Highlights • Gastrodin improves learning and memory abilities of Tg2576 mice. • Gastrodin attenuates intracellular oxidative stress in hippocampi of Tg2576 mice. • Gastrodin suppresses BACE1 ...expression and PKR/eIF2α pathway in hippocampi of Tg2576 mice. • Gastrodin suppresses BACE1 via inhibiting PKR/eIF2α in SH-SY5Y cells under oxidative stress.
Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms ...underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.
Remote-sensing change detection based on multitemporal, multispectral, and multisensor imagery has been developed over several decades and provided timely and comprehensive information for planning ...and decision-making. In practice, however, it is still difficult to select a suitable change-detection method, especially in urban areas, because of the impacts of complex factors. This paper presents a new method using multitemporal and multisensor data (SPOT-5 and Landsat data) to detect land-use changes in an urban environment based on principal-component analysis (PCA) and hybrid classification methods. After geometric correction and radiometric normalization, PCA was used to enhance the change information from stacked multisensor data. Then, a hybrid classifier combining unsupervised and supervised classification was performed to identify and quantify land-use changes. Finally, stratified random and user-defined plots sampling methods were synthetically used to obtain total 966 reference points for accuracy assessment. Although errors and confusion exist, this method shows satisfying results with an overall accuracy to be 89.54% and 0.88 for the kappa coefficient. When compared with the post-classification method, PCA-based change detection also showed a better accuracy in terms of overall, producer's, and user's accuracy and kappa index. The results suggested that significant land-use changes have occurred in Hangzhou City from 2000 to 2003, which may be related to rapid economy development and urban expansion. It is further indicated that most changes occurred in cropland areas due to urban encroachment.
The chemical composition, size, shape and surface characteristics of nanoparticles affect the way proteins bind to these particles, and this in turn influences the way in which nanoparticles interact ...with cells and tissues. Nanomaterials bound with proteins can result in physiological and pathological changes, including macrophage uptake, blood coagulation, protein aggregation and complement activation, but the mechanisms that lead to these changes remain poorly understood. Here, we show that negatively charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen, which promotes interaction with the integrin receptor, Mac-1. Activation of this receptor increases the NF-κB signalling pathway, resulting in the release of inflammatory cytokines. However, not all nanoparticles that bind to fibrinogen demonstrated this effect. Our results show that the binding of certain nanoparticles to fibrinogen in plasma offers an alternative mechanism to the more commonly described role of oxidative stress in the inflammatory response to nanomaterials.
A single nanoparticle platform has been developed through the modular and controlled layer-by-layer process to codeliver siRNA that knocks down a drug-resistance pathway in tumor cells and a ...chemotherapy drug to challenge a highly aggressive form of triple-negative breast cancer. Layer-by-layer films were formed on nanoparticles by alternately depositing siRNA and poly-l-arginine; a single bilayer on the nanoparticle surface could effectively load up to 3500 siRNA molecules, and the resulting LbL nanoparticles exhibit an extended serum half-life of 28 h. In animal models, one dose via intravenous administration significantly reduced the target gene expression in the tumors by almost 80%. By generating the siRNA-loaded film atop a doxorubicin-loaded liposome, we identified an effective combination therapy with siRNA targeting multidrug resistance protein 1, which significantly enhanced doxorubicin efficacy by 4 fold in vitro and led to up to an 8-fold decrease in tumor volume compared to the control treatments with no observed toxicity. The results indicate that the use of layer-by-layer films to modify a simple liposomal doxorubicin delivery construct with a synergistic siRNA can lead to significant tumor reduction in the cancers that are otherwise nonresponsive to treatment with Doxil or other common chemotherapy drugs. This approach provides a potential strategy to treat aggressive and resistant cancers, and a modular platform for a broad range of controlled multidrug therapies customizable to the cancer type in a singular nanoparticle delivery system.
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