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Biomedicine & Pharmacotherapy =... Sep 2023Both the accumulation of reactive oxygen species (ROS) and iron overload are significant variables that enhance the incidence of photoreceptor cell death and retinal...
BACKGROUND
Both the accumulation of reactive oxygen species (ROS) and iron overload are significant variables that enhance the incidence of photoreceptor cell death and retinal degeneration. The discovery of ferroptosis, which is characterized by iron-dependent lipid peroxidation, has led to a new perspective on how retinal degeneration develops. As a natural phenolic acid, salvianic acid A (SAA) from Salvia miltiorrhiza has promise in treating eye diseases. The purpose of this research was to learn more about SAA and its function in the development of iron-overload-induced retinal degeneration.
METHODS
Models of iron overload in Kunming mice and the murine photoreceptor cell line 661 W were established, then the protective and antiferroptotic properties of SAA were assessed in vivo and in vitro.
RESULTS
Biochemical and histopathological findings on the retina confirmed that SAA successfully alleviated retinal injury. In photoreceptor cells, iron overload caused cell death, mitochondrial dysfunction, ROS generation, and iron deposition. Salvianic acid A relieved lipid peroxidation and decreased iron accumulation by modulating Acyl-CoA synthetase long-chain family member 4, glutathione peroxidase 4, solute carrier family 7 member 11, and iron-metabolism-related proteins. The mitochondrial morphology suggests that the retinal protective effect of SAA is mediated via antiferroptotic action.
CONCLUSION
Ferroptosis plays an important role in the pathogenesis of iron-overload-induced retinal degeneration. New roles of SAA in ferroptosis prevention via iron deposit inhibition, lipid peroxidation inhibition, and mitochondrial dysfunction reduction, were identified.
Topics: Mice; Animals; Retinal Degeneration; Ferroptosis; Reactive Oxygen Species; Retina; Iron Overload; Iron
PubMed: 37429233
DOI: 10.1016/j.biopha.2023.115140 -
Journal of Nanobiotechnology Nov 2023Photoreceptor apoptosis is an important pathogenesis of retinal degeneration and a primary cause of vision loss with limited treatment methods. Mesenchymal stem/stromal...
Photoreceptor apoptosis is an important pathogenesis of retinal degeneration and a primary cause of vision loss with limited treatment methods. Mesenchymal stem/stromal cells-derived small extracellular vesicles (MSC-sEVs) have shown therapeutic value in various ocular disorders. Recent studies have revealed that hypoxic preconditioning can improve the effectiveness of MSC-sEVs in tissue regeneration. However, whether hypoxic preconditioned MSC-sEVs (Hyp-sEVs) exert superior effects on photoreceptor protection relative to normoxic conditioned MSC-sEVs (Nor-sEVs) remains unclear. Here, we reported that Hyp-sEVs further improved retinal structure, recovered retinal function, and suppressed photoreceptor apoptosis in N-methyl-N-nitrosourea (MNU)-induced mouse model compared with Nor-sEVs. Hyp-sEVs also exhibited enhanced anti-apoptotic roles in MNU-provoked 661 W cell injury in vitro. We then analyzed the protein profiles of Nor-sEVs and Hyp-sEVs by LC-MS/MS and found that growth-associated protein 43 (GAP43) was enriched in Hyp-sEVs. The knockdown of GAP43 abolished the retinal therapeutic effects of Hyp-sEVs. Mechanistically, hypoxic stimulation-induced hypoxia-inducible factor-1α (HIF-1α) activation was responsible for preventing tripartite motif-containing protein 25 (TRIM25)-mediated GAP43 ubiquitination and degradation, leading to the upregulation of GAP43 in Hyp-sEVs. Together, our findings uncover the efficacy and mechanism of Hyp-sEVs-based photoreceptor protection and highlight the potential of Hyp-sEVs as optimized therapeutics for retinal degeneration.
Topics: Mice; Animals; Retinal Degeneration; Chromatography, Liquid; Tandem Mass Spectrometry; Retina; Extracellular Vesicles; Hypoxia
PubMed: 38001463
DOI: 10.1186/s12951-023-02225-2 -
Protein & Cell Aug 2023Light adaptation enables the vertebrate visual system to operate over a wide range of ambient illumination. Regulation of phototransduction in photoreceptors is...
Light adaptation enables the vertebrate visual system to operate over a wide range of ambient illumination. Regulation of phototransduction in photoreceptors is considered a major mechanism underlying light adaptation. However, various types of neurons and glial cells exist in the retina, and whether and how all retinal cells interact to adapt to light/dark conditions at the cellular and molecular levels requires systematic investigation. Therefore, we utilized single-cell RNA sequencing to dissect retinal cell-type-specific transcriptomes during light/dark adaptation in mice. The results demonstrated that, in addition to photoreceptors, other retinal cell types also showed dynamic molecular changes and specifically enriched signaling pathways under light/dark adaptation. Importantly, Müller glial cells (MGs) were identified as hub cells for intercellular interactions, displaying complex cell‒cell communication with other retinal cells. Furthermore, light increased the transcription of the deiodinase Dio2 in MGs, which converted thyroxine (T4) to active triiodothyronine (T3). Subsequently, light increased T3 levels and regulated mitochondrial respiration in retinal cells in response to light conditions. As cones specifically express the thyroid hormone receptor Thrb, they responded to the increase in T3 by adjusting light responsiveness. Loss of the expression of Dio2 specifically in MGs decreased the light responsive ability of cones. These results suggest that retinal cells display global transcriptional changes under light/dark adaptation and that MGs coordinate intercellular communication during light/dark adaptation via thyroid hormone signaling.
Topics: Animals; Mice; Dark Adaptation; Light; Retina; Retinal Cone Photoreceptor Cells; Adaptation, Ocular; Neuroglia; Cell Communication; Thyroid Hormones
PubMed: 36930538
DOI: 10.1093/procel/pwad007 -
Proceedings of the National Academy of... Oct 2023Retinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but the mechanisms...
Retinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but the mechanisms involved in the digestion and recycling of POS lipids are poorly understood. Although it was frequently assumed that peroxisomes may play an essential role, this was never investigated. Here, we show that global as well as RPE-selective loss of peroxisomal β-oxidation in multifunctional protein 2 (MFP2) knockout mice impairs the digestive function of lysosomes in the RPE at a very early age, followed by RPE degeneration. This was accompanied by prolonged mammalian target of rapamycin activation, lipid deregulation, and mitochondrial structural anomalies without, however, causing oxidative stress or energy shortage. The RPE degeneration caused secondary photoreceptor death. Notably, the deterioration of the RPE did not occur in an mutant mouse line, characterized by absent POS shedding. Our findings prove that peroxisomal β-oxidation in the RPE is essential for handling the polyunsaturated fatty acids present in ingested POS and shed light on retinopathy in patients with peroxisomal disorders. Our data also have implications for gene therapy development as they highlight the importance of targeting the RPE in addition to the photoreceptor cells.
Topics: Mice; Humans; Animals; Retinal Pigment Epithelium; Lysosomes; Phagocytosis; Oxidative Stress; Mice, Knockout; Mammals
PubMed: 37862382
DOI: 10.1073/pnas.2301733120 -
ENeuro Sep 2023Rod and cone photoreceptors degenerate in inherited and age-related retinal degenerative diseases, ultimately leading to loss of vision. Thyroid hormone (TH) signaling...
Rod and cone photoreceptors degenerate in inherited and age-related retinal degenerative diseases, ultimately leading to loss of vision. Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and metabolism. Recent studies have shown a link between TH signaling and retinal degeneration. This work investigates the effects of excessive TH signaling on photoreceptor function and survival in mice. C57BL/6, , , , and the cone dominant mice received triiodothyronine (T3) treatment (5-20 μg/ml in drinking water) for 30 d, followed by evaluations of retinal function, photoreceptor survival/death, and retinal stress/damage. Treatment with T3 reduced light responses of rods and cones by 50-60%, compared with untreated controls. Outer nuclear layer thickness and cone density were reduced by ∼18% and 75%, respectively, after T3 treatment. Retinal sections prepared from T3-treated mice showed significantly increased numbers of TUNEL-positive, p-γH2AX-positive, and 8-OHdG-positive cells, and activation of Müller glial cells. Gene expression analysis revealed upregulation of the genes involved in oxidative stress, necroptosis, and inflammation after T3 treatment. Deletion of prevented T3-induced degeneration of rods but not cones, whereas deletion of preserved both rods and cones. Treatment with an antioxidant partially preserved photoreceptors and reduced retinal stress responses. This study demonstrates that excessive TH signaling induces oxidative stress/damage and necroptosis, induces photoreceptor degeneration, and impairs retinal function. The findings provide insights into the role of TH signaling in retinal degeneration and support the view of targeting TH signaling for photoreceptor protection.
Topics: Animals; Mice; Mice, Inbred C57BL; Retinal Degeneration; Retina; Thyroid Hormones; Retinal Cone Photoreceptor Cells
PubMed: 37596046
DOI: 10.1523/ENEURO.0058-23.2023 -
Neural Regeneration Research Nov 2024JOURNAL/nrgr/04.03/01300535-202419110-00032/figure1/v/2024-03-08T184507Z/r/image-tiff High intraocular pressure causes retinal ganglion cell injury in primary and...
JOURNAL/nrgr/04.03/01300535-202419110-00032/figure1/v/2024-03-08T184507Z/r/image-tiff High intraocular pressure causes retinal ganglion cell injury in primary and secondary glaucoma diseases, yet the molecular landscape characteristics of retinal cells under high intraocular pressure remain unknown. Rat models of acute hypertension ocular pressure were established by injection of cross-linked hyaluronic acid hydrogel (Healaflow®). Single-cell RNA sequencing was then used to describe the cellular composition and molecular profile of the retina following high intraocular pressure. Our results identified a total of 12 cell types, namely retinal pigment epithelial cells, rod-photoreceptor cells, bipolar cells, Müller cells, microglia, cone-photoreceptor cells, retinal ganglion cells, endothelial cells, retinal progenitor cells, oligodendrocytes, pericytes, and fibroblasts. The single-cell RNA sequencing analysis of the retina under acute high intraocular pressure revealed obvious changes in the proportions of various retinal cells, with ganglion cells decreased by 23%. Hematoxylin and eosin staining and TUNEL staining confirmed the damage to retinal ganglion cells under high intraocular pressure. We extracted data from retinal ganglion cells and analyzed the retinal ganglion cell cluster with the most distinct expression. We found upregulation of the B3gat2 gene, which is associated with neuronal migration and adhesion, and downregulation of the Tsc22d gene, which participates in inhibition of inflammation. This study is the first to reveal molecular changes and intercellular interactions in the retina under high intraocular pressure. These data contribute to understanding of the molecular mechanism of retinal injury induced by high intraocular pressure and will benefit the development of novel therapies.
PubMed: 38526288
DOI: 10.4103/1673-5374.389363 -
Frontiers in Cellular Neuroscience 2023Vision is our primary sense, and maintaining it throughout our lifespan is crucial for our well-being. However, the retina, which initiates vision, suffers from an...
Vision is our primary sense, and maintaining it throughout our lifespan is crucial for our well-being. However, the retina, which initiates vision, suffers from an age-related, irreversible functional decline. What causes this functional decline, and how it might be treated, is still unclear. Synapses are the functional hub for signal transmission between neurons, and studies have shown that aging is widely associated with synaptic dysfunction. In this study, we examined the first synapse of the visual system - the rod and cone photoreceptor ribbon synapse - in the mouse retina using light and electron microscopy at 2-3 months, ~1 year, and >2 years of age. We asked, whether age-related changes in key synaptic components might be a driver of synaptic dysfunction and ultimately age-related functional decline during normal aging. We found sprouting of horizontal and bipolar cells, formation of ectopic photoreceptor ribbon synapses, and a decrease in the number of rod photoreceptors and photoreceptor ribbon synapses in the aged retina. However, the majority of the photoreceptors did not show obvious changes in the structural components and protein composition of their ribbon synapses. Noteworthy is the increase in mitochondrial size in rod photoreceptor terminals in the aged retina.
PubMed: 38026697
DOI: 10.3389/fncel.2023.1291054 -
Bioactive Materials Dec 2023Age-related macular degeneration (AMD) causes blindness due to loss of retinal pigment epithelium (RPE) and photoreceptors (PRs), which comprise the two outermost layers...
Age-related macular degeneration (AMD) causes blindness due to loss of retinal pigment epithelium (RPE) and photoreceptors (PRs), which comprise the two outermost layers of the retina. Given the small size of the macula and the importance of direct contact between RPE and PRs, the use of scaffolds for targeted reconstruction of the outer retina in later stage AMD and other macular dystrophies is particularly attractive. We developed microfabricated, honeycomb-patterned, biodegradable poly(glycerol sebacate) (PGS) scaffolds to deliver organized, adjacent layers of RPE and PRs to the subretinal space. Furthermore, an optimized process was developed to photocure PGS, shortening scaffold production time from days to minutes. The resulting scaffolds robustly supported the seeding of human pluripotent stem cell-derived RPE and PRs, either separately or as a dual cell-layered construct. These advanced, economical, and versatile scaffolds can accelerate retinal cell transplantation efforts and benefit patients with AMD and other retinal degenerative diseases.
PubMed: 37575875
DOI: 10.1016/j.bioactmat.2023.07.019 -
Frontiers in Immunology 2023In multiple sclerosis (MS), chronic disability primarily stems from axonal and neuronal degeneration, a condition resistant to conventional immunosuppressive or...
INTRODUCTION
In multiple sclerosis (MS), chronic disability primarily stems from axonal and neuronal degeneration, a condition resistant to conventional immunosuppressive or immunomodulatory treatments. Recent research has indicated that selective sphingosine-1-phosphate receptor S1PR-1 and -5 modulators yield positive effects in progressive MS and mechanistic models of inflammation-driven neurodegeneration and demyelination.
METHODS
In this study, the S1PR-1/-5 modulator RP-101074 was evaluated as a surrogate for ozanimod in the non-inflammatory, primary degenerative animal model of light-induced photoreceptor loss (LI-PRL) in CX3CR1-GFP mice to assess potential neuroprotective effects, independent of its immunomodulatory mechanism of action.
RESULTS
Prophylactic administration of RP-101074 demonstrated protective effects in the preclinical, non-inflammatory LI-PRL animal model, following a bell-shaped dose-response curve. RP-101074 treatment also revealed activity-modulating effects on myeloid cells, specifically, CX3CR1+ cells, significantly reducing the marked infiltration occurring one week post-irradiation. Treatment with RP-101074 produced beneficial outcomes on both retinal layer thickness and visual function as evidenced by optical coherence tomography (OCT) and optomotor response (OMR) measurements, respectively. Additionally, the myelination status and the quantity of neural stem cells in the optic nerve suggest that RP-101074 may play a role in the activation and/or recruitment of neural stem cells and oligodendrocyte progenitor cells, respectively.
CONCLUSION/DISCUSSION
The data from our study suggest that RP-101074 may have a broader role in MS treatment beyond immunomodulation, potentially offering a novel approach to mitigate neurodegeneration, a core contributor to chronic disability in MS.
Topics: Animals; Mice; Central Nervous System Diseases; Multiple Sclerosis; Axons; Immunomodulation; Central Nervous System
PubMed: 37638037
DOI: 10.3389/fimmu.2023.1234984 -
Eye (London, England) Aug 2023Visual electrophysiology affords direct, quantitative, objective assessment of visual pathway function at different levels, and thus yields information complementary to,... (Review)
Review
Visual electrophysiology affords direct, quantitative, objective assessment of visual pathway function at different levels, and thus yields information complementary to, and not necessarily obtainable from, imaging or psychophysical testing. The tests available, and their indications, have evolved, with many advances, both in technology and in our understanding of the neural basis of the waveforms, now facilitating more precise evaluation of physiology and pathophysiology. After summarising the visual pathway and current standard clinical testing methods, this review discusses, non-exhaustively, several developments, focusing particularly on human electroretinogram recordings. These include new devices (portable, non-mydiatric, multimodal), novel testing protocols (including those aiming to separate rod-driven and cone-driven responses, and to monitor retinal adaptation), and developments in methods of analysis, including use of modelling and machine learning. It is likely that several tests will become more accessible and useful in both clinical and research settings. In future, these methods will further aid our understanding of common and rare eye disease, will help in assessing novel therapies, and will potentially yield information relevant to neurological and neuro-psychiatric conditions.
Topics: Humans; Electroretinography; Retinal Cone Photoreceptor Cells; Eye Diseases; Vision, Ocular; Electrophysiology
PubMed: 36928229
DOI: 10.1038/s41433-023-02491-2