RESUMO
High blood glucose results in high glucose levels in retina, because GLUT1, the sole glucose transporter between blood and retina, transports more glucose when blood glucose is high. This is the ultimate cause of diabetic retinopathy. Knockdown of GLUT1 by intraocular injections of a pool of siRNAs directed against SLC2A1 mRNA which codes for GLUT1 significantly reduced mean retinal glucose levels in diabetic mice. Systemic treatment of diabetic mice with forskolin or genistein, which bind GLUT1 and inhibit glucose transport, significantly reduced retinal glucose to the same levels seen in non-diabetics. 1,9-Dideoxyforskolin, which binds GLUT1 but does not stimulate adenylate cyclase had an equivalent effect to that of forskolin regarding lowering retinal glucose in diabetics indicating that cyclic AMP is noncontributory. GLUT1 inhibitors also reduced glucose and glycohemoglobin levels in red blood cells providing a peripheral biomarker for the effect. In contrast, brain glucose levels were not increased in diabetics and not reduced by forskolin. Treatment of diabetics with forskolin prevented early biomarkers of diabetic retinopathy, including elevation of superoxide radicals, increased expression of the chaperone protein ß2 crystallin, and increased expression of vascular endothelial growth factor (VEGF). These data identify GLUT1 as a promising therapeutic target for prevention of diabetic retinopathy.
Assuntos
Diabetes Mellitus Experimental/terapia , Retinopatia Diabética/prevenção & controle , Transportador de Glucose Tipo 1/antagonistas & inibidores , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica , Colforsina/análogos & derivados , Colforsina/uso terapêutico , Eritrócitos/química , Eritrócitos/metabolismo , Técnicas de Silenciamento de Genes , Inativação Gênica , Genisteína/uso terapêutico , Glucose/análise , Transportador de Glucose Tipo 1/genética , Masculino , Camundongos , Inibidores de Proteínas Quinases/uso terapêutico , Retina/química , Retina/efeitos dos fármacos , Retina/metabolismo , Superóxidos/análise , Fator A de Crescimento do Endotélio Vascular/biossíntese , Cadeia B de beta-Cristalina/biossínteseRESUMO
PURPOSE: Magnetically controlled growing rod (MCGR) for the treatment of early-onset scoliosis (EOS) is a relatively innovative technique. MCGR benefits over traditional growing rods are known but limitations and complications are being revealed. The purpose of this study was to examine the importance of tissue depth on rod lengthening. METHODS: A single-institution retrospective review of 72 MCGR patients was performed. Ultrasound measured rod distraction. Differences in programmed and actual distraction, and complications were recorded. Tissue depths and achieved length were averaged and used to construct a regression to account for variability. RESULTS: Percentage of std and offset orientation rod lengthening relative to the programmed distraction was inversely proportional to rod depth (std R = 0.50, p = 0.002) (offset R = 0.60, p < 0.001). Expected std rod lengthening achieved decreased by 1.46%/mm depth. Expected offset rod lengthening achieved decreased by 1.68%/mm depth. 28 pts (38.9%) sustained complications. Age, sex, BMI, standard tissue depth, and/or offset tissue depth had no predictive ability with respect to complications sustained (overall model R = 0.31, p = 0.36). CONCLUSION: In a series of EOS surgical patients treated with MCGRs, the relationship between percentage of programmed lengthening achieved as well as total lengthening was inversely proportional to tissue depth of the rod. There was a trend towards increasing frequency of complications recorded with decreasing tissue depth though this was not significant. These data can help with surgical planning during MCGR placement.
Assuntos
Osteogênese por Distração , Escoliose , Humanos , Osteogênese por Distração/efeitos adversos , Reoperação , Estudos Retrospectivos , Escoliose/diagnóstico por imagem , Escoliose/etiologia , Escoliose/cirurgia , UltrassonografiaRESUMO
TM601 is a synthetic polypeptide with sequence derived from the venom of the scorpion Leiurus quinquestriatus that has anti-neoplastic activity. It has recently been demonstrated to bind annexin A2 on cultured tumor and vascular endothelial cells and to suppress blood vessel growth on chick chorioallantoic membrane. In this study, we investigated the effects of TM601 in models of ocular neovascularization (NV). When administered by intraocular injection, intravenous injections, or periocular injections, TM601 significantly suppressed the development of choroidal NV at rupture sites in Bruch's membrane. Treatment of established choroidal NV with TM601 caused apoptosis of endothelial cells and regression of the NV. TM601 suppressed ischemia-induced and vascular endothelial growth factor-induced retinal NV and reduced excess vascular permeability induced by vascular endothelial growth factor. Immunostaining with an antibody directed against TM601 showed that after intraocular or periocular injection, TM601 selectively bound to choroidal or retinal NV and co-localized with annexin A2, which is undetectable in normal retinal and choroidal vessels, but is upregulated in endothelial cells participating in choroidal or retinal NV. Intraocular injection of plasminogen or tissue plasminogen activator, which like TM601 bind to annexin A2, also suppressed retinal NV. This study supports the hypothesis that annexin A2 is an important target for treatment of neovascular diseases and suggests that TM601, through its interaction with annexin A2, causes suppression and regression of ocular NV and reduces vascular leakage and thus may provide a new treatment for blinding diseases such as neovascular age-related macular degeneration and diabetic retinopathy.