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1.
Pharmaceutics ; 14(7)2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35890402

RESUMO

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia.

2.
J Med Chem ; 65(10): 7170-7192, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35546685

RESUMO

The identification of novel inhaled p38α/ß mitogen-activated protein kinases (MAPK) (MAPK14/11) inhibitors suitable for the treatment of pulmonary inflammatory conditions has been described. A rational drug design approach started from the identification of a novel tetrahydronaphthalene series, characterized by nanomolar inhibition of p38α with selectivity over p38γ and p38δ isoforms. SAR optimization of 1c is outlined, where improvements in potency against p38α and ligand-enzyme dissociation kinetics led to several compounds showing pronounced anti-inflammatory effects in vitro (inhibition of TNFα release). Targeting of the defined physicochemical properties allowed the identification of compounds 3h, 4e, and 4f, which showed, upon intratracheal instillation, low plasma levels, prolonged lung retention, and anti-inflammatory effects in a rat acute model of a bacterial endotoxin-induced pulmonary inflammation. Compound 4e, in particular, displayed remarkable efficacy and duration of action and was selected for progression in disease models of asthma and chronic obstructive pulmonary disease (COPD).


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Pneumonia , Inibidores de Proteínas Quinases , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Fosforilação , Pneumonia/tratamento farmacológico , Pneumonia/enzimologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
3.
Neurobiol Dis ; 121: 240-251, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30300675

RESUMO

Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and 15 mg/kg/24 h melatonin (proprietary formulation) administered at 2 h and 26 h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5 °C, 2-26 h) and vehicle (HT + V;n = 13); b) HT and 5 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-5;n = 4); c) HT and 15 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-15;n = 13). Intensive care was maintained for 48 h; brain MRS was acquired and cell death (TUNEL) evaluated at 48 h. Comparing HT + V with HT + Mel-5 and HT + Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24 h and 48 h was similar, ATP/phosphate pool was higher for HT + Mel-15 versus HT + V at 24 h (p = 0.038) but not 48 h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15 mg/kg melatonin group (HT + Mel-15 versus HT + V; p < 0.003) but not in the 5 mg/kg melatonin group (HT + Mel-5 versus HT + V; p = 0.808). Putative therapeutic melatonin levels were reached 8 h after HI (104 increase from baseline; ~15-30 mg/l). Mean ±â€¯SD peak plasma melatonin levels after the first infusion were 0.0014 ±â€¯0.0012 mg/l in the HT + V group, 3.97 ±â€¯1.53 mg/l in the HT + Mel-5 group and 16.8 ±â€¯8.3 mg/l in the HT + Mel-15 group. Protection was dose dependent; 15 mg/kg melatonin started 2 h after HI, given over 6 h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies.


Assuntos
Encéfalo/efeitos dos fármacos , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/terapia , Melatonina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/metabolismo , Melatonina/farmacologia , Fármacos Neuroprotetores/farmacologia , Sus scrofa , Pesquisa Translacional Biomédica
4.
J Lipid Res ; 59(10): 1880-1892, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30108154

RESUMO

Secreted pulmonary surfactant phosphatidylcholine (PC) has a complex intra-alveolar metabolism that involves uptake and recycling by alveolar type II epithelial cells, catabolism by alveolar macrophages, and loss up the bronchial tree. We compared the in vivo metabolism of animal-derived poractant alfa (Curosurf) and a synthetic surfactant (CHF5633) in adult male C57BL/6 mice. The mice were dosed intranasally with either surfactant (80 mg/kg body weight) containing universally 13C-labeled dipalmitoyl PC (DPPC) as a tracer. The loss of [U13C]DPPC from bronchoalveolar lavage and lung parenchyma, together with the incorporation of 13C-hydrolysis fragments into new PC molecular species, was monitored by electrospray ionization tandem mass spectrometry. The catabolism of CHF5633 was considerably delayed compared with poractant alfa, the hydrolysis products of which were cleared more rapidly. There was no selective resynthesis of DPPC and, strikingly, acyl remodeling resulted in preferential synthesis of polyunsaturated PC species. In conclusion, both surfactants were metabolized by similar pathways, but the slower catabolism of CHF5633 resulted in longer residence time in the airways and enhanced recycling of its hydrolysis products into new PC species.


Assuntos
Produtos Biológicos/metabolismo , Fragmentos de Peptídeos/metabolismo , Fosfatidilcolinas/metabolismo , Fosfolipídeos/metabolismo , Proteína B Associada a Surfactante Pulmonar/metabolismo , Proteína C Associada a Surfactante Pulmonar/metabolismo , Surfactantes Pulmonares/metabolismo , Animais , Produtos Biológicos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/farmacologia , Fosfatidilcolinas/biossíntese , Fosfatidilcolinas/farmacologia , Fosfolipídeos/farmacologia , Proteína B Associada a Surfactante Pulmonar/farmacologia , Proteína C Associada a Surfactante Pulmonar/farmacologia , Surfactantes Pulmonares/farmacologia
5.
Mol Nutr Food Res ; 54(10): 1452-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20397198

RESUMO

A simulated gastrointestinal digestion has been carried out on purified peach lipid transfer protein, one of the main allergens among the population of the Mediterranean area and the major allergen of peach allergic patients. The percentage of intact protein, after extensive digestion, measured by comparison with a non-digestible peptide analogue used as internal standard, was found to be about one-third of the original protein content. The peptides formed in digested fraction were characterized by means of LC/MS. The products of the digestion essentially derived from trypsin action, whereas the protein appeared to be resistant to pepsin and chymotrypsin. The identified peptides could be classified as low molecular weight and high molecular weight peptides. The latter consisted of the full protein, with the disulfide bridges still intact, deprived of the smaller peptides. The different digestion products, including the high and low molecular weight peptides, were purified by LC and assessed, together with the intact protein, by dot-blot analysis with sera of allergic patients, allowing to estimate their potential allergenicity. The intact protein and the high molecular weight peptides were found to be recognized by patients' sera, whereas the small peptides were found to be not reactive.


Assuntos
Alérgenos/imunologia , Alérgenos/metabolismo , Digestão , Imunoglobulina E/imunologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Prunus/imunologia , Sequência de Aminoácidos , Antígenos de Plantas/imunologia , Antígenos de Plantas/metabolismo , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Cromatografia Líquida de Alta Pressão , Proteínas Alimentares/imunologia , Proteínas Alimentares/metabolismo , Hipersensibilidade Alimentar/sangue , Hipersensibilidade Alimentar/imunologia , Frutas/química , Frutas/imunologia , Humanos , Hidrólise , Peso Molecular , Fragmentos de Peptídeos/isolamento & purificação , Fragmentos de Peptídeos/metabolismo , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Hidrolisados de Proteína/química , Prunus/química , Espectrometria de Massas por Ionização por Electrospray , Especificidade por Substrato , Fatores de Tempo , Tripsina/metabolismo
6.
J Agric Food Chem ; 55(26): 11057-62, 2007 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-18038997

RESUMO

Lipid transfer proteins (LTPs) are a family of low molecular mass (7-9 kDa) polypeptides, the members of which share 35-95% sequence homology. These proteins are widely distributed throughout the plant kingdom and are receiving attention for their biochemical characteristics and biological activity. LTPs are indeed studied in different research fields varying from allergy to food technology, and numerous molecules belonging to this class are progressively being identified and investigated. Proteins from pomegranate juice were fractioned by cation exchange chromatography and analyzed by SDS-PAGE. Two proteins were identified as putative LTPs on the basis of their molecular weights and their electrophoretic behaviors under reducing and nonreducing conditions. Finally, proteins were purified and characterized by mass spectrometry. This analysis confirmed that the two polypeptides are LTPs on the basis of an amino acid sequence common to LTPs from other plant sources and cysteine content. The two proteins, named LTP1a and LTP1b, showed similar molecular masses but different immunological profiles when immunodetected with rabbit antibodies specific for Pru p 3 and human IgE from a patient suffering from pomegranate allergy. The demonstration of the existence of two immunologically unrelated LTPs in pomegranate confirms the variability and the complexity of the plant LTP family. This should be taken into account when the role of these proteins as elicitors of allergies to fruits is investigated and could help to explain the contradictory literature data on pomegranate allergy.


Assuntos
Antígenos de Plantas/análise , Antígenos de Plantas/isolamento & purificação , Proteínas de Transporte/análise , Proteínas de Transporte/isolamento & purificação , Lythraceae/química , Proteínas de Plantas/análise , Proteínas de Plantas/isolamento & purificação , Antígenos de Plantas/química , Bebidas/análise , Proteínas de Transporte/química , Eletroforese em Gel de Poliacrilamida , Frutas/química , Immunoblotting , Proteínas de Plantas/química , Espectrometria de Massas por Ionização por Electrospray
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