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Frontiers in Pharmacology 2024Retinal pigment epithelial cell and neuroretinal damage in age-related macular degeneration (AMD) can lead to serious visual impairments and blindness. Studies have... (Review)
Review
Retinal pigment epithelial cell and neuroretinal damage in age-related macular degeneration (AMD) can lead to serious visual impairments and blindness. Studies have shown that mitophagy, a highly specialized cellular degradation system, is implicated in the pathogenesis of AMD. Mitophagy selectively eliminates impaired or non-functioning mitochondria via several pathways, such as the phosphatase and tensin homolog-induced kinase 1/Parkin, BCL2-interacting protein 3 and NIP3-like protein X, FUN14 domain-containing 1, and AMP-activated protein kinase pathways. This has a major impact on the maintenance of mitochondrial homeostasis. Therefore, the regulation of mitophagy could be a promising therapeutic strategy for AMD. Traditional Chinese medicine (TCM) uses natural products that could potentially prevent and treat various diseases, such as AMD. This review aims to summarize recent findings on mitophagy regulation pathways and the latest progress in AMD treatment targeting mitophagy, emphasizing methods involving TCM.
PubMed: 38828456
DOI: 10.3389/fphar.2024.1410998 -
Cureus May 2024Acute zonal occult outer retinopathy (AZOOR) manifests as the rapid loss of one or multiple large zones of the outer retinal layers, often with a distinct sectoral...
Acute zonal occult outer retinopathy (AZOOR) manifests as the rapid loss of one or multiple large zones of the outer retinal layers, often with a distinct sectoral distribution. Subtle fundus changes, such as pigmentary alterations around the optic nerve, are typically present in the early stages. Disease progression is characterized by the appearance of well-defined atrophic zones involving the outer retina, retinal pigment epithelium, and choroid. AZOOR lesions typically begin in the peripapillary region and then spread centrifugally toward the peripheral fundus. In this case report, we present the clinical and multimodal imaging characteristics of a 63-year-old woman with a symmetrical, peripheral-onset AZOOR variant with a very slow centrifugal progression. Most notably, the posterior pole was unaffected bilaterally.
PubMed: 38826932
DOI: 10.7759/cureus.59600 -
Cell Death & Disease Jun 2024Drusen, the yellow deposits under the retina, are composed of lipids and proteins, and represent a hallmark of age-related macular degeneration (AMD). Lipid droplets are...
Drusen, the yellow deposits under the retina, are composed of lipids and proteins, and represent a hallmark of age-related macular degeneration (AMD). Lipid droplets are also reported in the retinal pigment epithelium (RPE) from AMD donor eyes. However, the mechanisms underlying these disease phenotypes remain elusive. Previously, we showed that Pgc-1α repression, combined with a high-fat diet (HFD), induce drastic AMD-like phenotypes in mice. We also reported increased PGC-1α acetylation and subsequent deactivation in the RPE derived from AMD donor eyes. Here, through a series of in vivo and in vitro experiments, we sought to investigate the molecular mechanisms by which PGC-1α repression could influence RPE and retinal function. We show that PGC-1α plays an important role in RPE and retinal lipid metabolism and function. In mice, repression of Pgc-1α alone induced RPE and retinal degeneration and drusen-like deposits. In vitro inhibition of PGC1A by CRISPR-Cas9 gene editing in human RPE (ARPE19- PGC1A KO) affected the expression of genes responsible for lipid metabolism, fatty acid β-oxidation (FAO), fatty acid transport, low-density lipoprotein (LDL) uptake, cholesterol esterification, cholesterol biosynthesis, and cholesterol efflux. Moreover, inhibition of PGC1A in RPE cells caused lipid droplet accumulation and lipid peroxidation. ARPE19-PGC1A KO cells also showed reduced mitochondrial biosynthesis, impaired mitochondrial dynamics and activity, reduced antioxidant enzymes, decreased mitochondrial membrane potential, loss of cardiolipin, and increased susceptibility to oxidative stress. Our data demonstrate the crucial role of PGC-1α in regulating lipid metabolism. They provide new insights into the mechanisms involved in lipid and drusen accumulation in the RPE and retina during aging and AMD, which may pave the way for developing novel therapeutic strategies targeting PGC-1α.
Topics: Retinal Pigment Epithelium; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Animals; Lipid Metabolism; Humans; Mice; Lipid Droplets; Macular Degeneration; Mice, Inbred C57BL; Mitochondria; Male; Oxidative Stress
PubMed: 38824126
DOI: 10.1038/s41419-024-06762-y -
Acta Neuropathologica Communications May 2024Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also...
Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also occur in Nnt-intact 5xFAD mice and whether these biomarkers can be pharmacologically treated. Four-month-old wild-type or 5xFAD C57BL/6 substrains with either a null (B6J) Nnt or intact Nnt gene (B6NTac) and 5xFAD B6J mice treated for one month with either R-carvedilol + vehicle or only vehicle (0.01% DMSO) were studied. The contrast sensitivity (CS), external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness (a proxy for low pH-triggered water removal), profile shape of the hyperreflective band just posterior to the ELM (i.e., the mitochondrial configuration within photoreceptors per aspect ratio [MCP/AR]), and retinal laminar thickness were measured. Both wild-type substrains showed similar visual performance indices and dark-evoked ELM-RPE contraction. The lack of a light-dark change in B6NTac MCP/AR, unlike in B6J mice, is consistent with relatively greater mitochondrial efficiency. 5xFAD B6J mice, but not 5xFAD B6NTac mice, showed lower-than-WT CS. Light-adapted 5xFAD substrains both showed abnormal ELM-RPE contraction and greater-than-WT MCP/AR contraction. The inner retina and superior outer retina were thinner. Treating 5xFAD B6J mice with R-carvedilol + DMSO or DMSO alone corrected CS and ELM-RPE contraction but not supernormal MCP/AR contraction or laminar thinning. These results provide biomarker evidence for prodromal photoreceptor mitochondrial dysfunction/oxidative stress/oxidative damage, which is unrelated to visual performance, as well as the presence of the Nnt gene. This pathophysiology is druggable in 5xFAD mice.
Topics: Animals; Mice, Inbred C57BL; Mice; Dimethyl Sulfoxide; Biomarkers; Mice, Transgenic; Tomography, Optical Coherence; Retinal Rod Photoreceptor Cells; Contrast Sensitivity; Disease Models, Animal; Retinal Pigment Epithelium; Vision, Ocular
PubMed: 38822433
DOI: 10.1186/s40478-024-01799-8 -
Neural Regeneration Research Feb 2025Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and...
Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration. It causes local damage to photoreceptors, retinal pigment epithelium, and choroidal vessels, which leads to permanent central vision loss of patients with neovascular age-related macular degeneration. The pathogenesis of subretinal fibrosis is complex, and the underlying mechanisms are largely unknown. Therefore, there are no effective treatment options. A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments. The current article reviews several aspects of subretinal fibrosis, including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis; multimodal imaging techniques for subretinal fibrosis; animal models for studying subretinal fibrosis; cellular and non-cellular constituents of subretinal fibrosis; pathophysiological mechanisms involved in subretinal fibrosis, such as aging, infiltration of macrophages, different sources of mesenchymal transition to myofibroblast, and activation of complement system and immune cells; and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis, such as vascular endothelial growth factor, connective tissue growth factor, fibroblast growth factor 2, platelet-derived growth factor and platelet-derived growth factor receptor-β, transforming growth factor-β signaling pathway, Wnt signaling pathway, and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10. This review will improve the understanding of the pathogenesis of subretinal fibrosis, allow the discovery of molecular targets, and explore potential treatments for the management of subretinal fibrosis.
PubMed: 38819041
DOI: 10.4103/NRR.NRR-D-23-01642 -
Neural Regeneration Research Feb 2025Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and...
Retinal aging has been recognized as a significant risk factor for various retinal disorders, including diabetic retinopathy, age-related macular degeneration, and glaucoma, following a growing understanding of the molecular underpinnings of their development. This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches, focusing on the activation of transcription factor EB. Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies, such as exercise, calorie restriction, rapamycin, and metformin, in patients and animal models of these common retinal diseases. The review critically assesses the role of transcription factor EB in retinal biology during aging, its neuroprotective effects, and its therapeutic potential for retinal disorders. The impact of transcription factor EB on retinal aging is cell-specific, influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways. In vascular endothelial cells, transcription factor EB controls important processes, including endothelial cell proliferation, endothelial tube formation, and nitric oxide levels, thereby influencing the inner blood-retinal barrier, angiogenesis, and retinal microvasculature. Additionally, transcription factor EB affects vascular smooth muscle cells, inhibiting vascular calcification and atherogenesis. In retinal pigment epithelial cells, transcription factor EB modulates functions such as autophagy, lysosomal dynamics, and clearance of the aging pigment lipofuscin, thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization. These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis, neuronal synapse plasticity, energy metabolism, microvasculature, and inflammation, ultimately offering protection against retinal aging and diseases. The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases. Therefore, it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.
PubMed: 38819040
DOI: 10.4103/NRR.NRR-D-23-02033 -
Journal of Medical Genetics May 2024Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to...
BACKGROUND AND AIMS
Variants in underlie a disorder characterised by progressive portal fibrosis, portal hypertension and eventual liver decompensation. We aim to create an animal model to elucidate the pathogenic mechanism.
METHODS
knockout ( ) mice were generated and exposed to different liver toxins. Their livers were characterised at the tissue, cellular and molecular levels. Findings were compared with those in wild-type mice and in ZFYVE19-deficient patients. knockout and knockdown retinal pigment epithelial-1 cells and mouse embryonic fibroblasts were generated to study cell division and cell death.
RESULTS
The mice were normal overall, particularly with respect to hepatobiliary features. However, when challenged with α-naphthyl isothiocyanate, mice developed changes resembling those in ZFYVE19-deficient patients, including elevated serum liver injury markers, increased numbers of bile duct profiles with abnormal cholangiocyte polarity and biliary fibrosis. Failure of cell division, centriole and cilia abnormalities, and increased cell death were observed in knockdown/knockout cells. Increased cell death and altered mRNA expression of cell death-related signalling pathways was demonstrated in livers from mice and patients. Transforming growth factor-β (TGF-β) and Janus kinase-Signal Transducer and Activator of Transcription 3 (JAK-STAT3) signalling pathways were upregulated in vivo, as were chemokines such as C-X-C motif ligands 1, 10 and 12.
CONCLUSIONS
Our findings demonstrated that ZFYVE19 deficiency is a ciliopathy with novel histological features. Failure of cell division with ciliary abnormalities and cell death activates macrophages and may thus lead to biliary fibrosis via TGF-β pathway in the disease.
PubMed: 38816193
DOI: 10.1136/jmg-2023-109779 -
Journal of Biomedical Research Apr 2024The retinal pigment epithelium (RPE) is fundamental to sustaining retinal homeostasis. RPE abnormality leads to visual defects and blindness, including age-related...
The retinal pigment epithelium (RPE) is fundamental to sustaining retinal homeostasis. RPE abnormality leads to visual defects and blindness, including age-related macular degeneration (AMD). Although breakthroughs have been made in the treatment of neovascular AMD, effective intervention for atrophic AMD is largely absent. The inadequate knowledge of RPE pathology is hindered by a lack of patient RPE datasets, especially at the single-cell resolution. In this study, we delved into a large-scale single-cell resource of AMD donors in which RPE cells were occupied in a substantial proportion. Bulk RNA-seq datasets of atrophic AMD were integrated to extract molecular characteristics of RPE in the pathogenesis of atrophic AMD. Both and models revealed that carboxypeptidase X, M14 family member 2 (CPXM2) was specifically expressed in the RPE cells of atrophic AMD, which might be induced by oxidative stress and involved in the epithelial-mesenchymal transition of RPE cells. Additionally, silencing of inhibited the mesenchymal phenotype of RPE cells in an oxidative stress cell model. Thus, our results demonstrate that CPXM2 plays a crucial role in regulating atrophic AMD and may serve as a potential therapeutic target for atrophic AMD.
PubMed: 38808557
DOI: 10.7555/JBR.37.20230320 -
Proceedings. Biological Sciences May 2024The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and...
The ambient daylight variation is coded by melanopsin photoreceptors and their luxotonic activity increases towards midday when colour temperatures are cooler, and irradiances are higher. Although melanopsin and cone photoresponses can be mediated via separate pathways, the connectivity of melanopsin cells across all levels of the retina enables them to modify cone signals. The downstream effects of melanopsin-cone interactions on human vision are however, incompletely understood. Here, we determined how the change in daytime melanopsin activation affects the human cone pathway signals in the visual cortex. A 5-primary silent-substitution method was developed to evaluate the dependence of cone-mediated signals on melanopsin activation by spectrally tuning the lights and stabilizing the rhodopsin activation under a constant cone photometric luminance. The retinal (white noise electroretinogram) and cortical responses (visual evoked potential) were simultaneously recorded with the photoreceptor-directed lights in 10 observers. By increasing the melanopsin activation, a reverse response pattern was observed with cone signals being supressed in the retina by 27% ( = 0.03) and subsequently amplified by 16% ( = 0.01) as they reach the cortex. We infer that melanopsin activity can amplify cone signals at sites distal to retinal bipolar cells to cause a decrease in the psychophysical Weber fraction for cone vision.
Topics: Humans; Rod Opsins; Retinal Cone Photoreceptor Cells; Visual Cortex; Adult; Electroretinography; Evoked Potentials, Visual; Female; Male; Young Adult; Photic Stimulation
PubMed: 38808443
DOI: 10.1098/rspb.2023.2708 -
Clinical Interventions in Aging 2024Age-related macular degeneration (AMD) is a degenerative ocular disease primarily affecting central vision in the elderly. Its pathogenesis is complex, involving... (Review)
Review
Age-related macular degeneration (AMD) is a degenerative ocular disease primarily affecting central vision in the elderly. Its pathogenesis is complex, involving cellular senescence and immune homeostasis dysregulation. This review investigates the interaction between these two critical biological processes in AMD pathogenesis and their impact on disease progression. Initially, cellular senescence is analyzed, with particular emphasis on retinal damage induced by senescent retinal pigment epithelial cells. Subsequently, the occurrence of immune homeostasis dysregulation within the retina and its mechanistic role in AMD areis explored. Furthermore, the paper also discusses in detail the interplay between cellular senescence and immune responses, forming a vicious cycle that exacerbates retinal damage and may influence treatment outcomes. In summary, a deeper understanding of the interrelation between cellular senescence and immune dysregulation is vital for the developing innovative therapeutic strategies for AMD.
Topics: Humans; Macular Degeneration; Cellular Senescence; Homeostasis; Retinal Pigment Epithelium; Disease Progression; Retina
PubMed: 38807637
DOI: 10.2147/CIA.S463297