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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 (15 November 2023) | Viewed by 16158

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Dr. Minzhong Yu

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Guest Editor

Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA
Interests: genesis and molecular mechanism of therapies in ocular diseases; clinical trials of different therapies in ocular disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging, drug side-effects, immune-system disorders, and genetic mutations affect the cells and tissues of the retina and optic nerve, which often cause poor vision and lead to poor quality of life. For the diagnosis and treatment of those disorders, the mechanisms underlying the development of those disorders should be further investigated.

In this Special Issue, we welcome researchers and clinicians to contribute their original research and review articles describing in vitro and/or in vivo data, as well as clinical studies, to address the mechanisms by which genetic factors and protein molecules regulate ocular disorders, as well as novel diagnostic technologies and therapies for those diseases. The following topics are particularly welcome:

The potential effect of genetic mutations, aging, and drug side effects on eye diseases, including studies on novel mutations/biomarkers and signaling pathways.
Novel technologies, such as electrophysiology, spectral domain optical coherence tomography, optical coherence tomography angiography, artificial intelligence, clinical molecular genetic tests, etc., for diagnosis and monitoring of those eye diseases in the aspects of functional, morphological, and molecular characterization.
Therapeutic interventions for eye diseases, including drug, surgery, stem cell, cell, and gene therapies.

Key points: Our journal IJMS provides an advanced forum for molecular studies in biology and chemistry, with a strong emphasis on molecular biology and molecular medicine. Thus, pure clinical studies will not be suitable for our journal. But clinical or pure model submissions with biomolecular experiments are welcomed.

Submission Guideline:

1. type: research article/review/communication are welcomed, for theses retrospective/cohort/follow-up, narrative review, preliminary study, system/meta-analysis, health care/nursing, prediction/prognostic indicators/score/scale.
2. not considered topic, including clinical education, medical device/system/platform (Dentistry is ok), cadaver study, in vitro (cell lines and with clinical significance are excluded), textbook review, medicine cost, tobacco/alcohol, 3D print of stomatology filed and without clinical application, survey or questionnaire of clinical psychology filed.
3. for plan paper with company affiliation, if only promote the company product, will reject, otherwise, can be considered, and also need provide conflicts of interest.

Dr. Minzhong Yu
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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

retina
optic nerve
ocular disorder
retinal disease
genetic mutation
aging
drug side effects
novel mutations/biomarkers
signaling pathways
spectral domain optical coherence tomography
stem cell
gene therapy

Related Special Issue

Advances on Retinal Diseases 2.0 in International Journal of Molecular Sciences

Published Papers (9 papers)

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Research

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15 pages, 3244 KiB

Open AccessArticle

Retinal Responses to Visual Stimuli in Interphotoreceptor Retinoid Binding-Protein Knock-Out Mice

by Marci L. DeRamus, Jessica V. Jasien, Jess M. Eppstein, Pravallika Koala and Timothy W. Kraft

Int. J. Mol. Sci. 2023, 24(13), 10655; https://doi.org/10.3390/ijms241310655 - 26 Jun 2023

Cited by 1 | Viewed by 1269

Abstract

Interphotoreceptor retinoid-binding protein (IRBP) is an abundant glycoprotein in the subretinal space bound by the photoreceptor (PR) outer segments and the processes of the retinal pigmented epithelium (RPE). IRBP binds retinoids, including 11-cis-retinal and all-trans-retinol. In this study, visual function for demanding visual tasks was assessed in IRBP knock-out (KO) mice. Surprisingly, IRBP KO mice showed no differences in scotopic critical flicker frequency (CFF) compared to wildtype (WT). However, they did have lower photopic CFF than WT. IRBP KO mice had reduced scotopic and photopic acuity and contrast sensitivity compared to WT. IRBP KO mice had a significant reduction in outer nuclear layer (ONL) thickness, PR outer and inner segment, and full retinal thickness (FRT) compared to WT. There were fewer cones in IRBP KO mice. Overall, these results confirm substantial loss of rods and significant loss of cones within 30 days. Absence of IRBP resulted in cone circuit damage, reducing photopic flicker, contrast sensitivity, and spatial frequency sensitivity. The c-wave was reduced and accelerated in response to bright steps of light. This result also suggests altered retinal pigment epithelium activity. There appears to be a compensatory mechanism such as higher synaptic gain between PRs and bipolar cells since the loss of the b-wave did not linearly follow the loss of rods, or the a-wave. Scotopic CFF is normal despite thinning of ONL and reduced scotopic electroretinogram (ERG) in IRBP KO mice, suggesting either a redundancy or plasticity in circuits detecting (encoding) scotopic flicker at threshold even with substantial rod loss. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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14 pages, 4311 KiB

Open AccessArticle

Mitochondrial Quality Control and Metabolic Memory Phenomenon Associated with Continued Progression of Diabetic Retinopathy

by Renu A. Kowluru and Kumari Alka

Int. J. Mol. Sci. 2023, 24(9), 8076; https://doi.org/10.3390/ijms24098076 - 29 Apr 2023

Cited by 4 | Viewed by 1666

Abstract

Diabetic retinopathy continues to progress even when hyperglycemia is terminated, suggesting a ‘metabolic memory’ phenomenon. Mitochondrial dysfunction is closely associated with the development of diabetic retinopathy, and mitochondria remain dysfunctional. Quality control of mitochondria requires a fine balance between mitochondrial fission–fusion, removal of the damaged mitochondria (mitophagy) and formation of new mitochondria (biogenesis). In diabetes, while mitochondrial fusion protein (Mfn2) is decreased, fission protein (Drp1) is increased, resulting in fragmented mitochondria. Re-institution of normal glycemia fails to reverse mitochondrial fragmentation, and dysfunctional mitochondria continue to accumulate. Our aim was to investigate the direct effect of regulation of the mitochondrial fusion process during normal glycemia that follows a high glucose insult on mitochondrial quality control in the ‘metabolic memory’ phenomenon. Human retinal endothelial cells, incubated in 20 mM glucose for four days, followed by 5 mM glucose for four additional days, with or without the Mfn2 activator leflunomide, were analyzed for mitochondrial fission (live cell imaging), mitophagy (flow cytometry and immunofluorescence microscopy), and mitochondrial mass (mitochondrial copy numbers and MitoTracker labeling). Mitochondrial health was determined by quantifying mitochondrial reactive oxygen species (ROS), respiration rate (Seahorse XF96) and mitochondrial DNA (mtDNA) damage. Addition of leflunomide during normal glucose exposure that followed high glucose prevented mitochondrial fission, facilitated mitophagy and increased mitochondrial mass. Glucose-induced decrease in mitochondrial respiration and increase in ROS and mtDNA damage were also prevented. Thus, direct regulation of mitochondrial dynamics can help maintain mitochondrial quality control and interfere with the metabolic memory phenomenon, preventing further progression of diabetic retinopathy. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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16 pages, 2224 KiB

Open AccessArticle

New Insight into the Genotype-Phenotype Correlation of PRPH2-Related Diseases Based on a Large Chinese Cohort and Literature Review

by Yingwei Wang, Junwen Wang, Yi Jiang, Di Zhu, Jiamin Ouyang, Zhen Yi, Shiqiang Li, Xiaoyun Jia, Xueshan Xiao, Wenmin Sun, Panfeng Wang and Qingjiong Zhang

Int. J. Mol. Sci. 2023, 24(7), 6728; https://doi.org/10.3390/ijms24076728 - 4 Apr 2023

Cited by 1 | Viewed by 1733

Abstract

Variants in PRPH2 are a common cause of inherited retinal dystrophies with high genetic and phenotypic heterogeneity. In this study, variants in PRPH2 were selected from in-house exome sequencing data, and all reported PRPH2 variants were evaluated with the assistance of online prediction tools and the comparative validation of large datasets. All variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Individuals with pathogenic or likely pathogenic variants of PRPH2 were confirmed by Sanger sequencing. Clinical characteristics were summarized. Ten pathogenic or likely pathogenic variants of PRPH2 were identified in 14 families. In our cohort, the most frequent variant was p.G305Afs*19, accounting for 33.3% (5/15) of alleles, in contrast to the literature, where p.R172G (11.6%, 119/1028) was the most common variant. Nine in-house families (63.8%) were diagnosed with retinitis pigmentosa (RP), distinct from the phenotypic spectrum in the literature, which shows that RP accounts for 27.9% (283/1013) and macular degeneration is more common (45.2%, 458/1013). Patients carrying missense variants predicted as damaging by all seven prediction tools and absent in the gnomAD database were more likely to develop RP compared to those carrying missense variants predicted as damaging with fewer tools or with more than one allele number in the gnomAD database (p = 0.001). The population-specific genetic and phenotypic spectra of PRPH2 were explored, and novel insight into the genotype–phenotype correlation of PRPH2 was proposed. These findings demonstrated the importance of assessing PRPH2 variants in distinct populations and the value of providing practical suggestions for the genetic interpretation of PRPH2 variants. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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11 pages, 2721 KiB

Open AccessArticle

Retinal Venule Coverage by Pericytes Decreases in Multiparous Mice in a Time-Dependent Manner Post-Delivery

by Junie P. Warrington, Maria Jones-Muhammad, Rachael O. Thompson, Tyranny Pryor, Qingmei Shao and Manasa Gunturu

Int. J. Mol. Sci. 2023, 24(4), 3967; https://doi.org/10.3390/ijms24043967 - 16 Feb 2023

Viewed by 1459

Abstract

Structural changes in the retinal vasculature have been linked to increased cardiovascular risks and also change as a function of age. Because multiparity has been associated with poorer cardiovascular health scores, we hypothesized that changes in retinal vascular caliber would be observed in multiparous, compared to nulliparous, females and retired breeder males. Age-matched nulliparous (n = 6) and multiparous (n = 11, retired breeder females with 4 ± 1 litters), and male breeder (n = 7) SMA-GFP reporter mice were included for assessment of retinal vascular structure. Multiparous females had higher body mass, heart weight, and kidney weight compared to nulliparous mice, with lower kidney and higher brain weight compared to male breeders. There was no difference in number of retinal arterioles or venules, or arteriole or venule diameter among groups; however, venous pericyte density (number per venule area) decreased in multiparous vs. nulliparous mice and was negatively associated with the time since last litter and with age. Our results suggest that the time elapsed since delivery is an important factor to be considered in multiparity studies. Taken together, changes in vascular structure and potentially function, are time- and age-dependent. Ongoing and future work will determine whether structural changes are associated with functional consequences at the blood–retinal barrier. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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18 pages, 2593 KiB

Open AccessArticle

Selective Transcription Factor Blockade Reduces Human Retinal Endothelial Cell Expression of Intercellular Adhesion Molecule-1 and Leukocyte Binding

by Yuefang Ma, Liam M. Ashander, Binoy Appukuttan, Feargal J. Ryan, Alwin C. R. Tan, Janet M. Matthews, Michael Z. Michael, David J. Lynn and Justine R. Smith

Int. J. Mol. Sci. 2023, 24(4), 3304; https://doi.org/10.3390/ijms24043304 - 7 Feb 2023

Cited by 3 | Viewed by 1769

Abstract

The interaction between leukocytes and cytokine-activated retinal endothelium is an initiating step in non-infectious uveitis involving the posterior eye, mediated by cell adhesion molecules. However, because cell adhesion molecules are required for immune surveillance, therapeutic interventions would ideally be employed indirectly. Using 28 primary human retinal endothelial cell isolates, this study sought to identify transcription factor targets for reducing levels of the key retinal endothelial cell adhesion molecule, intercellular adhesion molecule (ICAM)-1, and limiting leukocyte binding to the retinal endothelium. Five candidate transcription factors—C2CD4B, EGR3, FOSB, IRF1, and JUNB—were identified by differential expression analysis of a transcriptome generated from IL-1β- or TNF-α-stimulated human retinal endothelial cells, interpreted in the context of the published literature. Further filtering involved molecular studies: of the five candidates, C2CD4B and IRF1 consistently demonstrated extended induction in IL-1β- or TNF-α-activated retinal endothelial cells and demonstrated a significant decrease in both ICAM-1 transcript and ICAM-1 membrane-bound protein expression by cytokine-activated retinal endothelial cells following treatment with small interfering RNA. RNA interference of C2CD4B or IRF1 significantly reduced leukocyte binding in a majority of human retinal endothelial cell isolates stimulated by IL-1β or TNF-α. Our observations suggest that the transcription factors C2CD4B and IRF1 may be potential drug targets for limiting leukocyte–retinal endothelial cell interactions in non-infectious uveitis involving the posterior eye. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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20 pages, 4776 KiB

Open AccessArticle

The Role of Interferon Regulatory Factor 1 in Regulating Microglial Activation and Retinal Inflammation

by Xu Yang, Valeria Diaz and Hu Huang

Int. J. Mol. Sci. 2022, 23(23), 14664; https://doi.org/10.3390/ijms232314664 - 24 Nov 2022

Cited by 2 | Viewed by 2203

Abstract

Microglia are resident immune cells in the central nervous system (CNS). Microglial activation plays a prominent role in neuroinflammation and CNS diseases. However, the underlying mechanisms of microglial activation are not well understood. Here, we report that the transcription factor interferon regulatory factor 1 (IRF1) plays critical roles in microglial activation and retinal inflammation by regulating pro- and anti-inflammatory gene expression. IRF1 expression was upregulated in activated retinal microglia compared to those at the steady state. IRF1 knockout (KO) in BV2 microglia cells (BV2^ΔIRF1) created by CRISPR/Cas9 genome-editing technique causes decreased microglia proliferation, migration, and phagocytosis. IRF1-KO decreased pro-inflammatory M1 marker gene expression induced by lipopolysaccharides (LPS), such as IL-6, COX-2, and CCL5, but increased anti-inflammatory M2 marker gene expression by IL-4/13, such as Arg-1, CD206, and TGF-β. Compared to the wild-type cells, microglial-conditioned media (MCM) of activated BV2^ΔIRF1 cell cultures reduced toxicity or death to several retinal cells, including mouse cone photoreceptor-like 661 W cells, rat retinal neuron precursor R28 cells, and human ARPE-19 cells. IRF1 knockdown by siRNA alleviated microglial activation and retinal inflammation induced by LPS in mice. Together, the findings suggest that IRF1 plays a vital role in regulating microglial activation and retinal inflammation and, therefore, may be targeted for treating inflammatory and degenerative retinal diseases. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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Review

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18 pages, 3298 KiB

Open AccessReview

Insights into Novel Choroidal and Retinal Clinical Signs in Neurofibromatosis Type 1

by Fabiana Mallone, Ludovico Alisi, Luca Lucchino, Valerio Di Martino, Marcella Nebbioso, Marta Armentano, Alessandro Lambiase and Antonietta Moramarco

Int. J. Mol. Sci. 2023, 24(17), 13481; https://doi.org/10.3390/ijms241713481 - 30 Aug 2023

Cited by 1 | Viewed by 1392

Abstract

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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15 pages, 632 KiB

Open AccessReview

The Association between Vascular Abnormalities and Glaucoma—What Comes First?

by Xiaosha Wang, Maoren Wang, Hanhan Liu, Karl Mercieca, Julia Prinz, Yuan Feng and Verena Prokosch

Int. J. Mol. Sci. 2023, 24(17), 13211; https://doi.org/10.3390/ijms241713211 - 25 Aug 2023

Cited by 7 | Viewed by 2364

Abstract

Glaucoma is a leading cause of irreversible blindness worldwide. While intraocular pressure (IOP) presents a major risk factor, the underlying pathophysiology still remains largely unclear. The correlation between vascular abnormalities and glaucoma has been deliberated for decades. Evidence for a role played by vascular factors in the pathogenesis of glaucomatous neurodegeneration has already been postulated. In addition, the fact that glaucoma causes both structural and functional changes to retinal blood vessels has been described. This review aims to investigate the published evidence concerning the relationship between vascular abnormalities and glaucoma, and to provide an overview of the “chicken or egg” dilemma in glaucoma. In this study, several biomarkers of glaucoma progression from a vascular perspective, including endothelin-1 (ET-1), nitric oxide, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs), were identified and subsequently assessed for their potential as pharmacological intervention targets. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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Other

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9 pages, 4760 KiB

Open AccessCase Report

Novel Variant IMPDH1 c.134A>G, p.(Tyr45Cys): Phenotype–Genotype Correlation Revealed Likely Benign Clinical Significance

by Mirjana Bjeloš, Ana Ćurić, Mladen Bušić, Benedict Rak, Biljana Kuzmanović Elabjer and Leon Marković

Int. J. Mol. Sci. 2023, 24(15), 11889; https://doi.org/10.3390/ijms241511889 - 25 Jul 2023

Viewed by 692

Abstract

Pathogenic variants in IMPDH1 are associated with autosomal dominant retinitis pigmentosa 10 (RP10), and Leber congenital amaurosis 11. This case report of a 13-year-old girl with Down’s syndrome and keratoglobus is aimed at linking the novel variant IMPDH1 c.134A>G, p.(Tyr45Cys), a variant of uncertain significance, to a clinical phenotype and to provide grounds for the objective assignment of its benign features. RP10 is characterized by the early onset and rapid progression of ocular symptoms, beginning with nyctalopia in childhood, accompanied by typical RP fundus changes. As evidenced via thorough clinical examination and testing, none of the RP10 characteristics were present in our patient. On the contrary, our patient who was heterozygous for IMPDH1 c.134A>G, p.(Tyr45Cys) showed no signs of peripheral retinal dystrophy, and did not manifest any disease characteristics typical of the IMPDH1 gene mutation. Consequently, we conclude that the variant did not contribute to the phenotype. According to standards and guidelines for the interpretation of sequence variants, IMPDH1 c.134A>G, p.(Tyr45Cys) revealed likely benign features. Full article

(This article belongs to the Special Issue Advances on Retinal Diseases)

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