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Luo S, Li J, Yang Y, Jiang Y, Jie Y, Ge W. Spatial transcriptomics and single-cell RNA-sequencing revealed dendritic cell-mediated inflammation in keratoconus. Ocul Surf 2025; 36:134-150. [PMID: 39837422 DOI: 10.1016/j.jtos.2025.01.008] [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: 11/13/2024] [Revised: 01/07/2025] [Accepted: 01/17/2025] [Indexed: 01/23/2025]
Abstract
Keratoconus (KC) is a corneal disorder characterized by central corneal protrusion and thinning. In this study, spatial transcriptomics was employed to investigate molecular and cellular variations in KC, revealing a distinct pattern of inflammatory responses across the cornea. Upregulation of inflammatory processes was observed in the central cornea, while downregulation was noted in the periphery, indicating complex regional inflammatory changes in the KC cornea. Integration with single-cell RNA sequencing (scRNA-seq) further identified enhanced interactions between dendritic cells (DCs) and stromal cells, particularly mediated via the IL-1β pathway, alongside increased matrix metalloproteinase (MMP) production by corneal stromal cells, underscoring the role of inflammation in KC pathogenesis. In vitro and in vivo experiments confirmed that activated DCs promoted the matrix degradation activity of stromal cells, thereby exacerbating KC pathology. Notably, inhibition of the IL-1β pathway effectively mitigated the progression of KC. These findings provide a comprehensive spatial, cellular, and molecular characterization of KC, demonstrating its inflammatory nature. The results also highlight the importance of inflammation in the peripheral cornea for early diagnosis and suggest that anti-inflammatory treatments could serve as potential adjuvant therapy for KC.
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Affiliation(s)
- Shiqi Luo
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China; Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China
| | - Jingying Li
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China
| | - Yan Yang
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China
| | - Yang Jiang
- Department of Ophthalmology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Ying Jie
- Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
| | - Wei Ge
- Department of Immunology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100730, China.
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Vought R, Greenstein SA, Gelles J, Hersh PS. The Pathophysiology of Keratoconus. Cornea 2025; 44:137-143. [PMID: 38830186 DOI: 10.1097/ico.0000000000003585] [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: 02/14/2024] [Accepted: 04/29/2024] [Indexed: 06/05/2024]
Abstract
PURPOSE Keratoconus is a progressive disease characterized by changes in corneal shape, resulting in loss of visual function. There remains a lack of comprehensive understanding regarding its underlying pathophysiology. This review aims to bridge this gap by exploring structural failures and inflammatory processes involved in the etiology and progression of keratoconus. METHODS A literature review was conducted using PubMed and Google Scholar databases, screening for articles published in English using the keyword combinations of "keratoconus" with "pathophysiology," "pathology," "metabolism," "inflammatory," "oxidative stress," "cytokines," "enzymes," "collagen," and "cornea." Articles published between January 1, 1970, and June 1, 2023, were queried and reviewed, with greater emphasis placed on more recent data. Fifty-six relevant studies were examined to develop a thorough review of the pathophysiological mechanisms at play in keratoconus. RESULTS Biomechanical structural failures in the cornea seem to be the primary militating factors in keratoconus etiology and progression. These include disruptions in the arrangement in the collagen lamellae, a decrease in collagen levels, a decrease in natural collagen crosslinking, and changes in lysosomal enzyme activity. Immunologic changes have also been identified in keratoconus, challenging the traditional view of the condition as noninflammatory. Elevated levels of proinflammatory cytokines like IL-1b, IL-6, IL-17, and TNF-α have been observed, along with increased apoptosis of keratocytes. Increased oxidative stress leads to the activation of collagenase and gelatinase enzymes. CONCLUSIONS Keratoconus is a complex condition influenced by both structural defects and inflammatory processes. Understanding these mechanisms can inform clinical management and potentially lead to more effective treatments.
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Affiliation(s)
- Rita Vought
- Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ; and
| | - Steven A Greenstein
- Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ; and
- Cornea and Laser Eye Institute, CLEI Center for Keratoconus, Teaneck, NJ
| | - John Gelles
- Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ; and
- Cornea and Laser Eye Institute, CLEI Center for Keratoconus, Teaneck, NJ
| | - Peter S Hersh
- Institute of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, NJ; and
- Cornea and Laser Eye Institute, CLEI Center for Keratoconus, Teaneck, NJ
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Saha S, Skeie JM, Schmidt GA, Eggleston T, Shevalye H, Sales CS, Phruttiwanichakun P, Dusane A, Field MG, Rinkoski TA, Fautsch MP, Baratz KH, Roy M, Jun AS, Pendleton C, Salem AK, Greiner MA. TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy. Redox Biol 2024; 77:103348. [PMID: 39332053 PMCID: PMC11470242 DOI: 10.1016/j.redox.2024.103348] [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: 08/16/2024] [Accepted: 09/08/2024] [Indexed: 09/29/2024] Open
Abstract
Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe2+) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe2+, basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD.
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Affiliation(s)
- Sanjib Saha
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA
| | - Jessica M Skeie
- Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Iowa Lions Eye Bank, Coralville, IA, 52241, USA
| | | | | | | | - Christopher S Sales
- Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Iowa Lions Eye Bank, Coralville, IA, 52241, USA
| | - Pornpoj Phruttiwanichakun
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA
| | - Apurva Dusane
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA
| | - Matthew G Field
- Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
| | - Tommy A Rinkoski
- Department of Ophthalmology, 200 1st St SW, Mayo Clinic, Rochester, MN, 55905, USA
| | - Michael P Fautsch
- Department of Ophthalmology, 200 1st St SW, Mayo Clinic, Rochester, MN, 55905, USA
| | - Keith H Baratz
- Department of Ophthalmology, 200 1st St SW, Mayo Clinic, Rochester, MN, 55905, USA
| | - Madhuparna Roy
- Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA
| | - Albert S Jun
- Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA
| | - Chandler Pendleton
- The University of Iowa College of Dentistry and Dental Clinics, Iowa City, IA, USA
| | - Aliasger K Salem
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA.
| | - Mark A Greiner
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA; Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA; Iowa Lions Eye Bank, Coralville, IA, 52241, USA.
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Singh RB, Koh S, Sharma N, Woreta FA, Hafezi F, Dua HS, Jhanji V. Keratoconus. Nat Rev Dis Primers 2024; 10:81. [PMID: 39448666 DOI: 10.1038/s41572-024-00565-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/25/2024] [Indexed: 10/26/2024]
Abstract
Keratoconus is a progressive eye disorder primarily affecting individuals in adolescence and early adulthood. The ectatic changes in the cornea cause thinning and cone-like steepening leading to irregular astigmatism and reduced vision. Keratoconus is a complex disorder with a multifaceted aetiology and pathogenesis, including genetic, environmental, biomechanical and cellular factors. Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression. On the cellular level, a complex interplay of hormonal changes, alterations in enzymatic activity that modify extracellular membrane stiffness, and changes in biochemical and biomechanical signalling pathways disrupt collagen cross-linking within the stroma, contributing to structural integrity loss and distortion of normal corneal anatomy. Clinically, keratoconus is diagnosed through clinical examination and corneal imaging. Advanced imaging platforms have improved the detection of keratoconus, facilitating early diagnosis and monitoring of disease progression. Treatment strategies for keratoconus are tailored to disease severity and progression. In early stages, vision correction with glasses or soft contact lenses may suffice. As the condition advances, rigid gas-permeable contact lenses or scleral lenses are prescribed. Corneal cross-linking has emerged as a pivotal treatment aimed at halting the progression of corneal ectasia. In patients with keratoconus with scarring or contact lens intolerance, surgical interventions are performed.
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Affiliation(s)
- Rohan Bir Singh
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
- Department of Ophthalmology, Leiden University Medical Center, Leiden, Netherlands
| | - Shizuka Koh
- Department of Innovative Visual Science, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Namrata Sharma
- Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
| | - Fasika A Woreta
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Farhad Hafezi
- ELZA Institute, Zurich, Switzerland
- EMAGine AG, Zug, Switzerland
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA
| | - Harminder S Dua
- Department of Ophthalmology, University of Nottingham, Nottingham, UK
| | - Vishal Jhanji
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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Sadeghi J, Barooti Y, Gharaei H, Shoeibi N, Sedaghat M, Yazdani N, Abasi Mehrabadi A, Motamed Shariati M. Retinal neurovascular assessment and choroidal vascularity index in patients with keratoconus. Sci Rep 2024; 14:24986. [PMID: 39443674 PMCID: PMC11500336 DOI: 10.1038/s41598-024-76464-0] [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: 08/30/2024] [Accepted: 10/14/2024] [Indexed: 10/25/2024] Open
Abstract
This study aims to evaluate the macular and the optic nerve head thickness and vascular profiles in KC patients and compare them with two groups of healthy emmetrope and subjects with myopic-astigmatism. This cross-sectional study was conducted at Khatam-Al-Anbia Eye Hospital between 2022 and 2023. Subjects aged 18 to 40 were prone to be included in the study. The participants in this study were grouped into three categories: emmetrope (E), myopic-astigmatic (MA), and keratoconus (KC). All participants underwent a comprehensive ocular examination, as well as macular and optic nerve head (ONH) optical coherence tomography angiography (OCTA). In this study, 143 subjects, 50 cases in the KCN group, 46 cases in the E group, and 47 cases in the MA group, enrolled. There was no difference between the three groups regarding age (p = 0.123) and gender (p = 0.632). The superficial and deep capillary densities at the fovea, parafovea, and perifovea were significantly lower in KC patients than in the control groups (p < 0.01). The radial peripapillary capillary (RPC)- all vessels' density is significantly lower in the KC group (p < 0.001). Besides, the choroidal vascularity index (CVI) and choroidal luminal area (CLA) were considerably higher in KC patients (p < 0.001). The macular and ONH vascular profile in KC patients significantly differs from the vascular profile of healthy controls. Further scientific evidence regarding the systemic implications of keratoconus on the vascular system would be desirable to understand the connections between KC and vascular disease.
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Affiliation(s)
- Javad Sadeghi
- Eye Research Centre, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| | - Yalda Barooti
- Eye Research Centre, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| | - Hamid Gharaei
- Eye Research Centre, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| | - Nasser Shoeibi
- Eye Research Centre, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| | - Mohammadreza Sedaghat
- Eye Research Centre, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran
| | - Negareh Yazdani
- Refractive Errors Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Abasi Mehrabadi
- Refractive Errors Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehrdad Motamed Shariati
- Eye Research Centre, Khatam Al-Anbia Eye Hospital, Mashhad University of Medical Sciences, Gharani Boulevard, Mashhad, Iran.
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Wu Y, Liu Y, Feng Y, Li X, Lu Z, Gu H, Li W, Hill LJ, Ou S. Evolution of therapeutic strategy based on oxidant-antioxidant balance for fuchs endothelial corneal dystrophy. Ocul Surf 2024; 34:247-261. [PMID: 39111696 DOI: 10.1016/j.jtos.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/11/2024] [Accepted: 08/02/2024] [Indexed: 08/18/2024]
Abstract
Fuchs endothelial corneal dystrophy (FECD) stands as the most prevalent primary corneal endothelial dystrophy worldwide, posing a significant risk to corneal homeostasis and clarity. Corneal endothelial cells exhibit susceptibility to oxidative stress, suggesting a nuanced relationship between oxidant-antioxidant imbalance and FECD pathogenesis, irrespective of FECD genotype. Given the constrained availability of corneal transplants, exploration into non-surgical interventions becomes crucial. This encompasses traditional antioxidants, small molecule compounds, biologics, and diverse non-drug therapies, such as gene-related therapy, hydrogen therapy and near infrared light therapy. This review concentrates on elucidating the mechanisms behind oxidant-antioxidant imbalance and the evolution of strategies to restore oxidant-antioxidant balance in FECD. It provides a comprehensive overview of both conventional and emerging therapeutic approaches, offering valuable insights for the advancement of non-surgical treatment modalities. The findings herein might establish a robust foundation for future research and the therapeutic strategy of FECD.
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Affiliation(s)
- Yiming Wu
- Department of Biomedical Sciences, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, B15 2TT, UK; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yanbo Liu
- Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Yuchong Feng
- Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Xiaoshuang Li
- Shenzhen Hospital of Guangzhou University of Chinese Medicine (Futian), Shenzhen, 518000, China
| | - Zhaoxiang Lu
- Institute of Microbiology and Infection, Department of Microbes, Infections and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, B15 2TT, UK
| | - Hao Gu
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550025, China
| | - Wei Li
- Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China; Department of Ophthalmology, Xiang'an Hospital of Xiamen University, Medical Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China
| | - Lisa J Hill
- Department of Biomedical Sciences, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, B15 2TT, UK.
| | - Shangkun Ou
- Department of Ophthalmology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550025, China; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen University Affiliated Xiamen Eye Center, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China.
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7
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Hefley BS, Ali AA, Bhattacharya P, Hjortdal J, Walker MK, Karamichos D. Systemic and Ocular Associations of Keratoconus. EXPERT REVIEW OF OPHTHALMOLOGY 2024; 19:379-391. [PMID: 39494085 PMCID: PMC11526800 DOI: 10.1080/17469899.2024.2368801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 06/12/2024] [Indexed: 11/05/2024]
Abstract
Introduction Keratoconus (KC) is the most prevalent corneal ectasia in the world and its pathogenesis is influenced by both ocular and systemic factors. This review explores the multifaceted associations between keratoconus and systemic health conditions, ocular characteristics, and various other environmental/exogenous factors, aiming to illuminate how these relationships influence the pathophysiology of the disease. Areas Covered This review will summarize the fundamental attributes of KC, review and discuss the systemic and ocular association of KC including molecular biomarkers, and provide an organized overview of the parallel alterations occurring within various biological pathways in KC. Expert Opinion Despite the substantial volume of research on keratoconus, the precise etiology of the disease remains elusive. Further studies are necessary to deepen our understanding of this intricate disorder and improve its management.
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Affiliation(s)
- Brenna S. Hefley
- North Texas EAye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
| | - Arsalan A. Ali
- Anne Burnett Marion School of Medicine, Texas Christian University, Fort Worth, TX, 76107, USA
| | - Pradipta Bhattacharya
- Department of Clinical Sciences, College of Optometry, University of Houston, TX, 77204, USA
- The Ocular Surface Institute, University of Houston College of Optometry, Houston, TX, 77204, USA
| | - Jesper Hjortdal
- Department of Ophthalmology, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Maria K. Walker
- Department of Clinical Sciences, College of Optometry, University of Houston, TX, 77204, USA
- The Ocular Surface Institute, University of Houston College of Optometry, Houston, TX, 77204, USA
| | - Dimitrios Karamichos
- North Texas EAye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
- Department of Pharmaceutical Sciences, College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA
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Cheng Y, Cai S, Wu H, Pan J, Su M, Wei X, Ye J, Ke L, Liu G, Chu C. Revolutionizing eye care: the game-changing applications of nano-antioxidants in ophthalmology. NANOSCALE 2024; 16:7307-7322. [PMID: 38533621 DOI: 10.1039/d4nr00611a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Since the theory of free radical-induced aging was proposed in 1956, it has been constantly proven that reactive oxygen species (ROS) produced by oxidative stress play a vital role in the occurrence and progression of eye diseases. However, the inherent limitations of traditional drug therapy hindered the development of ophthalmic disease treatment. In recent years, great achievements have been made in the research of nanomedicine, which promotes the rapid development of safe theranostics in ophthalmology. In this review, we focus on the applications of antioxidant nanomedicine in the treatment of ophthalmology. The eye diseases were mainly classified into two categories: ocular surface diseases and posterior eye diseases. In each part, we first introduced the pathology of specific diseases about oxidative stress, and then presented the representative application examples of nano-antioxidants in eye disease therapy. Meanwhile, the nanocarriers that were used, the mechanism of function, and the therapeutic effect were also presented. Finally, we summarized the latest research progress and limitations of antioxidant nanomedicine for eye disease treatment and put forward the prospects of future development.
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Affiliation(s)
- Yuhang Cheng
- Shen Zhen Research Institute of Xiamen University, Shenzhen 518057, China.
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Shundong Cai
- Shen Zhen Research Institute of Xiamen University, Shenzhen 518057, China.
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Han Wu
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jintao Pan
- Shen Zhen Research Institute of Xiamen University, Shenzhen 518057, China.
| | - Min Su
- Department of Pharmacy, Xiamen Medical College, Xiamen 361023, China.
| | - Xingyuan Wei
- Shen Zhen Research Institute of Xiamen University, Shenzhen 518057, China.
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jinfa Ye
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Lang Ke
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Gang Liu
- Shen Zhen Research Institute of Xiamen University, Shenzhen 518057, China.
| | - Chengchao Chu
- Shen Zhen Research Institute of Xiamen University, Shenzhen 518057, China.
- Xiamen University affiliated Xiamen Eye Center, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen, 361102, China
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9
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Liu R, Ma R, Yan X. Balanced activation of Nrf-2/ARE mediates the protective effect of sulforaphane on keratoconus in the cell mechanical microenvironment. Sci Rep 2024; 14:6937. [PMID: 38521828 PMCID: PMC10960822 DOI: 10.1038/s41598-024-57596-9] [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: 01/10/2024] [Accepted: 03/20/2024] [Indexed: 03/25/2024] Open
Abstract
Keratoconus (KC) is a progressive degenerative disease that usually occurs bilaterally and is characterized by corneal thinning and apical protrusion of the cornea. Oxidative stress is an indicator of the accumulation of reactive oxygen species (ROS), and KC keratocytes exhibit increased ROS production compared with that of normal keratocytes. Therefore, oxidative stress in KC keratocytes may play a major role in the development and progression of KC. Here, we investigated the protective effect of sulforaphane (SF) antioxidants using a hydrogel-simulated model of the cell mechanical microenvironment of KC. The stiffness of the KC matrix microenvironment in vitro was 16.70 kPa and the stiffness of the normal matrix microenvironment was 34.88 kPa. Human keratocytes (HKs) were cultured for 24 h before observation or drug treatment with H2O2 in the presence or absence of SF. The levels of oxidative stress, nuclear factor E2-related factor 2 (Nrf-2) and antioxidant response element (ARE) were detected. The high-stress state of HKs in the mechanical microenvironment of KC cells compensates for the activation of the Nrf-2/ARE signaling pathway. H2O2 leads to increased oxidative stress and decreased levels of antioxidant proteins in KC. In summary, SF can reduce endogenous and exogenous oxidative stress and increase the antioxidant capacity of cells.
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Affiliation(s)
- Ruixing Liu
- Department of Ophthalmology, Peking University First Hospital, Beijing, 100034, People's Republic of China
- People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou, 450003, People's Republic of China
| | - Ruojun Ma
- People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou, 450003, People's Republic of China
| | - Xiaoming Yan
- Department of Ophthalmology, Peking University First Hospital, Beijing, 100034, People's Republic of China.
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10
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Pan J, Pany S, Martinez-Carrasco R, Fini ME. Differential Efficacy of Small Molecules Dynasore and Mdivi-1 for the Treatment of Dry Eye Epitheliopathy or as a Countermeasure for Nitrogen Mustard Exposure of the Ocular Surface. J Pharmacol Exp Ther 2024; 388:506-517. [PMID: 37442618 PMCID: PMC10801785 DOI: 10.1124/jpet.123.001697] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 05/19/2023] [Accepted: 06/05/2023] [Indexed: 07/15/2023] Open
Abstract
The ocular surface comprises the wet mucosal epithelia of the cornea and conjunctiva, the associated glands, and the overlying tear film. Epitheliopathy is the common pathologic outcome when the ocular surface is subjected to oxidative stress. Whether different stresses act via the same or different mechanisms is not known. Dynasore and dyngo-4a, small molecules developed to inhibit the GTPase activity of classic dynamins DNM1, DNM2, and DNM3, but not mdivi-1, a specific inhibitor of DNM1L, protect corneal epithelial cells exposed to the oxidant tert-butyl hydroperoxide (tBHP). Here we report that, while dyngo-4a is the more potent inhibitor of endocytosis, dynasore is the better cytoprotectant. Dynasore also protects corneal epithelial cells against exposure to high salt in an in vitro model of dysfunctional tears in dry eye. We now validate this finding in vivo, demonstrating that dynasore protects against epitheliopathy in a mouse model of dry eye. Knockdown of classic dynamin DNM2 was also cytoprotective against tBHP exposure, suggesting that dynasore's effect is at least partially on target. Like tBHP and high salt, exposure of corneal epithelial cells to nitrogen mustard upregulated the unfolded protein response and inflammatory markers, but dynasore did not protect against nitrogen mustard exposure. In contrast, mdivi-1 was cytoprotective. Interestingly, mdivi-1 did not inhibit the nitrogen mustard-induced expression of inflammatory cytokines. We conclude that exposure to tBHP or nitrogen mustard, two different oxidative stress agents, cause corneal epitheliopathy via different pathologic pathways. SIGNIFICANCE STATEMENT: Results presented in this paper, for the first time, implicate the dynamin DNM2 in ocular surface epitheliopathy. The findings suggest that dynasore could serve as a new topical treatment for dry eye epitheliopathy and that mdivi-1 could serve as a medical countermeasure for epitheliopathy due to nitrogen mustard exposure, with potentially increased efficacy when combined with anti-inflammatory agents and/or UPR modulators.
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Affiliation(s)
- Jinhong Pan
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine (J.P., S.P., R.M.-C., M.E.F.) and Program in Pharmacology and Drug Development, Tufts Graduate School of Biomedical Sciences (M.E.F.), Tufts University, Boston, Massachusetts
| | - Satyabrata Pany
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine (J.P., S.P., R.M.-C., M.E.F.) and Program in Pharmacology and Drug Development, Tufts Graduate School of Biomedical Sciences (M.E.F.), Tufts University, Boston, Massachusetts
| | - Rafael Martinez-Carrasco
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine (J.P., S.P., R.M.-C., M.E.F.) and Program in Pharmacology and Drug Development, Tufts Graduate School of Biomedical Sciences (M.E.F.), Tufts University, Boston, Massachusetts
| | - M Elizabeth Fini
- New England Eye Center, Tufts Medical Center and Department of Ophthalmology, Tufts University School of Medicine (J.P., S.P., R.M.-C., M.E.F.) and Program in Pharmacology and Drug Development, Tufts Graduate School of Biomedical Sciences (M.E.F.), Tufts University, Boston, Massachusetts
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11
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Sedaghat MR, Shiri H, Tavakkol-Afshari J, Norouzmahani ME, Bahri F, Fooladi S, Momeni-Moghaddam H, Danesh Z, Nikpoor AR, Momeni-Moghaddam MA, Nematollahi MH, Sadeghi J. Impact of a 50bp insertion/deletion polymorphism of the superoxide dismutase-1 on oxidative stress status and risk of keratoconus. Exp Eye Res 2024; 238:109742. [PMID: 38040051 DOI: 10.1016/j.exer.2023.109742] [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: 10/29/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/03/2023]
Abstract
Keratoconus (KC) is characterized by the predominant primary ectatic disease, affecting the cornea, necessitating corneal transplants in some cases. While some loci associated with KC risk have been identified, the understanding of the disease remains limited. Superoxide dismutase (SOD) enzymes play a crucial role in countering the reactive oxygen species and providing protection against oxidative stress (OS). Accordingly, the objective of this study was to investigate a potential association of a 50 nucleotide base pairs (bp) insertion/deletion (I/D) within the SOD1 promoter, and the located 1684 bp upstream of the SOD1 ATG, with KC in the Iranian population. Additionally, an assessment was conducted on SOD activity and the total antioxidant capacity (TAC), as determined by the ferric reducing-antioxidant power assay, along with malondialdehyde (MDA) levels. In this case-control study, genomic DNA was extracted from the blood cells of KC (n = 402) and healthy (n = 331) individuals. The genotype of this gene was determined using the PCR technique. Furthermore, the amount of SOD enzyme activity and the MDA and TAC levels were measured in the serum of the study groups. The (I/I) genotype was present in 84.23%, the (I/D) genotype in 15.06%, and the (D/D) genotype in 0.69% of both groups. A statistically significant relationship was seen between different genotypes and TAC, MDA, and SOD1 activity indices (P < 0.05). Individuals with the D/D genotype exhibited a decrease in total antioxidant capacity, an increase in the amount of MDA, and a decrease in SOD1 enzyme activity (P < 0.05). Moreover, the logistic regression analysis of KC development indicated that elevated levels of MDA increased the risk of KC incidence in the patient group compared to the healthy group, while a higher activity of SOD1 and greater values of TAC decreased the KC risk. The removal of the 50 bp fragment reduced SOD1 activity and elevated OS levels, thereby impacting the oxidant-antioxidant balance. This could potentially play a significant role in individuals afflicted by KC.
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Affiliation(s)
| | - Hamidreza Shiri
- Department of Clinical Biochemistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Jalil Tavakkol-Afshari
- Immunogenetic and Cell Culture Department, Immunology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of allergy and immunology, School of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Faegheh Bahri
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Saba Fooladi
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA
| | - Hamed Momeni-Moghaddam
- Rehabilitation Sciences Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Zeynab Danesh
- Department of Optometry, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amin Reza Nikpoor
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | | | | | - Javad Sadeghi
- Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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12
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Aydemir GA, Kocabaş DO, Bilen A, Aydemir E, Bayat AH, Oren B, Kiziltoprak H. Evaluation of Retinal Layer Thicknesses in Patients with Keratoconus Using Retinal Layer Segmentation Analysis. Klin Monbl Augenheilkd 2023; 240:1199-1206. [PMID: 35320863 DOI: 10.1055/a-1743-3067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To conduct an evaluation of the effects of irregular astigmatism on the retinal nerve fiber layer (RNFL) and the retinal layers observed using spectral-domain optical coherence tomography (SD-OCT) in patients who had keratoconus (KC). MATERIALS AND METHODS A total of 255 eyes from 255 individuals, comprising 72 eyes of KC patients, 70 eyes of patients with astigmia, and 113 eyes of healthy controls were included in the analysis. RNFL scan maps (comprising global, temporal, superotemporal, inferotemporal, nasal, inferonasal, and superonasal maps) and macular thickness (MT) maps of a standard from the Early Treatment Diabetic Retinopathy Study (ETDRS) grid were assessed. The measurements were segmented automatically using Spectralis software, and included the RNFL, inner and outer plexiform layers (IPL, OPL), inner and outer nuclear layers (INL, ONL), ganglion cell layer, retinal pigment epithelium (RPE) in the central 6-mm ETDRS subfield. RESULTS The RNFL thickness in the KC group was lower when compared with the other two groups; however, statistically significant differences were noted in the global, temporal, superotemporal, and inferotemporal sectors (p < 0.05 for all). All of the central MT parameters showed significant variation among the groups, while a statistically significant decrease was noted in the KC group, except in the inferior outer sector (p = 0.741). In the segmentation analysis, the KC group had the significantly lowest IPL, ONL, RPE, and outer retinal layer (ORL) thickness among the groups (p < 0.05 for each). The astigmatic group was similar to the control group with regard to these parameters (p > 0.05 for each). CONCLUSION The eyes in the KC group appeared to have a thinner RNFL and MT when compared to those in the astigmatic and control groups. The ORLs, especially the ONL and RPE, were the most affected component of the macula in the KC group.
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Affiliation(s)
- Gozde Aksoy Aydemir
- Ophthalmology, Adiyaman Universitesi Egitim ve Arastirma Hastanesi, Adiyaman, Turkey
| | | | - Abdurrahman Bilen
- Ophthalmology, Adiyaman Universitesi Egitim ve Arastirma Hastanesi, Adiyaman, Turkey
| | - Emre Aydemir
- Ophthalmology, Adiyaman Universitesi Egitim ve Arastirma Hastanesi, Adiyaman, Turkey
| | - Alper Halil Bayat
- Ophyhalmology, Istanbul Medipol University, Birlik Mahallesi Bahçeler Caddesi No:5, Esenler/Istanbul, Turkey
| | - Burak Oren
- Ophthalmology, Adiyaman Universitesi Egitim ve Arastirma Hastanesi, Adiyaman, Turkey
| | - Hasan Kiziltoprak
- Ophthalmology, Adiyaman Universitesi Egitim ve Arastirma Hastanesi, Adiyaman, Turkey
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13
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Lin X, Moreno IY, Nguyen L, Gesteira TF, Coulson-Thomas VJ. ROS-Mediated Fragmentation Alters the Effects of Hyaluronan on Corneal Epithelial Wound Healing. Biomolecules 2023; 13:1385. [PMID: 37759785 PMCID: PMC10526416 DOI: 10.3390/biom13091385] [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: 06/26/2023] [Revised: 08/11/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
A buildup of reactive oxygen species (ROS) occurs in virtually all pathological conditions. Hyaluronan (HA) is a major extracellular matrix component and is susceptible to oxidation by reactive oxygen species (ROS), yet the precise chemical structures of oxidized HA products (oxHA) and their physiological properties remain largely unknown. This study characterized the molecular weight (MW), structures, and physiological properties of oxHA. For this, high-molecular-weight HA (HMWHA) was oxidized using increasing molar ratios of hydrogen peroxide (H2O2) or hypochlorous acid (HOCl). ROS lead to the fragmentation of HA, with the oxHA products produced by HOCl exhibiting an altered chemical structure while those produced by H2O2 do not. HMWHA promotes the viability of human corneal epithelial cells (hTCEpi), while low MWHA (LMWHA), ultra-LMWHA (ULMWHA), and most forms of oxHA do not. HMWHA and LMWHA promote hTCEpi proliferation, while ULMWHA and all forms of oxHA do not. LMWHA and some forms of oxHA promote hTCEpi migration, while HMWHA does not. Finally, all native forms of HA and oxHA produced by HOCl promote in vivo corneal wound healing, while oxHA produced by H2O2 does not. Taken together, our results show that HA fragmentation by ROS can alter the physiological activity of HA by altering its MW and structure.
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Affiliation(s)
| | | | | | | | - Vivien J. Coulson-Thomas
- College of Optometry, University of Houston, 4401 Martin Luther King Boulevard, Houston, TX 77204-2020, USA; (X.L.); (I.Y.M.); (L.N.); (T.F.G.)
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14
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Wu X, Deng Q, Han Z, Ni F, Sun D, Xu Y. Screening and identification of genes related to ferroptosis in keratoconus. Sci Rep 2023; 13:13956. [PMID: 37626095 PMCID: PMC10457308 DOI: 10.1038/s41598-023-41194-2] [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: 06/14/2023] [Accepted: 08/23/2023] [Indexed: 08/27/2023] Open
Abstract
Corneal keratoconus (KC) is a dilated (ectatic) corneal disease characterized by a central thinning of the cornea, which causes protrusion into a conical shape that seriously affects vision. However, due to the complex etiology of keratoconus, its entire mechanism remains unclear and there is no mechanism-directed treatment method. Ferroptosis is a novel programmed cell death mechanism related to lipid peroxidation, stress, and amino acid metabolism, which plays a crucial role in various diseases. This study aimed to explore the relationship between keratoconus and ferroptosis, to provide new insights into the mechanism of keratoconus development, and potential treatment options based on further elucidation of this mechanism. The corresponding mRNA microarray expression matrix data of KC patients were obtained from GEO database (GSE204791). Weighted co-expression network analysis (WGCNA) and support vector machine recursive feature elimination (SVM-RFE) were selected to screen hub genes, which were overlapped with ferroptosis genes (FRGs) from FerrDb. GO and GSEA were performed to analyze differential pathways, ssGSEA was used to determine immune status, and then, feasible drugs were predicted by gene-drug network. Additionally, we predicted the miRNA and IncRNA of hub genes to identify the underlying mechanism of disease so as to predict treatment for the disease. The epithelial transcriptome from keratoconus tissue mRNA microarray data (GSE204791) was extracted for the main analysis, including eight epithelial cells and eight epithelial control cells. The differential genes that were overlapped by WGCAN, SVM-RFE and FRGs were mainly related to oxidative stress, immune regulation, cellular inflammation, and metal ion transport. Through further analysis, aldo-keto reductase family 1 member C3 (AKR1C3) was selected, and negatively correlated with mature CD56 natural killer (NK) cells and macrophages. Then, gene-drug interaction network analysis and miRNA prediction were performed through the website. It was concluded that four immune-related drugs (INDOMETHACIN, DAUNORUBICIN, DOXORUBICIN, DOCETAXEL) and a miRNA (has-miR-184) were screened to predict potential drugs and targets for disease treatment. To our knowledge, this was the first report of KC being associated with ferroptosis and prompted search for differential genes to predict drug targets of gene immunotherapy. Our findings provided insight and a solid basis for the analysis and treatment of KC.
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Affiliation(s)
- Xiaojun Wu
- School of Pharmacology, Binzhou Medical University, Guanhai Rd 346, Yantai, 264003, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Yantai, 264003, China
| | - Qing Deng
- School of Pharmacology, Binzhou Medical University, Guanhai Rd 346, Yantai, 264003, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Yantai, 264003, China
| | - Zhe Han
- School of Pharmacology, Binzhou Medical University, Guanhai Rd 346, Yantai, 264003, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Yantai, 264003, China
| | - Feixue Ni
- School of Pharmacology, Binzhou Medical University, Guanhai Rd 346, Yantai, 264003, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Yantai, 264003, China
| | - Daxi Sun
- School of Pharmacology, Binzhou Medical University, Guanhai Rd 346, Yantai, 264003, China
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Yantai, 264003, China
| | - Yuxue Xu
- School of Pharmacology, Binzhou Medical University, Guanhai Rd 346, Yantai, 264003, China.
- Shandong Technology Innovation Center of Molecular Targeting and Intelligent Diagnosis and Treatment, Yantai, 264003, China.
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15
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Gross C, Guérin LP, Socol BG, Germain L, Guérin SL. The Ins and Outs of Clusterin: Its Role in Cancer, Eye Diseases and Wound Healing. Int J Mol Sci 2023; 24:13182. [PMID: 37685987 PMCID: PMC10488069 DOI: 10.3390/ijms241713182] [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: 06/30/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Clusterin (CLU) is a glycoprotein originally discovered in 1983 in ram testis fluid. Rapidly observed in other tissues, it was initially given various names based on its function in different tissues. In 1992, it was finally named CLU by consensus. Nearly omnipresent in human tissues, CLU is strongly expressed at fluid-tissue interfaces, including in the eye and in particular the cornea. Recent research has identified different forms of CLU, with the most prominent being a 75-80 kDa heterodimeric protein that is secreted. Another truncated version of CLU (55 kDa) is localized to the nucleus and exerts pro-apoptotic activities. CLU has been reported to be involved in various physiological processes such as sperm maturation, lipid transportation, complement inhibition and chaperone activity. CLU was also reported to exert important functions in tissue remodeling, cell-cell adhesion, cell-substratum interaction, cytoprotection, apoptotic cell death, cell proliferation and migration. Hence, this protein is sparking interest in tissue wound healing. Moreover, CLU gene expression is finely regulated by cytokines, growth factors and stress-inducing agents, leading to abnormally elevated levels of CLU in many states of cellular disturbance, including cancer and neurodegenerative conditions. In the eye, CLU expression has been reported as being severely increased in several pathologies, such as age-related macular degeneration and Fuch's corneal dystrophy, while it is depleted in others, such as pathologic keratinization. Nevertheless, the precise role of CLU in the development of ocular pathologies has yet to be deciphered. The question of whether CLU expression is influenced by these disorders or contributes to them remains open. In this article, we review the actual knowledge about CLU at both the protein and gene expression level in wound healing, and explore the possibility that CLU is a key factor in cancer and eye diseases. Understanding the expression and regulation of CLU could lead to the development of novel therapeutics for promoting wound healing.
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Affiliation(s)
- Christelle Gross
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| | | | - Bianca G. Socol
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
| | - Lucie Germain
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| | - Sylvain L. Guérin
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
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16
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Li X, Chen K, Wang Z, Li J, Wang X, Xie C, Tong J, Shen Y. The mTOR signalling in corneal diseases: A recent update. Biochem Pharmacol 2023; 213:115620. [PMID: 37217140 DOI: 10.1016/j.bcp.2023.115620] [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: 03/23/2023] [Revised: 05/16/2023] [Accepted: 05/16/2023] [Indexed: 05/24/2023]
Abstract
Corneal diseases affect 4.2 million people worldwide and are a leading cause of vision impairment and blindness. Current treatments for corneal diseases, such as antibiotics, steroids, and surgical interventions, have numerous disadvantages and challenges. Thus, there is an urgent need for more effective therapies. Although the pathogenesis of corneal diseases is not fully understood, it is known that injury caused by various stresses and postinjury healing, such as epithelial renewal, inflammation, stromal fibrosis, and neovascularization, are highly involved. Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, metabolism, and the immune response. Recent studies have revealed that activation of mTOR signalling extensively contributes to the pathogenesis of various corneal diseases, and inhibition of mTOR with rapamycin achieves promising outcomes, supporting the potential of mTOR as a therapeutic target. In this review, we detail the function of mTOR in corneal diseases and how these characteristics contribute to disease treatment using mTOR-targeted drugs.
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Affiliation(s)
- Xiang Li
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Kuangqi Chen
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zixi Wang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiayuan Li
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Xiawei Wang
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Chen Xie
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China.
| | - Jianping Tong
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China.
| | - Ye Shen
- Department of Ophthalmology, the First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China.
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17
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Ogando DG, Kim ET, Li S, Bonanno JA. Corneal Edema in Inducible Slc4a11 Knockout Is Initiated by Mitochondrial Superoxide Induced Src Kinase Activation. Cells 2023; 12:1528. [PMID: 37296649 PMCID: PMC10253072 DOI: 10.3390/cells12111528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 05/25/2023] [Accepted: 05/30/2023] [Indexed: 06/12/2023] Open
Abstract
PURPOSE Inducible Slc4a11 KO leads to corneal edema by disruption of the pump and barrier functions of the corneal endothelium (CE). The loss of Slc4a11 NH3-activated mitochondrial uncoupling leads to mitochondrial membrane potential hyperpolarization-induced oxidative stress. The goal of this study was to investigate the link between oxidative stress and the failure of pump and barrier functions and to test different approaches to revert the process. METHODS Mice which were homozygous for Slc4a11 Flox and Estrogen receptor -Cre Recombinase fusion protein alleles at 8 weeks of age were fed Tamoxifen (Tm)-enriched chow (0.4 g/Kg) for 2 weeks, and controls were fed normal chow. During the initial 14 days, Slc4a11 expression, corneal thickness (CT), stromal [lactate], Na+-K+ ATPase activity, mitochondrial superoxide levels, expression of lactate transporters, and activity of key kinases were assessed. In addition, barrier function was assessed by fluorescein permeability, ZO-1 tight junction integrity, and cortical cytoskeleton F-actin morphology. RESULTS Tm induced a rapid decay in Slc4a11 expression that was 84% complete at 7 days and 96% complete at 14 days of treatment. Superoxide levels increased significantly by day 7; CT and fluorescein permeability by day 14. Tight junction ZO-1 distribution and the cortical cytoskeleton were disrupted at day 14, concomitant with decreased expression of Cldn1, yet with increased tyrosine phosphorylation. Stromal lactate increased by 60%, Na+-K+ ATPase activity decreased by 40%, and expression of lactate transporters MCT2 and MCT4 significantly decreased, but MCT1 was unchanged at 14 days. Src kinase was activated, but not Rock, PKCα, JNK, or P38Mapk. Mitochondrial antioxidant Visomitin (SkQ1, mitochondrial targeted antioxidant) and Src kinase inhibitor eCF506 significantly slowed the increase in CT, with concomitant decreased stromal lactate retention, improved barrier function, reduced Src activation and Cldn1 phosphorylation, and rescued MCT2 and MCT4 expression. CONCLUSIONS Slc4a11 KO-induced CE oxidative stress triggered increased Src kinase activity that resulted in perturbation of the pump components and barrier function of the CE.
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Affiliation(s)
| | | | | | - Joseph A. Bonanno
- Vision Science Program, School of Optometry, Indiana University, Bloomington, IN 47405, USA; (D.G.O.); (E.T.K.); (S.L.)
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18
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Kosaruk W, Brown JL, Towiboon P, Punyapornwithaya V, Pringproa K, Thitaram C. Measures of Oxidative Status Markers in Relation to Age, Sex, and Season in Sick and Healthy Captive Asian Elephants in Thailand. Animals (Basel) 2023; 13:ani13091548. [PMID: 37174585 PMCID: PMC10177462 DOI: 10.3390/ani13091548] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Oxidative stress is a pathological condition that can have adverse effects on animal health, although little research has been conducted on wildlife species. In this study, blood was collected from captive Asian elephants for the assessment of five serum oxidative status markers (reactive oxygen species (ROS) concentrations; malondialdehyde, MDA; albumin; glutathione peroxidase, GPx; and catalase) in healthy (n = 137) and sick (n = 20) animals. Health problems consisted of weakness, puncture wounds, gastrointestinal distress, eye and musculoskeletal problems, and elephant endotheliotropic herpesvirus hemorrhagic disease (EEHV-HD). Fecal samples were also collected to assess glucocorticoid metabolites (fGCMs) as a measure of stress. All data were analyzed in relation to age, sex, sampling season, and their interactions using generalized linear models, and a correlation matrix was constructed. ROS and serum albumin concentrations exhibited the highest concentrations in aged elephants (>45 years). No sex differences were found for any biomarker. Interactions were observed for age groups and seasons for ROS and catalase, while GPx displayed a significant interaction between sex and season. In pairwise comparisons, significant increases in ROS and catalase were observed in summer, with higher ROS concentrations observed only in the adult female group. Lower catalase activity was exhibited in juvenile males, subadult males, adult females, and aged females compared to subadult and adult elephants (males and females) in winter and the rainy season. There was a positive association between catalase activity and fGCMs (r = 0.23, p < 0.05), and a number of red blood cell parameters were positively associated with several of these biomarkers, suggesting high oxidative and antioxidative activity covary in red cells (p < 0.05). According to health status, elephants with EEHV-HD showed the most significant changes in oxidative stress markers, with MDA, GPx, and catalase being higher and albumin being lower than in healthy elephants. This study provides an analysis of understudied health biomarkers in Asian elephants, which can be used as additional tools for assessing the health condition of this species and suggests age and season may be important factors in data interpretation.
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Affiliation(s)
- Worapong Kosaruk
- Doctoral Degree Program in Veterinary Science, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
- Center of Elephant and Wildlife Health, Chiang Mai University Animal Hospital, Chiang Mai 50100, Thailand
- Elephant, Wildlife, and Companion Animals Research Group, Chiang Mai University, Chiang Mai 50100, Thailand
| | - Janine L Brown
- Center of Elephant and Wildlife Health, Chiang Mai University Animal Hospital, Chiang Mai 50100, Thailand
- Elephant, Wildlife, and Companion Animals Research Group, Chiang Mai University, Chiang Mai 50100, Thailand
- Center for Species Survival, Smithsonian Conservation Biology Institute, Front Royal, VA 22630, USA
| | - Patcharapa Towiboon
- Center of Elephant and Wildlife Health, Chiang Mai University Animal Hospital, Chiang Mai 50100, Thailand
| | - Veerasak Punyapornwithaya
- Department of Food Animal Clinic, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
| | - Kidsadagon Pringproa
- Elephant, Wildlife, and Companion Animals Research Group, Chiang Mai University, Chiang Mai 50100, Thailand
- Department of Veterinary Bioscience and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
| | - Chatchote Thitaram
- Center of Elephant and Wildlife Health, Chiang Mai University Animal Hospital, Chiang Mai 50100, Thailand
- Elephant, Wildlife, and Companion Animals Research Group, Chiang Mai University, Chiang Mai 50100, Thailand
- Department of Companion Animal and Wildlife Clinic, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai 50100, Thailand
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19
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Bucolo C, Maugeri G, Giunta S, D’Agata V, Drago F, Romano GL. Corneal wound healing and nerve regeneration by novel ophthalmic formulations based on cross-linked sodium hyaluronate, taurine, vitamin B6, and vitamin B12. Front Pharmacol 2023; 14:1109291. [PMID: 36817120 PMCID: PMC9932323 DOI: 10.3389/fphar.2023.1109291] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
Introduction: To evaluate the pharmacological profile of ocular formulations based on cross-linked sodium hyaluronate (CL-SH), taurine (Tau), vitamin B6 (Vit B6) and vitamin B12 (Vit B12) using in vitro and in vivo paradigms. Methods: Rabbit corneal epithelial cells were used to assess wound healing and reactive oxygen species (ROS) formation by scratch assay and oxidative stress (0.3 mM H2O2; 30 min), respectively with or without ocular formulations exposure. In vivo studies were carried out on albino rabbits to evaluate corneal nerve regeneration and corneal wound healing with or without treatment with six different formulations. Animals were anesthetized, the corneal epithelium was removed, and formulations were topically administered (30 μL/eye; 3 times/day for 6 days). Slit-lamp observation was carried out at different time points. After 6 days the animals were killed, and corneas were collected to evaluate corneal re-innervation by immunohistochemistry of selective neuronal marker β-III tubulin. Results: Formulations containing the concentrations 0.16% or 0.32% of cross-linked sodium hyaluronate, taurine, vitamin B6 and vitamin B12 accelerated corneal wound healing. Cells exposed to H2O2 led to significant (p < 0.05) increase of reactive oxygen species concentration that was significantly (p < 0.05) counteract by formulations containing cross-linked sodium hyaluronate (0.32%) and taurine with or without vitamins. The extent of re-innervation, in terms of β-III tubulin staining, was 5-fold greater (p < 0.01) in the eye of rabbits treated with formulation containing 0.32% cross-linked sodium hyaluronate, taurine, vitamins (RenerviX®) compared with the control group (no treatment). Furthermore, re-innervation elicited by RenerviX® was significantly greater (p < 0.01) compared with the group treated with the formulation containing 0.32% cross-linked sodium hyaluronate and taurine without vitamins, and with the group treated with the formulation containing 0.5% linear sodium hyaluronate (SH), taurine, and vitamin B12, respectively. Discussion: In conclusion, among the formulations tested, the new ophthalmic gel RenerviX® was able to contrast oxidative stress, to accelerate corneal re-epithelization and to promote nerve regeneration.
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Affiliation(s)
- Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy,*Correspondence: Claudio Bucolo,
| | - Grazia Maugeri
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Salvatore Giunta
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Velia D’Agata
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Giovanni Luca Romano
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
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20
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Shu DY, Chaudhary S, Cho KS, Lennikov A, Miller WP, Thorn DC, Yang M, McKay TB. Role of Oxidative Stress in Ocular Diseases: A Balancing Act. Metabolites 2023; 13:187. [PMID: 36837806 PMCID: PMC9960073 DOI: 10.3390/metabo13020187] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/22/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Redox homeostasis is a delicate balancing act of maintaining appropriate levels of antioxidant defense mechanisms and reactive oxidizing oxygen and nitrogen species. Any disruption of this balance leads to oxidative stress, which is a key pathogenic factor in several ocular diseases. In this review, we present the current evidence for oxidative stress and mitochondrial dysfunction in conditions affecting both the anterior segment (e.g., dry eye disease, keratoconus, cataract) and posterior segment (age-related macular degeneration, proliferative vitreoretinopathy, diabetic retinopathy, glaucoma) of the human eye. We posit that further development of therapeutic interventions to promote pro-regenerative responses and maintenance of the redox balance may delay or prevent the progression of these major ocular pathologies. Continued efforts in this field will not only yield a better understanding of the molecular mechanisms underlying the pathogenesis of ocular diseases but also enable the identification of novel druggable redox targets and antioxidant therapies.
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Affiliation(s)
- Daisy Y. Shu
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Suman Chaudhary
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Kin-Sang Cho
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Anton Lennikov
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - William P. Miller
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - David C. Thorn
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
| | - Menglu Yang
- Department of Ophthalmology, Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, MA 02114, USA
| | - Tina B. McKay
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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21
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Sekhon AS, He B, Iovieno A, Yeung SN. Pathophysiology of Corneal Endothelial Cell Loss in Dry Eye Disease and Other Inflammatory Ocular Disorders. Ocul Immunol Inflamm 2023; 31:21-31. [PMID: 34678119 DOI: 10.1080/09273948.2021.1980808] [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] [Indexed: 01/27/2023]
Abstract
PURPOSE Dry eye disease (DED) and other inflammatory ocular disorders have been reported to be associated with decreased corneal endothelial cell density (CECD), however the mechanism of underlying endothelial cell loss remains unknown. METHODS We conducted a comprehensive literature search of English-written publications on dry eye disease, corneal endothelial cell loss, Sjögren's syndrome, and Graft Vs Host Disease (GVHD), to review the effects of DED and other inflammatory ocular surface conditions on CECD. RESULTS A total of 78 studies were included in our study. Loss of corneal neurotrophic support, cytotoxic stress, and a heightened immune response, all of which may occur secondarily to a common causative agent such as inflammation, are major contributors to reduced CECD. CONCLUSION More studies are needed to determine how the interrelated pathways of altered corneal nerve function and upregulated expression of inflammatory activity influence corneal endothelial cell loss.
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Affiliation(s)
- Amardeep S Sekhon
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada
| | - Bonnie He
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Alfonso Iovieno
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
| | - Sonia N Yeung
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada
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22
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Corneal epithelium in keratoconus underexpresses active NRF2 and a subset of oxidative stress-related genes. PLoS One 2022; 17:e0273807. [PMID: 36240204 PMCID: PMC9565379 DOI: 10.1371/journal.pone.0273807] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 08/15/2022] [Indexed: 11/07/2022] Open
Abstract
Keratoconus (KC) is a multifactorial progressive ectatic disorder characterized by local thinning of the cornea, leading to decreased visual acuity due to irregular astigmatism and opacities. Despite the evolution of advanced imaging methods, the exact etiology of KC remains unknown. Our aim was to investigate the involvement of corneal epithelium in the pathophysiology of the disease. Corneal epithelial samples were collected from 23 controls and from 2 cohorts of patients with KC: 22 undergoing corneal crosslinking (early KC) and 6 patients before penetrating keratoplasty (advanced KC). The expression of genes involved in the epidermal terminal differentiation program and of the oxidative stress pathway was assessed by real time PCR analysis. Presence of some of the differentially expressed transcripts was confirmed at protein level using immunofluorescence on controls and advanced KC additional corneal samples. We found statistically significant under-expression in early KC samples of some genes known to be involved in the mechanical resistance of the epidermis (KRT16, KRT14, SPRR1A, SPRR2A, SPRR3, TGM1 and TGM5) and in oxidative stress pathways (NRF2, HMOX1 and HMOX2), as compared to controls. In advanced KC samples, expression of SPRR2A and HMOX1 was reduced. Decreased expression of keratin (KRT)16 and KRT14 proteins was observed. Moreover, differential localization was noted for involucrin, another protein involved in the epidermis mechanical properties. Finally, we observed an immunofluorescence staining for the active form of NRF2 in control epithelia that was reduced in KC epithelia. These results suggest a defect in the mechanical resistance and the oxidative stress defense possibly mediated via the NRF2 pathway in the corneal keratoconic epithelium.
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23
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Tekin S, Seven E. Assessment of serum catalase, reduced glutathione, and superoxide dismutase activities and malondialdehyde levels in keratoconus patients. Eye (Lond) 2022; 36:2062-2066. [PMID: 34462580 PMCID: PMC9499963 DOI: 10.1038/s41433-021-01753-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/10/2021] [Accepted: 08/18/2021] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the relationship between keratoconus disease and the antioxidant activities of catalase (CAT), reduced glutathione (GSH) and superoxide dismutase (SOD) and the level of the oxidative stress marker malondialdehyde (MDA) in serum. METHODS The study included 50 patients diagnosed with keratoconus and 53 healthy age- and sex-matched control subjects. The keratoconus patients were grouped according to the four keratoconus stages based on the modified Krumeich keratoconus classification system. The CAT, GSH and SOD activities and MDA levels in the serum samples collected from the patient and control groups were compared. RESULTS The mean serum CAT, GSH, SOD and MDA levels in the keratoconus group were determined to be 0.075 (0.074-0.078)U/L, 0.002 (0.001-0.006) mmol/ml, 1.56 (1.51-1.62)U/L and 1.69 (1.65-1.99) mmol/L, respectively, and those in the control group were determined to be 0.024 (0.013-0.037)U/L, 0.029 (0.018-0.049) mmol/ml, 4.13 (4.01-4.17) U/L and 0.74 (0.65-0.82) mmol/L. The serum GSH levels and SOD activity were significantly lower in the keratoconus group (p < 0.001 for both) than in the control group while the CAT activity and MDA levels were significantly higher (p < 0.001 for both). CONCLUSION The low serum GSH levels and SOD activity and the high CAT activity and MDA levels observed in this study suggest the presence of oxidative stress and inadequate antioxidant defence mechanisms in keratoconus patients. The studied parameters may offer auxiliary markers for use in the diagnosis and treatment of the keratoconus disease and in its potential therapeutic targets in the future.
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Affiliation(s)
- Serek Tekin
- Department of Ophthalmology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey.
| | - Erbil Seven
- Department of Ophthalmology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
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24
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Goñi N, Martínez-Soroa I, Ibarrondo O, Azkargorta M, Elortza F, Galarreta DJ, Acera A. Tear proteome profile in eyes with keratoconus after intracorneal ring segment implantation or corneal crosslinking. Front Med (Lausanne) 2022; 9:944504. [PMID: 36203781 PMCID: PMC9531826 DOI: 10.3389/fmed.2022.944504] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
PurposeKeratoconus (KC) is a corneal ectasia characterized by structural changes, resulting in progressive thinning and biomechanical weakening that can lead to worsening visual acuity due to irregular astigmatism. Corneal collagen Crosslinking (CXL) and Intracorneal Ring Segment (ICRS) are widely used treatments in KC disease, but the alterations they cause in biomechanical mediators are still poorly understood. The aim of this study was to analyze the tear proteome profile before and after treatments to identify biomarkers altered by surgery.Materials and methodsAn observational, prospective, case-control pilot study was conducted, analyzing tear samples from KC patients by nano-liquid chromatography-mass spectrometry (nLC-MS/MS). Data are available via ProteomeXchange with identifier PXD035655. Patients with KC who underwent ICRS surgery (n = 4), CXL (n = 4), and healthy subjects (Ctrl, n = 4) were included in this study. Clinical parameters were measured and tear samples were collected before and 18 months after surgery. Proteins with ≥2 expression change and p-value < 0.05 between groups and times were selected to study their role in post-operative corneal changes.ResultsThese analyses led to the identification of 447 tear proteins, some of which were dysregulated in KC patients. In comparisons between the two surgical groups and Ctrls, the biological processes that were altered in KC patients at baseline were those that were dysregulated as a consequence of the disease and not of the surgical intervention. Among the biological processes seen to be altered were: immune responses, cytoskeleton components, protein synthesis and metabolic reactions. When comparing the two treatment groups (ICRS and CXL), the process related to cytoskeleton components was the most altered, probably due to corneal thinning which was more pronounced in patients undergoing CXL.ConclusionThe changes observed in tears after 18 months post-operatively could be due to the treatments performed and the pathology. Among the deregulated proteins detected, A-kinase anchor protein 13 (AKAP-13) deserves special attention for its involvement in corneal thinning, and for its strong overexpression in the tears of patients with more active KC and faster disease progression. However, it should be kept in mind that this is a pilot study conducted in a small number of patients.
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Affiliation(s)
- Nahia Goñi
- Department of Ophthalmology, Hospital Universitario Donostia, San Sebastian, Spain
- Department of Ophthalmology, University of the Basque Country UPV/EHU, Leioa, Spain
| | - Itziar Martínez-Soroa
- Department of Ophthalmology, Hospital Universitario Donostia, San Sebastian, Spain
- Department of Ophthalmology, University of the Basque Country UPV/EHU, Leioa, Spain
| | | | - Mikel Azkargorta
- Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, Derio, Spain
| | - Felix Elortza
- Proteomics Platform, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), CIBERehd, Derio, Spain
| | - David J. Galarreta
- Department of Ophthalmology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
| | - Arantxa Acera
- Department of Cell Biology and Histology, Experimental Ophthalmo-Biology Group (GOBE:www.ehu.eus/gobe), University of the Basque Country UPV/EHU, Leioa, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- *Correspondence: Arantxa Acera,
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25
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Varela-Fernández R, García-Otero X, Díaz-Tomé V, Regueiro U, López-López M, González-Barcia M, Isabel Lema M, Otero-Espinar FJ. Mucoadhesive PLGA Nanospheres and Nanocapsules for Lactoferrin Controlled Ocular Delivery. Pharmaceutics 2022; 14:pharmaceutics14040799. [PMID: 35456633 PMCID: PMC9029159 DOI: 10.3390/pharmaceutics14040799] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/25/2022] [Accepted: 04/01/2022] [Indexed: 12/13/2022] Open
Abstract
Background: the present work describes the preparation, characterization and optimization of eight types of PLGA-based nanosystems (nanospheres and nanocapsules) as innovative mucoadhesive drug delivery systems of lactoferrin, in order to achieve a preclinical consistent base as an alternative pharmacological treatment to different ocular syndromes and diseases. Methods: All different nanoparticles were prepared via two modified nanoprecipitation techniques, using a three-component mixture of drug/polymer/surfactant (Lf/PLGA/Poloxamer), as a way to overcome the inherent limitations of conventional PLGA NPs. These modified polymeric nanocarriers, intended for topical ophthalmic administration, were subjected to in vitro characterization, surface modification and in vitro and in vivo assessments. Results: An appropriate size range, uniform size distribution and negative ζ potential values were obtained for all types of formulations. Lactoferrin could be effectively included into all types of nanoparticles with appropriate encapsulation efficiency and loading capacity values. A greater, extended, and controlled delivery of Lf from the polymeric matrix was observed through the in vitro release studies. No instability or cytotoxicity was proved for all the formulations by means of organotypic models. Additionally, mucoadhesive in vitro and in vivo experiments show a significant increase in the residence time of the nanoparticles in the eye surface. Conclusions: all types of prepared PLGA nanoparticles might be a potential alternative for the topical ophthalmic administration of lactoferrin.
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Affiliation(s)
- Rubén Varela-Fernández
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus Vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (X.G.-O.); (V.D.-T.)
- Clinical Neurosciences Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (U.R.); (M.L.-L.)
| | - Xurxo García-Otero
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus Vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (X.G.-O.); (V.D.-T.)
- Molecular Imaging Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Victoria Díaz-Tomé
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus Vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (X.G.-O.); (V.D.-T.)
| | - Uxía Regueiro
- Clinical Neurosciences Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (U.R.); (M.L.-L.)
| | - Maite López-López
- Clinical Neurosciences Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; (U.R.); (M.L.-L.)
| | - Miguel González-Barcia
- Clinical Pharmacology Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
| | - María Isabel Lema
- Department of Surgery and Medical-Surgical Specialties, Ophthalmology Area, University of Santiago de Compostela (USC), Campus Vida, 15706 Santiago de Compostela, Spain
- Correspondence: (M.I.L.); (F.J.O.-E.)
| | - Francisco Javier Otero-Espinar
- Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela (USC), Campus Vida, 15782 Santiago de Compostela, Spain; (R.V.-F.); (X.G.-O.); (V.D.-T.)
- Institute of Materials Imatus, University of Santiago de Compostela (USC), Campus Vida, 15782 Santiago de Compostela, Spain
- Paraquasil Group, University Clinical Hospital, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Correspondence: (M.I.L.); (F.J.O.-E.)
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26
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de Barros MRM, Chakravarti S. Pathogenesis of keratoconus: NRF2-antioxidant, extracellular matrix and cellular dysfunctions. Exp Eye Res 2022; 219:109062. [PMID: 35385756 DOI: 10.1016/j.exer.2022.109062] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/19/2022] [Accepted: 03/30/2022] [Indexed: 11/04/2022]
Abstract
Keratoconus (KC) is a degenerative disease associated with cell and extracellular matrix (ECM) loss that causes gradual thinning and steepening of the cornea and loss of vision. Collagen cross linking with ultraviolet light treatment can strengthen the ECM and delay weakening of the cornea, but severe cases require corneal transplantation. KC is multifactorial and multigenic, but its pathophysiology is still an enigma. Multiple approaches are being pursued to elucidate the molecular changes that underlie the corneal phenotype to identify relevant genes for tailored candidate searches and to develop potential biomarkers and targets for therapeutic interventions. Recent proteomic and transcriptomic studies suggest dysregulations in oxidative stress, NRF2-regulated antioxidant programs, WNT-signaling, TGF-β, ECM and matrix metalloproteinases. This review aims to provide a broad update on the transcriptomic and proteomic studies of KC with a focus on findings that relate to oxidative stress, and dysregulations in cellular and extracellular matrix functions.
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Affiliation(s)
| | - Shukti Chakravarti
- Department of Ophthalmology, NYU Grossman School of Medicine, NY, 10016, USA; Department of Pathology, NYU Grossman School of Medicine, NY, 10016, USA.
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27
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Lasagni Vitar RM, Bonelli F, Rama P, Ferrari G. Nutritional and Metabolic Imbalance in Keratoconus. Nutrients 2022; 14:nu14040913. [PMID: 35215563 PMCID: PMC8876314 DOI: 10.3390/nu14040913] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 02/18/2022] [Indexed: 12/31/2022] Open
Abstract
Keratoconus (KC) is a progressive corneal degeneration characterized by structural changes consisting of progressive thinning and steepening of the cornea. These alterations result in biomechanical weakening and, clinically, in vision loss. While the etiology of KC has been the object of study for over a century, no single agent has been found. Recent reviews suggest that KC is a multifactorial disease that is associated with a wide variety of genetic and environmental factors. While KC is typically considered a disease of the cornea, associations with systemic conditions have been well described over the years. In particular, nutritional and metabolic imbalance, such as the redox status, hormones, metabolites, and micronutrients (vitamins and metal ions), can deeply influence KC initiation and progression. In this paper, we comprehensively review the different nutritional (vitamins and minerals) and metabolic (hormones and metabolites) factors that are altered in KC, discussing their possible implication in the pathophysiology of the disease.
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Affiliation(s)
| | | | | | - Giulio Ferrari
- Correspondence: ; Tel.: +39-02-26436186; Fax: +39-02-26436164
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28
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Yıldız E, Aydemir D, Zibandeh N, Kuşan E, Gümüş K, Saraç Öİ, Karslıoğlu MZ, Çağıl N, Şahin A. Investigation of Mitophagy Biomarkers in Corneal Epithelium of Keratoconus Patients. Curr Eye Res 2022; 47:661-669. [PMID: 35188027 DOI: 10.1080/02713683.2022.2025846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Erdost Yıldız
- Koç University Research Center for Translational Medicine, Koç University, 34450, Istanbul, Turkey
| | - Dilara Aydemir
- Koç University Research Center for Translational Medicine, Koç University, 34450, Istanbul, Turkey
| | - Noushin Zibandeh
- Koç University Research Center for Translational Medicine, Koç University, 34450, Istanbul, Turkey
| | - Eda Kuşan
- Koç University Research Center for Translational Medicine, Koç University, 34450, Istanbul, Turkey
| | - Koray Gümüş
- Department of Ophthalmology, Ankara Memorial Hospital, 06520, Ankara, Turkey
| | - Özge İlhan Saraç
- Department of Ophthalmology, Ankara Yıldırım Beyazıt University, 06010, Ankara, Turkey
| | | | - Nurullah Çağıl
- Department of Ophthalmology, Ankara Yıldırım Beyazıt University, 06010, Ankara, Turkey
| | - Afsun Şahin
- Koç University Research Center for Translational Medicine, Koç University, 34450, Istanbul, Turkey
- Department of Ophthalmology, Koç University Medical School, 34010, Istanbul, Turkey
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29
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Liu J, Guo C, Hao P, Wang P, Li L, Wang Y, Li X. Protection effect of thymosin β4 on ethanol injury in corneal stromal keratocyte. BMC Ophthalmol 2022; 22:33. [PMID: 35062902 PMCID: PMC8783420 DOI: 10.1186/s12886-022-02255-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 01/04/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose To investigate the protective effects of thymosin β4 (Tβ4) on ethanol injured human corneal keratocytes (HCKs). Methods HCKs and BALB/c mice were chosen as the study subject. Ethanol was used to treat the cells and corneal stroma of mice to build the ethanol injured model in vitro and vivo respectively. CCK-8 was used to evaluate the cell metabolic activity. DCFH-DA was used to detect the intracellular reactive oxygen species level. TUNEL was chose to detect the cell apoptosis rate. The cell proliferation and migration were investigated by using wound healing insert. Wound healing of corneal surface and stroma was observed by using fluorescein sodium eyedrop and HE stain. RT-qPCR, ELISA, and immunostaining were performed to detect gene and protein expression in keratocytes or corneal stroma tissue of mice. Results Ethanol induced oxidative stress injury and cell apoptosis on HCKs, and Tβ4 can alleviate it by up-regulating the expression of Bcl-2, catalase, and CuZnSOD, and inhibiting the expression of Caspase-3. Tβ4 promotes the proliferation of HCKs and the process of corneal wound healing. It may relevant to the up-regulated expression of Ki67. Conclusions Our study established an ethanol-injured corneal stroma model in both vitro and vivo. The present study confirmed that Tβ4 play a protective effect on the reconstruction process of ethanol-injured corneal stroma.
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Hashemi H, Heirani M, Ambrósio R, Hafezi F, Naroo SA, Khorrami-Nejad M. The link between Keratoconus and posterior segment parameters: An updated, comprehensive review. Ocul Surf 2021; 23:116-122. [PMID: 34890805 DOI: 10.1016/j.jtos.2021.12.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/26/2021] [Accepted: 12/06/2021] [Indexed: 02/07/2023]
Abstract
Keratoconus (KCN) has been typically known as a disorder with effects limited to the cornea. Because of this viewpoint, less attention has been devoted to its effects on the posterior segment structures. We aimed to provide a comprehensive review of the literature to understand the potential link between KCN and posterior segment structures and their functions. It is clear from the extensive evidence in the literature that KCN can be associated with morphological and functional changes in different parts of the posterior segment. It is worth noting that anatomical changes have been not only noted in several layers of the retina but also in the optic nerve head and the choroid. Several mechanisms have been proposed to explain this observation, including incidents induced by oxidative stress in keratoconic corneas and retinal adaptions to the distorted image that lands on the retina. Consequently, when KCN has been diagnosed, it seems practical to consider assessing the retinal and choroidal profile using optical coherence tomography and potentially functional abnormalities through electrophysiology procedures.
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Affiliation(s)
- Hassan Hashemi
- Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran
| | - Mohsen Heirani
- Translational Ophthalmology Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.
| | - Renato Ambrósio
- Department of Ophthalmology, Federal University of the State of Rio de Janeiro, Brazil
| | - Farhad Hafezi
- ELZA Institute, Dietikon, Zurich, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Shehzad A Naroo
- College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
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Anitua E, Muruzabal F, Pino A, Prado R, Azkargorta M, Elortza F, Merayo-Lloves J. Proteomic Characterization of Plasma Rich in Growth Factors and Undiluted Autologous Serum. Int J Mol Sci 2021; 22:ijms222212176. [PMID: 34830053 PMCID: PMC8618701 DOI: 10.3390/ijms222212176] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/03/2021] [Accepted: 11/09/2021] [Indexed: 12/21/2022] Open
Abstract
Over the last three decades, there has been special interest in developing drugs that mimic the characteristics of natural tears for use it in the treatment of several ocular surface disorders. Interestingly, the composition of blood plasma is very similar to tears. Therefore, different blood-derived products like autologous serum (AS) and plasma rich in growth factors (PRGF) have been developed for the treatment of diverse ocular pathologies. However, scarce studies have been carried out to analyze the differences between both types of blood-derived products. In the present study, blood from three healthy donors was drawn and processed to obtain AS and PRGF eye drops. Then, human corneal stromal keratocytes (HK) were treated with PRGF or undiluted AS. Proteomic analysis was carried out to analyze and characterize the differential protein profiles between PRGF and AS, and the differentially expressed proteins in HK cells after PRGF and AS treatment. The results obtained in the present study show that undiluted AS induces the activation of different pathways related to an inflammatory, angiogenic, oxidative stress and scarring response in HK cells regarding PRGF. These results suggest that PRGF could be a better alternative than AS for the treatment of ocular surface disorders.
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Affiliation(s)
- Eduardo Anitua
- BTI—Biotechnology Institute, 01007 Vitoria, Spain; (F.M.); (A.P.); (R.P.)
- University Institute for Regenerative Medicine and Oral Implantology—UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
- Correspondence:
| | - Francisco Muruzabal
- BTI—Biotechnology Institute, 01007 Vitoria, Spain; (F.M.); (A.P.); (R.P.)
- University Institute for Regenerative Medicine and Oral Implantology—UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Ander Pino
- BTI—Biotechnology Institute, 01007 Vitoria, Spain; (F.M.); (A.P.); (R.P.)
- University Institute for Regenerative Medicine and Oral Implantology—UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Roberto Prado
- BTI—Biotechnology Institute, 01007 Vitoria, Spain; (F.M.); (A.P.); (R.P.)
- University Institute for Regenerative Medicine and Oral Implantology—UIRMI (UPV/EHU-Fundación Eduardo Anitua), 01007 Vitoria, Spain
| | - Mikel Azkargorta
- Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, 48160 Derio, Spain; (M.A.); (F.E.)
| | - Felix Elortza
- Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, 48160 Derio, Spain; (M.A.); (F.E.)
| | - Jesús Merayo-Lloves
- Instituto Oftalmológico Fernández-Vega, Fundación de Investigación Oftalmológica, Universidad de Oviedo, 33012 Oviedo, Spain;
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Karamichos D, Escandon P, Vasini B, Nicholas SE, Van L, Dang DH, Cunningham RL, Riaz KM. Anterior pituitary, sex hormones, and keratoconus: Beyond traditional targets. Prog Retin Eye Res 2021; 88:101016. [PMID: 34740824 PMCID: PMC9058044 DOI: 10.1016/j.preteyeres.2021.101016] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 12/13/2022]
Abstract
"The Diseases of the Horny-coat of The Eye", known today as keratoconus, is a progressive, multifactorial, non-inflammatory ectatic corneal disorder that is characterized by steepening (bulging) and thinning of the cornea, irregular astigmatism, myopia, and scarring that can cause devastating vision loss. The significant socioeconomic impact of the disease is immeasurable, as patients with keratoconus can have difficulties securing certain jobs or even joining the military. Despite the introduction of corneal crosslinking and improvements in scleral contact lens designs, corneal transplants remain the main surgical intervention for treating keratoconus refractory to medical therapy and visual rehabilitation. To-date, the etiology and pathogenesis of keratoconus remains unclear. Research studies have increased exponentially over the years, highlighting the clinical significance and international interest in this disease. Hormonal imbalances have been linked to keratoconus, both clinically and experimentally, with both sexes affected. However, it is unclear how (molecular/cellular signaling) or when (age/disease stage(s)) those hormones affect the keratoconic cornea. Previous studies have categorized the human cornea as an extragonadal tissue, showing modulation of the gonadotropins, specifically luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Studies herein provide new data (both in vitro and in vivo) to further delineate the role of hormones/gonadotropins in the keratoconus pathobiology, and propose the existence of a new axis named the Hypothalamic-Pituitary-Adrenal-Corneal (HPAC) axis.
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Affiliation(s)
- 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, 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.
| | - Paulina Escandon
- 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, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA
| | - Brenda Vasini
- 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, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA
| | - Sarah E Nicholas
- 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, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA
| | - Lyly Van
- University of Oklahoma Health Sciences Center, 940 Stanton L Young, Oklahoma City, OK, USA; Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Deanna H Dang
- College of Medicine, University of Oklahoma Health Sciences Center, 940 Stanton L Young, Oklahoma City, OK, USA
| | - Rebecca L Cunningham
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA
| | - Kamran M Riaz
- Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Shi B, Tao X, Betancor MB, Lu J, Tocher DR, Meng F, Figueiredo-Silva C, Zhou Q, Jiao L, Jin M. Dietary chromium modulates glucose homeostasis and induces oxidative stress in Pacific white shrimp (Litopenaeus vannamei). AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2021; 240:105967. [PMID: 34555743 DOI: 10.1016/j.aquatox.2021.105967] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 06/13/2023]
Abstract
While chromium (Cr) has been recognized as an essential nutrient for all animals, and dietary supplementation can be beneficial, it can also be toxic. The present study aimed to investigate the contrasting effects of dietary chromium in Pacific white shrimp Litopenaeus vannamei. Five experimental diets were formulated to contain Cr at levels of 0.82 (Cr0.82, unsupplemented diet), 1.01 (Cr1.01), 1.22 (Cu1.22), 1.43 (Cr1.43) and 1.63 (Cr1.63) mg/kg and were fed to shrimp for 8 weeks. Highest weight gain was recorded in shrimp fed the diet containing 1.22 mg/kg Cr. Shrimp fed the diet containing the highest level of Cr (1.63 mg/kg) showed the lowest weight gain and clear signs of oxidative stress and apoptosis as evidenced by higher levels of H2O2, malondialdehyde and 8-hydroxydeoxyguanosine, and expression of caspase 2, 3, 5, and lower contents of total and oxidized glutathione, and expression of Cu/Zn sod, cat, gpx, mt, bcl2. Chromium supplementation promoted glycolysis and inhibited gluconeogenesis as shown by increased activities of hexokinase, phosphofructokinase and pyruvate kinase, and reduced activity of phosphoenolpyruvate carboxykinase in shrimp fed the diet containing 1.43 mg/kg Cr. Shrimp fed the diet with 1.63 mg/kg Cr had lowest contents of crustacean hyperglycemic hormone and insulin like peptide in hemolymph. Expression of genes involved in insulin signaling pathway and glycose metabolism including insr, irs1, pik3ca, pdpk1, akt, acc1, gys, glut1, pk, hk were up-regulated, and foxO1, gsk-3β, g6pc, pepck were down-regulated in shrimp fed the diets supplemented with Cr. This study demonstrated that optimum dietary supplementation of Cr had beneficial effects on glucose homeostasis and growth, whereas excess caused oxidative damage and impaired growth. The results contribute to our understanding of the biological functions of chromium in shrimp.
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Affiliation(s)
- Bo Shi
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Xinyue Tao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Mónica B Betancor
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, Scotland, UK
| | - Jingjing Lu
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Douglas R Tocher
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China
| | - Fanyi Meng
- Zinpro Corporation, Eden Prairie, Minnesota, USA
| | | | - Qicun Zhou
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Lefei Jiao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Min Jin
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
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Ates KM, Estes AJ, Liu Y. Potential underlying genetic associations between keratoconus and diabetes mellitus. ADVANCES IN OPHTHALMOLOGY PRACTICE AND RESEARCH 2021; 1:100005. [PMID: 34746916 PMCID: PMC8570550 DOI: 10.1016/j.aopr.2021.100005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 08/18/2021] [Accepted: 08/29/2021] [Indexed: 12/14/2022]
Abstract
Background Keratoconus (KC) is the most common ectatic corneal disease, characterized by significantly localized thinning of the corneal stroma. Genetic, environmental, hormonal, and metabolic factors contribute to the pathogenesis of KC. Additionally, multiple comorbidities, such as diabetes mellitus, may affect the risk of KC. Main Body Patients with diabetes mellitus (DM) have been reported to have lower risk of developing KC by way of increased endogenous collagen crosslinking in response to chronic hyperglycemia. However, this remains a debated topic as other studies have suggested either a positive association or no association between DM and KC. To gain further insight into the underlying genetic components of these two diseases, we reviewed candidate genes associated with KC and central corneal thickness in the literature. We then explored how these genes may be regulated similarly or differentially under hyperglycemic conditions and the role they play in the systemic complications associated with DM. Conclusion Our comprehensive review of potential genetic factors underlying KC and DM provides a direction for future studies to further determine the genetic etiology of KC and how it is influenced by systemic diseases such as diabetes.
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Affiliation(s)
- Kristin M. Ates
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Amy J. Estes
- Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Yutao Liu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, USA
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
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Tear Levels of Inflammatory Cytokines in Keratoconus: A Meta-Analysis of Case-Control and Cross-Sectional Studies. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6628923. [PMID: 34631885 PMCID: PMC8497143 DOI: 10.1155/2021/6628923] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 04/03/2021] [Accepted: 08/12/2021] [Indexed: 12/29/2022]
Abstract
Purpose To assess the tear levels of inflammatory cytokines in patients with keratoconus (KC). Design Systemic review and meta-analysis. Methods The following electronic databases and search engine were searched: PubMed, EMBASE, Web of Science, and Google Scholar. A systematic search of all relevant studies published through January 2021 was conducted, and the standardized mean difference (SMD) and 95% confidence interval (CI) of cytokine levels were calculated to estimate the pooled effects. Sensitivity analysis, subgroup analysis, and metaregression were applied to explore the sources of heterogeneity. Results A total of 7 studies with 374 participants (374 eyes) from clinical studies were included. The tear levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) were significantly increased in KC compared with normal controls. The SMD of IL-1β was 1.93 (95% CI 0.22 to 3.65, P = 0.03). The SMD of IL-6 was 1.22 (95% CI 0.59 to 1.84, P < 0.001). The SMD of TNF-α was 1.75 (95% CI 0.66 to 2.83, P = 0.002). There was no significant difference between the two groups on interleukin-4 (IL-4) and interleukin-10 (IL-10). The SMD for IL-4 was 2.36 (95% CI -0.28 to 5.00, P = 0.08) and for IL-10 was 0.30 (95% CI -1.29 to 1.89, P = 0.71). Meta-regression analysis indicated that the heterogeneity maybe significantly correlated with the method of detection, the different ages, and the source of population. Conclusions Our meta-analysis demonstrated that proinflammatory cytokines IL-1β, IL-6, and TNF-α were increased, indicating that cytokine profile changed in KC tears and inflammation may play an important role in the pathogenesis and development of KC.
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Nahar N, Mohamed S, Mustapha NM, Fong LS, Mohd Ishak NI. Gallic acid and myricetin-rich Labisia pumila extract mitigated multiple diabetic eye disorders in rats. J Food Biochem 2021; 45:e13948. [PMID: 34622461 DOI: 10.1111/jfbc.13948] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 12/15/2022]
Abstract
Diabetes affected about a quarter of a billion people globally, and one out of four diabetics has eye or vision problems. This study investigated whether gallic acid and myricetin-rich Labisia pumila extract (LP) consumption would help prevent diabetic eye disorders and some probable biochemistry involved relating to inflammation, vascular leakage, and oxidative tension. Male rats were divided into four groups (n = 6), namely healthy control, diabetic non-treated control, and hyperglycemic rats treated with 150 or 300 mg/kg LP. Intraperitoneal injection of 60 mg/kg streptozotocin was used to induce diabetes. Rats were fed in the morning and evening. Diabetic retinopathy was graded in rats using a dilated retinal digital ophthalmoscopy. Rats were sacrificed at 12 weeks and the retina, optic nerve, cornea, lens, sclera, ciliary bodies, iris, and conjunctiva were examined histologically. The diabetic rats consuming LP for 10 weeks showed dose-dependent, histopathologically-reduced eye abnormalities (keratopathy, cataract, sclera, conjunctiva, ciliary bodies, iris, limbus, corneal edema, epithelial barrier inefficiency, shallow punctate keratitis, lower basal layer cell density, retinopathy, glaucoma, and corneal changes). The LP significantly suppressed inflammation [increased serum tumor necrosis factor-α (TNF-α), prostaglandin-E2 (PGE2)], vascular leakage [claudin-1], abnormal vascularization [vascular endothelial growth factor (VEGF)], oxidative tension [malondialdehyde/reduced glutathione ratio], and hyperglycemia [fasting blood glucose] of the diabetic rats. The LP consumption was significantly protective against diabetic eye disorders and optic nerve dysfunction which were related to inflammation, vascular leakage, abnormal vascularization, and oxidative tension, which most likely influenced eye hemorrhage and collagen cross-linkage. PRACTICAL APPLICATIONS: The study shows that gallic acid and myricetin-rich Labisia pumila (LP) leaf consumption may be used as a complementary therapy for managing diabetes (fasting blood glucose) and preventing diabetic eye disorders (keratopathy, cataract, sclera, conjunctiva, ciliary bodies, iris, limbus, corneal edema, epithelial barrier inefficiency, shallow punctate keratitis, lower basal layer cell density, retinopathy, glaucoma, and corneal abnormalities). The LP consumptions reduced the serum biomarkers for inflammation (serum tumor necrosis factor-α TNF-α; prostaglandin-E2), vascular leakage/abnormalities (claudin-1 and vascular endothelial growth factor VEGF), and oxidative tension (malondialdehyde/reduced glutathione MDA/GSH ratio). The LP was eye-protective probably by normalizing fasting blood glucose, reducing inflammation, oxidative tension, vascular leakage, and irregular vascularization.
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Affiliation(s)
- Nazmun Nahar
- Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang, Serdang, Malaysia
| | - Suhaila Mohamed
- Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang, Serdang, Malaysia
| | | | - Lau Seng Fong
- Faculty of Veterinary Medicine, Universiti Putra Malaysia, UPM Serdang, Serdang, Malaysia
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Navel V, Malecaze J, Pereira B, Baker JS, Malecaze F, Sapin V, Chiambaretta F, Dutheil F. Oxidative and antioxidative stress markers in keratoconus: a systematic review and meta-analysis. Acta Ophthalmol 2021; 99:e777-e794. [PMID: 33354927 DOI: 10.1111/aos.14714] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/20/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE To conduct a systematic review and meta-analysis on the levels of oxidative stress markers and antioxidants in keratoconus compared to healthy subject. METHOD The PubMed, Cochrane Library, Embase, Science Direct and Google Scholar databases were searched on 1st June 2020 for studies reporting oxidative and antioxidative stress markers in keratoconus and healthy controls. Main meta-analysis was stratified by type of biomarkers, type of samples (tears, cornea, aqueous humour and blood) and type of corneal samples (stromal cells, epithelium and endothelium). RESULTS We included 36 articles, for a total of 1328 keratoconus patients and 1208 healthy controls. There is an overall increase in oxidative stress markers in keratoconus compared with healthy controls (standard mean deviation (SMD) = 0.94, 95% confidence interval (95% CI) 0.55-1.33), with a significant increase in reactive oxygen and nitrogen species (1.09, 0.41-1.78) and malondialdehyde (1.78, 0.83-2.73). There is an overall decrease in antioxidants in keratoconus compared with healthy controls (-0.63, -0.89 to -0.36), with a significant decrease in total antioxidant capacity/status (-1.65, -2.88 to -0.43), aldehyde/NADPH dehydrogenase (-0.77, -1.38 to -0.17), lactoferrin/transferrin/albumin (-1.92, -2.96 to -0.89) and selenium/zinc (-1.42, -2.23 to -0.61). Oxidative stress markers were higher in tears and in cornea of keratoconus than in aqueous humour, and antioxidants were decreased in tears, aqueous humour and blood without difference between sample type. Oxidative stress markers increased in stromal cells and antioxidants decreased in endothelium. CONCLUSION Oxidative stress markers and antioxidants were dysregulated in keratoconus, involving an imbalance of redox homeostasis in tears, cornea, aqueous humour and blood.
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Affiliation(s)
- Valentin Navel
- Ophthalmology CHU Clermont‐Ferrand University Hospital of Clermont‐Ferrand Clermont‐Ferrand France
- Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team CNRS UMR 6293 INSERM U1103 Université Clermont Auvergne Clermont‐Ferrand France
| | - Jean Malecaze
- Ophthalmology CHU Clermont‐Ferrand University Hospital of Clermont‐Ferrand Clermont‐Ferrand France
- Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team CNRS UMR 6293 INSERM U1103 Université Clermont Auvergne Clermont‐Ferrand France
| | - Bruno Pereira
- Clinical Research and Innovation Direction CHU Clermont–Ferrand University Hospital of Clermont Ferrand Clermont‐Ferrand France
| | - Julien S. Baker
- Department of Sport, Physical Education and Health Centre for Health and Exercise Science Research Hong Kong Baptist University Kowloon Tong Hong Kong
| | - François Malecaze
- Ophthalmology Department Pierre‐Paul Riquet Hospital University Hospital of Toulouse Toulouse France
| | - Vincent Sapin
- Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team CNRS UMR 6293 INSERM U1103 Université Clermont Auvergne Clermont‐Ferrand France
- Medical Biochemistry and Molecular Biology CHU Clermont‐Ferrand University Hospital of Clermont‐Ferrand Clermont‐Ferrand France
| | - Frédéric Chiambaretta
- Ophthalmology CHU Clermont‐Ferrand University Hospital of Clermont‐Ferrand Clermont‐Ferrand France
- Genetic Reproduction and Development Laboratory (GReD) Translational Approach to Epithelial Injury and Repair Team CNRS UMR 6293 INSERM U1103 Université Clermont Auvergne Clermont‐Ferrand France
| | - Frédéric Dutheil
- Preventive and Occupational Medicine CNRS, LaPSCo Physiological and Psychosocial Stress CHU Clermont‐Ferrand Université Clermont Auvergne University Hospital of Clermont‐Ferrand Clermont‐Ferrand France
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Nowak-Malczewska DM, Karolak JA, Swierkowska J, Jaworska MM, Kulinska KI, Polakowski P, Rydzanicz M, Ploski R, Szaflik JP, Gajecka M. Changes in Nuclear Gene Expression Related to Mitochondrial Function Affect Extracellular Matrix, Collagens, and Focal Adhesion in Keratoconus. Transl Vis Sci Technol 2021; 10:6. [PMID: 34478492 PMCID: PMC8419871 DOI: 10.1167/tvst.10.11.6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Purpose Mitochondrial DNA (mtDNA) abnormalities were previously found to be causative in the pathogenesis of various diseases. Here, comprehensive mitochondrial and nuclear sequence and transcript analyses, along with analyses of the methylation aspects of nuclear genes related to mitochondrial function, were performed in patients with keratoconus (KTCN) to evaluate their contribution to the KTCN pathogenesis. Methods Blood mtDNA of 42 KTCN and 51 non-KTCN individuals was Sanger sequenced and analyzed along with the previously obtained corneal RNA-sequencing data of 20 KTCN and 21 non-KTCN individuals. In addition, the expression and methylation of mtDNA genes and 1223 mitochondria-related nuclear genes were evaluated. Results The mtDNA sequence alterations detected in blood coincided with variants identified in transcripts of the matched corneal tissues. In KTCN corneas, 97 mitochondria-related genes were deregulated, including TGFB1, P4HB, and BCL2, which are involved in the extracellular matrix (ECM) organization, collagen formation, and focal adhesion pathways. No changes in the expression of mtDNA transcripts and no differentially methylated genes among the assessed mitochondrial–nuclear gene sets were found. Conclusions The absence of corneal-specific mtDNA variants indicates that there is no direct relationship between mitochondrial sequence variability and KTCN phenotype in the studied individuals. However, the identified KTCN-specific transcriptomic alterations of the nuclear genes directly related to the mitochondria functioning point to their possible involvement in the ECM organization, collagen formation, and focal adhesion. Translational Relevance The identification of abnormalities within nuclear genes regulating ECM formation, collagen synthesis, and/or focal adhesion may form the basis of future treatment strategies or predict the progression of corneal changes in KTCN.
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Affiliation(s)
- Dorota M Nowak-Malczewska
- Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Justyna A Karolak
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | | | - Marcelina M Jaworska
- Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland
| | - Karolina I Kulinska
- Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Polakowski
- Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland
| | | | - Rafal Ploski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
| | - Jacek P Szaflik
- Department of Ophthalmology, Medical University of Warsaw, Warsaw, Poland
| | - Marzena Gajecka
- Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, Poznan, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
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A purified human platelet pellet lysate rich in neurotrophic factors and antioxidants repairs and protects corneal endothelial cells from oxidative stress. Biomed Pharmacother 2021; 142:112046. [PMID: 34426259 DOI: 10.1016/j.biopha.2021.112046] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Human platelet lysate (HPL) is a complex mixture of potent bioactive molecules instrumental in tissue repair and regeneration. Due to their remarkable safety, cost-effective production, and availability at global level from collected platelet concentrates, HPLs can become a powerful biotherapy for various therapeutic applications, if standardized and carefully validated through pre-clinical and clinical studies. In this work, the possibility to use a tailor-made HPL as a corneal transplant alternative to treat the gradual decrease in the number of corneal endothelial cells (CECs) associated with aging, was evaluated. The HPL preparation was thoroughly characterized using various proteomics tools that revealed a remarkable richness in multiple growth factors and antioxidants. Treatment of B4G12 and BCE C/D-1b CECs with the HPL increased their viability, enhanced the wound closure rate, and maintained cell growth and typical hexagonal morphology. Besides, this HPL significantly protected against tert-butyl hydroperoxide (TBHP)-induced oxidative stress as evidenced by increasing CEC viability, decreased cell death and reactive oxygen species formation, and enhanced antioxidant capacity. Proteomics analysis of treated CECs confirmed that HPL treatment triggered the corneal healing pathway and enhanced oxidative stress. These data strongly support further pre-clinical evaluation of this tailor-made HPL as a novel CEC regeneration biotherapy. HPL treatment may eventually represent a pragmatic and cost-effective alternative to corneal transplant to treat damages of the corneal endothelium which is a major cause of blindness worldwide.
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Park S, Leonard BC, Raghunathan VK, Kim S, Li JY, Mannis MJ, Murphy CJ, Thomasy SM. Animal models of corneal endothelial dysfunction to facilitate development of novel therapies. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1271. [PMID: 34532408 PMCID: PMC8421955 DOI: 10.21037/atm-20-4389] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022]
Abstract
Progressive corneal endothelial disease eventually leads to corneal edema and vision loss due to the limited regenerative capacity of the corneal endothelium in vivo and is a major indication for corneal transplantation. Despite the relatively high success rate of corneal transplantation, there remains a pressing global clinical need to identify improved therapeutic strategies to address this debilitating condition. To evaluate the safety and efficacy of novel therapeutics, there is a growing demand for pre-clinical animal models of corneal endothelial dysfunction. In this review, experimentally induced, spontaneously occurring and genetically modified animal models of corneal endothelial dysfunction are described to assist researchers in making informed decisions regarding the selection of the most appropriate animal models to meet their research goals.
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Affiliation(s)
- Sangwan Park
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Brian C. Leonard
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Vijay Krishna Raghunathan
- The Ocular Surface Institute, College of Optometry, University of Houston, Houston, TX, USA
- Department of Basic Sciences, University of Houston, Houston, TX, USA
- Department of Biomedical Engineering, Cullen College of Engineering, University of Houston, Houston, TX, USA
| | - Soohyun Kim
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
| | - Jennifer Y. Li
- Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Davis, CA, USA
| | - Mark J. Mannis
- Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Davis, CA, USA
| | - Christopher J. Murphy
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
- Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Davis, CA, USA
| | - Sara M. Thomasy
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USA
- Department of Ophthalmology & Vision Science, School of Medicine, University of California Davis, Davis, CA, USA
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Liu R, Yan X. Oxidative stress in corneal stromal cells contributes to the development of keratoconus in a rabbit model. Eur J Ophthalmol 2021; 31:3518-3524. [PMID: 34213382 DOI: 10.1177/11206721211028745] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE To investigate the role of oxidative stress in keratocytes in the pathogenesis of keratoconus (KC) using the rabbit cornea as a model. METHODS Immerse the rabbit cornea in collagenase type II solution at room temperature for 30 min in the KC group. The central cornea thickness (CCT), and mean keratometry (Km) were examined before and after the procedure. Reactive oxygen species (ROS), the nuclear translocation of nuclear factor E2-related factor 2 (NRF-2), the expression of heme oxygenase-1 (HO-1) protein, and nicotinamide adenine dinucleotide phosphate (NADPH) Oxidase (NOX) family members NOX-2 and NOX-4 protein levels were examined by immunohistochemistry analysis and Western Blot. The expression levels of HO-1, NOX-2, NOX-4, and NRF-2 mRNA were quantitatively detected by Real-time PCR. RESULTS A significant increase in Km and a significant decrease in CCT were observed in the KC group compared with the control group after the surgery (both p < 0.001). Immunofluorescence staining showed the rabbit KC model induced a significant increase in ROS production (p < 0.001). The expression of HO-1, NOX-2, NOX-4, and NRF-2 proteins in the KC group were significantly higher than those in the control group (all p < 0.001). RT-PCR results showed the levels of HO-1, NOX-2, NOX-4, and NRF-2 mRNA in KC groups were all significantly increased compared with control groups (all p < 0.05). CONCLUSIONS Oxidative stress and compensatory activation of antioxidant proteins suggest oxidative stress injury in corneal stromal cells plays an important role in the development of KC in a rabbit model.
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Affiliation(s)
- Ruixing Liu
- Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, People's Hospital of Zhengzhou University, Henan University People's Hospital, Zhengzhou, Henan, China.,Department of Ophthalmology, The First Hospital of Peking University, Beijing, China
| | - Xiaoming Yan
- Department of Ophthalmology, The First Hospital of Peking University, Beijing, China
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Guo SP, Chang HC, Lu LS, Liu DZ, Wang TJ. Activation of kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2/antioxidant response element pathway by curcumin enhances the anti-oxidative capacity of corneal endothelial cells. Biomed Pharmacother 2021; 141:111834. [PMID: 34153850 DOI: 10.1016/j.biopha.2021.111834] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 01/24/2023] Open
Abstract
Fuchs endothelial corneal dystrophy is one of the most common indications for corneal transplantation, and impaired anti-oxidative function is observed in corneal endothelial cells (CECs). Curcumin is well-known for its anti-oxidative property; but, no study has examined the effect of curcumin on anti-oxidative therapeutic roles in corneal endothelial disease. In our experiments, oxidative stress 0.25 mM tert-butyl hydroperoxide for 2 h was induced in immortalized human CECs pretreated with curcumin. Cell behavior and viability, reactive oxygen species production, and the protein expression of the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element (ARE) pathway were examined; the Keap1/Nrf2/ARE pathway is crucial anti-oxidative pathway of curcumin. The results showed that pretreatment with 12.5 μM curcumin significantly reduced the ROS production and improved the survival of CECs under oxidative stress. In addition, curcumin pretreatment significantly increased the expression of nuclear Nrf2, and the productions of superoxide dismutase 1 and heme oxygenase-1, which were the target anti-oxidative enzymes of the Keap1/Nrf2/ARE pathway. Our findings showed that curcumin enhanced the growth and differentiation of CECs under oxidative stress. The activation of Keap1/Nrf2/ARE pathway by curcumin was crucial for CECs to improve their anti-oxidative capacity.
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Affiliation(s)
- Siao-Pei Guo
- Department of Ophthalmology, Taipei Medical University Hospital, Taipei 110301, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110301, Taiwan
| | - Hua-Ching Chang
- Department of Dermatology, Taipei Medical University Hospital, Taipei 110301, Taiwan
| | - Long-Sheng Lu
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 110301, Taiwan; Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110301, Taiwan
| | - Der-Zen Liu
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 110301, Taiwan; Medical and Pharmaceutical Industry Technology and Development Center, New Taipei City 248, Taiwan
| | - Tsung-Jen Wang
- Department of Ophthalmology, Taipei Medical University Hospital, Taipei 110301, Taiwan; Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, No. 250, Wuxing Street, Xinyi District, Taipei 110301, Taiwan.
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Liu X, Zheng T, Zhao C, Zhang Y, Liu H, Wang L, Liu P. Genetic mutations and molecular mechanisms of Fuchs endothelial corneal dystrophy. EYE AND VISION 2021; 8:24. [PMID: 34130750 PMCID: PMC8204469 DOI: 10.1186/s40662-021-00246-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 05/18/2021] [Indexed: 11/10/2022]
Abstract
Background Fuchs endothelial corneal dystrophy is a hereditary disease and the most frequent cause of corneal transplantation in the worldwide. Its main clinical signs are an accelerated decrease in the number of endothelial cells, thickening of Descemet’s membrane and formation of guttae in the extracellular matrix. The cornea’s ability to maintain stromal dehydration is impaired, causing painful epithelial bullae and loss of vision at the point when the amount of corneal endothelial cells cannot be compensated. At present, apart from corneal transplantation, there is no other effective treatment that prevents blindness. Main text In this review, we first summarized the mutations of COL8A2, TCF4, TCF8, SLC4A11 and AGBL1 genes in Fuchs endothelial corneal dystrophy. The molecular mechanisms associated with Fuchs endothelial corneal dystrophy, such as endoplasmic reticulum stress and unfolded protein response pathway, oxidative stress, mitochondrial dysregulation pathway, apoptosis pathway, mitophagy, epithelial-mesenchymal transition pathway, RNA toxicity and repeat-associated non-ATG translation, and other pathogenesis, were then explored. Finally, we discussed several potential treatments related to the pathogenesis of Fuchs endothelial corneal dystrophy, which may be the focus of future research. Conclusions The pathogenesis of Fuchs endothelial corneal dystrophy is very complicated. Currently, corneal transplantation is an important method in the treatment of Fuchs endothelial corneal dystrophy. It is necessary to continuously explore the pathogenesis of Fuchs endothelial corneal dystrophy and establish the scientific foundations for the development of next-generation corneal therapeutics.
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Affiliation(s)
- Xuerui Liu
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Tao Zheng
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Chuchu Zhao
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yi Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hanruo Liu
- The Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Liyuan Wang
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
| | - Ping Liu
- Department of Ophthalmology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
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Tummanapalli SS, Kuppusamy R, Yeo JH, Kumar N, New EJ, Willcox MDP. The role of nitric oxide in ocular surface physiology and pathophysiology. Ocul Surf 2021; 21:37-51. [PMID: 33940170 DOI: 10.1016/j.jtos.2021.04.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 12/31/2022]
Abstract
Nitric oxide (NO) has a wide array of biological functions including the regulation of vascular tone, neurotransmission, immunomodulation, stimulation of proinflammatory cytokine expression and antimicrobial action. These functions may depend on the type of isoform that is responsible for the synthesis of NO. NO is found in various ocular tissues playing a pivotal role in physiological mechanisms, namely regulating vascular tone in the uvea, retinal blood circulation, aqueous humor dynamics, neurotransmission and phototransduction in retinal layers. Unregulated production of NO in ocular tissues may result in production of toxic superoxide free radicals that participate in ocular diseases such as endotoxin-induced uveitis, ischemic proliferative retinopathy and neurotoxicity of optic nerve head in glaucoma. However, the role of NO on the ocular surface in mediating physiology and pathophysiological processes is not fully understood. Moreover, methods used to measure levels of NO in the biological samples of the ocular surface are not well established due to its rapid oxidation. The purpose of this review is to highlight the role of NO in the physiology and pathophysiology of ocular surface and propose suitable techniques to measure NO levels in ocular surface tissues and tears. This will improve the understanding of NO's role in ocular surface biology and the development of new NO-based therapies to treat various ocular surface diseases. Further, this review summarizes the biochemistry underpinning NO's antimicrobial action.
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Affiliation(s)
| | - Rajesh Kuppusamy
- School of Optometry & Vision Science, University of New South Wales, Australia; School of Chemistry, University of New South Wales, Australia
| | - Jia Hao Yeo
- The University of Sydney, School of Chemistry, NSW, 2006, Australia
| | - Naresh Kumar
- School of Chemistry, University of New South Wales, Australia
| | - Elizabeth J New
- The University of Sydney, School of Chemistry, NSW, 2006, Australia; The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, NSW, 2006, Australia
| | - Mark D P Willcox
- School of Optometry & Vision Science, University of New South Wales, Australia
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Guha S, Roy S. Enhanced expression of SLC4A11 by tert-Butylhydroquinone is mediated by direct binding of Nrf2 to the promoter of SLC4A11. Free Radic Biol Med 2021; 167:299-306. [PMID: 33744340 DOI: 10.1016/j.freeradbiomed.2021.03.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND SLC4A11, a Na + dependent OH- transporter, is highly expressed in the epithelium and endothelium of the cornea. Mutations in SLC4A11 cause congenital hereditary endothelial dystrophy (CHED), a progressive disease with gradual loss of vision and characterized by degeneration and dysfunction of corneal endothelial cells. SLC4A11 expression is also responsive to oxidative stress. Thus, understanding of SLC4A11 gene regulation is of utmost importance for therapeutic interventions. However, it remains elusive how SLC4A11 is regulated at transcriptional and translational level. METHODS Bioinformatics analysis of the SLC4A11 promoter was performed using TRANSFAC. SLC4A11 promoter constructs were generated and exposed to tert-Butylhydroquinone (tBHQ) or cotransfected with Nuclear factor erythroid 2-related factor 2 (Nrf2) expression plasmid and promoter activity was determined. The expression of SLC4A11 was also determined by quantitative PCR and immunoblot analysis. The binding of Nrf2 to the promoter of SLC4A11 was validated by chromatin immunoprecipitation assay. RESULTS Induction of Nrf2 by tBHQ or overexpression of Nrf2 caused increased expression of SLC4A11 in HeLa and human corneal endothelial cells. A conserved Nrf2 binding sequence was found in the promoter of SLC4A11 of several mammalian species. Reporter gene assays showed transcriptional activation of the SLC4A11 promoter in response to tBHQ treatment and Nrf2 overexpression. ChIP analysis validated Nrf2 binding to the conserved sequence of the SLC4A11 promoter. Induction of the Nrf2 pathway also resulted in increased endogenous SLC4A11 protein abundance. On the other hand, depletion of Nrf2 inhibited both transcriptional and translational activities of SLC4A11. CONCLUSION In summary, we determined direct Nrf2 binding to antioxidant responsive element site within the SLC4A11 promoter, and observed increased expression of SLC4A11 by Nrf2 inducers. To the best of our knowledge, this is the first study showing Nrf2 exerts an important role in regulation of SLC4A11 gene expression.
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Affiliation(s)
- Sanjukta Guha
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India; Manipal Academy of Higher Education, Manipal, India
| | - Sanhita Roy
- Prof. Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India.
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Özsaygılı C, Yıldırım Y. The Relationship Between Keratoconus Stage and the Thickness of the Retinal Layers. Turk J Ophthalmol 2021; 51:75-82. [PMID: 33951894 PMCID: PMC8109033 DOI: 10.4274/tjo.galenos.2020.84748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Objectives To examine the relationship between keratoconus (KC) stage and the thickness of the retinal layers. Materials and Methods Retinal layer thicknesses were compared between 85 eyes of 85 KC patients and 40 eyes of 40 controls similar in age, sex, and axial length. KC patients were staged as stage 1, 2, or 3 according to the Amsler-Krumeich staging system, and segmentation of the retinal layers was performed with spectral domain optical coherence tomography automatic segmentation program. The thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), and retinal pigment epithelium (RPE) in the central 1 mm Early Treatment Diabetic Retinopathy Study subfield was analyzed. Results There was no significant difference between the control and KC groups in the segmentation of the RNFL, GCL, IPL, or OPL (p=0.306; p=0.661; p=0.893, p=0.664, respectively). The INL differed significantly between control and stage 2 KC, control and stage 3 KC, stage 1 and 2 KC, and stage 2 and 3 KC, increasing in thickness with higher stage (p=0.004; p=0.005: p=0.001; p=0.002, respectively). The RPE also differed significantly between control and stage 2 KC, control and stage 3 KC, stage 1 and 2 KC, and stage 2 and 3 KC, showing decreased thickness with higher stage (p=0.03; p=0.001; p=0.001; p<0.001, respectively). The ONL also thinned as stage increased, but the results were not statistically significant (p=0.051). Conclusion More advanced KC stage was associated with increased thickness of the INL layer, where the neuroglial cell bodies are located, and decreased thickness in the outer retinal layers, especially the RPE.
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Affiliation(s)
- Cemal Özsaygılı
- Kayseri City Hospital, Clinic of Ophthalmology, Kayseri, Turkey
| | - Yener Yıldırım
- Kayseri City Hospital, Clinic of Ophthalmology, Kayseri, Turkey
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Gomez A, Serrano A, Salero E, Tovar A, Amescua G, Galor A, Keane RW, de Rivero Vaccari JP, Sabater AL. Tumor necrosis factor-alpha and interferon-gamma induce inflammasome-mediated corneal endothelial cell death. Exp Eye Res 2021; 207:108574. [PMID: 33848524 DOI: 10.1016/j.exer.2021.108574] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 03/19/2021] [Accepted: 04/06/2021] [Indexed: 12/27/2022]
Abstract
PURPOSE Chronic corneal endothelial cell (CEC) loss results in corneal edema and vision loss in conditions such as pseudophakic bullous keratopathy (PBK), Fuchs' dystrophy, and corneal graft failure. Low CEC density has been associated with an elevation of intraocular pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. These cytokines are capable of triggering pyroptosis, a programmed cell death mechanism mediated by the inflammasome, prompting the activation of the pro-inflammatory cytokine interleukin (IL)-1β, the perpetuation of inflammation, and subsequent damage of corneal endothelial tissue. Therefore, the purpose of this study was to determine the deleterious contribution of the inflammasome and pyroptosis to CEC loss. METHODS CECs from human donor corneas were treated ex vivo with TNF-α and IFN-γ for 48 h. Levels of caspase-1 and IL-1β were then assayed by ELISA, and the expression of caspase-1 and gasdermin-D (GSDM-D) were confirmed by immunofluorescence. Endothelial cell damage was analyzed by a lactate dehydrogenase (LDH) release assay, and oxidative stress was determined by measuring the levels of reactive oxygen species (ROS) in the culture media. RESULTS Inflammasome activation and oxidative stress were elevated in CECs following exposure to TNF-α and IFN-γ, which resulted in cell death by pyroptosis as determined by LDH release which was inhibited by the caspase-1 inhibitor Ac-YVAD-cmk. CONCLUSION CEC death is induced by the pro-inflammatory cytokines TNF-α and IFN-γ, which contribute to inflammasome activation. Moreover, the inflammasome is a promising therapeutic target for the treatment of chronic CEC loss.
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Affiliation(s)
- Angela Gomez
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andres Serrano
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Enrique Salero
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Arianna Tovar
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Guillermo Amescua
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anat Galor
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Robert W Keane
- Department of Physiology and Biophysics, University of Miami Miller School of Medicine, FL, USA
| | - Juan Pablo de Rivero Vaccari
- Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, FL, USA
| | - Alfonso L Sabater
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
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Cheung IM, Mcghee CN, Sherwin T. A new perspective on the pathobiology of keratoconus: interplay of stromal wound healing and reactive species‐associated processes. Clin Exp Optom 2021; 96:188-96. [DOI: 10.1111/cxo.12025] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Accepted: 10/30/2012] [Indexed: 12/13/2022] Open
Affiliation(s)
- Isabella My Cheung
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,
| | - Charles Nj Mcghee
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,
| | - Trevor Sherwin
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,
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49
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Cheung IMY, Mcghee CNJ, Sherwin T. Beneficial effect of the antioxidant riboflavin on gene expression of extracellular matrix elements, antioxidants and oxidases in keratoconic stromal cells. Clin Exp Optom 2021; 97:349-55. [DOI: 10.1111/cxo.12138] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2013] [Revised: 11/28/2013] [Accepted: 12/04/2013] [Indexed: 12/23/2022] Open
Affiliation(s)
- Isabella M Y Cheung
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,
| | - Charles N J Mcghee
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,
| | - Trevor Sherwin
- Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand,
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50
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Elfarargy MS, Al-Ashmawy GM, Abu-Risha S, Khattab H. Novel predictor markers for early differentiation between transient tachypnea of newborn and respiratory distress syndrome in neonates. Int J Immunopathol Pharmacol 2021; 35:20587384211000554. [PMID: 33722097 PMCID: PMC7970176 DOI: 10.1177/20587384211000554] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Neonatal Respiratory Distress Syndrome (RDS) and Transient Tachypnea of newborn
(TTN) are common similar neonatal respiratory diseases. Study the early
predictor markers in differentiation between TTN and RDS in neonates. A
prospective case control study which was done in Neonatal Intensive Care Unit
(NICU) of Tanta University Hospital (TUH) from September 2016 to March 2018.
Three groups of neonates were included in the study: RDS group (45 neonates),
TTN group (45 neonates), and control group (45 healthy neonates). There were
statistically significant difference (SSD) between our studied three groups as
regard serum Malondialdehyde (MDA), Superoxide dismutase SOD, Lactate
dehydrogenase (LDH), and blood PH and P-values were 0.001* for
these comparative parameters. The ROC curve of RDS cases revealed that the serum
MDA Cut off, sensitivity and specificity were 1.87 mmol/L, 98%, 96%,
respectively which had the highest sensitivity and specificity followed by the
serum SOD then the serum LDH and lastly the blood PH while in TTN cases, the
serum MDA Cut off, sensitivity and specificity were 0.74 mmol/L, 96%, 93%,
respectively then the serum SOD then the serum LDH and lastly the blood PH.
Serum MDA, SOD, LDH, and PH had a beneficial role as early predictors in
differentiation between TTN and RDS in neonates.
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Affiliation(s)
| | - Ghada M Al-Ashmawy
- Department of Biochemistry, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Sally Abu-Risha
- Department of Pharmacology& Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Haidy Khattab
- Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
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