The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch's membrane and the choriocapillaris on its ...basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.
Oxidative stress has been hypothesized to contribute to the development of age-related macular degeneration (AMD), the most common cause of blindness in the United States. At present, there is no ...treatment for early disease. Reactive oxygen species (ROS) play a physiological role in the retinal pigment epithelium (RPE), a key cell type in this disease, but with excessive ROS, oxidative damage or excessive innate immune system activation can result. The RPE has developed a robust antioxidant system driven by the transcription factor Nrf2. Impaired Nrf2 signaling can lead to oxidative damage or activate the innate immune response, both of which can lead to RPE apoptosis, a defining change in AMD. Several mouse models simulating environmental stressors or targeting specific antioxidant enzymes such as superoxide dismutase or Nrf2, have simulated some of the features of AMD. While ROS are short-lived, oxidatively damaged molecules termed oxidation specific epitopes (OSEs), can be long-lived and a source of chronic stress that activates the innate immune system through pattern recognition receptors (PRRs). The macula accumulates a number of OSEs including carboxyethylpyrrole, malondialdehyde, 4-hydroxynonenal, and advanced glycation endproducts, as well as their respective neutralizing PRRs. Excessive accumulation of OSEs results in pathologic immune activation. For example, mice immunized with the carboxyethylpyrrole develop cardinal features of AMD. Regulating ROS in the RPE by modulating antioxidant systems or neutralizing OSEs through an appropriate innate immune response are potential modalities to treat or prevent early AMD.
Age-related macular degeneration, the leading cause of irreversible visual loss among older adults in developed countries, is a chronic, multifactorial, and progressive disease with the development ...of painless, central vision loss. Retinal pigment epithelial cell dysfunction is a core change in age-related macular degeneration that results from aging and the accumulated effects of genetic and environmental factors that, in part, is both caused by and leads to oxidative stress. In this review, we describe the role of oxidative stress, the cytoprotective oxidative stress pathways, and the impact of oxidative stress on critical cellular processes involved in age-related macular degeneration pathobiology. We also offer targeted therapy that may define how antioxidant therapy can either prevent or improve specific stages of age-related macular degeneration.
•No treatment is available for early, dry age-related macular degeneration (AMD).•The retinal pigment epithelium is a major cell type involved in AMD pathobiology.•Oxidative stress is a known pathogenic factor, but its exact role is unclear.•Oxidative stress influences multiple processes of the RPE involved in AMD.•Antioxidants offer therapeutic potential for early AMD.
Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or "wet" form of AMD, no ...therapy is successful for the non-neovascular or "dry" form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.
Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly in western societies. While antioxidant micronutrient treatment is available for intermediate ...non-neovascular disease, and effective anti-vascular endothelial growth factor treatment is available for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. The role of lipids, which accumulate in the macula, and their oxidation, has emerged as an important factor in disease development. These oxidized lipids can either directly contribute to tissue injury or react with amine on proteins to form oxidation-specific epitopes, which can induce an innate immune response. If inadequately neutralized, the inflammatory response from these epitopes can incite tissue injury during disease development. This review explores how the accumulation of lipids, their oxidation, and the ensuing inflammatory response might contribute to the pathogenesis of AMD. This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder .
•Lipoprotein and lipid accumulation in the macula play an essential role in Age-related Macular Degeneration.•These lipids become oxidized and can induce tissue injuring inflammation unless neutralized by innate immunity.•Oxidized lipids form adducts, or oxidation-specific epitopes that can cause tissue injuring inflammation unless neutralized.
As a signaling hub, p62/sequestosome plays important roles in cell signaling and degradation of misfolded proteins. p62 has been implicated as an adaptor protein to mediate autophagic clearance of ...insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD), which is characterized by dysfunction of the retinal pigment epithelium (RPE). Our previous studies have shown that cigarette smoke (CS) induces oxidative stress and inhibits the proteasome pathway in cultured human RPE cells, suggesting that p62-mediated autophagy may become the major route to remove impaired proteins under such circumstances. In the present studies, we found that all p62 mRNA variants are abundantly expressed and upregulated by CS induced stress in cultured human RPE cells, yet isoform1 is the major translated form. We also show that p62 silencing exacerbated the CS induced accumulation of damaged proteins, both by suppressing autophagy and by inhibiting the Nrf2 antioxidant response, which in turn, increased protein oxidation. These effects of CS and p62 reduction were further confirmed in mice exposed to CS. We found that over-expression of p62 isoform1, but not its S403A mutant, which lacks affinity for ubiquitinated proteins, reduced misfolded proteins, yet simultaneously promoted an Nrf2-mediated antioxidant response. Thus, p62 provides dual, reciprocal enhancing protection to RPE cells from environmental stress induced protein misfolding and aggregation, by facilitating autophagy and the Nrf2 mediated antioxidant response, which might be a potential therapeutic target against AMD.
•p62 mRNA variants are expressed by RPE cells.•p62 isoform2 is not translated, but regulates isoform1 abundance with stress.•p62 has dual, reciprocal enhancing protection through its different binding domains.
Age-related macular degeneration (AMD) represents the leading cause of blindness in the elderly, yet no definitive therapy exists for early, dry disease. Several lines of evidence have implicated ...oxidative stress-induced damage to the retinal pigment epithelium (RPE) in the pathogenesis of AMD, suggesting that the aging RPE may exhibit increased susceptibility to cell damage induced by exogenous stressors. The transcription factor Nrf2 serves as the master regulator of a highly coordinated antioxidant response in virtually all cell types. We compared Nrf2 signaling in the RPE of young (2 months) and old (15 months) mice under unstressed and stressed (sodium iodate) conditions. The aging RPE expressed higher levels of the Nrf2 target genes NQO1, GCLM, and HO1 compared with the RPE of younger mice under unstressed conditions, suggesting an age-related increase in basal oxidative stress. Moreover, the RPE of older mice demonstrated impaired induction of the protective Nrf2 pathway following oxidative stress induced with sodium iodate. The RPE of old mice exposed to sodium iodate also exhibited higher levels of superoxide anion and malondialdehyde than young mice, suggesting inadequate protection against oxidative damage. Induction of Nrf2 signaling in response to sodium iodate was partially restored in the RPE of aging mice with genetic rescue, using conditional knockdown of the Nrf2 negative regulator Keap1 (Tam-Cre; Keap1loxP) compared to Keap1loxP mice. These data indicate that the aging RPE is vulnerable to oxidative damage due to impaired Nrf2 signaling, and that Nrf2 signaling is a promising target for novel pharmacologic or genetic therapeutic strategies.
•Nrf2 mediated transcription by the RPE of young and old mice was compared.•Aging RPE had elevated superoxide and malondialdehyde after sodium iodide compared to young RPE.•Aging RPE expressed higher basal levels of NQO1, GCLM, and HO1 than young RPE.•Aging RPE exhibited impaired induction of NQO1, GCLM, and HO1 after sodium iodide.•Genetic rescue by Keap1 knockdown in old mice restored NQO1 expression in the RPE.
The accumulation of lipids within drusen, the epidemiologic link of a high fat diet, and the identification of polymorphisms in genes involved in lipid metabolism that are associated with disease ...risk, have prompted interest in the role of lipid abnormalities in AMD. Despite intensive investigation, our understanding of how lipid abnormalities contribute to AMD development remains unclear. Lipid metabolism is tightly regulated, and its dysregulation can trigger excess lipid accumulation within the RPE and Bruch's membrane. The high oxidative stress environment of the macula can promote lipid oxidation, impairing their original function as well as producing oxidation-specific epitopes (OSE), which unless neutralized, can induce unwanted inflammation that additionally contributes to AMD progression. Considering the multiple layers of lipid metabolism and inflammation, and the ability to simultaneously target multiple pathways, microRNA (miRNAs) have emerged as important regulators of many age-related diseases including atherosclerosis and Alzheimer's disease. These diseases have similar etiologic characteristics such as lipid-rich deposits, oxidative stress, and inflammation with AMD, which suggests that miRNAs might influence lipid metabolism in AMD. In this review, we discuss the contribution of lipids to AMD pathobiology and introduce how miRNAs might affect lipid metabolism during lesion development. Establishing how miRNAs contribute to lipid accumulation in AMD will help to define the role of lipids in AMD, and open new treatment avenues for this enigmatic disease.
•Lipids accumulate in the macula in AMD.•Oxidative stress oxidizes lipids.•Oxidized lipids can damage tissue and induce innate immunity.•MicroRNAs are important regulators of lipid metabolism.•This review discusses how microRNAs might regulate lipid metabolism in AMD.
Robotic Vitreoretinal Surgery Channa, Roomasa; Iordachita, Iulian; Handa, James T
Retina (Philadelphia, Pa.)
37, Številka:
7
Journal Article
Recenzirano
Odprti dostop
To review the current literature on robotic assistance for ophthalmic surgery, especially vitreoretinal procedures.
MEDLINE, Embase, and Web of Science databases were searched from inception to ...August, 2016, for articles relevant to the review topic. Queries included combinations of the terms: robotic eye surgery, ophthalmology, and vitreoretinal.
In ophthalmology, proof-of-concept papers have shown the feasibility of performing many delicate anterior segment and vitreoretinal surgical procedures accurately with robotic assistance. Multiple surgical platforms have been designed and tested in animal eyes and phantom models. These platforms have the capability to measure forces generated and velocities of different surgical movements. "Smart" instruments have been designed to improve certain tasks such as membrane peeling and retinal vessel cannulations.
Ophthalmic surgery, particularly vitreoretinal surgery, might have reached the limits of human physiologic performance. Robotic assistance can help overcome biologic limitations and improve our surgical performance. Clinical studies of robotic-assisted surgeries are needed to determine safety and feasibility of using this technology in patients.
Lysosomes in retinal health and disease Boya, Patricia; Kaarniranta, Kai; Handa, James T ...
Trends in neurosciences (Regular ed.),
12/2023, Letnik:
46, Številka:
12
Journal Article
Recenzirano
Lysosomes play crucial roles in various cellular processes - including endocytosis, phagocytosis, and autophagy - which are vital for maintaining retinal health. Moreover, these organelles serve as ...environmental sensors and act as central hubs for multiple signaling pathways. Through communication with other cellular components, such as mitochondria, lysosomes orchestrate the cytoprotective response essential for preserving cellular homeostasis. This coordination is particularly critical in the retina, given its high metabolic rate and susceptibility to photo-oxidative stress. Consequently, impaired lysosomal function and dysregulated communication between lysosomes and other organelles contribute significantly to the pathobiology of major retinal degenerative diseases. This review explores the pivotal role of lysosomes in retinal cells and their involvement in retinal degenerative diseases.
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