N,N-dimethylacetamide targets neuroinflammation in Alzheimer's disease in in-vitro and ex-vivo models.

Alzheimer's disease (AD) is a chronic degenerative brain disorder with no clear pathogenesis or effective cure, accounting for 60-80% of cases of dementia. In recent years, the importance of neuroinflammation in the pathogenesis of AD and other neurodegenerative disorders has come into focus. Previously, we made the serendipitous discovery that the widely used drug excipient N,N-dimethylacetamide (DMA) attenuates endotoxin-induced inflammatory responses in vivo. In the current work, we investigate the effect of DMA on neuroinflammation and its mechanism of action in in-vitro and ex-vivo models of AD. We show that DMA significantly suppresses the production of inflammatory mediators, such as reactive oxygen species (ROS), nitric oxide (NO) and various cytokines and chemokines, as well as amyloid-ß (Aß), in cultured microglia and organotypic hippocampal slices induced by lipopolysaccharide (LPS). We also demonstrate that DMA inhibits Aß-induced inflammation. Finally, we show that the mechanism of DMA's effect on neuroinflammation is inhibition of the nuclear factor kappa-B (NF-κB) signaling pathway and we show how DMA dismantles the positive feedback loop between NF-κB and Aß synthesis. Taken together, our findings suggest that DMA, a generally regarded as safe compound that crosses the blood brain barrier, should be further investigated as a potential therapy for Alzheimer's disease and neuroinflammatory disorders.

Densely Connected U-Net with Criss-Cross Attention for Automatic Liver Tumor Segmentation in CT Images.

Automatic liver tumor segmentation plays a key role in radiation therapy of hepatocellular carcinoma. In this paper, we propose a novel densely connected U-Net model with criss-cross attention (CC-DenseUNet) to segment liver tumors in computed tomography (CT) images. The dense interconnections in CC-DenseUNet ensure the maximum information flow between encoder layers when extracting intra-slice features of liver tumors. Moreover, the criss-cross attention is used in CC-DenseUNet to efficiently capture only the necessary and meaningful non-local contextual information of CT images containing liver tumors. We evaluated the proposed CC-DenseUNet on the LiTS dataset and the 3DIRCADb dataset. Experimental results show that the proposed method reaches the state-of-the-art performance for liver tumor segmentation. We further experimentally demonstrate the robustness of the proposed method on a clinical dataset comprising 20 CT volumes.

N,N-Dimethylformamide Delays LPS-Induced Preterm Birth in a Murine Model by Suppressing the Inflammatory Response.

Preterm birth accounts for the majority of perinatal mortality worldwide, and there remains no FDA-approved drug to prevent it. Recently, we discovered that the common drug excipient, N,N-dimethylacetamide (DMA), delays inflammation-induced preterm birth in mice by inhibiting NF-κB. Since we reported this finding, it has come to light that a group of widely used, structurally related aprotic solvents, including DMA, N-methyl-2-pyrrolidone (NMP) and dimethylformamide (DMF), have anti-inflammatory efficacy. We show here that DMF suppresses LPS-induced TNFα secretion from RAW 264.7 cells and IL-6 and IL-8 secretion from HTR-8 cells at concentrations that do not significantly affect cell viability. Like DMA, DMF protects IκBα from degradation and prevents the p65 subunit of NF-κB from translocating to the nucleus. In vivo, DMF decreases LPS-induced inflammatory cell infiltration and expression of TNFα and IL-6 in the placental labyrinth, all to near baseline levels. Finally, DMF decreases the rate of preterm birth in LPS-induced pregnant mice (P<.0001) and the rate at which pups are spontaneously aborted (P<.0001). In summary, DMF, a widely used solvent structurally related to DMA and NMP, delays LPS-induced preterm birth in a murine model without overt toxic effects. Re-purposing the DMA/DMF/NMP family of small molecules as anti-inflammatory drugs is a promising new approach to delaying or reducing the incidence of inflammation-induced preterm birth and potentially attenuating other inflammatory disorders as well.

Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms.

Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60-70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid ß-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid ß-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-ß (GSK-3ß), which leads to increased tau phosphorylation. Both insulin and amyloid ß-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.

Development of Dual ARV-825 and Nintedanib-Loaded PEGylated Nano-Liposomes for Synergistic Efficacy in Vemurafnib-Resistant Melanoma.

A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. BRD4 proteolysis targeting chimera (ARV-825) and nintedanib co-loaded PEGylated nanoliposomes (ARNIPL) were developed to incorporate a synergistic cytotoxic ratio. Both the molecules have extremely poor aqueous solubility. A modified hydration method with citric acid was used to improve the loading of both the molecules in liposomes. ARNIPL with mean particle size 111.1 ± 6.55 nm exhibited more than 90% encapsulation efficiency for both the drugs and was found to be physically stable for a month at 4 °C. Both the molecules and ARNIPL showed significantly higher cytotoxicity, apoptosis and down-regulation of target proteins BRD4 and c-Myc in vemurafenib-resistant cell line (A375R). Vasculogenic mimicry and clonogenic potential of A375R were significantly inhibited by ARNIPL. Tumor growth inhibition in 3D spheroids with reduction of TGF-ß1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma.

A micro-CL system and its applications.

The computed laminography (CL) method is preferable to computed tomography for the non-destructive testing of plate-like objects. A micro-CL system is developed for three-dimensional imaging of plate-like objects. The details of the micro-CL system are described, including the system architecture, scanning modes, and reconstruction algorithm. The experiment results of plate-like fossils, insulated gate bipolar translator module, ball grid array packaging, and printed circuit board are also presented to demonstrate micro-CL's ability for 3D imaging of flat specimens and universal applicability in various fields.