RESUMEN
Diabetic retinopathy is the most common reason for blindness among employed adults worldwide. Hyperglycemia and the overaccumulation of vascular endothelial growth factor (VEGF) lead to diabetic retinopathy, pathological angiogenesis in diabetic retinopathy, and consequent visual impairment. Expression levels of thioredoxin-interacting protein (TXNIP) substantially increase in retinal endothelial cells in diabetic circumstances. The part of TXNIP in retinal angiogenesis combined with diabetes remains unclear. This study examined the effect of reduced TXNIP expression levels and determined how it affects diabetic retinal angiogenesis. Display of human retinal vascular endothelial cells (HRECs) to moderately high glucose (MHG) encouraged tube formation and cell migration, not cell proliferation. In response to MHG conditions, in HRECs, TXNIP knockdown inhibited the production of reactive oxygen species (ROS), cell migration, tube formation, and the Akt/mTOR activation pathway. In addition, gene silencing of TXNIP decreased the VEGF-triggered angiogenic response in HRECs by preventing activation of both VEGF receptor 2 and the downstream components of the Akt/mTOR pathway signaling. Furthermore, TXNIP knockout mice reduced VEGF-induced or VEGF- and MHG-triggered ex vivo retinal angiogenesis compared to wild-type mice. Finally, our findings revealed that TXNIP knockdown suppressed VEGF- and MHG-triggered angiogenic responses in HRECs and mouse retinas, indicating that TXNIP is a promising therapeutic window against the proliferation of diabetic patients' retinopathy.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Humanos , Ratones , Animales , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/farmacología , Células Endoteliales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Glucosa/farmacología , Glucosa/metabolismoRESUMEN
Long non-coding RNA (lncRNA) miR-17-92a-1 cluster host gene (MIR17HG) is oncogenic in several cancers. This study was aimed to probe into its expression characteristics and biological functions in retinoblastoma (RB) and to explore its role in regulating microRNA-155-5p (miR-155-5p) and hypoxia-inducible factor-1α (HIF-1α). In this study, paired RB samples were collected, and expression levels of MIR17HG, miR-155-5p, and HIF-1α were examined by quantitative real-time polymerase chain reaction (qRT-PCR); the proliferation, migration, and invasion of RB cells were detected by cell counting kit-8 (CCK-8) and transwell assays; qRT-PCR and Western blot were used to analyze the changes of miR-155-5p expression and HIF-1α expression. We found that MIR17HG expression was significantly up-regulated in RB samples, which was negatively correlated with miR-155-5p expression. The proliferation, migration, and invasion of RB cells were promoted by MIR17HG overexpression but inhibited by MIR17HG knockdown. MiR-155-5p suppressed the proliferation, migration, and invasion of RB cells. MIR17HG positively regulated the expression of HIF-1α on both mRNA and protein levels in RB cells. Additionally, miR-155-5p was identified as a target of MIR17HG. The data in this study suggest that MIR17HG exerts oncogenic effects in RB via the miR-155-5p/HIF-1α axis.
Asunto(s)
MicroARNs , ARN Largo no Codificante , Neoplasias de la Retina , Retinoblastoma , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , Neoplasias de la Retina/genética , Retinoblastoma/genética , Regulación hacia ArribaRESUMEN
The present anti-angiogenic therapies for neovascular age-related macular degeneration require effective drug delivery systems for transfer drug molecules. Ranibizumab is an active humanized monoclonal antibody that counteracts active forms of vascular endothelial growth factor A in the neovascular age-related macular degeneration therapy. The development of ranibizumab-related therapies, we have designed the effective drug career with engineered magnetic nanoparticles (Fe3O4) as a facile platform of ranibizumab delivery for the treatment of neovascular age-related macular degeneration. Ranibizumab conjugated iron oxide (Fe3O4)/PEGylated poly lactide-co-glycolide (PEG-PLGA) was successfully designed and the synthesized materials are analyzed different analytical techniques. The microscopic techniques (Scanning Electron Microscopy (SEM) & Transmission Electron Microscopy (TEM)) are clearly displayed that spherical nanoparticles into the PEG-PLGA matrix and presence of elements and chemical interactions confirmed by the results of energy dispersive X-ray analysis (EDX) and Fourier trans-form infrared (FTIR) spectroscopic methods. The in vitro anti-angiogenic evaluation of Fe3O4/PEG-PLGA polymer nanomaterial efficiently inhibits the tube formation in the Matrigel-based assay method by using human umbilical vein endothelial cells. Ranibizumab treated Fe3O4/PEG-PLGA polymer nanomaterials not disturbed cell proliferation and the results could not display the any significant differences in human endothelial cells. The present investigated results describe that Fe3O4/PEG-PLGA polymer nanomaterials can be highly favorable and novel formulation for the treatment of neovascular age-related macular degeneration.