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Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are common retinal diseases responsible for most blindness in working-age and elderly populations. Oxidative stress and mitochondrial dysfunction play roles in these pathogenesis, and new therapies counteracting these contributors could be of great interest. Some molecules, like coenzyme Q10 (CoQ10), are considered beneficial to maintain mitochondrial homeostasis and contribute to the prevention of cellular apoptosis. We investigated the impact of adding CoQ10 (Q) to a nutritional antioxidant complex (Nutrof Total®; N) on the mitochondrial status and apoptosis in an in vitro hydrogen peroxide (H2O2)-induced oxidative stress model in human retinal pigment epithelium (RPE) cells. H2O2 significantly increased 8-OHdG levels (p < 0.05), caspase-3 (p < 0.0001) and TUNEL intensity (p < 0.01), and RANTES (p < 0.05), caspase-1 (p < 0.05), superoxide (p < 0.05), and DRP-1 (p < 0.05) levels, and also decreased IL1ß, SOD2, and CAT gene expression (p < 0.05) vs. control. Remarkably, Q showed a significant recovery in IL1ß gene expression, TUNEL, TNFα, caspase-1, and JC-1 (p < 0.05) vs. H2O2, and NQ showed a synergist effect in caspase-3 (p < 0.01), TUNEL (p < 0.0001), mtDNA, and DRP-1 (p < 0.05). Our results showed that CoQ10 supplementation is effective in restoring/preventing apoptosis and mitochondrial stress-related damage, suggesting that it could be a valid strategy in degenerative processes such as AMD or DR.
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Apoptosis , Peróxido de Hidrógeno , Estrés Oxidativo , Epitelio Pigmentado de la Retina , Ubiquinona , Humanos , Ubiquinona/análogos & derivados , Ubiquinona/farmacología , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Antioxidantes/farmacología , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Línea Celular , Suplementos DietéticosRESUMEN
BACKGROUND: The objective of this study was to evaluate the association of the presence of conjunctival ultraviolet autofluorescence (CUVAF) with the level and progression of myopia and the impact of reduced sunlight exposure during the COVID-19 pandemic confinement (PC). METHODS: A retrospective observational study was carried out using three cohorts, children (9-17 years old), young adults (18-25 years old), and adults (>40 years old) with myopia (≤0.75D) and at least three annual eye examinations (before and after PC). All participants underwent an automatic objective refraction and CUVAF area analysis. All the participants filled out a questionnaire regarding lifestyle and myopia history. RESULTS: The 298 recruited participants showed that during the PC, children's and young adults' myopia progression rate increased on average by -0.50 and -0.30 D/year, respectively, compared with the pre-pandemic level (p < 0.0001 and p < 0.01). A significantly greater progression was observed in those with low baseline myopia compared to those with moderate or high myopia (p < 0.01). CUVAF shows its protective effect associated with outdoor activity (OA) with regard to the age of onset of myopia and mean diopters (p < 0.01). In fact, although there were no differences in the increase in diopters between children with and without CUVAF during the PC, those who had CUVAF started with lower gains (-0.3 D/year) compared to those who did not (-0.5 D/year; p < 0.05). The myopia treatments (atropine drops, Ortho-K, and MiSight® contact lenses) showed a reduction effect in myopic progression rate post-PC in comparison with non-treated children (p < 0.0001, p < 0.0001 and p < 0.01, respectively). CONCLUSIONS: The strict restriction of OA during PC led to the rate of myopia progression doubling among children and young adults. This progression occurred mainly in children with previously low myopia, and CUVAF, as a biomarker of OA, reflects its potential to provide benefits in the form of recommended behavioral changes to protect against the development of myopia.
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Outdoor exposure is considered the primary modifiable risk factor in preventing the development of myopia. This effect is thought to be attributed to the light-induced synthesis and release of dopamine in the retina. However, until recent years, there was no objective quantifiable method available to measure the association between time spent outdoors and myopia. It is only recently that the conjunctival ultraviolet autofluorescence (CUVAF) area, serving as a biomarker for sun exposure, has begun to be utilized in numerous studies. To provide a comprehensive summary of the relevant evidence pertaining to the association between the CUVAF area and myopia across different geographic regions and age groups, a systematic review and meta-analysis were conducted. The search encompassed multiple databases, including MEDLINE, SCIENCE DIRECT, GOOGLE SCHOLAR, WEB OF SCIENCE, and SCOPUS, and utilized specific search terms such as "conjunctival ultraviolet autofluorescence", "CUVAF", "UVAF", "objective marker of ocular sun exposure", "myopia", "degenerative myopia", and "high myopia". The bibliographic research included papers published between the years 2006 and 2022. A total of 4051 records were initially identified, and after duplicates were removed, 49 articles underwent full-text review. Nine articles were included in the systematic review. These studies covered myopia and outdoor exposure across different regions (Australia, Europe and India) with a total population of 3615 individuals. They found that myopes generally had smaller CUVAF areas compared to non-myopes. The meta-analysis confirmed this, revealing statistically smaller CUVAF areas in myopic patients, with a mean difference of - 3.30 mm2 (95% CI - 5.53; - 1.06). Additionally, some studies showed a positive correlation between more outdoor exposure and larger CUVAF areas. In terms of outdoor exposure time, myopic patients reported less time outdoors than non-myopic individuals, with a mean difference of - 3.38 h/week (95% CI - 4.66; - 2.09). Overall, these findings highlight the connection between outdoor exposure, CUVAF area and myopia, with regional variations playing a significant role. The results of this meta-analysis validate CUVAF as a quantitative method to objectively measure outdoor exposure in relation with myopia development.
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Miopía , Rayos Ultravioleta , Humanos , Rayos Ultravioleta/efectos adversos , Luz Solar/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Estudios Transversales , Conjuntiva , Miopía/epidemiología , BiomarcadoresRESUMEN
PURPOSE: To assess the suitability of machine learning (ML) techniques in predicting the development of fibrosis and atrophy in patients with neovascular age-related macular degeneration (nAMD), receiving anti-VEGF treatment over a 36-month period. METHODS: An extensive analysis was conducted on the use of ML to predict fibrosis and atrophy development on nAMD patients at 36 months from start of anti-VEGF treatment, using only data from the first 12 months. We use data collected according to real-world practice, which includes clinical and genetic factors. RESULTS: The ML analysis consistently identified ETDRS as a relevant factor for predicting the development of atrophy and fibrosis, confirming previous statistical analyses. Also, it was shown that genetic variables did not demonstrate statistical relevance in the prediction. Despite the complexity of predicting macular degeneration, our model was able to obtain a balance accuracy of 63% and an AUC of 0.72 when predicting the development of atrophy or fibrosis at 36 months. CONCLUSION: This study demonstrates the potential of ML techniques in predicting the development of fibrosis and atrophy in nAMD patients receiving long-term anti-VEGF treatment. The findings highlight the importance of clinical factors, particularly ETDRS (early treatment diabetic retinopathy study) visual acuity test, in predicting these outcomes. The lessons learned from this research can guide future ML-based prediction tasks in the field of ophthalmology and contribute to the design of data collection processes.
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Inhibidores de la Angiogénesis , Fibrosis , Inyecciones Intravítreas , Aprendizaje Automático , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda , Humanos , Inhibidores de la Angiogénesis/uso terapéutico , Masculino , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/tratamiento farmacológico , Femenino , Anciano , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tomografía de Coherencia Óptica/métodos , Atrofia , Estudios de Seguimiento , Anciano de 80 o más Años , Estudios Retrospectivos , Ranibizumab/administración & dosificación , Ranibizumab/uso terapéutico , Angiografía con Fluoresceína/métodos , Fondo de OjoRESUMEN
Age-related macular degeneration (AMD) is a leading cause of severe vision loss in older individuals in developed countries. Despite advances in our understanding of AMD, its pathophysiology remains poorly understood. Matrix metalloproteinases (MMPs) have been proposed to play a role in AMD development. In this study, we aimed to characterize MMP-13 in AMD. We used retinal pigment epithelial cells, a murine model of laser-induced choroidal neovascularization, and plasma samples from patients with neovascular AMD to conduct our study. Our results show that MMP13 expression significantly increased under oxidative stress conditions in cultured retinal pigment epithelial cells. In the murine model, MMP13 was overexpressed in both retinal pigment epithelial cells and endothelial cells during choroidal neovascularization. Additionally, the total MMP13 levels in the plasma of patients with neovascular AMD were significantly lower than those in the control group. This suggests a reduced diffusion from the tissues or release from circulating cells in the bloodstream, given that the number and function of monocytes have been reported to be deficient in patients with AMD. Although more studies are needed to elucidate the role of MMP13 in AMD, it could be a promising therapeutic target for treating AMD.
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Age-related macular degeneration (AMD) is currently the main cause of severe visual loss among older adults in developed countries. The pathophysiology has not been clarified, but oxidative stress is believed to play a major role. Matrix metalloproteinases (MMP) may play a prominent role in several steps of the pathophysiology of AMD, especially in its neovascular form; therefore, there is of great interest in understanding their role in choroidal neovascularisation. This study aimed to elucidate the role of MMP10 in the development of choroidal neovascularisation (CNV). We have demonstrated that MMP10 was expressed by retinal pigment epithelium cells and endothelial cells of the neovascular membrane, in cell culture, mouse and human retina. MMP10 expression and activity increased under oxidative stress conditions in ARPE-19 cells. MMP10-/- mice developed smaller laser-induced areas of CNV. Furthermore, to exclude a systemic MMP10 imbalance in these patients, plasma MMP10 concentrations were assessed in an age- and sex-matched sample of 52 control patients and 52 patients with neovascular AMD and no significant differences were found between the groups, demonstrating that MMP10 induction is a local phenomenon. Our findings suggest that MMP10 participates in the development of choroidal neovascularisation and promotes MMP10 as a possible new therapeutic target.
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Myopia is the most common refractive error worldwide. This cannot be explained by genetic factors alone, therefore, environmental factors may play an important role. Hence, the main objective of this study was to analyse whether outdoor exposure could exert a protective effect against the development of myopia in a cohort of young adults and to investigate ultraviolet autofluorescence (CUVAF), as a biomarker of time spent outdoors. A cross-sectional observational study was carried out using two cohorts. A total of 208 participants were recruited, 156 medical students and 52 environmental science students. The data showed that 66.66% of the medical students were myopic, while 50% of the environmental science students were myopic (p = 0.021). Environmental science students spent significantly more hours per week doing outdoor activities than medical students (p < 0.0001), but there was no significant difference with respect to near work activities between them. In both cohorts, the degree of myopia was inversely associated with CUVAF, and a statistically significant positive correlation was observed between spherical equivalent and CUVAF (Pearson's r = 0.248). In conclusion, outdoor activities could reduce the onset and progression of myopia not only in children, but also in young adults. In addition, CUVAF represents an objective, non-invasive biomarker of outdoor exposure that is inversely associated with myopia.
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PURPOSE: To assess the effect of clinical factors on the development and progression of atrophy and fibrosis in patients with neovascular age-related macular degeneration (nAMD) receiving long-term treatment in the real world. METHODS: An ambispective 36-month multicentre study, involving 359 nAMD patients from 17 Spanish hospitals treated according to the Spanish Vitreoretinal Society guidelines, was designed. The influence of demographic and clinical factors, including the presence and location of retinal fluid, on best-corrected visual acuity (BCVA) and progression to atrophy and/or fibrosis were analysed. RESULTS: After 36 months of follow-up and an average of 13.8 anti-VEGF intravitreal injections, the average BCVA gain was +1.5 letters, and atrophy and/or fibrosis were present in 54.8% of nAMD patients (OR = 8.54, 95% CI = 5.85-12.47, compared to baseline). Atrophy was associated with basal intraretinal fluid (IRF) (OR = 1.87, 95% CI = 1.09-3.20), whereas basal subretinal fluid (SRF) was associated with a lower rate of atrophy (OR = 0.40, 95% CI = 0.23-0.71) and its progression (OR = 0.44, 95% CI = 0.26-0.75), leading to a slow progression rate (OR = 0.34, 95% CI = 0.14-0.83). Fibrosis development and progression were related to IRF at any visit (p < 0.001). In contrast, 36-month SRF was related to a lower rate of fibrosis (OR = 0.49, 95% CI = 0.29-0.81) and its progression (OR = 0.50, 95% CI = 0.31-0.81). CONCLUSION: Atrophy and/or fibrosis were present in 1 of 2 nAMD patients treated for 3 years. Both, especially fibrosis, lead to vision loss. Subretinal fluid (SRF) was associated with good visual outcomes and lower rates of atrophy and fibrosis, whereas IRF yields worse visual results and a higher risk of atrophy and especially fibrosis in routine clinical practice.
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Degeneración Macular/fisiopatología , Líquido Subretiniano/metabolismo , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis , Atrofia/fisiopatología , Atrofia/prevención & control , Progresión de la Enfermedad , Femenino , Fibrosis/fisiopatología , Fibrosis/prevención & control , Humanos , Inyecciones Intravítreas , Masculino , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
The purpose of this study was to assess vascular and histological alterations in two COVID-19 and three control post-mortem retinas. The macular areas of flat-mounted samples were processed for immunofluorescence. Lectin and collagen IV positive vessels were captured under confocal microscopy, and endothelium loss and tortuosity were analyzed. Expression of ACE2 (angiotensin-converting enzyme 2) (the receptor for SARS-CoV-2), Iba1 (ionized calcium-binding adaptor molecule 1) and GFAP (glial fibrillary acidic protein) were quantified in retinal sections. The number of lectin vessels in COVID-19 retinas decreased by 27% compared to the control (p < 0.01) and the tortuosity increased in COVID-19 retinas (7.3 ± 0.2) vs. control retinas (6.8 ± 0.07) (p < 0.05). Immunofluorescence analysis revealed an increase in ACE2 (2.3 ± 1.3 vs. 1.0 ± 0.1; p < 0.0001) and Iba1 expression (3.06 ± 0.6 vs. 1.0 ± 0.1; p < 0.01) in COVID-19 sections whereas no changes in GFAP were observed. Analysis of the COVID-19 macular retinal tissue suggested that endothelial cells are a preferential target of SARS-CoV-2 with subsequent changes through their ACE2 receptor expression and morphology. Thus, microglial activation was hyperactive when facing an ensuing immunological challenge after SARS-CoV-2 infection.
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Age related macular degeneration (AMD) is the main cause of legal blindness in developed countries. It is a multifactorial disease in which a combination of genetic and environmental factors contributes to increased risk of developing this vision-incapacitating condition. Oxidative stress plays a central role in the pathophysiology of AMD and recent publications have highlighted the importance of mitochondrial dysfunction and endoplasmic reticulum stress in this disease. Although treatment with vascular endothelium growth factor inhibitors have decreased the risk of blindness in patients with the exudative form of AMD, the search for new therapeutic options continues to prevent the loss of photoreceptors and retinal pigment epithelium cells, characteristic of late stage AMD. In this review, we explain how mitochondrial dysfunction and endoplasmic reticulum stress participate in AMD pathogenesis. We also discuss a role of several antioxidants (bile acids, resveratrol, melatonin, humanin, and coenzyme Q10) in amelioration of AMD pathology.
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The purpose of this study is evaluate the efficacy and safety of medicinal products containing the original Age-Related Eye Disease group (AREDS) formulation at doses approved in Europe (EU, control group; n = 59) with a product that adds DHA, lutein, zeaxanthin, resveratrol and hydroxytyrosol to the formula (intervention group; n = 50). This was a multicenter, randomized, observer-blinded trial conducted in patients aged 50 years or older diagnosed with unilateral exudative Age related Macular Degeneration AMD. At month 12, the intervention did not have a significant differential effect on visual acuity compared with the control group, with an estimated treatment difference in Early Treatment Diabetic Retinopathy Study (ETDRS) of -1.63 (95% CI -0.83 to 4.09; p = 0.192). The intervention exhibited a significant and, in most cases, relevant effect in terms of a reduction in some inflammatory cytokines and a greater improvement in the fatty acid profile and serum lutein and zeaxantin concentration. In patients with unilateral wet AMD, the addition of lutein, zeaxanthin, resveratrol, hydroxytyrosol and DHA to the AREDS EU recommended doses in the short-term did not have a differential effect on visual acuity compared to a standard AREDS EU formula but, in addition to improving the fatty acid profile and increasing carotenoid serum levels, may provide a beneficial effect in improving the proinflammatory and proangiogenic profile of patients with AMD.
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Suplementos Dietéticos/efectos adversos , Degeneración Macular/dietoterapia , Nutrientes/administración & dosificación , Anciano , Anciano de 80 o más Años , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/efectos adversos , Femenino , Humanos , Luteína/administración & dosificación , Luteína/efectos adversos , Degeneración Macular/sangre , Degeneración Macular/diagnóstico , Masculino , Persona de Mediana Edad , Nutrientes/efectos adversos , Alcohol Feniletílico/administración & dosificación , Alcohol Feniletílico/efectos adversos , Alcohol Feniletílico/análogos & derivados , Resveratrol/administración & dosificación , Resveratrol/efectos adversos , Resultado del Tratamiento , Agudeza Visual , Xantófilas/administración & dosificación , Zeaxantinas/administración & dosificación , Zeaxantinas/efectos adversosRESUMEN
Age-related macular degeneration (AMD) is a multifactorial disease of the retina featured by dysfunction of retinal pigmented epithelial (RPE) and loss of photoreceptor cells under oxidative stress and inflammatory conditions. Vitamin D and antioxidants have beneficial effects against retinal degenerative diseases, such as AMD. We investigated the impact of associating vitamin D (ND) with a nutritional antioxidant complex (Nutrof Total®; N) on oxidative stress and inflammation-like induced conditions by H2O2 and LPS, respectively, in human retinal epithelial (ARPE-19) and human retinal endothelial (HREC) cells. Application of either N or ND treatments to H2O2-induced media in ARPE-19 cells counteracted late apoptosis, attenuated oxidative DNA damage, and increased cell proliferation. Significant reduction in the expression levels of MCP1, IL-8, and IL6 cytokines was observed following application of either N or ND treatments under LPS-induced conditions in ARPE-19 cells and in MCP-1 and IL12p70 cytokine levels in HREC cells. ND and not N revealed significant downregulation of IFNγ in ARPE-19 cells, and of IL-6 and IL-18 in HREC cells. In conclusion, adding vitamin D to Nutrof Total® protects in a synergistic way against oxidative and inflammatory stress-induced conditions in retinal epithelial and endothelial cells.
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Antiinflamatorios/farmacología , Células Endoteliales/patología , Degeneración Macular/patología , Epitelio Pigmentado de la Retina/patología , Vitamina D/farmacología , 8-Hidroxi-2'-Desoxicoguanosina/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Células Endoteliales/efectos de los fármacos , Humanos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Epitelio Pigmentado de la Retina/efectos de los fármacosRESUMEN
PURPOSE: To assess the effect of fluid status at baseline (BL) and at the end of the loading phase (LP) of three different ranibizumab regimens: treat-and-extend (T&E), fixed bimonthly (FBM) injections and pro re nata (PRN), in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Post hoc analysis of the In-Eye study (phase IV clinical trial). METHODS: Patients were randomized 1:1:1 to the three study arms and were treated accordingly. The presence and type of fluid, intraretinal fluid (IRF) or subretinal fluid (SRF) and the anatomical and visual outcomes were analysed. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), the mean change from baseline BCVA (BL BCVA), and the proportion of eyes gaining more than 15 letters or losing more than five letters were analysed. Morphological characteristics including the subtype of choroidal neovascular membrane and the development of atrophy and fibrosis were also evaluated. RESULTS: Patients with SRF at LP had better visual outcomes than patients with IRF. The persistence of SRF did not affect the mean change from BL BCVA among the three treatment regimens. However, in patients with IRF mean change from BL BCVA was significantly lower in the FBM group. The presence of IRF at BL and at the end of the loading phase was associated with the development of fibrosis at the end of the study; this result was contrary to that observed for patients with SRF. CONCLUSIONS: While SRF is compatible with good visual and anatomical outcomes, IRF leads to worse results in patients with nAMD; our results suggest that patients with IRF have better outcomes when individualized treatment regimens are used (PRN or T&E) in contrast with a FBM regimen.
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Mácula Lútea/diagnóstico por imagen , Ranibizumab/administración & dosificación , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravítreas , Mácula Lútea/efectos de los fármacos , Masculino , Estudios Prospectivos , Líquido Subretiniano , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatologíaRESUMEN
We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19; migration), and (RF/6A; angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients' needs.
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Diabetic retinopathy is a vision-threatening microvascular complication of diabetes and is one of the leading causes of blindness. Oxidative stress and inflammation play a major role in its pathogenesis, and new therapies counteracting these contributors could be of great interest. In the current study, we investigated the role of vitamin D against oxidative stress and inflammation in human retinal pigment epithelium (RPE) and human retinal endothelial cell lines. We demonstrate that vitamin D effectively counteracts the oxidative stress induced by hydrogen peroxide (H2O2). In addition, the increased levels of proinflammatory proteins such as Interleukin (IL)-6, IL-8, Monocyte chemoattractant protein (MCP)-1, Interferon (IFN)-γ, and tumor necrosis factor (TNF)-α triggered by lipopolysaccharide (LPS) exposure were significantly decreased by vitamin D addition. Interestingly, the increased IL-18 only decreased by vitamin D addition in endothelial cells but not in RPE cells, suggesting a main antiangiogenic role under inflammatory conditions. Moreover, H2O2 and LPS induced the alteration and morphological damage of tight junctions in adult retinal pigment epithelium (ARPE-19) cells that were restored under oxidative and inflammatory conditions by the addition of vitamin D to the media. In conclusion, our data suggest that vitamin D could protect the retina by enhancing antioxidant defense and through exhibiting anti-inflammatory properties.
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Retinal pigment epithelium (RPE) is a key regulator of retinal function and is directly related to the transport, delivery, and metabolism of long-chain n-3 polyunsaturated fatty acids (n3-PUFA), in the retina. Due to their functions and location, RPE cells are constantly exposed to oxidative stress. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown to have antioxidant effects by different mechanisms. For this reason, we designed an in vitro study to compare 10 formulations of DHA and EPA supplements from different origins and combined in different proportions, evaluating their effect on cell viability, cell proliferation, reactive oxygen species production, and cell migration using ARPE-19 cells. Furthermore, we assessed their ability to rescue RPE cells from the oxidative conditions seen in diabetic retinopathy. Our results showed that the different formulations of n3-PUFAs have a beneficial effect on cell viability and proliferation and are able to restore oxidative induced RPE damage. We observed that the n3-PUFA provided different results alone or combined in the same supplement. When combined, the best results were obtained in formulations that included a higher proportion of EPA than DHA. Moreover, n3-PUFA in the form of ethyl-esters had a worse performance when compared with triglycerides or phospholipid based formulations.
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High myopia and the subsequent degenerative changes of the retina, choroid, and sclera, known as myopic maculopathy (MM), are a serious visual problem in many Asian countries, and are beginning to be so in the south of Europe, especially in the Mediterranean. It is therefore necessary to carry out genetic and environmental studies to determine the possible causes of this disease. This study aims to verify if the genetic factors that have been most related to Asian populations are also associated in two Spanish cohorts. Eight SNPs from six genes (PAX6, SCO2, CCDC102B, BLID, chromosome 15q14, and COL8A1) along with demographic, ophthalmic and environmental factors were analysed in two cohorts from a total of 365 highly myopic subjects and 177 control subjects. The genetic analysis showed that COL8A1 SNP rs13095226 was associated with the development of choroidal neovascularization (CNV) and also seems to play an important role in the increase of axial length. The SNP rs634990 of chromosome 15q14 also showed a significant association with MM, although this was lost after the Bonferroni correction. Additional demographic and environmental factors, namely age, sex, smoking status, and pregnancy history, were also found to be associated with MM and CNV in this population.
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Ambiente , Degeneración Macular/epidemiología , Degeneración Macular/genética , Miopía/complicaciones , Adulto , Anciano , Alelos , Ojo/metabolismo , Femenino , Genotipo , Humanos , Degeneración Macular/complicaciones , Masculino , Persona de Mediana Edad , España/epidemiologíaRESUMEN
Age-related macular degeneration (AMD) is a progressive retinal disorder characterized by imbalanced pro- and antiangiogenic signals. The aim of this study was to evaluate the effect of ex vivo cell-based gene therapy with stable expression of human pigment epithelium-derived factor (PEDF) release using the non-viral Sleeping Beauty (SB100X) transposon system delivered by miniplasmids free of antibiotic resistance markers (pFAR4). Retinal pigment epithelial (RPE) cells and iris pigment epithelial (IPE) cells were co-transfected with pFAR4-inverted terminal repeats (ITRs) CMV-PEDF-BGH and pFAR4-CMV-SB100X-SV40 plasmids. Laser-induced choroidal neovascularization (CNV) was performed in rats, and transfected primary cells (transfected RPE [tRPE] and transfected IPE [tIPE] cells) were injected into the subretinal space. The leakage and CNV areas, vascular endothelial growth factor (VEGF), PEDF protein expression, metalloproteinases 2 and 9 (MMP-2/9), and microglial/macrophage markers were measured. Injection with tRPE/IPE cells significantly reduced the leakage area at 7 and 14 days and the CNV area at 7 days. There was a significant increase in PEDF and the PEDF/VEGF ratio with tRPE cells and a reduction in the MMP-2 activity. Our data demonstrated that ex vivo non-viral gene therapy reduces CNV and could be an effective and safe therapeutic option for angiogenic retinal diseases.
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Purpose: To explore the relationship between plasma C-reactive protein (CRP) levels, the main ARMS2 gene single nucleotide polymorphism (SNP), and gender in patients with neovascular age-related macular degeneration (wet AMD). Methods: Our study included 131 patients with wetAMD [age-related eye disease study (AREDS) category 4] and 153 control participants (AREDS category 1) from two Spanish retinal units. CRP levels were determined on blood samples by high-sensitivity ELISA assay. According to their CRP level, subjects were categorized into three well-established CRP categories: low (<1.00 mg/L, L-CRP), moderate (1-2.99 mg/L, M-CRP), and high (>3.00 mg/L, H-CRP). Genomic DNA was extracted from oral swabs using QIAcube (Qiagen, Hilden, Germany) and the A69S; rs10490924 of ARMS2 gene was genotyped by allelic discrimination with validated TaqMan assays (Applied Biosystems, Foster City, CA, USA). Univariate and multivariate logistic regression adjusted for age was used to analyze the genomic frequencies and to calculate odds ratio (OR) using SNPStats software. Results: Considering CRP risk categories, H-CRP group showed a significant [OR 4.0 (1.9-8.3)] association with wetAMD compared to L-CRP group. The risk genotypes of A69S (TT) SNPs showed an association with wetAMD risk [OR 14.0 (4.8-40.8)]. Interestingly, the gender stratification of the CRP categories showed a significant increase in CRP levels in wetAMD women compared with control women [OR 6.9 (2.2-22.3)] and with wetAMD men [OR 4.6 (1.3-16.9)]. In addition, the subgroup analysis of CRP within A69S genotype and gender showed a link in women between the A69S and CRP levels in the AMD group compared to controls [OR 4.2 (1.4-12.6)]. Conclusion: Our study shows, for the first time, that a different genetic association related with gender could contribute to AMD risk. As a consequence, the risk of female gender in the different CRP levels and A69S SNP frequencies could be taken into consideration to the established risk relationship of high levels of CRP and its association with risk A69S genotype.
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Alelos , Sustitución de Aminoácidos , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Polimorfismo de Nucleótido Simple , Degeneración Macular Húmeda/etiología , Degeneración Macular Húmeda/metabolismo , Factores de Edad , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores Sexuales , Degeneración Macular Húmeda/patologíaRESUMEN
PURPOSE: We sought to determine if specific genetic single nucleotide polymorphisms (SNPs) influence vascular endothelial growth factor inhibition response to ranibizumab in neovascular age-related macular degeneration (AMD). METHODS: A total of 403 Caucasian patients diagnosed with exudative AMD were included. After a three-injection loading phase, a pro re nata regimen was followed. Nine SNPs from six different genes (CFH, CFB, ARMS2, SERPINF1, VEGFR1, VEGF) were genotyped. Non-genetic risk factors (gender, smoking habit and hypertension) were also assessed. Patients were classified as good or poor responders (GR or PR) according to functional (visual acuity), anatomical (foveal thickness measured by OCT) and fluid criteria (fluid/no fluid measured by OCT). RESULTS: Hypertension was the environmental factor with the strongest poor response association with ranibizumab in the anatomical measure after the loading phase (p = 0.0004; OR 3.7; 95% CI, 2.4-5.8) and after 12 months of treatment (p = 10-5 ; OR 2.3; 95% CI, 1.5-3.4). The genetic variants rs12614 (CFB), rs699947 (VEGFA) and rs7993418 (VEGFR1) predisposed patients to a good response, while rs12603486 and rs1136287 (SERPINF1) were associated with a poor response. The protective genotype of rs800292 variant (CFH) was also associated with a poor anatomical response (p 0.0048). CONCLUSION: All these data suggest that genetics play an important role in treatment response in AMD patients.