RESUMEN
BACKGROUND: The brain is one of the most vulnerable metastasis sites in lung cancer; approximately 40-50% of lung cancer patients develop brain metastasis during the disease course, contributing to the poor prognosis and high mortality of lung cancer patients. Therefore, it is important to clarify the molecular mechanism underlying brain metastasis of lung cancer for improving the overall survival of lung cancer patients. The present study aimed to investigate the potential role of blood-brain barrier (BBB) permeability in the development of brain metastasis of lung cancer and explore the effect of aspirin in an in-vitro BBB model. METHODS: An in-vitro BBB model was established. The expression of heat shock protein 70 (HSP 70), zonula occludens-1 (ZO-1), and occludin in rat brain microvascular endothelial cells was detected using Western blot at different time points following the administration of aspirin. RESULTS: HSP70, ZO-1, and occludin expressions did not show significant changes before aspirin administration, but increased noticeably after aspirin administration. Tumor necrosis factor-α (TNF-α) could significantly attenuate the increased expression of these proteins induced by aspirin. Additionally, TNF-α also significantly reversed the aspirin-induced decrease of BBB permeability. CONCLUSIONS: Aspirin may inhibit brain metastasis of lung cancer in a time-dependent manner via upregulating tight junction proteins to reduce BBB permeability, and this effect can be reversed by TNF-α.
Asunto(s)
Neoplasias Encefálicas , Neoplasias Pulmonares , Ratas , Animales , Humanos , Proteínas de Uniones Estrechas/metabolismo , Ocludina/genética , Ocludina/metabolismo , Ocludina/farmacología , Células Endoteliales/metabolismo , Regulación hacia Arriba , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Aspirina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Barrera Hematoencefálica , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Uniones Estrechas/metabolismoRESUMEN
With a long history of application in Chinese traditional medicine, berberine (BBR) was reported to exhibit healthspan-extending properties in some age-related diseases, such as type 2 diabetes and atherosclerosis. However, the antiaging mechanism of BBR is not completely clear. By means of hydrogen peroxide- (H2O2-) induced premature cellular senescence model, we found that a low-concentration preconditioning of BBR could resist premature senescence in human diploid fibroblasts (HDFs) measured by senescence-associated ß-galactosidase (SA-ß-gal), accompanied by a decrease in loss of mitochondrial membrane potential and production of intracellular reactive oxygen species (ROS). Moreover, the low-concentration preconditioning of BBR could make cells less susceptible to subsequent H2O2-induced cell cycle arrest and growth inhibition. Experimental results further showed that the low concentration of BBR could induce a slight increase of ROS and upregulate the expression level of sirtuin 1 (SIRT1), an important longevity regulator. H2O2-induced activation of checkpoint kinase 2 (Chk2) was significantly attenuated after the preconditioning of BBR. The present findings implied that the low-concentration preconditioning of BBR could have a mitohormetic effect against cellular senescence triggered by oxidative stress in some age-related diseases through the regulation of SIRT1.
Asunto(s)
Berberina/farmacología , Senescencia Celular/efectos de los fármacos , Fibroblastos/metabolismo , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Sirtuina 1/metabolismo , Línea Celular , Quinasa de Punto de Control 2/metabolismo , HumanosRESUMEN
In this content, a small molecular ligand of prostate specific membrane antigen (SMLP) conjugated poly (caprolactone) (PCL)-b-poly (ethylene glycol) (PEG) copolymers with different block lengths were synthesized to construct a satisfactory drug delivery system. Four different docetaxel-loaded polymeric micelles (DTX-PMs) were prepared by dialysis with particle sizes less than 60 nm as characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). Optimization of the prepared micelles was conducted based on short-term stability and drug-loading content. The results showed that optimized systems were able to remain stable over 7 days. Compared with Taxotere, DTX-PMs with the same ratio of hydrophilic/hydrophobic chain length displayed similar sustained release behaviors. The cytotoxicity of the optimized targeted DTX-PCL12K-PEG5K-SMLP micelles (DTX-PMs2) and non-targeted DTX-PCL12K-mPEG5K micelles (DTX-PMs1) were evaluated by MTT assays using prostate specific membrane antigen (PSMA) positive prostate adenocarcinoma cells (LNCaP). The results showed that the targeted micelles had a much lower IC50 than their non-targeted counterparts (48 h: 0.87 ± 0.27 vs 13.48 ± 1.03 µg/ml; 72 h: 0.02 ± 0.008 vs 1.35 ± 0.54 µg/ml). In vitro cellular uptake of PMs2 showed 5-fold higher fluorescence intensity than that of PMs1 after 4 h incubation. According to these results, the novel nano-sized drug delivery system based on DTX-PCL-PEG-SMLP offers great promise for the treatment of prostatic cancer.
Asunto(s)
Antígenos de Superficie/administración & dosificación , Sistemas de Liberación de Medicamentos , Glutamato Carboxipeptidasa II/administración & dosificación , Próstata/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Masculino , Micelas , Próstata/patología , Neoplasias de la Próstata/patologíaRESUMEN
In this work, micelles composed of doxorubicin-conjugated Y-shaped copolymers (YMs) linked via an acid-labile linker were constructed. Y-shaped copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin)2 and linear copolymers of mPEG-b-poly(glutamate-hydrazone-doxorubicin) were synthesized and characterized. Particle size, size distribution, morphology, drug loading content (DLC) and drug release of the micelles were determined. Alterations in size and DLC of the micelles could be achieved by varying the hydrophobic block lengths. Moreover, at fixed DLCs, YMs showed a smaller diameter than micelles composed of linear copolymers (LMs). Also, all prepared micelles showed sustained release behaviors under physiological conditions over 72 h. DOX loaded in YMs was released more completely, with 30% more drug released in acid. The anti-tumor efficacy of the micelles against HeLa cells was evaluated by MTT assays, and YMs exhibited stronger cytotoxic effects than LMs in a dose- and time-dependent manner. Cellular uptake studied by CLSM indicated that YMs and LMs were readily taken up by HeLa cells. According to the results of this study, doxorubicin-conjugated Y-shaped PEG-(polypeptide)2 copolymers showed advantages over linear copolymers, like assembling into smaller nanoparticles, faster drug release in acid, which may correspond to higher cellular uptake and enhanced extracellular/intracellular drug release, indicating their potential in constructing nano-sized drug delivery systems.