International Journal of Molecular Sciences

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13 pages, 2892 KiB

Open AccessArticle

CHAC1 as a Novel Contributor of Ferroptosis in Retinal Pigment Epithelial Cells with Oxidative Damage

by Ye Liu, Di Wu, Qiuli Fu, Shengjie Hao, Yuzhou Gu, Wei Zhao, Shuying Chen, Feiyin Sheng, Yili Xu, Zhiqing Chen and Ke Yao

Int. J. Mol. Sci. 2023, 24(2), 1582; https://doi.org/10.3390/ijms24021582 - 13 Jan 2023

Cited by 19 | Viewed by 2559

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly population. With aging and the accumulated effects of environmental stress, retinal pigment epithelial (RPE) cells are particularly susceptible to oxidative damage, which can lead to retinal degeneration. However, [...] Read more.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the elderly population. With aging and the accumulated effects of environmental stress, retinal pigment epithelial (RPE) cells are particularly susceptible to oxidative damage, which can lead to retinal degeneration. However, the underlying molecular mechanisms of how RPE responds and progresses under oxidative damage are still largely unknown. Here, we reveal that exogenous oxidative stress led to ferroptosis characterized by Fe²⁺ accumulation and lipid peroxidation in RPE cells. Glutathione specific gamma-glutamylcyclotransferase 1 (Chac1), as a component of the unfolded protein response (UPR) pathway, plays a pivotal role in oxidative-stress-induced cell ferroptosis via the regulation of glutathione depletion. These results indicate the biological significance of Chac1 as a novel contributor of oxidative-stress-induced ferroptosis in RPE, suggesting its potential role in AMD. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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12 pages, 3042 KiB

Open AccessArticle

The Protective Role of Apelin in the Early Stages of Diabetic Retinopathy

by Jing Feng, Weiqiang Yang, Fuxiao Luan, Fang Ma, Yingjie Wang, Yiquan Zhang, Xuhui Liu, Li Chen, Xiaofeng Hu and Yong Tao

Int. J. Mol. Sci. 2022, 23(23), 14680; https://doi.org/10.3390/ijms232314680 - 24 Nov 2022

Cited by 1 | Viewed by 1784

Abstract

Diabetic retinopathy (DR) is one of the most common and serious microvascular complications of diabetes. Although current treatments can control the progression of DR to a certain extent, there is no effective treatment for early DR. Apart from vascular endothelial growth factor, it [...] Read more.

Diabetic retinopathy (DR) is one of the most common and serious microvascular complications of diabetes. Although current treatments can control the progression of DR to a certain extent, there is no effective treatment for early DR. Apart from vascular endothelial growth factor, it has been noted that the apelin/APJ system contributes to the pathogenesis of DR. We used a high-fat diet/streptozotocin-induced type 2 diabetic mouse model. The mice were divided into a lentivirus control group (LV-EGFP), an apelin-overexpression group (LV-Apelin+), and an apelin-knockdown group (LV-Apelin−), all of which were administrated intravitreal injections. LV-Apelin+ ameliorated the loss of pericytes in DR mice, whereas LV-Apelin− aggravated the loss of pericytes. Similarly, LV-Apelin+ reduced the leakage of retinal vessels, whereas LV-Apelin− exacerbated it. The genes and signaling pathway related to cell adhesion molecules were downregulated, whereas the cell–cell tight junctions and anti-apoptotic genes were upregulated in response to apelin overexpression. However, the alterations of these same genes and signaling pathways were reversed in the case of apelin knockdown. Additionally, LV-Apelin+ increased ZO-1 and occludin levels, whereas LV-Apelin− decreased them. Our results suggest that apelin can reduce vascular leakage by protecting pericytes, which offers a promising new direction for the early treatment of DR. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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18 pages, 3285 KiB

Open AccessArticle

Targeting Phospholipase D Pharmacologically Prevents Phagocytic Function Loss of Retinal Pigment Epithelium Cells Exposed to High Glucose Levels

by Vicente Bermúdez, Paula Estefanía Tenconi, María Sol Echevarría, Aram Asatrian, Jorgelina Muriel Calandria, Norma María Giusto, Nicolas Guillermo Bazan and Melina Valeria Mateos

Int. J. Mol. Sci. 2022, 23(19), 11823; https://doi.org/10.3390/ijms231911823 - 5 Oct 2022

Viewed by 1440

Abstract

We previously described the participation of canonical phospholipase D isoforms (PLD1 and PLD2) in the inflammatory response of retinal pigment epithelium (RPE) cells exposed to high glucose concentrations (HG). Here, we studied the role of the PLD pathway in RPE phagocytic function. For [...] Read more.

We previously described the participation of canonical phospholipase D isoforms (PLD1 and PLD2) in the inflammatory response of retinal pigment epithelium (RPE) cells exposed to high glucose concentrations (HG). Here, we studied the role of the PLD pathway in RPE phagocytic function. For this purpose, ARPE-19 cells were exposed to HG (33 mM) or to normal glucose concentration (NG, 5.5 mM) and phagocytosis was measured using pHrodo™ green bioparticles^® or photoreceptor outer segments (POS). HG exposure for 48 and 72 h reduced phagocytic function of ARPE-19 cells, and this loss of function was prevented when cells were treated with 5 μM of PLD1 (VU0359595 or PLD1i) or PLD2 (VU0285655-1 or PLD2i) selective inhibitors. Furthermore, PLD1i and PLD2i did not affect RPE phagocytosis under physiological conditions and prevented oxidative stress induced by HG. In addition, we demonstrated PLD1 and PLD2 expression in ABC cells, a novel human RPE cell line. Under physiological conditions, PLD1i and PLD2i did not affect ABC cell viability, and partial silencing of both PLDs did not affect ABC cell POS phagocytosis. In conclusion, PLD1i and PLD2i prevent the loss of phagocytic function of RPE cells exposed to HG without affecting RPE function or viability under non-inflammatory conditions. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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19 pages, 4621 KiB

Open AccessArticle

Quantitative Proteomics Reveals Molecular Network Driving Stromal Cell Differentiation: Implications for Corneal Wound Healing

by Krishnatej Nishtala, Trailokyanath Panigrahi, Rohit Shetty, Dhanananajay Kumar, Pooja Khamar, Rajiv R. Mohan, Vrushali Deshpande and Arkasubhra Ghosh

Int. J. Mol. Sci. 2022, 23(5), 2572; https://doi.org/10.3390/ijms23052572 - 25 Feb 2022

Cited by 1 | Viewed by 2500

Abstract

The differentiation of keratocytes to fibroblasts and myofibroblasts is an essential requisite during corneal wound closure. The aim of this study is to uncover factors involved in differentiation-dependent alteration in the protein profile of human corneal stromal cells using quantitative proteomics. Human corneal [...] Read more.

The differentiation of keratocytes to fibroblasts and myofibroblasts is an essential requisite during corneal wound closure. The aim of this study is to uncover factors involved in differentiation-dependent alteration in the protein profile of human corneal stromal cells using quantitative proteomics. Human corneal fibroblasts were cultured and differentiated into keratocytes in serum-free media and myofibroblasts through treatment with TGF-β. The protein cell lysates from the donors were tryptic and were digested and labeled using a 3-plex iTRAQ kit. The labeled peptides were subjected to LCMS analysis. Biological functional analysis revealed a set of crucial proteins involved in the differentiation of human corneal stromal cells which were found to be significantly enriched. The selected proteins were further validated by immunohistochemistry. Quantitative proteomics identified key differentially expressed proteins which are involved in cellular signaling pathways. Proteins involved in integrin signaling (Ras-RAP1b, TLN and FN) and SLIT-ROBO pathways (PFN1, CAPR1, PSMA5) as well as extracellular matrix proteins (SERPINH1, SPARC, ITGβ1, CRTAP) showed enhanced expression in corneal fibroblasts and myofibroblasts compared to keratocytes, indicating their possible role in wound healing. Corneal stromal cell differentiation is associated with the activation of diverse molecular pathways critical for the repair of fibroblasts and myofibroblasts. Identified proteins such as profilin 1 and talin could play a tentative role in corneal healing and serve as a potential target to treat corneal fibrosis. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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15 pages, 2400 KiB

Open AccessArticle

The Differential Reactive Oxygen Species Production of Tear Neutrophils in Response to Various Stimuli In Vitro

by Yutong Jin, Brian Dixon, Lyndon Jones and Maud Gorbet

Int. J. Mol. Sci. 2021, 22(23), 12899; https://doi.org/10.3390/ijms222312899 - 29 Nov 2021

Cited by 6 | Viewed by 2073

Abstract

A large number of polymorphonuclear neutrophils (PMNs) invade the ocular surface during prolonged eye closure (sleep); these leukocytes are commonly referred as tear PMNs. PMNs contribute to homeostasis and possess an arsenal of inflammatory mediators to protect against pathogens and foreign materials. This [...] Read more.

A large number of polymorphonuclear neutrophils (PMNs) invade the ocular surface during prolonged eye closure (sleep); these leukocytes are commonly referred as tear PMNs. PMNs contribute to homeostasis and possess an arsenal of inflammatory mediators to protect against pathogens and foreign materials. This study examined the ability of tear PMNs to generate reactive oxygen species (ROS), an essential killing mechanism for PMNs which can lead to oxidative stress and imbalance. Cells were collected after sleep from healthy participants using a gentle eye wash. ROS production in stimulated (phorbol-12-myristate-13-acetate (PMA), lipopolysaccharides (LPS) or N-Formylmethionyl-leucyl-phenylalanine (fMLP)) and unstimulated tear PMNs was measured using luminol-enhanced chemiluminescence for 60 min. A high level of constitutive/spontaneous ROS production was observed in tear PMNs in the absence of any stimulus. While tear PMNs were able to produce ROS in response to PMA, they failed to appropriately respond to LPS and fMLP, although fMLP-stimulated tear PMNs generated ROS extracellularly in the first three minutes. Higher ROS generation was observed in isolated tear PMNs which may be due to priming from the magnetic bead cell separation system. The differential responses of tear PMNs in ROS generation provide further evidence of their potential inflammatory roles in ocular complications involving oxidative stress. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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Review

Jump to: Research

32 pages, 3287 KiB

Open AccessReview

Ocular Vascular Diseases: From Retinal Immune Privilege to Inflammation

by Xudong Wang, Tianxi Wang, Enton Lam, David Alvarez and Ye Sun

Int. J. Mol. Sci. 2023, 24(15), 12090; https://doi.org/10.3390/ijms241512090 - 28 Jul 2023

Cited by 8 | Viewed by 2069

Abstract

The eye is an immune privileged tissue that insulates the visual system from local and systemic immune provocation to preserve homeostatic functions of highly specialized retinal neural cells. If immune privilege is breached, immune stimuli will invade the eye and subsequently trigger acute [...] Read more.

The eye is an immune privileged tissue that insulates the visual system from local and systemic immune provocation to preserve homeostatic functions of highly specialized retinal neural cells. If immune privilege is breached, immune stimuli will invade the eye and subsequently trigger acute inflammatory responses. Local resident microglia become active and release numerous immunological factors to protect the integrity of retinal neural cells. Although acute inflammatory responses are necessary to control and eradicate insults to the eye, chronic inflammation can cause retinal tissue damage and cell dysfunction, leading to ocular disease and vision loss. In this review, we summarized features of immune privilege in the retina and the key inflammatory responses, factors, and intracellular pathways activated when retinal immune privilege fails, as well as a highlight of the recent clinical and research advances in ocular immunity and ocular vascular diseases including retinopathy of prematurity, age-related macular degeneration, and diabetic retinopathy. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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16 pages, 1519 KiB

Open AccessReview

Shhedding New Light on the Role of Hedgehog Signaling in Corneal Wound Healing

by Xin Zhang, Stéphane Mélik-Parsadaniantz, Christophe Baudouin, Annabelle Réaux-Le Goazigo and Nathan Moreau

Int. J. Mol. Sci. 2022, 23(7), 3630; https://doi.org/10.3390/ijms23073630 - 26 Mar 2022

Cited by 6 | Viewed by 2285

Abstract

The cornea, an anterior ocular tissue that notably serves to protect the eye from external insults and refract light, requires constant epithelium renewal and efficient healing following injury to maintain ocular homeostasis. Although several key cell populations and molecular pathways implicated in corneal [...] Read more.

The cornea, an anterior ocular tissue that notably serves to protect the eye from external insults and refract light, requires constant epithelium renewal and efficient healing following injury to maintain ocular homeostasis. Although several key cell populations and molecular pathways implicated in corneal wound healing have already been thoroughly investigated, insufficient/impaired or excessive corneal wound healing remains a major clinical issue in ophthalmology, and new avenues of research are still needed to further improve corneal wound healing. Because of its implication in numerous cellular/tissular homeostatic processes and oxidative stress, there is growing evidence of the role of Hedgehog signaling pathway in physiological and pathological corneal wound healing. Reviewing current scientific evidence, Hedgehog signaling and its effectors participate in corneal wound healing mainly at the level of the corneal and limbal epithelium, where Sonic Hedgehog-mediated signaling promotes limbal stem cell proliferation and corneal epithelial cell proliferation and migration following corneal injury. Hedgehog signaling could also participate in corneal epithelial barrier homeostasis and in pathological corneal healing such as corneal injury-related neovascularization. By gaining a better understanding of the role of this double-edged sword in physiological and pathological corneal wound healing, fascinating new research avenues and therapeutic strategies will undoubtedly emerge. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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21 pages, 1607 KiB

Open AccessReview

Ocular Surface Infection Mediated Molecular Stress Responses: A Review

by Samayitree Das, Sharon D’Souza, Bhavya Gorimanipalli, Rohit Shetty, Arkasubhra Ghosh and Vrushali Deshpande

Int. J. Mol. Sci. 2022, 23(6), 3111; https://doi.org/10.3390/ijms23063111 - 14 Mar 2022

Cited by 4 | Viewed by 3500

Abstract

Infection mediated ocular surface stress responses are activated as early defense mechanisms in response to host cell damage. Integrated stress responses initiate the host response to different types of infections and modulate the transcription of key genes and translation of proteins. The crosstalk [...] Read more.

Infection mediated ocular surface stress responses are activated as early defense mechanisms in response to host cell damage. Integrated stress responses initiate the host response to different types of infections and modulate the transcription of key genes and translation of proteins. The crosstalk between host and pathogen results in profound alterations in cellular and molecular homeostasis triggering specific stress responses in the infected tissues. The amplitude and variations of such responses are partly responsible for the disease severity and clinical sequelae. Understanding the etiology and pathogenesis of ocular infections is important for early diagnosis and effective treatment. This review considers the molecular status of infection mediated ocular surface stress responses which may shed light on the importance of the host stress-signaling pathways. In this review, we collated literature on the molecular studies of all ocular surface infections and summarize the results from such studies systematically. Identification of important mediators involved in the crosstalk between the stress response and activation of diverse signaling molecules in host ocular surface infection may provide novel molecular targets for maintaining the cellular homeostasis during infection. These targets can be then explored and validated for diagnostic and therapeutic purposes. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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27 pages, 2951 KiB

Open AccessReview

The Role of Vitamin A in Retinal Diseases

by Jana Sajovic, Andrej Meglič, Damjan Glavač, Špela Markelj, Marko Hawlina and Ana Fakin

Int. J. Mol. Sci. 2022, 23(3), 1014; https://doi.org/10.3390/ijms23031014 - 18 Jan 2022

Cited by 32 | Viewed by 9325

Abstract

Vitamin A is an essential fat-soluble vitamin that occurs in various chemical forms. It is essential for several physiological processes. Either hyper- or hypovitaminosis can be harmful. One of the most important vitamin A functions is its involvement in visual phototransduction, where it [...] Read more.

Vitamin A is an essential fat-soluble vitamin that occurs in various chemical forms. It is essential for several physiological processes. Either hyper- or hypovitaminosis can be harmful. One of the most important vitamin A functions is its involvement in visual phototransduction, where it serves as the crucial part of photopigment, the first molecule in the process of transforming photons of light into electrical signals. In this process, large quantities of vitamin A in the form of 11-cis-retinal are being isomerized to all-trans-retinal and then quickly recycled back to 11-cis-retinal. Complex machinery of transporters and enzymes is involved in this process (i.e., the visual cycle). Any fault in the machinery may not only reduce the efficiency of visual detection but also cause the accumulation of toxic chemicals in the retina. This review provides a comprehensive overview of diseases that are directly or indirectly connected with vitamin A pathways in the retina. It includes the pathophysiological background and clinical presentation of each disease and summarizes the already existing therapeutic and prospective interventions. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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25 pages, 2848 KiB

Open AccessReview

Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

by Felix Yemanyi, Kiran Bora, Alexandra K. Blomfield, Zhongxiao Wang and Jing Chen

Int. J. Mol. Sci. 2021, 22(21), 11877; https://doi.org/10.3390/ijms222111877 - 2 Nov 2021

Cited by 19 | Viewed by 4752

Abstract

The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood–retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological [...] Read more.

The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood–retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina’s extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood–brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium. Full article

(This article belongs to the Special Issue Molecular Research on Stress Response and Ocular Homeostasis 2.0)

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