Recalde, S. (Sergio)
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- Effects of lutein and docosahexaenoic Acid supplementation on macular pigment optical density in a randomized controlled trial(MDPI, 2013) Garcia-Layana, A. (Alfredo); Salinas-Alaman, A. (Ángel); Fernandez-Robredo, P. (Patricia); Recalde, S. (Sergio)We studied the macular pigment ocular density (MPOD) in patients with early age macular degeneration (AMD) before and 1 year after nutritional supplementation with lutein and docosahexaenoic acid (DHA). Forty-four patients with AMD were randomly divided into two groups that received placebo (n = 21) or a nutritional supplement (n = 23, 12 mg of lutein and 280 mg of DHA daily). Heterochromatic flicker photometry was used to determine the MPOD. At baseline, the MPOD in AMD patients with placebo was 0.286 ± 0.017 meanwhile in AMD patients with supplementation it was 0.291 ± 0.016. One year later, the mean MPOD had increased by 0.059 in the placebo group and by 0.162 in patients receiving lutein and DHA. This difference between groups was significant (p < 0.05). Lutein and DHA supplementation is effective in increasing the MPOD and may aid in prevention of age related macular degeneration.
- Preclinical evaluation of a cell-based gene therapy using the sleeping beauty transposon system in choroidal neovascularization(Elsevier BV, 2019) Ivics, Z. (Zoltán); Garcia-Garcia, L. (Laura); Marie, C. (Corinne); Johnen, S. (S.); Rodriguez-Madoz, J.R. (Juan Roberto); Scherman, D. (Daniel); Pouillot, S. (Severine); Garcia-Layana, A. (Alfredo); Izsvák, Z. (Zsuzsanna); Thumann, G. (Gabriele); Diarra, S. (Sabine); Bezunartea, J. (Jaione); Miskey, C. (Csaba); Fernandez-Robredo, P. (Patricia); Sebe, A. (Attila); Prosper-Cardoso, F. (Felipe); Kropp, M. (Martina); Hernandez, M. (María); Recalde, S. (Sergio)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.
- HGF-rs12536657 and ocular biometric parameters in hyperopic children, emmetropic adolescents, and young adults: A multicenter quantitative trait study(Hindawi Limited, 2019) Santos, J.L. (José Luis); Patiño-García, A. (Ana); Noval, S. (Susana); Bonet-Farriol, M.E. (María Elvira); Alfonso-Bartolozzi, B. (Belén); Barrio-Barrio, J. (Jesús); Pueyo, V. (Victoria); Breeze, C.E. (Charles E.); Galdós, M. (Marta); Recalde, S. (Sergio)Introduction. Even though ocular refractive state is highly heritable and under strong genetic control, the identification of susceptibility genes remains a challenge. Several HGF (hepatocyte growth factor) gene variants have been associated with ocular refractive errors and corneal pathology. Purpose. Here, we assess the association of an HGF gene variant, previously reported as associated with hyperopia, and ocular biometric parameters in a multicenter Spanish cohort. Methods. An observational prospective multicenter cross-sectional study was designed, including a total of 403 unrelated subjects comprising 188 hyperopic children (5 to 17 years) and 2 control groups: 52 emmetropic adolescents (13 to 17 years) and 163 emmetropic young adults (18 to 28 years). Each individual underwent a comprehensive eye examination including cycloplegic refraction, and topographic and ocular biometric analysis. Genomic DNA was extracted from oral swabs. HGF single nucleotide polymorphism (SNP) rs12536657 was genotyped. Genotypic, allelic, and logistic regression analyses were performed comparing the different groups. A quantitative trait association test analyzing several biometric parameters was also performed using generalized estimating equations (GEEs) adjusting for age and gender. Results. No association between rs12536657 and hyperopia was found through gender-adjusted logistic regression comparing the hyperopic children with either of the two control groups. Significant associations between mean topographic corneal curvature and rs12536657 for G/ A (slope � +0.32; CI 95%: 0.04–0.60; p � 0.023) and A/A (slope � +0.76; CI 95%: 0.12–1.40; p � 0.020) genotypes were observed with the age- and gender-adjusted univariate GEE model. Both flat and steep corneal topographic meridians were also significantly associated with rs12536657 for the G/A and A/A genotypes. No association was found between rs12536657 and any other topographic or biometric measurements. Conclusions. Our results support a possible role for HGF gene variant rs12536657 in corneal curvature in our population. To our knowledge, this is the first multicenter quantitative trait association study of HGF genotypes and ocular biometric parameters comprising a pediatric cohort.
- Suitability of machine learning for atrophy and fibrosis development in neovascular age-related macular degeneration(John Wiley & Sons Ltd, 2023) Fuente-Cedeño, J. (Jesús) de la; Hernandez-Sanchez, M. (María); Llorente-González, S. (Sara); Garcia-Layana, A. (Alfredo); Ochoa, I. (Idoia); Fernandez-Robredo, P. (Patricia); Recalde, S. (Sergio)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 36months from start of anti-VEGF treatment, using only data from the first 12months. 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 36months. Conclusion: This study demonstrates the potential of ML techniques in predicting the development of fibrosis and atrophy in nAMD patients receiving longterm 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.
- Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains(Rockefeller University Press, 2007-06-11) Rodriguez-de-Cordoba, S. (Santiago); Cook, H.T. (H. Terence); Garcia-Layana, A. (Alfredo); Pickering, M.C. (Matthew C.); Goicoechea-de-Jorge, E. (Elena); Walport, M.J. (Mark J.); Martinez-Barricarte, R. (Rubén); Moss, J. (Jill); Botto, M. (Marina); Recalde, S. (Sergio); Rose, K.L. (Kirsten L.)Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype-phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.
- Current treatment limitations in age-related macular degeneration and future approaches based on cell therapy and tissue engineering(Hindawi Publishing Corporation, 2014) Groll, J. (Jürgen); Johnen, S. (S.); Gama, N. (N.); Sancho, A. (A.); Garcia-Layana, A. (Alfredo); Thumann, G. (Gabriele); Fernandez-Robredo, P. (Patricia); Recalde, S. (Sergio)Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. With an ageing population, it is anticipated that the number of AMD cases will increase dramatically, making a solution to this debilitating disease an urgent requirement for the socioeconomic future of the European Union and worldwide. The present paper reviews the limitations of the current therapies as well as the socioeconomic impact of the AMD. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options show several side effects, are of high cost, and only treat the consequence, not the cause of the pathology. For that reason, many options involving cell therapy mainly based on retinal and iris pigment epithelium cells as well as stem cells are being tested. Moreover, tissue engineering strategies to design and manufacture scaffolds to mimic Bruch's membrane are very diverse and under investigation. Both alternative therapies are aimed to prevent and/or cure AMD and are reviewed herein.
- Matrix metalloproteinase 13 is associated with age-related choroidal neovascularization(2023) González-Zamora, J. (Jorge); Montoliu-Antón, A. (Ana); Llorente-González, S. (Sara); Garcia-Layana, A. (Alfredo); Bilbao-Malavé, V. (Valentina); Bezunartea, J. (Jaione); Fernandez-Robredo, P. (Patricia); Hernandez, M. (María); Recalde, S. (Sergio)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.
- A higher proportion of eicosapentaenoic acid (EPA) when combined with docosahexaenoic acid (DHA) in omega-3 dietary supplements provides higher antioxidant effects in human retinal cells(MDPI, 2020) Saenz-de-Viteri, M. (Manuel); González-Zamora, J. (Jorge); Garcia-Garcia, L. (Laura); Ispizua, N. (Nahia); Garcia-Layana, A. (Alfredo); Bilbao-Malavé, V. (Valentina); Fernandez-Robredo, P. (Patricia); Hernandez, M. (María); Recalde, S. (Sergio)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.
- Effect of lutein and antioxidant supplementation on VEGF expression, MMP-2 activity, and ultrastructural alterations in apolipoprotein E-deficient mouse(Hindawi Publishing Corporation, 2013) Sadaba-Echarri, L.M. (Luis M.); Rodriguez, J.A. (José Antonio); Garcia-Layana, A. (Alfredo); Salinas-Alaman, A. (Ángel); Fernandez-Robredo, P. (Patricia); Recalde, S. (Sergio)Oxidative stress is involved in the pathogenesis of several diseases such as atherosclerosis and age-related macular degeneration (AMD). ApoE-deficient mice (apoE(-/-)) are a well-established model of genetic hypercholesterolemia and develop retinal alterations similar to those found in humans with AMD. Thus supplementation with lutein or multivitamin plus lutein and glutathione complex (MV) could prevent the onset of these alterations. ApoE(-/-) mice (n = 40, 3 months old) were treated daily for 3 months with lutein (AE-LUT) or MV (two doses): AE-MV15 (15 mg/kg/day) and AE-MV50 (50 mg/kg/day) and were compared to controls with vehicle (AE-C). Wild-type mice (n = 10) were also used as control (WT-C). ApoE(-/-) mice showed higher retinal lipid peroxidation and increased VEGF expression and MMP-2 activity, associated with ultrastructural alterations such as basal laminar deposits, vacuoles, and an increase in Bruch's membrane thickness. While lutein alone partially prevented the alterations observed in apoE(-/-) mice, MV treatment substantially reduced VEGF levels and MMP-2 activity and ameliorated the retinal morphological alterations. These results suggest that oxidative stress in addition to an increased expression and activity of proangiogenic factors could participate in the onset or development of retinal alterations of apoE(-/-) mice. Moreover, these changes could be prevented by efficient antioxidant treatments.
- Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis(WB Saunders, 2008) Banales, J.M. (Jesús M.); Oude-Elferink, R.P.J. (Ronald P.J.); Salas, J.T. (January T.); Sarvide, S. (Sarai); Uriarte, I. (Iker); Medina, J.F. (Juan Francisco); Prieto, J. (Jesús); Ferrer, A. (Álex); Recalde, S. (Sergio)BACKGROUND & AIMS: Cl(-)/HCO(3)(-) anion exchanger 2 (AE2) is involved in intracellular pH (pH(i)) regulation and transepithelial acid-base transport, including secretin-stimulated biliary bicarbonate excretion. AE2 gene expression was found to be reduced in liver biopsy specimens and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic nonsuppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. In mice with widespread Ae2 gene disruption, we previously reported altered spermiogenesis and reduced gastric acid secretion. We now describe the hepatobiliary and immunologic changes observed in these Ae2(a.b)-deficient mice. METHODS: In this murine model, splenocyte pH(i) and T-cell populations were studied by flow cytometry. CD3-stimulated cytokine secretion was estimated using cytokine arrays. AMA were evaluated by immunoblotting and proteomics. Hepatobiliary changes were assessed by immunohistopathology, flow cytometry, and serum biochemistry. Cholangiocyte gene expression was analyzed by real-time polymerase chain reaction. RESULTS: Ae2(a,b)(-/-) mice exhibit splenomegaly, elevated pH(i) in splenocytes, increased production of interleukin-12p70 and interferon gamma, expanded CD8(+) T-cell population, and under represented CD4(+)FoxP3(+)/regulatory T cells. Most Ae2(a,b)(-/-) mice tested positively for AMA, showing increased serum levels of immunoglobulin M and G, and liver-specific alkaline phosphatase. About one third of Ae2(a,b)(-/-) mice had extensive portal inflammation with CD8(+) and CD4(+) T lymphocytes surrounding damaged bile ducts. Cholangiocytes isolated from Ae2(a,b)(-/-) mice showed gene expression changes compatible with oxidative stress and increased antigen presentation. CONCLUSIONS: Ae2 deficiency alters pH(i) homeostasis in immunocytes and gene expression profile in cholangiocytes, leading to immunologic and hepatobiliary changes that resemble PBC.