RESUMEN
The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13ß, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX-2, IL-6, IL-1ß, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further in vivo studies in murine model of LPS-induced acute lung injury (ALI) showed that 1 possessed more potent protective effects than the well-known anti-inflammatory drug dexamethasone by inhibiting myeloperoxidase (MPO) activity, reducing total cells and neutrophils, and suppressing inflammatory cytokines expression, and thus ameliorating the histopathological conditions of the injured lung tissue. In conclusion, compound 1 could be developed as a promising anti-inflammatory agent for intervention of LPS-induced ALI.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/administración & dosificación , Ácido Oleanólico/administración & dosificación , Lesión Pulmonar Aguda/genética , Lesión Pulmonar Aguda/inmunología , Animales , Antiinflamatorios/síntesis química , Líquido del Lavado Bronquioalveolar/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Femenino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Lipopolisacáridos/efectos adversos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/síntesis química , Peroxidasa/genética , Peroxidasa/inmunología , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
We aimed to evaluate whether the enhancement of the liver accumulation and anti-inflammatory activity of dexamethasone acetate (DXMA) could be achieved by incorporating it into nanostructured lipid carrier (NLCs). DXMA-NLCs were prepared using a film dispersion-ultrasonication method and characterized in terms of particle size, PDI, zeta potential, differential scanning calorimetry, drug loading capacity, encapsulation efficiency, and in vitro release. The biodistribution and pharmacokinetics of DXMA-NLCs in mice were significantly different from those of the DXMA solution (DXMA-sol). The peak concentration of DXMA-NLCs was obtained half an hour after intravenous administration. More than 55.62% of the total administrated dose was present in the liver. An increase of 2.57 fold in the area under the curve was achieved when compared with that of DXMA-sol. DXMA-NLCs exhibited a significant anti-inflammatory and hepatoprotective effect on carrageenan-induced rats and carbon tetrachloride-induced mice compared with DXMA-sol. However, the effect was not in proportion to the dosage. The intermediate and low dosages presented better effects than DXMA-sol. All results indicate that NLCs, as a novel carrier for DXMA, has potential for the treatment of liver diseases, increasing the cure efficiency and decreasing the side effects on other tissues.
Asunto(s)
Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Dexametasona/análogos & derivados , Hígado/efectos de los fármacos , Hígado/metabolismo , Nanopartículas/administración & dosificación , Nanopartículas/química , Animales , Tetracloruro de Carbono/toxicidad , Carragenina/toxicidad , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Técnicas In Vitro , Liposomas/administración & dosificación , Liposomas/química , Hepatopatías/tratamiento farmacológico , Ratones , Nanomedicina , Nanopartículas/ultraestructura , Ratas , Ratas Wistar , Distribución TisularRESUMEN
<p><b>OBJECTIVE</b>To investigate the effects of interactions among environmental factors, bone morphogenetic protein-4 (BMP4) and transforming growth factor beta-3 (TGF-β(3)) polymorphisms on nonsyndromic cleft lip and cleft palate (NSCLP).</p><p><b>METHODS</b>The data of environmental exposures were collected with questionnaires. Genotypes were determined with techniques of polymerase chain reaction-restriction fragment length polymorphism. Interactions between genes, environmental factors and NSCLP were analyzed using multifactor dimensionality reduction (MDR) method. The interactions were validated by logistic regression analysis.</p><p><b>RESULTS</b>There was no correlation between three single nucleotide polymorphism (SNP) associated with NSCLP. The developmental accident of NSCLP had higher risk in the interaction between BMP4 T538C, maternal passive smoking and infection in first trimester pregnancy, as well as in the interaction of six factors between TGF-β(3) G15572-, maternal passive smoking, infections, multivitamin supplement in the first trimester pregnancy, paternal smoking and high risk drinking before realizing pregnancy than in other interactions of environmental factors. The results could be validated by logistic regression analysis.</p><p><b>CONCLUSIONS</b>The NSCLP is induced by the interactions between genes and environmental risk factors.</p>
Asunto(s)
Femenino , Humanos , Embarazo , Proteína Morfogenética Ósea 4 , Genética , Encéfalo , Anomalías Congénitas , Labio Leporino , Genética , Fisura del Paladar , Genética , Genotipo , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Fumar , Factor de Crecimiento Transformador beta , Factor de Crecimiento Transformador beta3 , GenéticaRESUMEN
The objective of the present study was to develop a novel solid lipid nanoparticle (SLN) for the lung-targeting delivery of dexamethasone acetate (DXM) by intravenous administration. DXM loaded SLN colloidal suspensions were prepared by the high pressure homogenization method. The mean particle size, drug loading capacity and drug entrapment efficiency (EE%) of SLNs were investigated. In vitro drug release was also determined. The biodistribution and lung-targeting efficiency of DXM-SLNs and DXM-solutions (DXM-sol) in mice after intravenous administration were studied using reversed-phase high-performance liquid chromatography (HPLC). The results (expressed as mean +/- SD) showed that the DXM-SLNs had an average diameter of 552 +/- 6.5 nm with a drug loading capacity of 8.79 +/- 0.04% and an entrapment efficiency of 92.1 +/- 0.41%. The in vitro drug release profile showed that the initial burst release of DXM from DXM-SLNs was about 68% during the first 2 h, and then the remaining drug was released gradually over the following 48 hours. The biodistribution of DXM-SLNs in mice was significantly different from that of DXM-sol. The concentration of DXM in the lung reached a maximum level at 0.5 h post DXM-SLNs injection. A 17.8-fold larger area under the curve of DXM-SLNs was achieved compared to that of DXM-sol. These results indicate that SLN may be promising lung-targeting drug carrier for lipophilic drugs such as DXM.