Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Pharmaceutics ; 15(1)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36678896

RESUMO

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.

2.
Biochim Biophys Acta Biomembr ; 1861(10): 182994, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31145899

RESUMO

Research on lipid/drug interactions at the nanoscale underpins the emergence of synergistic mechanisms for topical drug administration. The structural understanding of bio-mimetic systems employing 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as a lung surfactant model mixed with antibiotics, as well as their biophysical properties, is of critical importance to modulate the effectiveness of therapeutic agents released directly to the airways. In this paper, we investigate the structural details of the interaction between Levofloxacin, 'a respiratory quinolone', and the macrolide Clarithromycin, with DPPC monolayers at the air-water interface, using a combination of Brewster angle microscopy, polarization modulation-infrared reflection-adsorption spectroscopy (PM-IRRAS), surface pressure isotherms and neutron reflectometry (NR) to describe the structural details of this interaction. The results allowed association of changes in the π-A isotherm profile with changes in the molecular organization and the co-localization of the antibiotics within the lipid monolayer by NR measurements. Overall, both antibiotics are able to increase the thickness of the acyl tails in DPPC monolayers with a corresponding reduction in tail tilt as well as to interact with the phospholipid headgroups as shown by PM-IRRAS experiments. The effects on the DPPC monolayers are correlated with the physical-chemical properties of each antibiotic and dependent on its concentration.


Assuntos
1,2-Dipalmitoilfosfatidilcolina/análogos & derivados , Claritromicina/química , Levofloxacino/química , 1,2-Dipalmitoilfosfatidilcolina/química , 1,2-Dipalmitoilfosfatidilcolina/metabolismo , Adsorção , Ar , Claritromicina/metabolismo , Levofloxacino/metabolismo , Bicamadas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Membranas Artificiais , Microscopia/métodos , Modelos Biológicos , Fosfolipídeos/química , Surfactantes Pulmonares/química , Espectrofotometria Infravermelho/métodos , Propriedades de Superfície/efeitos dos fármacos , Água/química
3.
Colloids Surf B Biointerfaces ; 158: 689-696, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28778052

RESUMO

The molecular-level interaction of levofloxacin with lung surfactant was investigated using Langmuir monolayers and atomistic molecular dynamics (MD) simulations. In the simulation, the DPPC/POPC mixed monolayer was used as a lung surfactant model and the molecules of levofloxacin were placed at the air-lipid interface to mimic the adsorption process on the lung surfactant model. The simulation results indicate that amphoteric levofloxacin expands the lung surfactant, also stabilizing the film for levofloxacin fractions until 10% w/w at least. The Langmuir monolayers made with the lung surfactant Curosurf had expanded isotherms upon incorporation of levofloxacin, without changes in monolayer elasticity. In fact, levofloxacin induced film stability with increased collapse pressures in the Curosurf isotherms and delayed the phase transition, according to Brewster angle microscopy (BAM) imaging. Using polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS), we found that levofloxacin is preferentially located in the head group region, inducing an increased organization of the Curosurf film. This location of levofloxacin was confirmed with MD simulations. The stability inferred demonstrates that the lung surfactant can be used as a drug delivery system for the administration via inhalation or intratracheal instillation of levofloxacin to treat lung diseases such as pneumonia and respiratory distress syndrome.


Assuntos
Levofloxacino/química , Água/química , 1,2-Dipalmitoilfosfatidilcolina/química , Simulação de Dinâmica Molecular , Surfactantes Pulmonares/química , Espectrofotometria Infravermelho , Propriedades de Superfície , Tensoativos/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...