RESUMEN
Targeted gemcitabine (GEB) loaded 5-N-acetyl-neuraminic acid (Neu5Ac) assembled chitosan nanoparticles (CA-NPs) were formulated by ionotropic gelation process and evaluated for physicochemical and morphological characterization, in vitro and in vivo studies in A-549 cells and lung cancer mice model, respectively. The mean diameter of GEB-CA-Neu5Ac-NPs determined by dynamic light scattering was 161.16 ± 7.70 nm with a polydispersity index (PDI) value of 0.303 ± 0.011 and its zeta potential and entrapment efficiency (%EE) were 40.3 ± 3.45 mv and 66.11 ± 1.94%, respectively. The in vitro cellular uptake studies showed that glycan receptor-targeted nanoparticles deliver significantly more amount (p < 0.001) of GEB into the A-549 lung cancerous cells than non-targeted nanoparticles. The cytotoxicity study using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated that GEB-CA-Neu5Ac-NPs have lower IC50 value (6.39 ± 3.78 µg/ml) than others groups that showed that the greater lung cancerous cells inhibition potential of targeted nanoparticles. The in vivo biodistribution of the GEB-loaded 5-N-acetyl-neuraminic acid conjugated chitosan nanoparticles was revealed that targeted nanoparticles showed higher accumulation and retention for an extended period of time due to the active targeting ability of Neu5Ac to glycan receptors. Histopathological examination showed significant recovery in the physiological architecture upon administration of targeted nanoparticles. The glycan receptor-targeted nanoparticles treated groups showed a significant decline in the number of metastatic lung epithelial cells, as compared to the untreated positive control group (p < 0.001) confirming higher anticancer efficacy of the GEB-CA-Neu5Ac-NPs.
Asunto(s)
Quitosano , Neoplasias Pulmonares , Nanopartículas , Ratones , Animales , Gemcitabina , Neoplasias Pulmonares/tratamiento farmacológico , Benzo(a)pireno/uso terapéutico , Quitosano/química , Distribución Tisular , Microambiente Tumoral , Pulmón , Nanopartículas/química , Portadores de Fármacos/química , Línea Celular TumoralRESUMEN
Benzo[a]pyrene (BaP) is an environmental pollutant produced by combustion processes and is present in grilled foods as well as in tobacco smoke. BaP acts as an agonist for the aryl hydrocarbon receptor (AHR), and is metabolized by AHR-inducing enzymes. BaP metabolism can result in either detoxification or metabolic activation, the latter leads to an increased risk of disease, particularly lung cancer and cardiovascular disease, in a context-dependent manner. Although AHR activation has been thought to protect against inflammatory bowel disease, it remains unknown whether BaP exerts a protective or deleterious effect on colitis. In this study, we examined the effect of oral BaP administration on colitis induced by dextran sulfate sodium (DSS) in mice, an animal model of inflammatory bowel disease. BaP administration attenuated weight loss, shortening of the colon, disease activity index scores, and histological damage in DSS-induced colitis mice. BaP also suppressed colonic expression of inflammation-associated genes and plasma interleukin-6 secretion induced by DSS treatment. BaP-DNA adduct formation, a marker of BaP metabolic activation, was not enhanced in the colon after DSS treatment. Thus, oral BaP exerts an anti-inflammatory effect on DSS-induced colitis, without the toxicity associated with metabolic activation. The results provide insights into the disease-specific roles of BaP.
Asunto(s)
Benzo(a)pireno/uso terapéutico , Colitis/tratamiento farmacológico , Administración Oral , Animales , Antiinflamatorios/uso terapéutico , Colitis/inducido químicamente , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Interleucina-6/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
El síndrome de las uñas amarillas (SUA) es un cuadro clínico del que se han descrito alrededor de 130 casos en la literatura. La triada clásica la componen pigmentación amarillenta de las uñas, linfedema y derrame pleural, si bien se considera suficiente para la realización del diagnóstico la presencia de las uñas amarillas y otra de las manifestaciones del síndrome. Presentamos dos casos de SUA y revisamos la literatura. Caso 1: Mujer de 14 años que presenta uñas amarillas en pies y manos desde el nacimiento excepto en dedos meñiques. Ingresa para estudio de linfedema en extremidad inferior derecha que llega hasta rodilla. En los exámenes complementarios realizados no se han encontrado hallazgos de interés salvo enfisema del lóbulo superior izquierdo pulmonar. Durante el año de seguimiento ha recibido tratamiento con 5-6 benzopireno a dosis de 3'5 ml/8h por via oral que ha conseguido estabilizar el linfedema y ha aclarado la coloración de las uñas. Caso 2: Varón de 66 años no fumador y sin antecedentes de interés que ingresa por infección respiratoria de vías bajas. En la exploración se apreciaba una alteración trófica de las uñas, junto a coloración pardo-amarillenta que el paciente refería desde hacía tres años. En los últimos nueve meses el paciente notó la aparición de un linfedema progresivo en extremidades inferiores (AU)
Asunto(s)
Adolescente , Anciano , Femenino , Masculino , Humanos , Enfermedades de la Uña/diagnóstico , Linfedema/diagnóstico , Derrame Pleural/diagnóstico , Enfermedades de la Uña/tratamiento farmacológico , Linfedema/tratamiento farmacológico , Derrame Pleural/tratamiento farmacológico , Benzo(a)pireno/uso terapéutico , Radiografía TorácicaRESUMEN
Our earlier study revealed that 1- and 3-nitrobenzo[a]pyrene (NBP), 1,6- and 3,6-dinitrobenzo[a]pyrene (DNBP), nitrated derivatives of benzo[a]BP (BP), are present in the environment. These derivatives are potent mutagens for Salmonella tester strains and we have preliminarily reported them to be carcinogenic in F344/DuCrj rats. In this study, the tumorigenic action of 1- and 3-NBP, 1.6- and 3,6-DNBP, and BP induced by subcutaneous injection into rats was found to differ according to the NO2-substitution in the BP structure. The chemicals were suspended in equal volumes of beeswax and tricaprylin, and rats were subcutaneously injected with single doses of 500, 1000, and 2000 microg for 1- and 3-NBP, and of 8, 40, 200, and 1000 microg for 3,6- and 1,6-DNBP, and BP as a positive control. 3,6-DNBP and BP induced tumors in a dose-dependent manner at the injection site. Rats given 1000 microg of 3,6-DNBP (2924 nmol) and BP (3968 nmol) developed subcutaneous tumors at the rate of 70 and 80%, respectively, and those given a minimum dose of 23 nmol for 3.6-DNBP and 32 nmol for BP per rat developed tumors at a rate of 4.8 and 18.2%, respectively. However, rats given 500 and 1000 microg of 1- and 3-NBP did not develop any tumors while those given a high dose, 2000 microg, of each chemical developed tumors at only one of ten animals used. It was concluded, therefore, that these chemicals are weak carcinogens. Histologically, most of the tumors were malignant fibrous histiocytomas. Rats given various doses of 1,6-DNBP did not develop any tumors at the injection site. The failure of 1,6-DNBP to induce tumors may involve its metabolites because of the lower mutagenicity of its reduction products, 1-nitroso-6-NBP and 1-amino-6-NBP. It is suggested, therefore, that tumorigenicities of NBPs and DNBPs differ according to the NO2-substitution on the chemical structure, which may be due to the possible nitroreduction of the chemicals.
Asunto(s)
Benzo(a)pireno/análogos & derivados , Benzopirenos/toxicidad , Carcinógenos/toxicidad , Animales , Benzo(a)pireno/uso terapéutico , Benzo(a)pireno/toxicidad , Peso Corporal/efectos de los fármacos , Pruebas de Carcinogenicidad , Inyecciones Subcutáneas , Masculino , Ratas , Ratas Endogámicas F344 , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Relación Estructura-ActividadRESUMEN
The effects of a monoclonal anti-idiotypic antibody (Ab), internal image of conjugated benzo(a)pyrene [B(a)P], called AIB1, on B(a)P-induced malignant sarcomas in Sprague-Dawley (SD) female rats were evaluated at different times after B(a)P-administration. As previously described, circulating anti-"phosphatidylinositol (PtdIns)-like" autoantibody levels were found to be significantly higher in B(a)P-treated rat sera. They were decreased after AIB1 Ab-treatment. Furthermore, the tumor growth was slowed down compared with that of controls and animal survival was slightly increased. These results showed the relationships between metabolic pathways involving possible "B(a)P-like" endogenous ligand/cytosolic receptor(s) and the PtdIns.
Asunto(s)
Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Benzo(a)pireno/uso terapéutico , Sarcoma Experimental/tratamiento farmacológico , Animales , Femenino , Ratas , Ratas Sprague-DawleyRESUMEN
Lower cell density was found in cultures of ataxia telangiectasia lymphocytes as compared to control lymphocyte cultures. This fits with the earlier observations of decreased incorporation of 3H-Thymidine into lymphocytes of ataxia telangiectasia (AT) patients. However, the finding that there was no significant difference in proliferation rate index between AT and control cultures was unexpected. This may indicate that both cell count and measurements of thymidine incorporation in lymphocyte cultures characterize cell populations distinct from that of proliferating cells.