RESUMO
Ischemia/reperfusion is known to greatly increase oxidative stress in the penumbra, which results in brain damage. Integrin αvß3 is selectively up-regulated with ischemic injury to the brain and remains elevated throughout reperfusion. We determined whether or not a new compound biotinylated-LXW7-ceria nanoparticle (CeNP) (bLXW7-CeNP) plays a role in brain protection in the rat model of middle cerebral artery occlusion/reperfusion and shows better effects than CeNPs alone in improving the outcomes of focal oxidative stress and apoptosis more effectively. Male Sprague-Dawley rats were subjected to focal cerebral ischemia for 2 h followed by a 24-h reperfusion. Drug treatment was intravenously administered via the caudal vein 1 h after occlusion. Rats were randomly divided into the following 4 groups: bLXW7-CeNP treatment group (0.5 mg/kg); CeNP treatment group (0.5 mg/kg); control saline group; and sham group. Brains were harvested 24 h after reperfusion, and the neurologic deficit scores, infarction volume, blood-brain barrier (BBB) disruption, and the level of oxidative stress and apoptosis were determined. Results showed that the bLXW7-CeNP and CeNP treatments could improve neurologic deficit scores, infarction volume, BBB disruption, and the level of oxidative stress and apoptosis. Compound bLXW7-CeNP treatment exhibited better effects than CeNp treatment and showed remarkable statistical differences in the infarction volume, the degree of BBB breakdown, the apoptosis and oxidative stress, apart from neurologic deficit scores. Thus, we concluded that bLXW7-CeNP protects against acute cerebral ischemia/reperfusion injury. BLXW7, as a ligand of integrin αvß3, may be able to effectively localize the anti-oxidant CeNPs to the ischemic penumbra region, which may provide more adequate opportunities for CeNPs to exert anti-oxidative stress effects and subsequently reduce apoptosis in acute cerebral ischemia/reperfusion.
Assuntos
Antioxidantes/uso terapêutico , Cério/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Nanopartículas/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Apoptose , Barreira Hematoencefálica/metabolismo , Cério/administração & dosagem , Cério/farmacocinética , Combinação de Medicamentos , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Estresse Oxidativo , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
The antisense transcript long non-coding RNA (lncRNA) (antisense non-coding RNA in the INK4 locus, ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF). In the context of gene regulation, ANRIL is responsible for directly recruiting polycomb group (PcG) proteins, including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2), to modify the epigenetic chromatin state and subsequently inhibit gene expression in cis-regulation. On the other hand, previous reports have indicated that ANRIL is capable of binding to a specific site or sequence, including the Alu element, E2F transcription factor 1 (E2F1), and CCCTC-binding factor (CTCF), to achieve trans-regulation functions. In addition to its function in cell proliferation, adhesion and apoptosis, ANRIL is very closely associated with atherosclerosis- related diseases. The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis. Linear transcripts have been shown to be a risk factor for atherosclerosis, whereas circular transcripts are protective against atherosclerosis. Furthermore, ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation, which is considered to be one of the causes of atherosclerosis. Collectively, ANRIL plays an important role in the formation of atherosclerosis, and the artificial modification of ANRIL transcripts should be considered following the development of this disease.
Assuntos
Aterosclerose/genética , Inibidor de Quinase Dependente de Ciclina p15/genética , Epigênese Genética , Predisposição Genética para Doença , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Processamento Alternativo , Elementos Alu , Aterosclerose/metabolismo , Aterosclerose/patologia , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Cromossomos Humanos Par 9 , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Humanos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
The antisense transcript long non-coding RNA (1ncRNA) (antisense non-coding RNA in the INK4 locus,ANRIL) is an antisense of the cyclin-dependent kinase inhibitor 2B (CDKN2B) gene on chromosome 9p21 that contains an overlapping 299-bp region and shares a bidirectional promoter with alternate open reading frame (ARF).In the context of gene regulation,ANRIL is responsible for directly recruiting polycomb group (PcG) proteins,including polycomb repressive complex-1 (PRC-1) and polycomb repressive complex-2 (PRC-2),to modify the epigenetic chrornatin state and subsequently inhibit gene expression in cis-regulation.On the other hand,previous reports have indicated that ANRIL is capable of binding to a specific site or sequence,including the Alu element,E2F transcription factor 1 (E2F1),and CCCTC-binding factor (CTCF),to achieve trans-regulation functions.In addition to its function in cell proliferation,adhesion and apoptosis,ANRIL is very closely associated with atherosclerosis-related diseases.The different transcripts and the SNPs that are related to atherosclerotic vascular diseases (ASVD-SNPs) are inextricably linked to the development and progression of atherosclerosis.Linear transcripts have been shown to be a risk factor for atherosclerosis,whereas circular transcripts are protective against atherosclerosis.Furthermore,ANRIL also acts as a component of the inflammatory pathway involved in the regulation of inflammation,which is considered to be one of the causes of atherosclerosis.Collectively,ANRIL plays an important role in the formation of atherosclerosis,and the artificial modification of ANRIL transcripts should be considered following the development of this disease.
