The objective of this research is to investigate the plasma pharmacokinetics and bio-distribution of liposomal daunorubicin plus tamoxifen in breast cancer murine models through intravenous administration. Daunorubicin and tamoxifen plasma levels in pharmacokinetics studies were determined using HPLC. Biodistributions of various carriers loaded with a cyanine dye (cy7) were evaluated using in vivo imaging. After administration, free daunorubicin and tamoxifen were rapidly cleared out from the blood following a two-compartment kinetic model. The clearances and AUC (0-N) of daunorubicin were (means AE SD): 0.028 AE 0.005 L h À1 kg À1 and 367.489 AE 56.979 mg mL À1 h À1 (liposomes), and 2.235 AE 0.347 L h À1 kg À1 and 4.546 AE 0.704 mg mL À1 h À1 (free drug). By ex vivo imaging 24 h after injection, the fluorescence intensity of liposomal cy7 plus tamoxifen in tumor region was obviously higher than that of free liposomal cy7. In conclusion, tamoxifen can improve pharmacokinetics profile of liposomal daunorubicin with enhanced therapy for breast cancer. Materials and methods MaterialsDaunorubicin hydrochloride was purchased from Nanjing Tianzun Zezhong Chemicals, Co. Ltd, (Nanjing, China).

No abstract

Glioblastoma is a type of primary brain tumor with poor prognosis. The hallmark phenotype of glioblastoma is its aggressive invasion. Understanding the molecular mechanism of the invasion behavior of glioblastoma is essential for the development of effective treatment of the disease. In our present study, we found that the expression levels of a homeobox transcription factor, MSX1, were significantly reduced in glioblastoma compared to normal brain tissues. The levels of MSX1 in glioblastoma tissues were also correlated with the survival of the patients. In cultured glioblastoma cells, MSX1 was a negative regulator of cell migration and invasion. Loss of MSX1 enhanced cell migration and induced mesenchymal transition as characterized by the downregulation of E-cadherin and the upregulation of N-cadherin. Overexpression of MSX1 on the other hand led to the inhibition of both cell migration and mesenchymal transition. We also found that MSX1 was able to inhibit the Wnt/β-catenin signaling pathway, and that the ability to regulate the Wnt/β-catenin signaling pathway is critical for MSX1 to suppress glioblastoma cell migration and invasion.

Background/Aims: Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Methods: Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. Results: SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. Conclusion: This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation.

It is well known that puerarin attenuates ischemia-reperfusion injury and promotes function recovery of ischemic region. However, due to its reverse physiochemical properties, puerarin does not easily cross the blood-brain barrier. The aim of the present study is to create puerarin nanoparticles which increase and prolong the puerarin concentration in the brain. Using emulsion solvent evaporation techniques, we designed puerarin-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles. Hydroxypropyl beta cyclodextrin (HP-β-CD) was used to increase the solubility of puerarin and gelatin to enhance viscosity of inner water phase, which improved puerarin entrapment. The drug release kinetics and nanoparticle degradation in phosphate buffered saline (PBS) were analyzed by electronic microscopy and high-performance liquid chromatography. Computerized tomography scans were used to detect the infarction volume and electroencephalogram (EEG) was recorded to estimate the recovery of brain function. The results showed that the combined HP-β-CD and gelatin significantly improved the entrapment efficiency. The infarction volume was significantly decreased on days 3 and 7 after the administration of puerarin nanoparticles compared with that of control and pure puerarin. EEG was also significantly improved. Puerarin nanoparticles are potentially applicable for the brain injury induced by ischemic-reperfusion.