RESUMO
Bronchopulmonary dysplasia (BPD) is characterized by lifelong obstructive lung disease and profound, refractory bronchospasm. It is observed among survivors of premature birth who have been treated with prolonged supplemental oxygen. Therapeutic options are limited. Using a neonatal mouse model of BPD, we show that hyperoxia increases activity and expression of a mediator of endogenous bronchoconstriction, S-nitrosoglutathione (GSNO) reductase. MicroRNA-342-3p, predicted in silico and shown in this study in vitro to suppress expression of GSNO reductase, was decreased in hyperoxia-exposed pups. Both pretreatment with aerosolized GSNO and inhibition of GSNO reductase attenuated airway hyperresponsiveness in vivo among juvenile and adult mice exposed to neonatal hyperoxia. Our data suggest that neonatal hyperoxia exposure causes detrimental effects on airway hyperreactivity through microRNA-342-3p-mediated upregulation of GSNO reductase expression. Furthermore, our data demonstrate that this adverse effect can be overcome by supplementing its substrate, GSNO, or by inhibiting the enzyme itself. Rates of BPD have not improved over the past two decades; nor have new therapies been developed. GSNO-based therapies are a novel treatment of the respiratory problems that patients with BPD experience.
Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Hipersensibilidade Respiratória/tratamento farmacológico , S-Nitrosoglutationa/uso terapêutico , Aerossóis/farmacologia , Aldeído Oxirredutases/antagonistas & inibidores , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Animais , Animais Recém-Nascidos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/patologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperóxia/complicações , Hiperóxia/tratamento farmacológico , Hiperóxia/genética , Hiperóxia/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Hipersensibilidade Respiratória/complicações , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/patologia , S-Nitrosoglutationa/farmacologia , TransfecçãoRESUMO
Pyruvate,orthophosphate dikinase (PPDK) plays a controlling role in the PEP-regeneration phase of the C(4) photosynthetic pathway. Earlier studies have fully documented its biochemical properties and its post-translational regulation by the PPDK regulatory protein (PDRP). However, the question of its evolution into the C(4) pathway has, until recently, received little attention. One assumption concerning this evolution is that changes in catalytic and regulatory properties of PPDK were necessary for the enzyme to fulfil its role in the C(4) pathway. In this study, the functional evolution of PPDK from its ancient origins in the Archaea to its ascension as a photosynthetic enzyme in modern C(4) angiosperms is reviewed. This analysis is accompanied by a comparative investigation into key catalytic and regulatory properties of a C(3) PPDK isoform from Arabidopsis and the C(4) PPDK isoform from Zea mays. From these analyses, it is proposed that PPDK first became functionally seated in C(3) plants as an ancillary glycolytic enzyme and that its transition into a C(4) pathway enzyme involved only minor changes in enzyme properties per se.
Assuntos
Archaea/enzimologia , Magnoliopsida/enzimologia , Magnoliopsida/genética , Piruvato Ortofosfato Diquinase/genética , Piruvato Ortofosfato Diquinase/metabolismo , Trifosfato de Adenosina/metabolismo , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Archaea/genética , Archaea/metabolismo , Evolução Biológica , Cloroplastos/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Concentração de Íons de Hidrogênio , Luz , Magnoliopsida/metabolismo , Fosfoenolpiruvato/metabolismo , Fosforilação , Fotossíntese/genética , Fotossíntese/fisiologia , Folhas de Planta/enzimologia , Folhas de Planta/genética , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/enzimologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvatos/metabolismo , Fatores de Tempo , Zea mays/enzimologia , Zea mays/genética , Zea mays/metabolismoRESUMO
The data reported in the Technical Comments by Fitz et al., Price et al., Tesseur et al., and Veeraraghavalu et al. replicate and validate our central conclusion that bexarotene stimulates the clearance of soluble ß-amyloid peptides and results in the reversal of behavioral deficits in mouse models of Alzheimer's disease (AD). The basis of the inability to reproduce the drug-stimulated microglial-mediated reduction in plaque burden is unexplained. However, we concluded that plaque burden is functionally unrelated to improved cognition and memory elicited by bexarotene.