. Ocul Surf 2023; 29:131-149. [PMID: 37209968 DOI: 10.1016/j.jtos.2023.05.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/01/2023] [Accepted: 05/16/2023] [Indexed: 05/22/2023]
Abstract
The structural composition, integrity and regular curvature of the cornea contribute to the maintenance of its transparency and vision. Disruption of its integrity caused by injury results in scarring, inflammation and neovascularization followed by losses in transparency. These sight compromising effects is caused by dysfunctional corneal resident cell responses induced by the wound healing process. Upregulation of growth factors/cytokines and neuropeptides affect development of aberrant behavior. These factors trigger keratocytes to first transform into activated fibroblasts and then to myofibroblasts. Myofibroblasts express extracellular matrix components for tissue repair and contract the tissue to facilitate wound closure. Proper remodeling following primary repair is critical for restoration of transparency and visual function. Extracellular matrix components contributing to the healing process are divided into two groups; a group of classical tissue structural components and matrix macromolecules that modulate cell behaviors/activities besides being integrated into the matrix structure. The latter components are designated as matricellular proteins. Their functionality is elicited through mechanisms which modulate the scaffold integrity, cell behaviors, activation/inactivation of either growth factors or cytoplasmic signaling regulation. We discuss here the functional roles of matricellular proteins in mediating injury-induced corneal tissue repair. The roles are described of major matricellular proteins, which include tenascin C, tenascin X and osteopontin. Focus is directed towards dealing with their roles in modulating individual activities of wound healing-related growth factors, e. g., transforming growth factor β (TGF β). Modulation of matricellular protein functions could encompass a potential novel strategy to improve the outcome of injury-induced corneal wound healing.
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Affiliation(s)
- Takayoshi Sumioka
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan.
| | - Ken-Ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Head Office for Research and Academic Information, Shimane University, 89-1 Enya-cho, Izumo, 693-8501, Japan
| | - Peter Sol Reinach
- Department of Biological. Sciences SUNY Optometry, New York, NY, 10036, USA
| | - Shizuya Saika
- Department of Ophthalmology, Wakayama Medical University School of Medicine, 811-1 Kimiidera, 641-0012, Japan
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Le PM, Pal-Ghosh S, Menko AS, Stepp MA. Immune Cells Localize to Sites of Corneal Erosions in C57BL/6 Mice. Biomolecules 2023; 13:1059. [PMID: 37509096 PMCID: PMC10377654 DOI: 10.3390/biom13071059] [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: 05/23/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation following treatment with mitomycin C reduce erosion formation in mice after sterile debridement injury, additional factors have been identified related to cytokine expression and immune cell activation. The relationship between recruitment of immune cells to the region of the cornea where erosions form and their potential roles in erosion formation and/or erosion repair remains unexplored in the C57BL/6 mouse recurrent erosion model. Here, high resolution imaging of mouse corneas was performed at D1, D7, and D28 after dulled-blade debridement injury in C57BL/6 mice. Around 50% of these mice have frank corneal erosions at D28 after wounding. A detailed assessment of corneas revealed the involvement of M2 macrophages in both frank and developing erosions at early stages of their formation.
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Affiliation(s)
- Phuong M Le
- Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Sonali Pal-Ghosh
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA
| | - A Sue Menko
- Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Mary Ann Stepp
- Department of Anatomy and Cell Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA
- Department of Ophthalmology, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA
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Guo XX, Pu Q, Hu JJ, Chang XJ, Li AL, Li XY. The role of regulated necrosis in inflammation and ocular surface diseases. Exp Eye Res 2023:109537. [PMID: 37302745 DOI: 10.1016/j.exer.2023.109537] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/28/2023] [Accepted: 06/08/2023] [Indexed: 06/13/2023]
Abstract
In recent decades, numerous types of regulated cell death have been identified, including pyroptosis, ferroptosis and necroptosis. Regulated necrosis is characterized by a series of amplified inflammatory responses that result in cell death. Therefore, it has been suggested to play an essential role in the pathogenesis of ocular surface diseases. The cell morphological features and molecular mechanisms of regulated necrosis are discussed in this review. Furthermore, it summarizes the role of ocular surface diseases, such as dry eye, keratitis, and cornea alkali burn, as potential disease prevention and treatment targets.
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Affiliation(s)
- Xiao-Xiao Guo
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Qi Pu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Jing-Jie Hu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xue-Jiao Chang
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ao-Ling Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xin-Yu Li
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Chen Q, Gao N, Yu FS. Interleukin-36 Receptor Signaling Attenuates Epithelial Wound Healing in C57BL/6 Mouse Corneas. Cells 2023; 12:1587. [PMID: 37371057 PMCID: PMC10297323 DOI: 10.3390/cells12121587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 05/31/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The IL-36 cytokines are known to play various roles in mediating the immune and inflammatory response to tissue injury in a context-dependent manner. This study investigated the role of IL-36R signaling in mediating epithelial wound healing in normal (NL) and diabetic (DM) C57BL/6 mouse corneas. The rate of epithelial wound closure was significantly accelerated in IL-36 receptor-deficient (IL-36R-/-) compared to wild-type (WT) mice. Wounding increased IL-36α and -36γ but repressed IL-36R antagonist (IL-36Ra) expression in B6 mouse corneal epithelial cells. The wound-induced proinflammatory cytokines CXCL1 and CXCL2 were dampened, while the antimicrobial peptides (AMPs) S100A8 and A9 were augmented in IL-36R-/- mouse corneas. Intriguingly, the expression of AMP LCN2 was augmented at the mRNA level. LCN2 deficiency resulted in an acceleration of epithelial wound healing. IL-36R deficiency also greatly increased the healing rate of the corneal epithelial wound in DM mice. IL-36R deficiency also suppressed IL-1β, IL-1Ra, and ICAM expression in unwounded-DM mice and wounded NL corneas. Opposing IL-1β and ICAM, the expression of IL-Ra in DM corneas of IL-36R-/- mice was augmented. The presence of recombinant IL-1Ra and IL-36Ra accelerated epithelial wound closure in T1DM corneas of B6 mice. Our study revealed an unprecedented role of IL-36R signaling in controlling corneal epithelial wound healing in normal (NL) and diabetic (DM) mice. Our data suggest that IL-36Ra, similar to IL-1Ra, might be a therapeutic reagent for improving wound healing and reducing wound-associated ulceration, particularly in the cornea and potentially in the skin of DM patients.
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Affiliation(s)
| | | | - Fu-Shin Yu
- Departments of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, MI 48201, USA (N.G.)
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Amorim M, Martins B, Fernandes R. Immune Fingerprint in Diabetes: Ocular Surface and Retinal Inflammation. Int J Mol Sci 2023; 24:9821. [PMID: 37372968 DOI: 10.3390/ijms24129821] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/29/2023] [Accepted: 06/02/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetes is a prevalent global health issue associated with significant morbidity and mortality. Diabetic retinopathy (DR) is a well-known inflammatory, neurovascular complication of diabetes and a leading cause of preventable blindness in developed countries among working-age adults. However, the ocular surface components of diabetic eyes are also at risk of damage due to uncontrolled diabetes, which is often overlooked. Inflammatory changes in the corneas of diabetic patients indicate that inflammation plays a significant role in diabetic complications, much like in DR. The eye's immune privilege restricts immune and inflammatory responses, and the cornea and retina have a complex network of innate immune cells that maintain immune homeostasis. Nevertheless, low-grade inflammation in diabetes contributes to immune dysregulation. This article aims to provide an overview and discussion of how diabetes affects the ocular immune system's main components, immune-competent cells, and inflammatory mediators. By understanding these effects, potential interventions and treatments may be developed to improve the ocular health of diabetic patients.
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Affiliation(s)
- Madania Amorim
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Beatriz Martins
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Rosa Fernandes
- Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-531 Coimbra, Portugal
- Clinical Academic Center of Coimbra (CACC), 3004-561 Coimbra, Portugal
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Luo Y, Vivaldi Marrero E, Choudhary V, Bollag WB. Phosphatidylglycerol to Treat Chronic Skin Wounds in Diabetes. Pharmaceutics 2023; 15:1497. [PMID: 37242739 PMCID: PMC10222993 DOI: 10.3390/pharmaceutics15051497] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/02/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
This review proposes the use of dioleoylphosphatidylglycerol (DOPG) to enhance diabetic wound healing. Initially, the characteristics of diabetic wounds are examined, focusing on the epidermis. Hyperglycemia accompanying diabetes results in enhanced inflammation and oxidative stress in part through the generation of advanced glycation end-products (AGEs), in which glucose is conjugated to macromolecules. These AGEs activate inflammatory pathways; oxidative stress results from increased reactive oxygen species generation by mitochondria rendered dysfunctional by hyperglycemia. These factors work together to reduce the ability of keratinocytes to restore epidermal integrity, contributing to chronic diabetic wounds. DOPG has a pro-proliferative action on keratinocytes (through an unclear mechanism) and exerts an anti-inflammatory effect on keratinocytes and the innate immune system by inhibiting the activation of Toll-like receptors. DOPG has also been found to enhance macrophage mitochondrial function. Since these DOPG effects would be expected to counteract the increased oxidative stress (attributable in part to mitochondrial dysfunction), decreased keratinocyte proliferation, and enhanced inflammation that characterize chronic diabetic wounds, DOPG may be useful in stimulating wound healing. To date, efficacious therapies to promote the healing of chronic diabetic wounds are largely lacking; thus, DOPG may be added to the armamentarium of drugs to enhance diabetic wound healing.
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Affiliation(s)
- Yonghong Luo
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
| | - Edymarie Vivaldi Marrero
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
| | - Vivek Choudhary
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA
| | - Wendy B. Bollag
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; (Y.L.); (E.V.M.); (V.C.)
- Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA
- Department of Dermatology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
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Lanza M, Mozzillo E, Boccia R, Fedi L, Di Candia F, Tinto N, Melillo P, Simonelli F, Franzese A. Analysis of Corneal Deformation in Paediatric Patients Affected by Maturity Onset Diabetes of the Young Type 2. Diagnostics (Basel) 2023; 13:diagnostics13081500. [PMID: 37189601 DOI: 10.3390/diagnostics13081500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/15/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND To evaluate corneal deformation in Maturity Onset Diabetes of the Young type 2 (MODY2), paediatric subjects were analysed using a Scheimpflug-based device. The purpose of this analysis was to find new biomarkers for MODY2 disease and to gain a better understanding of the pathogenesis of the disease. METHODS A total of 15 patients with genetic and metabolic diagnoses of MODY2 (mean age 12.8 ± 5.66 years) and 15 age-matched healthy subjects were included. The biochemical and anthropometric data of MODY2 patients were collected from clinical records, and a complete ophthalmic check with a Pentacam HR EM-3000 Specular Microscope and Corvis ST devices was performed in both groups. RESULTS Highest concavity (HC) deflection length, Applanation 1 (A1) deflection amplitude, and A1 deflection area showed significantly lower values in MODY2 patients compared to healthy subjects. A significant positive correlation was observed between Body Mass Index (BMI) and HC deflection area and between waist circumference (WC) and the following parameters: maximum deformation amplitude, HC deformation amplitude, and HC deflection area. The glycosylated hemoglobin level (HbA1c) showed a significant positive correlation with Applanation 2 time and HC time. CONCLUSIONS The obtained results show, for the first time, differences regarding corneal distortion features in the MODY2 population compared with healthy eyes.
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Affiliation(s)
- Michele Lanza
- Multidisciplinary Department of Medical Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Enza Mozzillo
- Department of Translational Medical Sciences, Regional Center of Pediatric Diabetes, Federico II University of Naples, 80131 Naples, Italy
| | - Rosa Boccia
- Multidisciplinary Department of Medical Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Ludovica Fedi
- Department of Translational Medical Sciences, Regional Center of Pediatric Diabetes, Federico II University of Naples, 80131 Naples, Italy
| | - Francesca Di Candia
- Department of Translational Medical Sciences, Regional Center of Pediatric Diabetes, Federico II University of Naples, 80131 Naples, Italy
| | - Nadia Tinto
- Department of Molecular Medicine and Medical Biotechnology, CEINGE Advanced Biotechnologies, Federico II University of Naples, 80131 Naples, Italy
| | - Paolo Melillo
- Multidisciplinary Department of Medical Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Francesca Simonelli
- Multidisciplinary Department of Medical Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
| | - Adriana Franzese
- Department of Translational Medical Sciences, Regional Center of Pediatric Diabetes, Federico II University of Naples, 80131 Naples, Italy
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49
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Ayilam Ramachandran R, Sanches JM, Robertson DM. The roles of autophagy and mitophagy in corneal pathology: current knowledge and future perspectives. Front Med (Lausanne) 2023; 10:1064938. [PMID: 37153108 PMCID: PMC10160402 DOI: 10.3389/fmed.2023.1064938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/16/2023] [Indexed: 05/09/2023] Open
Abstract
The cornea is the clear dome that covers the front portion of the globe. The primary functions of the cornea are to promote the refraction of light and to protect the eye from invading pathogens, both of which are essential for the preservation of vision. Homeostasis of each cellular layer of the cornea requires the orchestration of multiple processes, including the ability to respond to stress. One mechanism whereby cells respond to stress is autophagy, or the process of "self-eating." Autophagy functions to clear damaged proteins and organelles. During nutrient deprivation, amino acids released from protein breakdown via autophagy are used as a fuel source. Mitophagy, a selective form of autophagy, functions to clear damaged mitochondria. Thus, autophagy and mitophagy are important intracellular degradative processes that sustain tissue homeostasis. Importantly, the inhibition or excessive activation of these processes result in deleterious effects on the cell. In the eye, impairment or inhibition of these mechanisms have been associated with corneal disease, degenerations, and dystrophies. This review summarizes the current body of knowledge on autophagy and mitophagy at all layers in the cornea in both non-infectious and infectious corneal disease, dystrophies, and degenerations. It further highlights the critical gaps in our understanding of mitochondrial dysfunction, with implications for novel therapeutics in clinical practice.
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Affiliation(s)
| | - Jose Marcos Sanches
- Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Danielle M Robertson
- Department of Ophthalmology, The University of Texas Southwestern Medical Center, Dallas, TX, United States
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Fowler TE, Choudhary V, Melnyk S, Farsi M, Chang LY, Fortingo N, Chen X, Watsky MA, Bollag WB. Dioleoylphosphatidylglycerol Inhibits Heat Shock Protein B4 (HSPB4)-Induced Inflammatory Pathways In Vitro. Int J Mol Sci 2023; 24:5839. [PMID: 36982926 PMCID: PMC10059050 DOI: 10.3390/ijms24065839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 03/06/2023] [Accepted: 03/13/2023] [Indexed: 03/22/2023] Open
Abstract
Our previous work shows that dioleoylphosphatidylglycerol (DOPG) accelerates corneal epithelial healing in vitro and in vivo by unknown mechanisms. Prior data demonstrate that DOPG inhibits toll-like receptor (TLR) activation and inflammation induced by microbial components (pathogen-associated molecular patterns, PAMPs) and by endogenous molecules upregulated in psoriatic skin, which act as danger-associated molecular patterns (DAMPs) to activate TLRs and promote inflammation. In the injured cornea, sterile inflammation can result from the release of the DAMP molecule, heat shock protein B4 (HSPB4), to contribute to delayed wound healing. Here, we show in vitro that DOPG inhibits TLR2 activation induced in response to HSPB4, as well as DAMPs that are elevated in diabetes, a disease that also slows corneal wound healing. Further, we show that the co-receptor, cluster of differentiation-14 (CD14), is necessary for PAMP/DAMP-induced activation of TLR2, as well as of TLR4. Finally, we simulated the high-glucose environment of diabetes to show that elevated glucose levels enhance TLR4 activation by a DAMP known to be upregulated in diabetes. Together, our results demonstrate the anti-inflammatory actions of DOPG and support further investigation into its development as a possible therapy for corneal injury, especially in diabetic patients at high risk of vision-threatening complications.
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Affiliation(s)
- Teresa E. Fowler
- Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Vivek Choudhary
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
| | - Samuel Melnyk
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Mishma Farsi
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Luke Y. Chang
- Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Nyemkuna Fortingo
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Xunsheng Chen
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Mitchell A. Watsky
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
| | - Wendy B. Bollag
- Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
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