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MOTIVATION: Many ophthalmic disease biomarkers have been identified through comprehensive multiomics profiling, and hold significant potential in advancing the diagnosis, prognosis, and management of diseases. Meanwhile, the eye itself serves as a natural biomarker for several systemic diseases including neurological, renal, and cardiovascular systems. We aimed to collect and standardize this eye biomarkers information and construct the eye biomarker database (EBD) to provide ophthalmologists with a platform to search, analyze, and download these eye biomarker data. RESULTS: In this study, we present the EBD
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Investigación Biomédica , Biomarcadores , Bases de Datos Factuales , MultiómicaRESUMEN
PITX2 and FOXC1 are the most common pathogenic genes associated with Axenfeld-Rieger syndrome (ARS). In this study, we aimed to explore the variation spectrum of PITX2 and FOXC1 and their associated phenotype based on data from our study and previously reported literatures. Whole exome sequencing was performed on eight probands in our study. Multistep bioinformatic and co-segregation analyses were performed to detect pathogenic variants. Genotype-phenotype correlations of PITX2 and FOXC1 and the differences between them were determined. We detected three variants of FOXC1 and two variants of PITX2 in five unrelated families with ARS. Macular retinoschisis had been observed in AR1 with variant in PITX2 and it is not reported before. Additionally, a review of published literature and our study led to the identification of 593 families with variants of PITX2 or FOXC1, including 316 families with heterozygous variants in FOXC1, 251 families with heterozygous variants in PITX2, 13 families with variants in double genes, seven families with homozygous or compound heterozygous variants in FOXC1, and six families with variants in ADAMTS17, PRDM5, COL4A1 or CYP1B1. Significant differences were observed between the prevalence of missense and in-frame, truncation, and large deletion variants in PITX2 (32.00%, 42.67%, and 25.33%, respectively) and FOXC1 (34.49%, 35.13%, 30.38%, respectively) (p = 1.16E-43). Enrichment and frequency analyses revealed that missense variants were concentrated in the forkhead domain of FOXC1 (76.14%) and homeodomain of PITX2 (87.50%). The percentage of Caucasians with variants in FOXC1 was significantly higher than that of PITX2 (p = 2.00E-2). Significant differences between PITX2 and FOXC1 were observed in glaucoma (p = 3.00E-2), corectopia (p = 3.050E-6), and polycoria (p = 5.21E-08). Additionally, we observed a significant difference in best-corrected visual acuity (BCVA) between FOXC1 and PITX2 (p = 3.80E-2). Among all the family members with PITX2 or FOXC1 variants, the prevalence of systemic abnormalities was significantly higher in PITX2 than in FOXC1 (89.16% vs. 58.77%, p = 5.44E-17). In conclusion, macular retinoschisis as a novel phenotype had been observed in patient with variant in PITX2. Significant differences were detected in phenotypes and genotypes between PITX2 and FOXC1.
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Anomalías del Ojo , Enfermedades Hereditarias del Ojo , Proteínas de Homeodominio , Humanos , Segmento Anterior del Ojo , Anomalías del Ojo/genética , Enfermedades Hereditarias del Ojo/genética , Factores de Transcripción Forkhead/genética , Estudios de Asociación Genética , Proteínas de Homeodominio/genética , Mutación , Linaje , Retinosquisis , Proteína del Homeodomínio PITX2RESUMEN
Diabetic retinopathy (DR) has been considered to involve mitochondrial alterations and be related to the nucleotide-binding oligomerization domain-like receptors 3 (NLRP3) inflammasome activation. The voltage-dependent anion channel 1 (VDAC1) protein is one of the key proteins that regulates the metabolic and energetic functions of the mitochondria. To explore the involvement of VDAC1 in mitophagy regulation of NLRP3 inflammasome activation under high-glucose (HG) conditions, this study examined expressions of VDAC1, mitochondrial function and mitophagy-related proteins, and NLRP3 inflammasome-related proteins in human retinal capillary endothelial cells (HRCECs) cultured with 30 mM of glucose in the presence or absence of mitophagy inhibitor (Mdivi-1) using Western blot. Mitochondrial membrane potential and mitochondrial reactive oxygen species (mtROS) were detected using flow cytometry. GFP-tagged pAdTrack-VDAC1 adenovirus was used to overexpress VDAC1. Cell biological behaviors, including proliferation, migration, tubule formation, and apoptosis, were also observed. Our results showed that when compared to the normal glucose and high mannitol groups, increased amounts of mitochondrial fragments, reduced mitochondrial membrane potential, increased expression of mitochondrial fission protein Drp 1, decreased expression of mitochondrial fusion protein Mfn 2, accumulation of mtROS, and activation of the NLRP3 inflammasome were observed in the HG group. Meanwhile, HG markedly reduced the protein expressions of PINK1, Parkin and VDAC1. Inhibition of mitophagy reduced PINK1 expression, enhanced NLRP3 expression, but failed to alter VDAC1. VDAC1 overexpression promoted PINK1 expression, inhibited NLRP3 activation and changed the cell biological behaviors under HG conditions. These findings demonstrate that VDAC1-mediated mitophagy plays a crucial role in regulating NLRP3 inflammasome activation in retinal capillary endothelial cells under HG conditions, suggesting that VDAC1 may be a potential target for preventing or treating DR.
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Células Endoteliales/metabolismo , Regulación de la Expresión Génica , Inflamasomas/genética , Mitofagia/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Canal Aniónico 1 Dependiente del Voltaje/biosíntesis , Canal Aniónico 1 Dependiente del Voltaje/genética , Apoptosis , Capilares/metabolismo , Capilares/ultraestructura , Células Cultivadas , Células Endoteliales/ultraestructura , Endotelio Vascular/metabolismo , Endotelio Vascular/ultraestructura , Humanos , Inflamasomas/metabolismo , Potencial de la Membrana Mitocondrial/fisiología , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Proteína con Dominio Pirina 3 de la Familia NLR/biosíntesis , ARN/genética , Vasos Retinianos/metabolismo , Vasos Retinianos/ultraestructuraRESUMEN
PURPOSE: We previously found the mutation frequency of cytoskeleton-associated protein 2 (CKAP2) was significantly increased in proliferative diabetic retinopathy (PDR) patients through whole exome sequencing. The present study was conducted to explore the expression and possible mechanism of CKAP2 in PDR patients and human retinal capillary endothelial cells (HRCECs) under high-glucose (HG) conditions. METHODS: Expression of CKAP2 and p53 in the vitreous fluid and fibrovascular membrane (FVM) of PDR patients and HRCECs under HG conditions was observed. Cell proliferation, migration and tubule formation were assessed. Ranibizumab and siRNA transfection were used in the inhibition assay. RESULTS: CKAP2 and p53 were significantly increased in the ocular tissues of PDR patients. HG combined with VEGF treatment significantly up-regulated expression of CKAP2 and p53 in HRCECs. Inhibition of CKAP2 attenuated the abilities of cell proliferation, migration and tube formation under HG conditions. Blocking VEGF or p53 significantly decreased CKAP2 expression, whereas inhibition of CKAP2 failed to alter the level of VEGF or p53. CONCLUSIONS: CKAP2 is involved in the pathogenesis of PDR and regulated by VEGF and p53 under HG conditions.
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Proteínas del Citoesqueleto/metabolismo , Retinopatía Diabética/metabolismo , Retina/citología , Proteína p53 Supresora de Tumor/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Anciano , Línea Celular , Proliferación Celular/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Glucosa/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Ranibizumab/farmacología , Retina/efectos de los fármacos , Retina/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
The diversity of bacterial communities and their metabolic function in the waters of the Weihe River Basin are of great significance for water pollution remediation, ecological restoration, and water quality assessment. Illumina MiSeq high-throughput sequencing technology was applied to study the bacterial community distribution characteristics after the comprehensive treatment of the Shaanxi part of the Weihe River Basin. Furthermore, the correlation between the bacterial communities and environmental factors was analyzed by redundancy analysis (RDA), and the PICRUSt method was adopted to evaluate the ecological function of the bacterial communities. The results showed that Proteobacteria, Actinobacteria, Cyanobacteria, and Bacteroidetes were the main bacterial communities in the water, accounting for 85% of the total microbial community. Additionally, these bacteria showed a significant positive correlation (P=0.02, <0.05) with the TP, NO2--N, NO3--N, and TN. The bacteria community richness of water samples collected in Zaohe River was the lowest of all samples, while which in the downstream of the junction of Bahe river and Weihe river was the highest. In addition, water in the Weihe River Basin had great impact on the endocrine systems of aquatic organisms, and also had a possibility of infectious diseases for humans. Our research provides a theoretical basis for the safe and sustainable development of the water environment in the Weihe River Basin.