RESUMO
Aim: To investigate the effect of incorporating bis(monoacylglycerol)phosphate (BMP) lipid into a lipid nanoparticle and the functional transport of mRNA by the formulated nanoparticles in vivo. Materials & methods: The nanoparticles were prepared from ionizable lipid, 1,2-distearoyl-sn-glycerol-3-phosphocholine, cholesterol, 1,2-dimyristoyl-sn-glycerol PEG 2000, BMP and formulated mRNA encoding human erythropoietin. We measured the effect of BMP on physicochemical properties and impact on functional efficacy to transport mRNA to its target cells/tissue as measured by protein expression both in vitro and in vivo. Results: Lipid nanoparticles composed of BMP displayed increased endosomal membrane fusion and improved mRNA delivery to the cytosol. Conclusion: The results establish the foundation for future development of these nanoparticulated entities by designing new BMP derivatives and correlating structures to enhanced pharmacokinetic profiles.
Assuntos
Nanopartículas , Fosfatos , Humanos , Monoglicerídeos/metabolismo , Nanopartículas/química , RNA MensageiroRESUMO
The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-zeta/lambda and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Animais , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Deleção de Genes , Glucose/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Coração/fisiopatologia , Resistência à Insulina/genética , Estimativa de Kaplan-Meier , Fator Inibidor de Leucemia/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Camundongos Knockout , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genéticaRESUMO
Vascular endothelial growth factor D (VEGF-D) is a member of the VEGF/PDGF superfamily that has been implicated in angiogenesis and lymphangiogenesis. We have isolated a chick cDNA that shows homology with VEGF-D (also known as FIGF, c-fos-induced growth factor) of other species. Here, we describe the expression pattern of cVegf-D in chick embryos. In the limb buds, cVegf-D shows a dynamic expression pattern that is restricted to the mesenchyme of the posterior region. cVegf-D expression is also detected in the ectoderm and mesenchyme of the head region, somites, notochord and pharyngeal arches. We also report on the capability of Sonic hedgehog and retinoic acid to regulate cVegf-D expression.
