Effective therapy for Alzheimer’s disease is a major challenge in the pharmaceutical sciences. There are six FDA approved drugs (e.g., donepezil, memantine) that show some effectiveness; however, they only relieve symptoms. Two factors hamper research. First, the cause of Alzheimer’s disease is not fully understood. Second, the blood-brain barrier restricts drug efficacy. This review summarized current knowledge relevant to both of these factors. First, we reviewed the pathophysiology of Alzheimer’s disease. Next, we reviewed the structural and biological properties of the blood-brain barrier. We then described the most promising drug delivery systems that have been developed in recent years; these include polymeric nanoparticles, liposomes, metallic nanoparticles and cyclodextrins. Overall, we aim to provide ideas and clues to design effective drug delivery systems for penetrating the blood-brain barrier to treat Alzheimer’s disease.

Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1^Tg) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1^Tg AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1^Tg mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases.

Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1^Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1^Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important “find-me” signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.

Boron nitride nanopores with circular, hexagonal, quadrangular and triangular shape were studied for their potential in DNA detection.

A novel Fe-catalyzed β-functionalization of ketones with amines for constructing enaminones has been demonstrated.