Assuntos
Apoptose/genética , Autofagia/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , MicroRNAs/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Linhagem Celular Tumoral , Biologia Computacional , Regulação para Baixo/genética , Técnicas de Silenciamento de Genes , HumanosRESUMO
Understanding the function and molecular relevance of distinct miRNAs in endothelial cells (ECs) paves avenues for possible therapeutic intervention by targeting epigenetic mechanisms in vascular endothelial dysfunction, one of the major complications of type 2 diabetes mellitus (T2DM). MiR-342-3p, an obesity-associated miRNA, has recently been shown to be significantly upregulated in human angiosarcoma compared to benign hemangioma, indicating its potential involvement as a proangiogenic factor. Herein, we show that endothelial miR-342-3p expression was significantly compromised in T2DM organisms and this inhibition powerfully blocked vasculogenesis in vivo by repressing endothelial proliferation and migration. From a mechanistic standpoint, miR-342-3p promoted the transactivation of fibroblast growth factor 11 (FGF11) by directly targeting its 3' untranslated regions (3'UTRs). Functionally, overexpression of exogenous FGF11 successfully rescued miR-342-3p deficiency-impaired endothelial proliferation and migration. Thus, perturbation of miR-342-3p/FGF11 cascade by hyperinsulinemia plays a causative role in the induction of vascular dysfunction in T2DM. Overall, the current study underscore an endothelial facet of miR-342-3p, which may operate as a novel epigenetic integrator linking adipogenic homeostasis and angiogenesis.
Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Fatores de Crescimento de Fibroblastos/genética , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/fisiopatologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperinsulinismo/genética , Hiperinsulinismo/patologia , Hiperinsulinismo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Neovascularização Patológica/genética , Neovascularização Patológica/fisiopatologia , Transdução de Sinais , Ativação TranscricionalRESUMO
The regulatory transcriptional factor PATZ1 is abnormally up-regulated in diabetic endothelial cells (ECs) where it acts as an anti-angiogenic factor via modulation of fatty acid-binding protein 4 (FABP4) signaling. The aim of the present work was to elucidate the upstream molecular events regulating PATZ1 expression in diabetic angiogenesis. The bioinformatics search for microRNAs (miRNAs) able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-24 since the multiple targets of miR-24, which have so far been identified in beta cells, cardiomyocytes and macrophages, are all involved in diabetic complications. miR-24 expression was significantly impaired in the ECs isolated from diabetic hearts. Functionally, endothelial migration was profoundly inhibited by miR-24 suppression in Ctrl ECs, whereas miR-24 overexpression by mimics treatment effectively restored the migration rate in diabetic ECs. Mechanistically, miR-24 directly targeted the 3'untranslated region (3'UTR) of PATZ1, and miR-24 accumulation potentiated endothelial migration by reducing the mRNA stability of PATZ1. Together, these results suggest a novel mechanism regulating endothelial PATZ1 expression based on the down-regulation of miR-24 expression caused by hyperglycemia. Interfering with PATZ1 expression via miRNAs or miRNA mimics could potentially represent a new way to target endothelial PATZ1-dependent signaling of vascular dysfunction in diabetes.
Assuntos
Domínio BTB-POZ , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Células Endoteliais/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Repressoras/metabolismo , Animais , Células Cultivadas , Angiopatias Diabéticas/prevenção & controle , Células Endoteliais/patologia , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To explore the human papilloma virus (HPV) infection and genotypes distribution in female patients with cervical intraepithelial neoplasia so as to provide rationales for preventing and treating HPV and developing HPV vaccine. METHODS: Polymerase chain reaction (PCR) amplification, flow-through hybridization and gene chip were used to identify 23 HPV genotypes in cervical cells collected from 823 female patients with cervical intraepithelial neoplasia at Third Municipal People's Hospital and Central Municipal Hospital during January 2011 and December 2013. RESULTS: Among them, HPV infections were detected in 47.51% (391/823). From 2011 to 2013, there was a trend of increase year by year and the difference was statistically significant (P < 0.05). With the greater degree of cervical intraepithelial neoplasia, LR-HPV and HR-HPV infection rate increased. And there were statistically significant differences (P < 0.05). And single or double genotype infection dominated (86.19%). Multiple genotype infection accounted for 0.51%. And 76.21% of HPV infections were high-risk genotypes and most of them belonged to HPV16. Otherwise, most low-risk genotypes were HPV6. Besides, HPV39 and HPV82 were not detected. CONCLUSION: HPV infections, particularly high-risk ones, are widespread among female patients with condyloma acuminatum or cervical erosion in Qingdao. Thus active clinical therapy should be provided.