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1
Jadeja, Ravirajsinh N., and Pamela M. Martin. "Oxidative Stress and Inflammation in Retinal Degeneration." Antioxidants 10, no. 5 (May 17, 2021): 790. http://dx.doi.org/10.3390/antiox10050790.
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Inflammation and oxidative stress play prominent roles in the pathogenesis of many degenerative diseases of the retina, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion, and retinitis pigmentosa [...]
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Napoli, Debora, Martina Biagioni, Federico Billeri, Beatrice Di Marco, Noemi Orsini, Elena Novelli, and Enrica Strettoi. "Retinal Pigment Epithelium Remodeling in Mouse Models of Retinitis Pigmentosa." International Journal of Molecular Sciences 22, no. 10 (May 20, 2021): 5381. http://dx.doi.org/10.3390/ijms22105381.
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In retinitis pigmentosa (RP), one of many possible genetic mutations causes rod degeneration, followed by cone secondary death leading to blindness. Accumulating evidence indicates that rod death triggers multiple, non-cell-autonomous processes, which include oxidative stress and inflammation/immune responses, all contributing to cone demise. Inflammation relies on local microglia and recruitment of immune cells, reaching the retina through breakdowns of the inner blood retinal barrier (iBRB). Leakage in the inner retina vasculature suggests similarly altered outer BRB, formed by junctions between retinal pigment epithelium (RPE) cells, which are crucial for retinal homeostasis, immune response, and privilege. We investigated the RPE structural integrity in three models of RP (rd9, rd10, and Tvrm4 mice) by immunostaining for zonula occludens-1 (ZO-1), an essential regulatory component of tight junctions. Quantitative image analysis demonstrated discontinuities in ZO-1 profiles in all mutants, despite different degrees of photoreceptor loss. ZO-1 interruption zones corresponded to leakage of in vivo administered, fluorescent dextran through the choroid-RPE interface, demonstrating barrier dysfunction. Dexamethasone, administered to rd10 mice for rescuing cones, also rescued RPE structure. Thus, previously undetected, stereotyped abnormalities occur in the RPE of RP mice; pharmacological targeting of inflammation supports a feedback loop leading to simultaneous protection of cones and the RPE.
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Karlen, Sarah J., Eric B. Miller, and Marie E. Burns. "Microglia Activation and Inflammation During the Death of Mammalian Photoreceptors." Annual Review of Vision Science 6, no. 1 (September 15, 2020): 149–69. http://dx.doi.org/10.1146/annurev-vision-121219-081730.
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Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.
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Gallenga, Carla Enrica, Maria Lonardi, Sofia Pacetti, Sara Silvia Violanti, Paolo Tassinari, Francesco Di Virgilio, Mauro Tognon, and Paolo Perri. "Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa." Antioxidants 10, no. 6 (May 26, 2021): 848. http://dx.doi.org/10.3390/antiox10060848.
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Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor’s daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.
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Viringipurampeer, Ishaq A., Abu E. Bashar, Cheryl Y. Gregory-Evans, Orson L. Moritz, and Kevin Gregory-Evans. "Targeting Inflammation in Emerging Therapies for Genetic Retinal Disease." International Journal of Inflammation 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/581751.
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Genetic retinal diseases such as age-related macular degeneration and monogenic diseases such as retinitis pigmentosa account for some of the commonest causes of blindness in the developed world. Diverse genetic abnormalities and environmental causes have been implicated in triggering multiple pathological mechanisms such as oxidative stress, lipofuscin deposits, neovascularisation, and programmed cell death. In recent years, inflammation has also been highlighted although whether inflammatory mediators play a central role in pathogenesis or a more minor secondary role has yet to be established. Despite this, numerous interventional studies, particularly targeting the complement system, are underway with the promise of novel therapeutic strategies for these important blinding conditions.
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Woude, Logan Vander, Ramak Roohipour, and Gibran Syed Khurshid. "Phthisis Bulbi in a Retinitis Pigmentosa Patient after Argus II Implantation." Case Reports in Ophthalmological Medicine 2020 (August 17, 2020): 1–4. http://dx.doi.org/10.1155/2020/5608058.
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Purpose. To report a previously unreported complication of phthisis after Argus II prosthesis implantation in a retinitis pigmentosa (RP) patient. Case. A 61-year-old male with advanced RP presented to the retina clinic. The patient had a history of vitrectomy in both eyes (OU) in Cuba in 1996. Pre-op visual acuity (VA) was no light perception (NLP) in the right eye and light perception (LP) in the left eye. The patient met the criteria for Argus II implantation and elected to proceed with surgery in his left eye in December 2017. The surgical implantation of the Argus II was successful without any complications. On postoperative day 1, his VA was stable at LP. He was satisfied with his ambulatory vision after the electrodes were turned on. Four months after surgery, the patient was complaining of aching pain; he was found to have preseptal cellulitis and was started on antibiotics. This swelling improved over two weeks, but when the patient returned, he had a two mm hyphema associated with mild ocular inflammation without an inciting event or reason on exam. The hyphema was treated and resolved after two weeks. However, one month after the hyphema resolved, at postoperative month six, the patient’s vision in his left eye became NLP and began to demonstrate phthisical changes, including hypotony, Descemet membrane folds, and a vascular posterior capsular membrane. Discussion. The theoretical causes of phthisis bulbi after Argus II implantation include fibrous downgrowth, ciliary shut down due to immune reaction, inflammation, or trauma. While the cause of phthisis in this Argus patient is not certain and possibly multifactorial, it is important to note that phthisis is a possible complication of an Argus II implant, as this patient had no other obvious insult or reason for the phthisical change.
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Hong, Yingying, Hongzhe Li, Yang Sun, and Yinghong Ji. "A Review of Complicated Cataract in Retinitis Pigmentosa: Pathogenesis and Cataract Surgery." Journal of Ophthalmology 2020 (December 21, 2020): 1–14. http://dx.doi.org/10.1155/2020/6699103.
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Retinitis pigmentosa (RP) is a set of inherited retinal degenerative diseases that affect photoreceptor and retinal pigment epithelial cells (RPEs), possibly associated with some ocular complications, including cataract. The complicated cataract formation is most likely the result of RP-related inflammation response, and the most common morphology category is posterior subcapsular cataract (PSC). Despite the absence of curative pharmacologic treatment, phacoemulsification with intraocular lens implantation to deal with opacification in the lens is preferred due to the considerable visual outcomes. However, the incidence of intraocular and postoperative complications is higher in RP patients than those without, including intraoperative phototoxic retinal damage, posterior capsular opacification (PCO), capsular contraction syndrome (CCS), pseudophakic cystoid macular edema (PCME), increased postoperative intraocular pressure (IOP), and intraocular lens (IOL) dislocation. Hence, it needs much attention to surgery progress and close follow-up. In this review, we discuss the current understanding of RP patients with complicated cataracts from morphology to potential pathogenesis to cataract surgical procedure and provide a concise description and the recommended management of related surgery complications to broaden the knowledge and lower the latent risks to yield better clinical outcomes.
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Cantó, Antolín, Javier Martínez-González, Inmaculada Almansa, Rosa López-Pedrajas, Vicente Hernández-Rabaza, Teresa Olivar, and María Miranda. "Time-Course Changes in Oxidative Stress and Inflammation in the Retinas of rds Mice: A Retinitis Pigmentosa Model." Antioxidants 11, no. 10 (September 29, 2022): 1950. http://dx.doi.org/10.3390/antiox11101950.
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(1) Background: Retinitis pigmentosa (RP) is characterized by progressive photoreceptor death. A Prph2Rd2 or an rds mouse is an RP model that closely reflects human RP. The objective of this study was to investigate the relationship of rod and cone death with oxidative stress and inflammation in rds mice. (2) Methods: The retinas of control and rds mice on postnatal days (PN) 11, 17, 21, 28, 35, and 42 were used. Oxidative damage to macromolecules, glutathione (GSH and GSSG), GSH synthesis enzymes, glial fibrillar acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), and cluster of differentiation 68 (CD68) was studied. (3) Results: The time sequence of oxidative stress and inflammation changes in rds mice occurs as follows: (i) At PN11, there is a small increase in photoreceptor death and in the microglial cells; (ii) at PN17, damage to the macromolecules is observed; (iii) at PN21, the maximum photoreceptor death rate is detected and there is an increase in GSH-GSSG and GFAP; (iv) at PN21, the microglial cells are activated; and(v) at PN28, there is a decrease in GSH synthesis enzymes. (4) Conclusions: These findings contribute to the understanding of RP physiopathology and help us to understand whether oxidative stress and inflammation are therapeutic targets. These findings contribute to our understanding that, in RP, oxidative stress and inflammation evolution and their relationship are time-dependent. In this sense, it is important to highlight that both processes are potential therapeutic targets in this disease.
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Li, Xing, Reem Hasaballah Alhasani, Yanqun Cao, Xinzhi Zhou, Zhiming He, Zhihong Zeng, Niall Strang, and Xinhua Shu. "Gypenosides Alleviate Cone Cell Death in a Zebrafish Model of Retinitis Pigmentosa." Antioxidants 10, no. 7 (June 29, 2021): 1050. http://dx.doi.org/10.3390/antiox10071050.
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Retinitis pigmentosa (RP) is a group of visual disorders caused by mutations in over 70 genes. RP is characterized by initial degeneration of rod cells and late cone cell death, regardless of genetic abnormality. Rod cells are the main consumers of oxygen in the retina, and after the death of rod cells, the cone cells have to endure high levels of oxygen, which in turn leads to oxidative damage and cone degeneration. Gypenosides (Gyp) are major dammarane-type saponins of Gynostemma pentaphyllum that are known to reduce oxidative stress and inflammation. In this project we assessed the protective effect of Gyp against cone cell death in the rpgrip1 mutant zebrafish, which recapitulate the classical pathological features found in RP patients. Rpgrip1 mutant zebrafish were treated with Gyp (50 µg/g body weight) from two-months post fertilization (mpf) until 6 mpf. Gyp treatment resulted in a significant decrease in cone cell death compared to that of untreated mutant zebrafish. A markedly low level of reactive oxygen species and increased expression of antioxidant genes were detected in Gyp-incubated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Similarly, the activities of catalase and superoxide dismutase and the level of glutathione were significantly increased in Gyp-treated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Gyp treatment also decreased endoplasmic reticulum stress in rpgrip1 mutant eyes. Expression of proinflammatory cytokines was also significantly decreased in Gyp-treated mutant zebrafish eyes compared to that of untreated mutant zebrafish. Network pharmacology analysis demonstrated that the promotion of cone cell survival by Gyp is possibly mediated by multiple hub genes and associated signalling pathways. These data suggest treatment with Gyp will benefit RP patients.
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Olivares-González, Lorena, Sheyla Velasco, Isabel Campillo, and Regina Rodrigo. "Retinal Inflammation, Cell Death and Inherited Retinal Dystrophies." International Journal of Molecular Sciences 22, no. 4 (February 20, 2021): 2096. http://dx.doi.org/10.3390/ijms22042096.
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Inherited retinal dystrophies (IRDs) are a group of retinal disorders that cause progressive and severe loss of vision because of retinal cell death, mainly photoreceptor cells. IRDs include retinitis pigmentosa (RP), the most common IRD. IRDs present a genetic and clinical heterogeneity that makes it difficult to achieve proper treatment. The progression of IRDs is influenced, among other factors, by the activation of the immune cells (microglia, macrophages, etc.) and the release of inflammatory molecules such as chemokines and cytokines. Upregulation of tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, is found in IRDs. This cytokine may influence photoreceptor cell death. Different cell death mechanisms are proposed, including apoptosis, necroptosis, pyroptosis, autophagy, excessive activation of calpains, or parthanatos for photoreceptor cell death. Some of these cell death mechanisms are linked to TNFα upregulation and inflammation. Therapeutic approaches that reduce retinal inflammation have emerged as useful therapies for slowing down the progression of IRDs. We focused this review on the relationship between retinal inflammation and the different cell death mechanisms involved in RP. We also reviewed the main anti-inflammatory therapies for the treatment of IRDs.
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Kaur, Geetika, and Nikhlesh K. Singh. "The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases." International Journal of Molecular Sciences 23, no. 1 (December 30, 2021): 386. http://dx.doi.org/10.3390/ijms23010386.
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Retinal neurodegeneration is predominantly reported as the apoptosis or impaired function of the photoreceptors. Retinal degeneration is a major causative factor of irreversible vision loss leading to blindness. In recent years, retinal degenerative diseases have been investigated and many genes and genetic defects have been elucidated by many of the causative factors. An enormous amount of research has been performed to determine the pathogenesis of retinal degenerative conditions and to formulate the treatment modalities that are the critical requirements in this current scenario. Encouraging results have been obtained using gene therapy. We provide a narrative review of the various studies performed to date on the role of inflammation in human retinal degenerative diseases such as age-related macular degeneration, inherited retinal dystrophies, retinitis pigmentosa, Stargardt macular dystrophy, and Leber congenital amaurosis. In addition, we have highlighted the pivotal role of various inflammatory mechanisms in the progress of retinal degeneration. This review also offers an assessment of various therapeutic approaches, including gene-therapies and stem-cell-based therapies, for degenerative retinal diseases.
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Proulx, Caroline, Jinqiang Zhang, David Sabatino, Sylvain Chemtob, Huy Ong, and William D. Lubell. "Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)." Biomedicines 8, no. 8 (July 23, 2020): 241. http://dx.doi.org/10.3390/biomedicines8080241.
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The innovative development of azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) has produced selective modulators of the cluster of differentiation 36 receptor (CD36). The azapeptide CD36 modulators curb macrophage-driven inflammation and mitigate atherosclerotic and angiogenic pathology. In macrophages activated with Toll-like receptor-2 heterodimer agonist, they reduced nitric oxide production and proinflammatory cytokine release. In a mouse choroidal explant microvascular sprouting model, they inhibited neovascularization. In murine models of cardiovascular injury, CD36-selective azapeptide modulators exhibited cardioprotective and anti-atherosclerotic effects. In subretinal inflammation models, they altered activated mononuclear phagocyte metabolism and decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury associated with retinitis pigmentosa, diabetic retinopathy and age-related macular degeneration. The translation of GHRP-6 to potent and selective linear and cyclic azapeptide modulators of CD36 is outlined in this review which highlights the relevance of turn geometry for activity and the biomedical potential of prototypes for the beneficial treatment of a wide range of cardiovascular, metabolic and immunological disorders.
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Ortega, Joseph Thomas, and Beata Jastrzebska. "Neuroinflammation as a Therapeutic Target in Retinitis Pigmentosa and Quercetin as Its Potential Modulator." Pharmaceutics 13, no. 11 (November 16, 2021): 1935. http://dx.doi.org/10.3390/pharmaceutics13111935.
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The retina is a multilayer neuronal tissue located in the back of the eye that transduces the environmental light into a neural impulse. Many eye diseases caused by endogenous or exogenous harm lead to retina degeneration with neuroinflammation being a major hallmark of these pathologies. One of the most prevalent retinopathies is retinitis pigmentosa (RP), a clinically and genetically heterogeneous hereditary disorder that causes a decline in vision and eventually blindness. Most RP cases are related to mutations in the rod visual receptor, rhodopsin. The mutant protein triggers inflammatory reactions resulting in the activation of microglia to clear degenerating photoreceptor cells. However, sustained insult caused by the abnormal genetic background exacerbates the inflammatory response and increases oxidative stress in the retina, leading to a decline in rod photoreceptors followed by cone photoreceptors. Thus, inhibition of inflammation in RP has received attention and has been explored as a potential therapeutic strategy. However, pharmacological modulation of the retinal inflammatory response in combination with rhodopsin small molecule chaperones would likely be a more advantageous therapeutic approach to combat RP. Flavonoids, which exhibit antioxidant and anti-inflammatory properties, and modulate the stability and folding of rod opsin, could be a valid option in developing treatment strategies against RP.
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Nagasaka, Yosuke, Yasuki Ito, Shinji Ueno, and Hiroko Terasaki. "Number of Hyperreflective Foci in the Outer Retina Correlates with Inflammation and Photoreceptor Degeneration in Retinitis Pigmentosa." Ophthalmology Retina 2, no. 7 (July 2018): 726–34. http://dx.doi.org/10.1016/j.oret.2017.07.020.
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Karska-Basta, Izabella, Bożena Romanowska-Dixon, Dorota Pojda-Wilczek, and Natalia Mackiewicz. "Ocular Toxoplasmosis Associated with Unilateral Pigmentary Retinopathy That May Mimic Retinitis Pigmentosa: Diagnostic Dilemmas." Medicina 57, no. 9 (August 27, 2021): 892. http://dx.doi.org/10.3390/medicina57090892.
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We report a unique case of coexisting pigmentary retinopathy and ocular toxoplasmosis in a young male patient. A 23-year-old man presented with sudden visual deterioration in the left eye (LE). The fundus findings revealed bone spicule-shaped pigment deposits, a slightly pale optic disc, arteriole constriction, cystoid macular edema with an epiretinal membrane, and two small inflammatory chorioretinal scars in the right eye, with a concentric narrowing of the visual field and a nonrecordable multifocal electroretinogram (ERG). An active inflammatory lesion at the border of a pre-existing chorioretinal scar in the macula was found in the LE, with a central scotoma in the visual field. Moreover, the patient tested positive for anti-Toxoplasma gondii immunoglobulin G antibodies and showed positive results in polymerase chain reaction testing of aqueous humor. Fluorescein angiography revealed hyperfluorescence in the early phase with fluorescein leakage. A multifocal ERG of the LE showed selective loss of responses from the central 10 degrees. Genetic testing revealed heterozygosity in the RP1 and CELSR1 genes. Our case illustrates challenges in the diagnosis of unilateral pigmentary retinopathy. Based on the typical toxoplasmic lesions in the LE and two scars likely caused by inflammation, our patient was diagnosed with pigmentary retinopathy probably related to toxoplasmosis. Genetic consultation did not confirm the diagnosis of retinitis pigmentosa, but more advanced tests might be needed to definitively exclude it.
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Chen, Sheng, Guo Liu, Xin Liu, Yun Wang, Fen He, Danyao Nie, Xinhua Liu, and Xuyang Liu. "RNA-seq analysis reveals differentially expressed inflammatory chemokines in a rat retinal degeneration model induced by sodium iodate." Journal of International Medical Research 50, no. 8 (August 2022): 030006052211193. http://dx.doi.org/10.1177/03000605221119376.
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Objective Retinal degeneration (RD) is a group of serious blinding eye diseases characterized by photoreceptor cell apoptosis and progressive degeneration of retinal neurons. However, the underlying mechanism of its pathogenesis remains unclear. Methods In this study, retinal tissues from sodium iodate (NaIO3)-induced RD and control rats were collected for transcriptome analysis using RNA-sequencing (RNA-seq). Analysis of white blood cell-related parameters was conducted in patients with retinitis pigmentosa (RP) and age-related cataract (ARC) patients. Results In total, 334 mRNAs, 77 long non-coding RNAs (lncRNAs), and 20 other RNA types were identified as differentially expressed in the retinas of NaIO3-induced RD rats. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that differentially expressed mRNAs were mainly enriched in signaling pathways related to immune inflammation. Moreover, we found that the neutrophil-to-lymphocyte ratio was significantly higher in RP patients than in ARC patients. Conclusion Overall, this study suggests that multiple chemokines participating in systemic inflammation may contribute to RD pathogenesis.
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Choudhary, Mayur, and Goldis Malek. "Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases." Journal of Biomolecular Screening 21, no. 10 (July 28, 2016): 1007–18. http://dx.doi.org/10.1177/1087057116659856.
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Collectively, retinal diseases, including age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy, result in severe vision impairment worldwide. The absence and/or limited availability of successful drug therapies for these blinding disorders necessitates further understanding their pathobiology and identifying new targetable signaling pathways. Nuclear receptors are transcription regulators of many key aspects of human physiology, as well as pathophysiology, with reported roles in development, aging, and disease. Some of the pathways regulated by nuclear receptors include, but are not limited to, angiogenesis, inflammation, and lipid metabolic dysregulation, mechanisms also important in the initiation and development of several retinal diseases. Herein, we present an overview of the biology of three diseases affecting the posterior eye, summarize a growing body of evidence that suggests direct or indirect involvement of nuclear receptors in disease progression, and discuss the therapeutic potential of targeting nuclear receptors for treatment.
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Shu, Wanting, and Joshua Dunaief. "Potential Treatment of Retinal Diseases with Iron Chelators." Pharmaceuticals 11, no. 4 (October 22, 2018): 112. http://dx.doi.org/10.3390/ph11040112.
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Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.
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Olivares-González, Lorena, Sheyla Velasco, Idoia Gallego, Marina Esteban-Medina, Gustavo Puras, Carlos Loucera, Alicia Martínez-Romero, María Peña-Chilet, José Luis Pedraz, and Regina Rodrigo. "An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in rd10 Mice." Antioxidants 12, no. 1 (December 30, 2022): 98. http://dx.doi.org/10.3390/antiox12010098.
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Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in rd10 mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in rd10 mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.
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Morita, Yuji, Yukihiro Miwa, Kenta Jounai, Daisuke Fujiwara, Toshihide Kurihara, and Osamu Kanauchi. "Lactobacillus paracasei KW3110 Prevents Blue Light-Induced Inflammation and Degeneration in the Retina." Nutrients 10, no. 12 (December 15, 2018): 1991. http://dx.doi.org/10.3390/nu10121991.
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Age-related macular degeneration and retinitis pigmentosa are leading causes of blindness and share a pathological feature, which is photoreceptor degeneration. To date, the lack of a potential treatment to prevent such diseases has raised great concern. Photoreceptor degeneration can be accelerated by excessive light exposure via an inflammatory response; therefore, anti-inflammatory agents would be candidates to prevent the progress of photoreceptor degeneration. We previously reported that a lactic acid bacterium, Lactobacillus paracasei KW3110 (L. paracasei KW3110), activated macrophages suppressing inflammation in mice and humans. Recently, we also showed that intake of L. paracasei KW3110 could mitigate visual display terminal (VDT) load-induced ocular disorders in humans. However, the biological mechanism of L. paracasei KW3110 to retain visual function remains unclear. In this study, we found that L. paracasei KW3110 activated M2 macrophages inducing anti-inflammatory cytokine interleukin-10 (IL-10) production in vitro using bone marrow-derived M2 macrophages. We also show that IL-10 gene expression was significantly increased in the intestinal immune tissues 6 h after oral administration of L. paracasei KW3110 in vivo. Furthermore, we demonstrated that intake of L. paracasei KW3110 suppressed inflammation and photoreceptor degeneration in a murine model of light-induced retinopathy. These results suggest that L. paracasei KW3110 may have a preventive effect against degrative retinal diseases.
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Idelfonso-García, Osiris Germán, Brisa Rodope Alarcón-Sánchez, Verónica Rocío Vásquez-Garzón, Rafael Baltiérrez-Hoyos, Saúl Villa-Treviño, Pablo Muriel, Héctor Serrano, Julio Isael Pérez-Carreón, and Jaime Arellanes-Robledo. "Is Nucleoredoxin a Master Regulator of Cellular Redox Homeostasis? Its Implication in Different Pathologies." Antioxidants 11, no. 4 (March 30, 2022): 670. http://dx.doi.org/10.3390/antiox11040670.
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Nucleoredoxin (NXN), an oxidoreductase enzyme, contributes to cellular redox homeostasis by regulating different signaling pathways in a redox-dependent manner. By interacting with seven proteins so far, namely disheveled (DVL), protein phosphatase 2A (PP2A), phosphofructokinase-1 (PFK1), translocation protein SEC63 homolog (SEC63), myeloid differentiation primary response gene-88 (MYD88), flightless-I (FLII), and calcium/calmodulin-dependent protein kinase II type alpha (CAMK2A), NXN is involved in the regulation of several key cellular processes, including proliferation, organogenesis, cell cycle progression, glycolysis, innate immunity and inflammation, motility, contraction, protein transport into the endoplasmic reticulum, neuronal plasticity, among others; as a result, NXN has been implicated in different pathologies, such as cancer, alcoholic and polycystic liver disease, liver fibrogenesis, obesity, Robinow syndrome, diabetes mellitus, Alzheimer’s disease, and retinitis pigmentosa. Together, this evidence places NXN as a strong candidate to be a master redox regulator of cell physiology and as the hub of different redox-sensitive signaling pathways and associated pathologies. This review summarizes and discusses the current insights on NXN-dependent redox regulation and its implication in different pathologies.
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Moore, Spencer M., and John B. Christoforidis. "Advances in Ophthalmic Epigenetics and Implications for Epigenetic Therapies: A Review." Genes 14, no. 2 (February 5, 2023): 417. http://dx.doi.org/10.3390/genes14020417.
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The epigenome represents a vast molecular apparatus that writes, reads, and erases chemical modifications to the DNA and histone code without changing the DNA base-pair sequence itself. Recent advances in molecular sequencing technology have revealed that epigenetic chromatin marks directly mediate critical events in retinal development, aging, and degeneration. Epigenetic signaling regulates retinal progenitor (RPC) cell cycle exit during retinal laminar development, giving rise to retinal ganglion cells (RGCs), amacrine cells, horizontal cells, bipolar cells, photoreceptors, and Müller glia. Age-related epigenetic changes such as DNA methylation in the retina and optic nerve are accelerated in pathogenic conditions such as glaucoma and macular degeneration, but reversing these epigenetic marks may represent a novel therapeutic target. Epigenetic writers also integrate environmental signals such as hypoxia, inflammation, and hyperglycemia in complex retinal conditions such as diabetic retinopathy (DR) and choroidal neovascularization (CNV). Histone deacetylase (HDAC) inhibitors protect against apoptosis and photoreceptor degeneration in animal models of retinitis pigmentosa (RP). The epigenome represents an intriguing therapeutic target for age-, genetic-, and neovascular-related retinal diseases, though more work is needed before advancement to clinical trials.
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Terauchi, Ryo, Hideo Kohno, Sumiko Watanabe, Saburo Saito, Akira Watanabe, and Tadashi Nakano. "Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa." PLOS ONE 16, no. 4 (April 22, 2021): e0239108. http://dx.doi.org/10.1371/journal.pone.0239108.
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Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.
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Wang, Tiantian, Jingyu Yao, Lin Jia, Patrice E. Fort, and David N. Zacks. "Loss of αA or αB-Crystallin Accelerates Photoreceptor Cell Death in a Mouse Model of P23H Autosomal Dominant Retinitis Pigmentosa." International Journal of Molecular Sciences 23, no. 1 (December 22, 2021): 70. http://dx.doi.org/10.3390/ijms23010070.
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Inherited retinal degenerations (IRD) are a leading cause of visual impairment and can result from mutations in any one of a multitude of genes. Mutations in the light-sensing protein rhodopsin (RHO) is a leading cause of IRD with the most common of those being a missense mutation that results in substitution of proline-23 with histidine. This variant, also known as P23H-RHO, results in rhodopsin misfolding, initiation of endoplasmic reticulum stress, the unfolded protein response, and activation of cell death pathways. In this study, we investigate the effect of α-crystallins on photoreceptor survival in a mouse model of IRD secondary to P23H-RHO. We find that knockout of either αA- or αB-crystallin results in increased intraretinal inflammation, activation of apoptosis and necroptosis, and photoreceptor death. Our data suggest an important role for the ⍺-crystallins in regulating photoreceptor survival in the P23H-RHO mouse model of IRD.
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Olivares-González, Lorena, Sheyla Velasco, Isabel Campillo, David Salom, Emilio González-García, José Miguel Soriano del Castillo, and Regina Rodrigo. "Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice." Antioxidants 10, no. 7 (June 26, 2021): 1033. http://dx.doi.org/10.3390/antiox10071033.
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Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.
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Perdices, Lorena, Lorena Fuentes-Broto, Francisco Segura, Nicolás Cuenca, Elvira Orduna-Hospital, and Isabel Pinilla. "Epigallocatechin Gallate Slows Retinal Degeneration, Reduces Oxidative Damage, and Modifies Circadian Rhythms in P23H Rats." Antioxidants 9, no. 8 (August 8, 2020): 718. http://dx.doi.org/10.3390/antiox9080718.
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Retinitis pigmentosa (RP) includes a group of genetic disorders that involve the loss of visual function due to mutations mainly in photoreceptors but also in other retinal cells. Apoptosis, retinal disorganization, and inflammation are common in the progression of the disease. Epigallocatechin gallate (EGCG) has been proved as beneficial in different eye diseases. Pigmented heterozygous P23H rat was used as an animal model of RP. Visual function was assessed by optomotor and electroretinogram (ERG) and circadian rhythms were evaluated by telemetry. Hepatic oxidative damage and antioxidant defenses were assessed using biochemical tests. The visual function of the EGCG P23H group was preserved, with a deterioration in the activity period and lower values in the interdaily stability parameter. Control rats treated with EGCG were less active than the sham group. EGCG increased antioxidant levels in P23H rats but reduced total hepatic antioxidant capacity by almost 42% in control rats compared to the sham group. We conclude that treatment with EGCG improves visual function and antioxidant status in P23H rats but diminishes antioxidant defenses in wild-type control animals, and slightly worsens activity circadian rhythms. Further studies are necessary to clarify the beneficial effects in disease conditions and in healthy organisms.
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Alambiaga-Caravaca, Adrián M., Antolín Cantó, Vicent Rodilla, María Miranda, and Alicia López-Castellano. "Topical Ocular Administration of Progesterone Decreases Photoreceptor Cell Death in Retinal Degeneration Slow (rds) Mice." Pharmaceuticals 15, no. 3 (March 9, 2022): 328. http://dx.doi.org/10.3390/ph15030328.
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Retinitis pigmentosa (RP) is an inherited eye disorder which triggers a cascade of retinal disorders leading to photoreceptor cell death and for which there is currently no effective treatment. The purpose of this research was to study whether ocular administration of a solution of progesterone (PG) in β-cyclodextrins (CD) could delay photoreceptor cell death and counteract the gliosis process in an animal model of RP (rds mice). The possible effect of PG reaching the contralateral eye through the circulatory system was also evaluated. Finally, this research discusses and evaluates the diffusion of the drug from possible topical formulations for ocular administration of PG. A group of rds mice received one drop of a solution of PG in CD every 12 h for 10 days to the left eye, while the right eye was left untreated. Another group of rds mice (control) received the drug vehicle (PBS) on the left eye and, again, the right eye was left untreated. Once the treatment was finished on postnatal day 21, the animals were euthanized and histological immunofluorescence studies (TUNEL, GFAP, and DAPI staining) were carried out. Our results showed that the administration of a solution of PG in CD (CD-PG) as drops significantly decreased cell death and inflammation in the retina of the PG-treated eyes of rds mice. No effect was seen in the contralateral eye from PG that may have entered systemic circulation. In conclusion, CD-PG applied topically as drops to the eye decreases photoreceptor cell death in the early stages of RP, delaying vision loss and decreasing gliosis.
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Patel, R., A. Sallagonda, R. Florence, and L. West. "A New Insight Into Ectopic Sebaceous Glands in the Vagina: A Result of Surgery?" American Journal of Clinical Pathology 158, Supplement_1 (November 1, 2022): S81—S82. http://dx.doi.org/10.1093/ajcp/aqac126.169.
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Abstract Introduction/Objective Ectopic sebaceous glands with or without hair follicles are well documented in a variety of sites including the vulva, cervix, esophagus, and male genitalia. Ectopic sebaceous glands in the vagina, however, are extremely rare, with only 2 case reports and a third case described in a journal correspondence letter in the English literature. Methods/Case Report We present a 39-year-old patient with Laurence-Moon-Biedl syndrome with pseudotumor cerebri, retinitis pigmentosa/macular degeneration, chronic kidney disease status post renal transplant, obesity, diabetes insipidus, and a urethrovaginal fistula and hypoplastic vagina status post repair and vaginoplasty at age 3 months. High grade squamous intraepithelial lesion on a cervicovaginal Pap test prompted colposcopy, during which a confluent plaque non-staining with Lugol’s solution was noted on the right vaginal sidewall extending from the introitus to 4 cm distal to the cervix. Biopsy of this area revealed hyper- and parakeratosis along with sebaceous glands and hair follicles in the subepithelial stroma. Two theories are proposed in the literature regarding the origin of vaginal ectopic sebaceous glands/cutaneous adnexal structures. The first is a developmental anomaly with aberrant differentiation in-utero, as the lower two thirds of the vagina is normally endodermal in origin and the upper one third is derived from mesoderm, while cutaneous adnexal structures are ectodermal in origin. The second postulates sebaceous glands in the vagina arise from a metaplastic process after prolonged irritation or inflammation. We add a third possibility in this patient, that vaginal plastic surgery performed at 3 months of age involved tissue re- arrangement or grafting which introduced ectodermal structures to the vagina. The patient’s vaginal surgical records were not available for review. Results (if a Case Study enter NA) NA. Conclusion We add a fourth case of ectopic cutaneous adnexal structures in the vagina in a patient with Laurence-Moon-Biedl syndrome to the literature. The origin of these structures may have resulted from vaginal surgery as an infant rather than from a developmental anomaly or metaplasia.
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Zhao, Ling, Chen Hou, and Naihong Yan. "Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system." Frontiers in Immunology 13 (October 27, 2022). http://dx.doi.org/10.3389/fimmu.2022.1059947.
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Retinitis pigmentosa (RP) is an important cause of irreversible blindness worldwide and lacks effective treatment strategies. Although mutations are the primary cause of RP, research over the past decades has shown that neuroinflammation is an important cause of RP progression. Due to the abnormal activation of immunity, continuous sterile inflammation results in neuron loss and structural destruction. Therapies targeting inflammation have shown their potential to attenuate photoreceptor degeneration in preclinical models. Regardless of variations in genetic background, inflammatory modulation is emerging as an important role in the treatment of RP. We summarize the evidence for the role of inflammation in RP and mention therapeutic strategies where available, focusing on the modulation of innate immune signals, including TNFα signaling, TLR signaling, NLRP3 inflammasome activation, chemokine signaling and JAK/STAT signaling. In addition, we describe epigenetic regulation, the gut microbiome and herbal agents as prospective treatment strategies for RP in recent advances.
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Gimeno-Hernández, Roberto, Antolin Cantó, Angel Fernández-Carbonell, Teresa Olivar, Vicente Hernández-Rabaza, Inmaculada Almansa, and María Miranda. "Thioredoxin Delays Photoreceptor Degeneration, Oxidative and Inflammation Alterations in Retinitis Pigmentosa." Frontiers in Pharmacology 11 (December 23, 2020). http://dx.doi.org/10.3389/fphar.2020.590572.
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Retinitis pigmentosa (RP) is an inherited ocular disorder with no effective treatment. RP onset and progression trigger a cascade of retinal disorders that lead to the death of photoreceptors. After photoreceptors death, neuronal, glial and vascular remodeling can be observed in the retina. The purpose of this study was to study if thioredoxin (TRX) administration is able to decrease photoreceptor death in an animal model of RP (rd1 mouse), but also if it is able to modulate the retinal oxidative stress, glial and vascular changes that can be observed as the disease progresses. Wild type and rd1 mice received several doses of TRX. After treatment, animals were euthanized at postnatals days 11, 17, or 28. Glutathione (GSH) and other thiol compounds were determined by high performance liquid chromatography (HPLC). Glial fibrilary acidic protein (GFAP) and anti-ionized calcium binding adaptor molecule 1 (Iba1) were studied by immunohistochemistry. Vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF) expression were determined by western blot. TRX administration significantly diminished cell death in rd1 mouse retinas and increased GSH retinal concentrations at postnatal day 11 (PN11). TRX was also able to reverse glial alterations at PN11 and PN17. No alterations were observed in retinal VEGF and HGF expression in rd1 mice. In conclusion, TRX treatment decreases photoreceptor death in the first stages of RP and this protective effect may be due in part to the GSH system activation and to a partially decrease in inflammation.
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Canto, Antolín, Javier Martínez-González, María Miranda, Teresa Olivar, Inma Almansa, and Vicente Hernández-Rabaza. "Sulforaphane Modulates the Inflammation and Delays Neurodegeneration on a Retinitis Pigmentosa Mice Model." Frontiers in Pharmacology 13 (March 1, 2022). http://dx.doi.org/10.3389/fphar.2022.811257.
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The term retinitis pigmentosa (RP) describes a large group of hereditary retinopathies. From a cellular view, retinal degeneration is prompted by an initial death of rods, followed later by cone degeneration. This cellular progressive degeneration is translated clinically in tunnel vision, which evolves to complete blindness. The mechanism underlying the photoreceptor degeneration is unknown, but several mechanisms have been pointed out as main co-stars, inflammation being one of the most relevant. Retinal inflammation is characterized by proliferation, migration, and morphological changes in glial cells, in both microglia and Müller cells, as well as the increase in the expression of inflammatory mediators. Retinal inflammation has been reported in several animal models and clinical cases of RP, but the specific role that inflammation plays in the pathology evolution remains uncertain. Sulforaphane (SFN) is an antioxidant natural compound that has shown anti-inflammatory properties, including the modulation of glial cells activation. The present work explores the effects of SFN on retinal degeneration and inflammation, analyzing the modulation of glial cells in the RP rd10 mice model. A daily dose of 20 mg/kg of sulforaphane was administered intraperitoneally to control (C57BL/6J wild type) and rd10 (Pde6brd10) mice, from postnatal day 14 to day 20. On postnatal day 21, euthanasia was performed. Histological retina samples were used to assess cellular degeneration, Müller cells, and microglia activation. SFN administration delayed the loss of photoreceptors. It also ameliorated the characteristic reactive gliosis, assessed by retinal GFAP expression. Moreover, sulforaphane treatment regulated the microglia activation state, inducing changes in the microglia morphology, migration, and expression through the retina. In addition, SFN modulated the expression of the interleukins 1β, 4, Ym1, and arginase inflammatory mediators. Surprisingly, M2 polarization marker expression was increased at P21 and was reduced by SFN treatment. To summarize, SFN administration reduced retinal neurodegeneration and modified the inflammatory profile of RP, which may contribute to the SFN neuroprotective effect.
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Mohan, K. Varsha, Alaknanda Mishra, Abaranjitha Muniyasamy, Prakriti Sinha, Parul Sahu, Ashwani Kesarwani, Kshama Jain, et al. "Immunological consequences of compromised ocular immune privilege accelerate retinal degeneration in retinitis pigmentosa." Orphanet Journal of Rare Diseases 17, no. 1 (October 17, 2022). http://dx.doi.org/10.1186/s13023-022-02528-x.
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Abstract Background Retinitis pigmentosa (RP) is a hereditary retinal disease which leads to visual impairment. The onset and progression of RP has physiological consequences that affects the ocular environment. Some of the key non-genetic factors which hasten the retinal degeneration in RP include oxidative stress, hypoxia and ocular inflammation. In this study, we investigated the status of the ocular immune privilege during retinal degeneration and the effect of ocular immune changes on the peripheral immune system in RP. We assessed the peripheral blood mononuclear cell stimulation by retinal antigens and their immune response status in RP patients. Subsequently, we examined alterations in ocular immune privilege machineries which may contribute to ocular inflammation and disease progression in rd1 mouse model. Results In RP patients, we observed a suppressed anti-inflammatory response to self-retinal antigens, thereby indicating a deviated response to self-antigens. The ocular milieu in rd1 mouse model indicated a significant decrease in immune suppressive ligands and cytokine TGF-B1, and higher pro-inflammatory ocular protein levels. Further, blood–retinal-barrier breakdown due to decrease in the expression of tight junction proteins was observed. The retinal breach potentiated pro-inflammatory peripheral immune activation against retinal antigens and caused infiltration of the peripheral immune cells into the ocular tissue. Conclusions Our studies with RP patients and rd1 mouse model suggest that immunological consequences in RP is a contributing factor in the progression of retinal degeneration. The ocular inflammation in the RP alters the ocular immune privilege mechanisms and peripheral immune response. These aberrations in turn create an auto-reactive immune environment and accelerate retinal degeneration.
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Mercau, Maria E., Yemsratch T. Akalu, Francesca Mazzoni, Gavin Gyimesi, Emily J. Alberto, Yong Kong, Brian P. Hafler, Silvia C. Finnemann, Carla V. Rothlin, and Sourav Ghosh. "Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk -associated retinitis pigmentosa." Science Advances 9, no. 3 (January 20, 2023). http://dx.doi.org/10.1126/sciadv.ade9459.
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Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation are determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3 . Here, we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk −/− mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration–associated with Mertk loss of function.
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Yang, Chunbo, Maria Georgiou, Robert Atkinson, Joseph Collin, Jumana Al-Aama, Sushma Nagaraja-Grellscheid, Colin Johnson, et al. "Pre-mRNA Processing Factors and Retinitis Pigmentosa: RNA Splicing and Beyond." Frontiers in Cell and Developmental Biology 9 (July 28, 2021). http://dx.doi.org/10.3389/fcell.2021.700276.
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Retinitis pigmentosa (RP) is the most common inherited retinal disease characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium that eventually results in blindness. Mutations in pre-mRNA processing factors (PRPF3, 4, 6, 8, 31, SNRNP200, and RP9) have been linked to 15–20% of autosomal dominant RP (adRP) cases. Current evidence indicates that PRPF mutations cause retinal specific global spliceosome dysregulation, leading to mis-splicing of numerous genes that are involved in a variety of retina-specific functions and/or general biological processes, including phototransduction, retinol metabolism, photoreceptor disk morphogenesis, retinal cell polarity, ciliogenesis, cytoskeleton and tight junction organization, waste disposal, inflammation, and apoptosis. Importantly, additional PRPF functions beyond RNA splicing have been documented recently, suggesting a more complex mechanism underlying PRPF-RPs driven disease pathogenesis. The current review focuses on the key RP-PRPF genes, depicting the current understanding of their roles in RNA splicing, impact of their mutations on retinal cell’s transcriptome and phenome, discussed in the context of model species including yeast, zebrafish, and mice. Importantly, information on PRPF functions beyond RNA splicing are discussed, aiming at a holistic investigation of PRPF-RP pathogenesis. Finally, work performed in human patient-specific lab models and developing gene and cell-based replacement therapies for the treatment of PRPF-RPs are thoroughly discussed to allow the reader to get a deeper understanding of the disease mechanisms, which we believe will facilitate the establishment of novel and better therapeutic strategies for PRPF-RP patients.
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"Inflammation in the Pathogenesis of Progressive Retinal Dystrophies." Journal of Ophthalmic Research and Vision Care, October 11, 2021. http://dx.doi.org/10.54289/jorvc2100103.
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Retinal degenerative diseases include inherited pathologies such as retinitis pigmentosa (RP) and multifactorial diseases such as age-related macular degeneration (AMD). AMD, a leading cause of blindness in the Western world, typically causes visual distortion and loss of central vision. In those affected, RP causes early-onset loss of night vision, followed by loss of peripheral vision and ultimately blindness. Due to the need for more effective treatments with the eventual goal of preventing blindness, researchers are investigating new potential targets and technologies to address these diseases. In a preclinical setting, various animal models are available for evaluation of investigational therapies, and investigational drugs and drug delivery methods have shown promise in both preclinical and subsequent clinical trials. Recent efforts include research into the role of inflammation in AMD and RP, and the use of anti-inflammatory drugs in preventing or even reversing retinal damage. The aim of this manuscript is to review past and current works on models for these diseases, the inflammatory processes associated with them, and potential targets for pharmacotherapy as they relate to these progressive retinal dystrophies.
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Yu, Yang, Licheng Li, Shu Lin, and Jianmin Hu. "Update of application of olfactory ensheathing cells and stem cells/exosomes in the treatment of retinal disorders." Stem Cell Research & Therapy 13, no. 1 (January 10, 2022). http://dx.doi.org/10.1186/s13287-021-02685-z.
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AbstractAge-related macular degeneration, diabetic retinopathy, retinitis pigmentosa and other retinal disorders are the main causes of visual impairment worldwide. In the past, these retinal diseases, especially dry age-related macular degeneration, proliferative diabetic retinopathy and retinitis pigmentosa, were treated with traditional surgery and drugs. However, the effect was moderate. In recent years, researchers have used embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, olfactory ensheathing cells and other stem cells to conduct experiments and found that stem cells can inhibit inflammation, regulate immune response, secrete neurotrophic factors, and differentiate into retinal cells to replace and promote restoration of the damaged parts. These stem cells have the potential to treat retinal diseases. Whether it is in animal experiments or clinical trials, the increase in the number of retinal cells, maintenance of function and improvement of visual function all reflect the advanced of stem cells to treat retinal diseases, but its risk preserves the donor’s hidden pathogenic genes, immune rejection and tumorigenicity. With the development of exosomes study, researchers have discovered that exosomes come from a wide range of sources and can be secreted by almost all types of cells. Using exosomes with stem cell to treat retinal diseases is more effective than using stem cells alone. This review article summarizes the recent advances in the application of olfactory ensheathing cells and stem cells/exosomes in the treatment of retinal disorders.
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Eandi, Chiara M., Hugo Charles Messance, Sébastien Augustin, Elisa Dominguez, Sophie Lavalette, Valérie Forster, Shulong Justin Hu, et al. "Subretinal mononuclear phagocytes induce cone segment loss via IL-1β." eLife 5 (July 20, 2016). http://dx.doi.org/10.7554/elife.16490.
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Photo-transduction in cone segments (CS) is crucial for high acuity daytime vision. For ill-defined reasons, CS degenerate in retinitis pigmentosa (RP) and in the transitional zone (TZ) of atrophic zones (AZ), which characterize geographic atrophy (GA). Our experiments confirm the loss of cone segments (CS) in the TZ of patients with GA and show their association with subretinal CD14+mononuclear phagocyte (MP) infiltration that is also reported in RP. Using human and mouse MPs in vitro and inflammation-prone Cx3cr1GFP/GFP mice in vivo, we demonstrate that MP-derived IL-1β leads to severe CS degeneration. Our results strongly suggest that subretinal MP accumulation participates in the observed pathological photoreceptor changes in these diseases. Inhibiting subretinal MP accumulation or Il-1β might protect the CS and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation, such as AMD and RP.
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Kutsyr, Oksana, Agustina Noailles, Natalia Martínez-Gil, Lucía Maestre-Carballa, Manuel Martinez-Garcia, Victoria Maneu, Nicolás Cuenca, and Pedro Lax. "Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation." Proceedings of the National Academy of Sciences 118, no. 43 (October 19, 2021). http://dx.doi.org/10.1073/pnas.2100566118.
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Significance The retina is considered a window to the brain, and retinal degenerative diseases involve the same mechanisms as those of other neurodegenerative disorders. Neuronal degeneration is a complex process involving environmental stress, which can affect vulnerable neurons. High-fat diet–induced metabolic alterations may influence retinal homeostasis and exacerbate retinal degenerative diseases. This study provides evidence that short-term high-fat feeding promotes glucose intolerance, gut microbiome dysbiosis, retinal oxidative stress, and inflammation and accelerates the pathologic processes in retinal disease.
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Simon, Maria Victoria, Sandip K. Basu, Bano Qaladize, Richard C. Grambergs, Nora P. Rotstein, and Nawajes Mandal. "Sphingolipids as Critical Players in Retinal Physiology and Pathology." Journal of Lipid Research, September 18, 2020, jlr.TR120000972. http://dx.doi.org/10.1194/jlr.tr120000972.
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Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is, therefore, crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) emerges as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide-1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.
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Huang, Yanxia, Lamei Yuan, Guiyun He, Yanna Cao, Xiong Deng, and Hao Deng. "Novel compound heterozygous variants in the USH2A gene associated with autosomal recessive retinitis pigmentosa without hearing loss." Frontiers in Cell and Developmental Biology 11 (February 15, 2023). http://dx.doi.org/10.3389/fcell.2023.1129862.
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Background: Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies characterized by the primary degeneration of rod photoreceptors and the subsequent loss of cone photoreceptors because of cell death. It is caused by different mechanisms, including inflammation, apoptosis, necroptosis, pyroptosis, and autophagy. Variants in the usherin gene (USH2A) have been reported in autosomal recessive RP with or without hearing loss. In the present study, we aimed to identify causative variants in a Han-Chinese pedigree with autosomal recessive RP.Methods: A six-member, three-generation Han-Chinese family with autosomal recessive RP was recruited. A full clinical examination, whole exome sequencing, and Sanger sequencing, as well as co-segregation analysis were performed.Results: Three heterozygous variants in the USH2A gene, c.3304C>T (p.Q1102*), c.4745T>C (p.L1582P), and c.14740G>A (p.E4914K), were identified in the proband, which were inherited from parents and transmitted to the daughters. Bioinformatics analysis supported the pathogenicity of the c.3304C>T (p.Q1102*) and c.4745T>C (p.L1582P) variants.Conclusions: Novel compound heterozygous variants in the USH2A gene, c.3304C>T (p.Q1102*) and c.4745T>C (p.L1582P), were identified as the genetic causes of autosomal recessive RP. The findings may enhance the current knowledge of the pathogenesis of USH2A-associated phenotypes, expand the spectrum of the USH2A gene variants, and contribute to improved genetic counseling, prenatal diagnosis, and disease management.
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Rosa, Robert H., Wankun Xie, Min Zhao, Shu-Huai Tsai, Travis W. Hein, and Lih Kuo. "Intravitreal Administration of Stanniocalcin-1 Rescues Photoreceptor Degeneration with Reduced Oxidative Stress and Inflammation in a Porcine Model of Retinitis Pigmentosa." American Journal of Ophthalmology, March 2022. http://dx.doi.org/10.1016/j.ajo.2022.03.014.
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Tuekprakhon, Aekkachai, Siripakorn Sangkitporn, Adisak Trinavarat, Aulia Rahmi Pawestri, Visit Vamvanij, Monchai Ruangchainikom, Panya Luksanapruksa, et al. "Intravitreal autologous mesenchymal stem cell transplantation: a non-randomized phase I clinical trial in patients with retinitis pigmentosa." Stem Cell Research & Therapy 12, no. 1 (January 9, 2021). http://dx.doi.org/10.1186/s13287-020-02122-7.
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Abstract Background Retinitis pigmentosa (RP) is a progressive inherited retinal disease with great interest for finding effective treatment modalities. Stem cell-based therapy is one of the promising candidates. We aimed to investigate the safety, feasibility, and short-term efficacy of intravitreal injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) in participants with advanced stage RP. Methods This non-randomized phase I clinical trial enrolled 14 participants, categorized into three groups based on a single dose intravitreal BM-MSC injection of 1 × 106, 5 × 106, or 1 × 107 cells. We evaluated signs of inflammation and other adverse events (AEs). We also assessed the best corrected visual acuity (BCVA), visual field (VF), central subfield thickness (CST), and subjective experiences. Results During the 12-month period, we noticed several mild and transient AEs. Interestingly, we found statistically significant improvements in the BCVA compared to baseline, although they returned to the baseline at 12 months. The VF and CST were stable, indicating no remarkable disease progression. We followed 12 participants beyond the study period, ranging from 1.5 to 7 years, and observed one severe but manageable AE at year 3. Conclusion Intravitreal injection of BM-MSCs appears to be safe and potentially effective. All adverse events during the 12-month period required observation without any intervention. For the long-term follow-up, only one participant needed surgical treatment for a serious adverse event and the vision was restored. An enrollment of larger number of participants with less advanced RP and long-term follow-up is required to evaluate the safety and efficacy of this intervention. Trial registration ClinicalTrials.gov, NCT01531348. Registered on February 10, 2012
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Tuekprakhon, Aekkachai, Siripakorn Sangkitporn, Adisak Trinavarat, Aulia Rahmi Pawestri, Visit Vamvanij, Monchai Ruangchainikom, Panya Luksanapruksa, et al. "Intravitreal autologous mesenchymal stem cell transplantation: a non-randomized phase I clinical trial in patients with retinitis pigmentosa." Stem Cell Research & Therapy 12, no. 1 (January 9, 2021). http://dx.doi.org/10.1186/s13287-020-02122-7.
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Abstract Background Retinitis pigmentosa (RP) is a progressive inherited retinal disease with great interest for finding effective treatment modalities. Stem cell-based therapy is one of the promising candidates. We aimed to investigate the safety, feasibility, and short-term efficacy of intravitreal injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) in participants with advanced stage RP. Methods This non-randomized phase I clinical trial enrolled 14 participants, categorized into three groups based on a single dose intravitreal BM-MSC injection of 1 × 106, 5 × 106, or 1 × 107 cells. We evaluated signs of inflammation and other adverse events (AEs). We also assessed the best corrected visual acuity (BCVA), visual field (VF), central subfield thickness (CST), and subjective experiences. Results During the 12-month period, we noticed several mild and transient AEs. Interestingly, we found statistically significant improvements in the BCVA compared to baseline, although they returned to the baseline at 12 months. The VF and CST were stable, indicating no remarkable disease progression. We followed 12 participants beyond the study period, ranging from 1.5 to 7 years, and observed one severe but manageable AE at year 3. Conclusion Intravitreal injection of BM-MSCs appears to be safe and potentially effective. All adverse events during the 12-month period required observation without any intervention. For the long-term follow-up, only one participant needed surgical treatment for a serious adverse event and the vision was restored. An enrollment of larger number of participants with less advanced RP and long-term follow-up is required to evaluate the safety and efficacy of this intervention. Trial registration ClinicalTrials.gov, NCT01531348. Registered on February 10, 2012
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Adamus, Grazyna. "Importance of Autoimmune Responses in Progression of Retinal Degeneration Initiated by Gene Mutations." Frontiers in Medicine 8 (December 2, 2021). http://dx.doi.org/10.3389/fmed.2021.672444.
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Inherited retinal diseases (IRDs) are clinically and genetically heterogeneous rare disorders associated with retinal dysfunction and death of retinal photoreceptor cells, leading to blindness. Among the most frequent and severe forms of those retinopathies is retinitis pigmentosa (RP) that affects 1:4,000 individuals worldwide. The genes that have been implicated in RP are associated with the proteins present in photoreceptor cells or retinal pigment epithelium (RPE). Asymmetric presentation or sudden progression in retinal disease suggests that a gene mutation alone might not be responsible for retinal degeneration. Immune responses could directly target the retina or be site effect of immunity as a bystander deterioration. Autoantibodies against retinal autoantigens have been found in RP, which led to a hypothesis that autoimmunity could be responsible for the progression of photoreceptor cell death initiated by a genetic mutation. The other contributory factor to retinal degeneration is inflammation that activates the innate immune mechanisms, such as complement. If autoimmune responses contribute to the progression of retinopathy, this could have an implication on treatment, such as gene replacement therapy. In this review, we provide a perspective on the current role of autoimmunity/immunity in RP pathophysiology.
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Zhang, Jia, Pengdong Li, Guifang Zhao, Siqi He, Di Xu, Weijie Jiang, Qian Peng, et al. "Mesenchymal stem cell-derived extracellular vesicles protect retina in a mouse model of retinitis pigmentosa by anti-inflammation through miR-146a-Nr4a3 axis." Stem Cell Research & Therapy 13, no. 1 (August 3, 2022). http://dx.doi.org/10.1186/s13287-022-03100-x.
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Abstract Background Retinitis pigmentosa is a rod-cone degenerative disease that induces irreversible vision loss. This study probed the protective capacity of mesenchymal stem cell-derived small EVs (MSC-EVs) on the retinas of rd10 mice and the underlying mechanism. Methods MSC-EVs were injected into the vitreous of rd10 mice at postnatal day 14 and P21; morphology and function were examined at P28. The mechanism of action was explored by using co-culture of photoreceptor cell line 661 W and microglia cell line BV2. Results Treatment with MSC-EVs increased the survival of photoreceptors and preserved their structure. Visual function, as reflected by optomotor and electroretinogram responses, was significantly enhanced in MSC-EVs-treated rd10 mice. Mechanistically, staining for Iba1, GFAP, F4/80, CD68 and CD206 showed that MSC-EVs suppressed the activation of microglial, Müller glial and macrophages. Furthermore, western blotting showed that the treatment inhibited the NF-κB pathway. RNA-seq and qPCR showed that MSC-EVs upregulated anti-inflammatory cytokines while downregulating pro-inflammatory cytokines. MSC-EVs application in vitro decreased the number of TUNEL-positive 661 W cells co-cultured with LPS-stimulated BV2, with similar impact on the cytokine expression as in vivo study. Genetic screening predicted miR-146a to be the downstream target of MSC-EVs, which was detected in MSC-EVs and upregulated in co-cultured 661 W cells and BV2 cells after MSC-EVs treatment. Upregulation of miR-146a by using its mimic decreased the expression of the transcription factor Nr4a3, and its downregulation inhibition promoted Nr4a3 expression in both 661 W and BV2 cells. Nr4a3 was further identified as the target gene of miR-146a by dual-luciferase assay. Furthermore, overexpressing miR-146a significantly decreased the expression of LPS-induced pro-inflammatory cytokines in BV2 cells. Conclusions MSC-EVs delays retinal degeneration in rd10 mice mainly by its anti-inflammatory effect via the miR-146a-Nr4a3axis. Hence, MSC-EVs may be used in the treatment of neurodegenerative diseases.
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Brown, Christina, Patrina Agosta, Christina McKee, Keegan Walker, Matteo Mazzella, Ali Alamri, David Svinarich, and G. Rasul Chaudhry. "Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in rd12 mouse model of retinitis pigmentosa." Stem Cell Research & Therapy 13, no. 1 (April 8, 2022). http://dx.doi.org/10.1186/s13287-022-02828-w.
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Abstract Background Currently, there is no treatment for retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP). Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. Thus far, primarily adult mesenchymal stem cells (MSCs) have been investigated in preclinical and clinical studies, and the results have not been convincing. We applied a new approach in which primitive (p) MSC-derived retinal progenitor cells (RPCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Methods Well-characterized pMSCs and RPCs labeled with PKH26 were intravitreally injected into rd12 mice. The vision and retinal function of transplanted animals were analyzed using electroretinography. Animals were killed 4 and 8 weeks after cell transplantation for histological, immunological, molecular, and transcriptomic analyses of the retina. Results Transplanted RPCs significantly improved vision and retinal thickness as well as function in rd12 mice. pMSCs and RPCs homed to distinct retinal layers. pMSCs homed to the retinal pigment epithelium, and RPCs migrated to the neural layers of the retina, where they improved the thickness of the respective layers and expressed cell-specific markers. RPCs induced anti-inflammatory and neuroprotective responses as well as upregulated the expression of genes involved in neurogenesis. The transcriptomic analysis showed that RPCs promoted neurogenesis and functional recovery of the retina through inhibition of BMP and activation of JAK/STAT and MAPK signaling pathways. Conclusions Our study demonstrated that RPCs countered inflammation, provided retinal protection, and promoted neurogenesis resulting in improved retinal structure and physiological function in rd12 mice.
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Micera, Alessandra, Bijorn Omar Balzamino, Antonio Di Zazzo, Lucia Dinice, Stefano Bonini, and Marco Coassin. "Biomarkers of Neurodegeneration and Precision Therapy in Retinal Disease." Frontiers in Pharmacology 11 (January 18, 2021). http://dx.doi.org/10.3389/fphar.2020.601647.
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Vision-threatening retinal diseases affect millions of people worldwide, representing an important public health issue (high social cost) for both technologically advanced and new-industrialized countries. Overall RD group comprises the retinitis pigmentosa, the age-related macular degeneration (AMD), the diabetic retinopathy (DR), and idiopathic epiretinal membrane formation. Endocrine, metabolic, and even lifestyles risk factors have been reported for these age-linked conditions that represent a “public priority” also in this COVID-19 emergency. Chronic inflammation and neurodegeneration characterize the disease evolution, with a consistent vitreoretinal interface impairment. As the vitreous chamber is significantly involved, the latest diagnostic technologies of imaging (retina) and biomarker detection (vitreous) have provided a huge input at both medical and surgical levels. Complement activation and immune cell recruitment/infiltration as well as detrimental intra/extracellular deposits occur in association with a reactive gliosis. The cell/tissue aging route shows a specific signal path and biomolecular profile characterized by the increased expression of several glial-derived mediators, including angiogenic/angiostatic, neurogenic, and stress-related factors (oxidative stress metabolites, inflammation, and even amyloid formation). The possibility to access vitreous chamber by collecting vitreous reflux during intravitreal injection or obtaining vitreous biopsy during a vitrectomy represents a step forward for an individualized therapy. As drug response and protein signature appear unique in each single patient, therapies should be individualized. This review addresses the current knowledge about biomarkers and pharmacological targets in these vitreoretinal diseases. As vitreous fluids might reflect the early stages of retinal sufferance and/or late stages of neurodegeneration, the possibility to modulate intravitreal levels of growth factors, in combination to anti-VEGF therapy, would open to a personalized therapy of retinal diseases.
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Olivares-González, Lorena, David Salom, Emilio González-García, David Hervás, Natalia Mejía-Chiqui, Mar Melero, Sheyla Velasco, et al. "NUTRARET: Effect of 2-Year Nutraceutical Supplementation on Redox Status and Visual Function of Patients With Retinitis Pigmentosa: A Randomized, Double-Blind, Placebo-Controlled Trial." Frontiers in Nutrition 9 (March 21, 2022). http://dx.doi.org/10.3389/fnut.2022.847910.
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Oxidative stress plays a major role in the pathogenesis of retinitis pigmentosa (RP). The main goal of this study was to evaluate the effect of 2-year nutritional intervention with antioxidant nutraceuticals on the visual function of RP patients. Secondly, we assessed how nutritional intervention affected ocular and systemic redox status. We carried out a randomized, double-blind, placebo-controlled study. Thirty-one patients with RP participated in the study. RP patients randomly received either a mixture of nutraceuticals (NUT) containing folic acid, vitamin B6, vitamin A, zinc, copper, selenium, lutein, and zeaxanthin or placebo daily for 2 years. At baseline and after 2-year of the nutritional supplementation, visual function, dietetic-nutritional evaluations, serum concentration of nutraceuticals, plasma and aqueous humor concentration of several markers of redox status and inflammation were assessed. Retinal function and structure were assessed by multifocal electroretinogram (mfERG), spectral domain-optical coherence tomography (SD-OCT) and automated visual field (VF) tests. Nutritional status was estimated with validated questionnaires. Total antioxidant capacity, extracellular superoxide dismutase (SOD3), catalase (CAT), and glutathione peroxidase (GPx) activities, protein carbonyl adducts (CAR) content, thiobarbituric acid reactive substances (TBARS) formation (as indicator of lipid peroxidation), metabolites of the nitric oxide (NOX) and cytokine (interleukin 6 and tumor necrosis factor alpha) concentrations were assessed by biochemical and immunological techniques in aqueous humor or/and blood. Bayesian approach was performed to determine the probability of an effect. Region of practical equivalence (ROPE) was used. At baseline, Bayesian analysis revealed a high probability of an altered ocular redox status and to a lesser extent systemic redox status in RP patients compared to controls. Twenty-five patients (10 in the treated arm and 15 in the placebo arm) completed the nutritional intervention. After 2 years of supplementation, patients who received NUT presented better retinal responses (mfERG responses) compared to patients who received placebo. Besides, patients who received NUT showed better ocular antioxidant response (SOD3 activity) and lower oxidative damage (CAR) than those who received placebo. This study suggested that long-term NUT supplementation could slow down visual impairment and ameliorate ocular oxidative stress.
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Liang, Qingling, Qiyou Li, Bangqi Ren, and Zheng Qin Yin. "Intravenous infusion of small umbilical cord mesenchymal stem cells could enhance safety and delay retinal degeneration in RCS rats." BMC Ophthalmology 22, no. 1 (February 11, 2022). http://dx.doi.org/10.1186/s12886-021-02171-3.
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Abstract Background Human umbilical cord mesenchymal stem cells (UCMSCs) transplantation is a promising therapy for the treatment of retinitis pigmentosa (RP). However, intravenously infused cells may be blocked in the lung, increasing the risk of vascular obstruction, which needs to be optimized to further improve safety and efficacy. Methods We derived small UCMSCs (S-UCMSCs) from filtering UCMSCs with a 10-μm filter, and compared with UCMSCs by flow cytometry, directional differentiation culture and transcriptome sequencing. Then the S-UCMSCs and UCMSCs were intravenously infused in the Royal College Surgeons (RCS) rats to evaluate the safety and the efficacy. Results The diameter of S-UCMSCs ranged from 5.568 to 17.231 μm, with an average diameter of 8.636 ± 2.256 μm, which was significantly smaller than that of UCMSCs. Flow cytometry, immunofluorescence and transcriptome sequencing demonstrated that the S-UCMSCs and UCMSCs were the same kind of MSCs, and the S-UCMSCs were more proliferative. After the S-UCMSCs and UCMSCs were intravenously infused into the Royal College of Surgeons (RCS) rats at a dose of 1 × 106 cells/rat, the S-UCMSCs blocked in the lungs were significantly fewer and disappeared more quickly than UCMSCs. The b wave of the flash electroretinogram was improved at 7 d, and the retinal outer nuclear layer thickness was thicker at 7 d and 14 d. The expression level of inflammation was inhibited, and the expression level of neurotrophic factors was upregulated in the retina and serum after transplantation. Conclusions S-UCMSCs intravenous infusion was safer than UCMSCs and could delay retinal degeneration and protect visual function in RCS rats, which may be a preferable therapeutic approach for RP.
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Park, Elli A., Rachel M. Huckfeldt, Jason I. Comander, and Lucia Sobrin. "Peripheral Leakage on Ultra-Widefield Fluorescein Angiography in Patients With Inherited Retinal Degeneration." Journal of VitreoRetinal Diseases, September 21, 2020, 247412642095198. http://dx.doi.org/10.1177/2474126420951988.
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Purpose: This report illustrates that peripheral vascular leakage on ultra-widefield fluorescein angiography (FA) can occur in patients with inherited retinal degeneration (IRD) without evidence of a separate cause of leakage. Methods: We searched the electronic medical records of the Massachusetts Eye and Ear Infirmary from 2010 to 2019 for patients with an IRD diagnosis and examination with an ultra-widefield FA. Images from FAs were evaluated in masked fashion by 2 retina specialists. Documentation of an evaluation for alternative causes of vascular leakage was recorded, as well as results from electroretinography, Goldmann perimetry, and genetic testing. Results: A total of 305 patients with an IRD diagnosis and FA procedure code were identified. Of these, 26 patients had both a clinical diagnosis of IRD and ultra-widefield FA on detailed medical-record review. Three patients had FA to evaluate a Coats-like response and were excluded. Of the remaining 23, 4 patients (17%) had significant peripheral leakage on FA. Of these, 1 had pericentral retinitis pigmentosa (for which the genetic cause of disease was undefined), 1 had Refsum disease with confirmed biallelic PHYH mutations, 1 had a CRB1-associated macular dystrophy, and 1 had CERKL-associated macular dystrophy. There was no evidence of ocular inflammation from history, examination, or laboratory testing to account for the FA findings. Of the 19 patients without significant leakage, 4 had minimal leakage and 15 had no peripheral leakage. Conclusions: Peripheral retinal vascular leakage can be seen on ultra-widefield FA in patients with IRD that is likely due to the IRD disease process itself rather than to an additional, distinct eye condition.