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1.
J Gene Med ; 22(11): e3259, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32776410

RESUMO

BACKGROUND: pH-sensitive peptides are a relatively new strategy for conquering the poor endosomal release of cationic polymer-mediated transfection. Modification of antimicrobial peptides by exchanging positively-charged residues with negatively-charged glutamic acid residues (Glu) greatly improves its lytic activity at the endosomal pH, which could improve cationic polymer-mediated transfection. METHODS: In the present study, we investigated the effect of the number of Glu substituted for positively-charged residues on the endosomal escape activity of AR-23 and the ability of mutated AR-23 with respect to enhancing cationic polymer-mediated transfection. Three analogs were synthesized by replacing the positively-charged residues in the AR-23 sequence with Glu one-by-one. RESULTS: The pH-sensitive lysis ability of the peptides, the effect of peptides on the physicochemical characteristics, the intracellular trafficking, the transfection efficiency and the cytotoxicity of the polyplexes were determined. Increased lytic activity of peptides was observed with the increased number of Glu replacement in the AR-23 sequence at acidic pH. The number of Glu substituted for positively-charged residues of AR-23 dramatically affects its lysis ability at neutral pH. Triple-Glu substitution in the AR-23 sequence greatly improved poly(l-lysine)-mediated gene transfection efficiency at the same time as maintaining low cytotoxicity. CONCLUSIONS: The results indicate that replacement of positively-charged residues with sufficient Glu residues may be considered as a method for designing pH-sensitive peptides, which could be applied as potential enhancers for improving cationic polymer-mediated transfection.


Assuntos
DNA/administração & dosagem , Endossomos/efeitos dos fármacos , Terapia Genética , Hemólise/efeitos dos fármacos , Neoplasias/terapia , Polilisina/química , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Apoptose , Proliferação de Células , Técnicas de Transferência de Genes , Humanos , Concentração de Íons de Hidrogênio , Neoplasias/genética , Neoplasias/patologia , Proteínas Citotóxicas Formadoras de Poros/química , Células Tumorais Cultivadas
2.
J Zhejiang Univ Sci B ; 15(12): 1032-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25471832

RESUMO

The p53 tumor suppressor protein coordinates the cellular responses to a broad range of cellular stresses, leading to DNA repair, cell cycle arrest or apoptosis. The stability of p53 is essential for its tumor suppressor function, which is tightly controlled by ubiquitin-dependent degradation primarily through its negative regulator murine double minute 2 (Mdm2). To better understand the regulation of p53, we tested the interaction between p53 and USP11 using co-immunoprecipitation. The results show that USP11, an ubiquitin-specific protease, forms specific complexes with p53 and stabilizes p53 by deubiquitinating it. Moreover, down-regulation of USP11 dramatically attenuated p53 induction in response to DNA damage stress. These findings reveal that USP11 is a novel regulator of p53, which is required for p53 activation in response to DNA damage.


Assuntos
Dano ao DNA , Tioléster Hidrolases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina/metabolismo , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Cicloeximida/química , Reparo do DNA , Células HEK293 , Humanos , Plasmídeos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Ubiquitinação
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