Vitexin inhibits APEX1 to counteract the flow-induced endothelial inflammation.

Vascular endothelial cells are exposed to shear stresses with disturbed vs. laminar flow patterns, which lead to proinflammatory vs. antiinflammatory phenotypes, respectively. Effective treatment against endothelial inflammation and the consequent atherogenesis requires the identification of new therapeutic molecules and the development of drugs targeting these molecules. Using Connectivity Map, we have identified vitexin, a natural flavonoid, as a compound that evokes the gene-expression changes caused by pulsatile shear, which mimics laminar flow with a clear direction, vs. oscillatory shear (OS), which mimics disturbed flow without a clear direction. Treatment with vitexin suppressed the endothelial inflammation induced by OS or tumor necrosis factor-α. Administration of vitexin to mice subjected to carotid partial ligation blocked the disturbed flow-induced endothelial inflammation and neointimal formation. In hyperlipidemic mice, treatment with vitexin ameliorated atherosclerosis. Using SuperPred, we predicted that apurinic/apyrimidinic endonuclease1 (APEX1) may directly interact with vitexin, and we experimentally verified their physical interactions. OS induced APEX1 nuclear translocation, which was inhibited by vitexin. OS promoted the binding of acetyltransferase p300 to APEX1, leading to its acetylation and nuclear translocation. Functionally, knocking down APEX1 with siRNA reversed the OS-induced proinflammatory phenotype, suggesting that APEX1 promotes inflammation by orchestrating the NF-κB pathway. Animal experiments with the partial ligation model indicated that overexpression of APEX1 negated the action of vitexin against endothelial inflammation, and that endothelial-specific deletion of APEX1 ameliorated atherogenesis. We thus propose targeting APEX1 with vitexin as a potential therapeutic strategy to alleviate atherosclerosis.

Disturbed Flow-Facilitated Margination and Targeting of Nanodisks Protect against Atherosclerosis.

Disturbed blood flow induces endothelial pro-inflammatory responses that promote atherogenesis. Nanoparticle-based therapeutics aimed at treating endothelial inflammation in vasculature where disturbed flow occurs may provide a promising avenue to prevent atherosclerosis. By using a vertical-step flow apparatus and a microfluidic chip of vascular stenosis, herein, it is found that the disk-shaped versus the spherical nanoparticles exhibit preferential margination (localization and adhesion) to the regions with the pro-atherogenic disturbed flow. By employing a mouse model of carotid partial ligation, superior targeting and higher accumulation of the disk-shaped particles are also demonstrated within disturbed flow areas than that of the spherical particles. In hyperlipidemia mice, administration of disk-shaped particles loaded with hypomethylating agent decitabine (DAC) displays greater anti-inflammatory and anti-atherosclerotic effects compared with that of the spherical counterparts and exhibits reduced toxicity than "naked" DAC. The findings suggest that shaping nanoparticles to disk is an effective strategy for promoting their delivery to atheroprone endothelia.

Rational Construction of an Exceptionally Stable MOF Catalyst with Metal-Adeninate Vertices toward CO2 Cycloaddition under Mild and Cocatalyst-Free Conditions.

CO2 is considered as the primary greenhouse gas, resulting in a series of serious environmental problems that affect people's life and health. Carbon capture and sequestration has been implemented as one of the most appealing pathways to control and use CO2 . Here, we rationally integrate various functional sites within the confined nanospace of a microporous metal-organic framework (MOF) material, which is constructed by mixed-ligand strategy based on metal-adeninate vertices. It not only exhibits excellent stability but also can efficiently transform CO2 and epoxides to cyclic carbonates under mild and cocatalyst-free conditions. Additionally, this catalyst shows extraordinary recyclability for the CO2 cycloaddition reaction.

STAT3 down-regulation induces mitochondria-dependent G2/M cell cycle arrest and apoptosis in oesophageal carcinoma cells.

STAT3 is persistently activated in a wide variety of human tumours, and aberrant STAT3 activity promotes tumour growth, invasion and metastasis. To explore STAT3 down-regulation in human oesophageal cancer cells, cell proliferation, apoptosis and mitochondrial mechanisms were explored in oesophageal carcinoma TE1 cell cultures. We demonstrate for the first time that STAT3 down-regulation by RNAi is sufficient to inhibit oesophageal cancer cell proliferation inducing cell apoptosis. Further, we demonstrate that mitochondrial transmembrane potential is impaired thereby leading to collapsed mitochondrial membrane potential, abnormal mitochondrial membrane depolarization, nuclear DNA fragmentation and cell cycle G2/M arrest under the conditions of STAT3 down-regulation. Thus, our results suggest that STAT3 inhibition is a valid approach to induce oesophageal carcinoma cell mitochondrial-dependent apoptosis in therapeutic strategies against oesophageal cancers.