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Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0
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Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 January 2024) | Viewed by 10914

Special Issue Editor

Prof. Dr. M. Elizabeth Fini

E-Mail Website
Guest Editor
1. New England Eye Center of Tufts Medical Center, Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, USA
2. Program in Pharmacology and Drug Development, Tufts Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
Interests: eye; cornea; ocular surface; dry eye; ocular hypertension; glaucoma; matrix metalloproteinase; molecular chaperone; mucin; pathophysiology; therapeutic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue follows the publication of the first edition on “Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches (https://www.mdpi.com/journal/ijms/special_issues/Eye_Diseases_Mechanism)”.

The eye is a remarkable organ of incredible functional complexity. Each of its structures, including the cornea and ocular surface, trabecular meshwork and sclera, ciliary body, iris and lens, neuroretina, and optic nerve, have their own specialized biology. These structures present problems of interest for every molecular scientist. Developmental geneticists discovered the first “master control gene” in the eye, a long-sought developmental regulator with the capacity to switch on an entire genetic program for organ formation. Neuroscientists have investigated the retina as the most accessible part of the central nervous system. Special features of the cornea have made it an important model for cell biological breakthroughs in regeneration and stem cell biology. The aqueous outflow pathways, a marvel of hydrodynamics, still hold many mysteries currently under intense investigation by molecular biologists, biophysicists, and bioengineers. This Special Issue of IJMS invites articles that provide new insights into the underlying mechanisms of diseases of the eye, as well as work on new diagnostic tools/biomarkers and novel therapeutic strategies. Diseases include dry eye, pinguecula and pterygium, ocular hypertension, cataract, glaucoma, and retinal degeneration. Both preclinical and clinical studies with an emphasis on molecular biology approaches are of interest, and animal models of disease are encouraged.

Prof. Dr. M. Elizabeth Fini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • eye
  • ocular surface
  • cornea
  • trabecular meshwork
  • sclera
  • iris
  • ciliary body
  • lens
  • retina
  • optic nerve
  • pathophysiology
  • therapeutic

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Published Papers (7 papers)

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Research

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15 pages, 1558 KiB  
Article
The Severity of Diabetic Retinopathy Corresponds with Corneal Nerve Alterations and Ocular Discomfort of the Patient
by Anna Machalińska, Agnieszka Kuligowska, Alicja Ziontkowska-Wrzałek, Beata Stroynowska, Ewa Pius-Sadowska, Krzysztof Safranow, Jan Machaliński, Katarzyna Mozolewska-Piotrowska and Bogusław Machaliński
Int. J. Mol. Sci. 2024, 25(11), 6072; https://doi.org/10.3390/ijms25116072 - 31 May 2024
Viewed by 587
Abstract
Diabetic retinopathy (DR) remains the leading cause of blindness in the working-age population. Its progression causes gradual damage to corneal nerves, resulting in decreased corneal sensitivity (CS) and disruption of anterior-eye-surface homeostasis, which is clinically manifested by increased ocular discomfort and dry eye [...] Read more.
Diabetic retinopathy (DR) remains the leading cause of blindness in the working-age population. Its progression causes gradual damage to corneal nerves, resulting in decreased corneal sensitivity (CS) and disruption of anterior-eye-surface homeostasis, which is clinically manifested by increased ocular discomfort and dry eye disease (DED). This study included 52 DR patients and 52 sex- and age-matched controls. Ocular Surface Disease Index (OSDI) survey, tear film-related parameters, CS, and in vivo corneal confocal microscopy (IVCM) of the subbasal plexus were performed. Furthermore, all patients underwent tear sampling for neurotrophin and cytokine analysis. OSDI scores were greater in DR patients than in controls (p = 0.00020). No differences in the Schirmer test score, noninvasive tear film-break-up time (NIBUT), tear meniscus or interferometry values, bulbar redness, severity of blepharitis or meibomian gland loss were found. In the DR group, both the CS (p < 0.001), and the scotopic pupil diameter (p = 0.00008) decreased. IVCM revealed reduced corneal nerve parameters in DR patients. The stage of DR was positively correlated with the OSDI (Rs = +0.51, 95% CI: + 0.35–+0.64, p < 0.001) and negatively correlated with IVCM corneal nerve parameters and scotopic pupillometry (Rs = −0.26, 95% CI: −0.44–−0.06, p = 0.0097). We found negative correlations between the OSDI and IVCM corneal innervation parameters. The DR group showed lower tear film-brain-derived neurotrophic factor (BDNF) levels (p = 0.0001) and no differences in nerve growth factor (NGF)-β, neurotrophin (NT)-4, vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-4, IL-5, IL-6, or IL-12 concentrations. Tumor necrosis factor (TNF)-α, IL-2, IL-8, IL-10, granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon (IFN)-γ levels were decreased among patients with DR. Corneal innervation defects have a direct impact on patients’ subjective feelings. The evolution of DR appears to be associated with corneal nerve alterations, emphasizing the importance of IVCM. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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14 pages, 2528 KiB  
Article
Simultaneous Comparison of Aqueous Humor and Serum Metabolic Profiles of Diabetic and Nondiabetic Patients Undergoing Cataract Surgery—A Targeted and Quantitative Metabolomics Study
by Emil Tomasz Grochowski, Karolina Pietrowska, Adrian Godlewski, Wioleta Gosk, Angelika Buczynska, Malgorzata Wojnar, Joanna Konopinska, Adam Kretowski, Michal Ciborowski and Diana Anna Dmuchowska
Int. J. Mol. Sci. 2023, 24(16), 12671; https://doi.org/10.3390/ijms241612671 - 11 Aug 2023
Cited by 2 | Viewed by 1333
Abstract
The aim of this study was to compare the aqueous humor (AH) and serum concentrations of metabolites in diabetic (n = 36) and nondiabetic (n = 36) senior adults undergoing cataract surgery. Blood samples were collected before surgery and AH during [...] Read more.
The aim of this study was to compare the aqueous humor (AH) and serum concentrations of metabolites in diabetic (n = 36) and nondiabetic (n = 36) senior adults undergoing cataract surgery. Blood samples were collected before surgery and AH during surgery. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based targeted metabolomic and lipidomic analyses of samples were performed using the AbsoluteIDQ® p180 kit. Out of 188 metabolites targeted by the kit, 41 and 133 were detected in >80% of AH and serum samples, respectively. Statistical analysis performed to indicate metabolites differentiating diabetic and nondiabetic patients showed 8 and 20 significant metabolites in AH and serum, respectively. Pathway analysis performed for significant metabolites revealed that galactose metabolism is mostly affected in the AH, while arginine biosynthesis is mostly affected in the serum. Among metabolites that differentiate diabetic and nondiabetic patients, arginine was the only metabolite common to both serum and AH samples, as well as the only one with a decreased concentration in both body fluids of diabetic patients. Concentrations of the rest were elevated in AH and lowered in serum. This may suggest different mechanisms of diabetes-related dysregulation of the local metabolism in the eye in comparison to systemic changes observed in the blood. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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15 pages, 5326 KiB  
Article
Sigma-1 Receptor Agonist Fluvoxamine Ameliorates Fibrotic Response of Trabecular Meshwork Cells
by Judit Hodrea, Minh Ngoc Tran, Balazs Besztercei, Timea Medveczki, Attila J. Szabo, Laszlo Őrfi, Illes Kovacs and Andrea Fekete
Int. J. Mol. Sci. 2023, 24(14), 11646; https://doi.org/10.3390/ijms241411646 - 19 Jul 2023
Viewed by 1571
Abstract
Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and [...] Read more.
Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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20 pages, 1405 KiB  
Article
Unravelling the Impact of Cyclic Mechanical Stretch in Keratoconus—A Transcriptomic Profiling Study
by Theresa Akoto, Jingwen Cai, Sarah Nicholas, Hayden McCord, Amy J. Estes, Hongyan Xu, Dimitrios Karamichos and Yutao Liu
Int. J. Mol. Sci. 2023, 24(8), 7437; https://doi.org/10.3390/ijms24087437 - 18 Apr 2023
Cited by 5 | Viewed by 2246
Abstract
Biomechanical and molecular stresses may contribute to the pathogenesis of keratoconus (KC). We aimed to profile the transcriptomic changes in healthy primary human corneal (HCF) and KC-derived cells (HKC) combined with TGFβ1 treatment and cyclic mechanical stretch (CMS), mimicking the pathophysiological condition in [...] Read more.
Biomechanical and molecular stresses may contribute to the pathogenesis of keratoconus (KC). We aimed to profile the transcriptomic changes in healthy primary human corneal (HCF) and KC-derived cells (HKC) combined with TGFβ1 treatment and cyclic mechanical stretch (CMS), mimicking the pathophysiological condition in KC. HCFs (n = 4) and HKCs (n = 4) were cultured in flexible-bottom collagen-coated 6-well plates treated with 0, 5, and 10 ng/mL of TGFβ1 with or without 15% CMS (1 cycle/s, 24 h) using a computer-controlled Flexcell FX-6000T Tension system. We used stranded total RNA-Seq to profile expression changes in 48 HCF/HKC samples (100 bp PE, 70–90 million reads per sample), followed by bioinformatics analysis using an established pipeline with Partek Flow software. A multi-factor ANOVA model, including KC, TGFβ1 treatment, and CMS, was used to identify differentially expressed genes (DEGs, |fold change| ≥ 1.5, FDR ≤ 0.1, CPM ≥ 10 in ≥1 sample) in HKCs (n = 24) vs. HCFs (n = 24) and those responsive to TGFβ1 and/or CMS. PANTHER classification system and the DAVID bioinformatics resources were used to identify significantly enriched pathways (FDR ≤ 0.05). Using multi-factorial ANOVA analyses, 479 DEGs were identified in HKCs vs. HCFs including TGFβ1 treatment and CMS as cofactors. Among these DEGs, 199 KC-altered genes were responsive to TGFβ1, thirteen were responsive to CMS, and six were responsive to TGFβ1 and CMS. Pathway analyses using PANTHER and DAVID indicated the enrichment of genes involved in numerous KC-relevant functions, including but not limited to degradation of extracellular matrix, inflammatory response, apoptotic processes, WNT signaling, collagen fibril organization, and cytoskeletal structure organization. TGFβ1-responsive KC DEGs were also enriched in these. CMS-responsive KC-altered genes such as OBSCN, CLU, HDAC5, AK4, ITGA10, and F2RL1 were identified. Some KC-altered genes, such as CLU and F2RL1, were identified to be responsive to both TGFβ1 and CMS. For the first time, our multi-factorial RNA-Seq study has identified many KC-relevant genes and pathways in HKCs with TGFβ1 treatment under CMS, suggesting a potential role of TGFβ1 and biomechanical stretch in KC development. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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11 pages, 1549 KiB  
Article
Stimulating the Melanocortin System in Uveitis and Diabetes Preserves the Structure and Anti-Inflammatory Activity of the Retina
by Tat Fong Ng and Andrew W. Taylor
Int. J. Mol. Sci. 2023, 24(8), 6928; https://doi.org/10.3390/ijms24086928 - 8 Apr 2023
Cited by 5 | Viewed by 1667
Abstract
The endogenous neuropeptide α-Melanocyte Stimulating Hormone (α-MSH) is a potent suppressor of inflammation and has an essential role in maintaining the normal anti-inflammatory microenvironment of the retina. While the therapeutic use of α-MSH peptide in uveitis and diabetic retinopathy models has been demonstrated, [...] Read more.
The endogenous neuropeptide α-Melanocyte Stimulating Hormone (α-MSH) is a potent suppressor of inflammation and has an essential role in maintaining the normal anti-inflammatory microenvironment of the retina. While the therapeutic use of α-MSH peptide in uveitis and diabetic retinopathy models has been demonstrated, its short half-life and instability limit its use as a therapeutic drug. A comparable analog, PL-8331, which has a stronger affinity to melanocortin receptors, longer half-life, and, so far, is functionally identical to α-MSH, has the potential to deliver melanocortin-based therapy. We examined the effects of PL-8331 on two mouse models of retinal disease, Experimental Autoimmune Uveoretinitis (EAU) and Diabetic Retinopathy (DR). PL-8331 therapy applied to mice with EAU suppressed EAU and preserved retinal structures. In diabetic mice, PL-8331 enhanced the survival of retinal cells and suppressed VEGF production in the retina. In addition, retinal pigment epithelial cells (RPE) from PL-8331-treated diabetic mice retained normal anti-inflammatory activity. The results demonstrated that the pan-melanocortin receptor agonist PL-8331 is a potent therapeutic drug to suppress inflammation, prevent retinal degeneration, and preserve the normal anti-inflammatory activity of RPE. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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18 pages, 1810 KiB  
Article
A Pilot Study to Evaluate Genipin in Staphylococcus aureus and Pseudomonas aeruginosa Keratitis Models: Modulation of Pro-Inflammatory Cytokines and Matrix Metalloproteinases
by Marcela Huertas-Bello, Jerson Andrés Cuéllar-Sáenz, Cristian Nicolas Rodriguez, Jesús Alfredo Cortés-Vecino, Myriam Lucia Navarrete, Marcel Yecid Avila and Elena Koudouna
Int. J. Mol. Sci. 2023, 24(8), 6904; https://doi.org/10.3390/ijms24086904 - 7 Apr 2023
Cited by 2 | Viewed by 1809
Abstract
Infectious keratitis is a vision-threatening microbial infection. The increasing antimicrobial resistance and the fact that severe cases often evolve into corneal perforation necessitate the development of alternative therapeutics for effective medical management. Genipin, a natural crosslinker, was recently shown to exert antimicrobial effects [...] Read more.
Infectious keratitis is a vision-threatening microbial infection. The increasing antimicrobial resistance and the fact that severe cases often evolve into corneal perforation necessitate the development of alternative therapeutics for effective medical management. Genipin, a natural crosslinker, was recently shown to exert antimicrobial effects in an ex vivo model of microbial keratitis, highlighting its potential to serve as a novel treatment for infectious keratitis. This study aimed to evaluate the antimicrobial and anti-inflammatory effects of genipin in an in vivo model of Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) keratitis. Clinical scores, confocal microscopy, plate count, and histology were carried out to evaluate the severity of keratitis. To assess the effect of genipin on inflammation, the gene expression of pro- and anti-inflammatory factors, including matrix metalloproteinases (MMPs), were evaluated. Genipin treatment alleviated the severity of bacterial keratitis by reducing bacterial load and repressing neutrophil infiltration. The expression of interleukin 1B (IL1B), interleukin 6 (IL6), interleukin 8 (IL8), interleukin 15 (IL15), tumor necrosis factor-α (TNF-α), and interferon γ (IFNγ), as well as MMP2 and MMP9, were significantly reduced in genipin-treated corneas. Genipin promoted corneal proteolysis and host resistance to S. aureus and P. aeruginosa infection by suppressing inflammatory cell infiltration, regulating inflammatory mediators, and downregulating the expression of MMP2 and MMP9. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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Review

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12 pages, 1958 KiB  
Review
The Ocular Glymphatic System—Current Understanding and Future Perspectives
by Christine Delle, Xiaowei Wang and Maiken Nedergaard
Int. J. Mol. Sci. 2024, 25(11), 5734; https://doi.org/10.3390/ijms25115734 - 24 May 2024
Viewed by 988
Abstract
The ocular glymphatic system subserves the bidirectional polarized fluid transport in the optic nerve, whereby cerebrospinal fluid from the brain is directed along periarterial spaces towards the eye, and fluid from the retina is directed along perivenous spaces following upon its axonal transport [...] Read more.
The ocular glymphatic system subserves the bidirectional polarized fluid transport in the optic nerve, whereby cerebrospinal fluid from the brain is directed along periarterial spaces towards the eye, and fluid from the retina is directed along perivenous spaces following upon its axonal transport across the glial lamina. Fluid homeostasis and waste removal are vital for retinal function, making the ocular glymphatic fluid pathway a potential route for targeted manipulation to combat blinding ocular diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Several lines of work investigating the bidirectional ocular glymphatic transport with varying methodologies have developed diverging mechanistic models, which has created some confusion about how ocular glymphatic transport should be defined. In this review, we provide a comprehensive summary of the current understanding of the ocular glymphatic system, aiming to address misconceptions and foster a cohesive understanding of the topic. Full article
(This article belongs to the Special Issue Pathophysiologic Mechanisms of Eye Diseases and Novel Therapeutic Approaches 2.0)
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