An artificial “closed‐loop” system that mimics the glucose‐responsive insulin secretion of pancreas β‐cells can potentially improve the treatment efficacy for diabetes. Herein, a lipid bilayer‐coated ...polymeric nanoparticle (NP) with “core–shell” structure is designed. As far as it is known, it is the first and only intravenous nanoplatform utilizing enzymatic‐oxidation scheme to achieve glucose‐responsive insulin delivery so far. Ethoxy acetal–derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as “inner core” loaded with insulin, and coloading glucose oxidase (GOx) and catalase (CAT) endow the “inner core” excellent glucose‐sensitive ability. Red blood cell membrane (RBCm)‐derived coating is adopted as “outer shell.” It collectively provides a closed microenvironment for GOx‐based enzymatic‐oxidation scheme and camouflages it from elimination. Above all, the anchored glucose transporters (GLUTs) on the “outer shell” are able to sense blood glucose levels and facilitate the transport of outer blood glucose getting inside. Under a hyperglycemic condition, the internalized glucose is catalytically converted into gluconic acid with the aid of the GOx and subsequently triggers acid degradation of the “inner core” to secrete insulin. By governing the blood glucose levels on an automatic and continuous basis, the RBCm‐Ace‐DEX NPs can effectively respond to hyperglycemia and turn to resting conditions under normoglycemia.
Ethoxy acetal derivatized dextran nanoparticles (Ace‐DEX NPs) are constructed as “inner core” and red blood cell membrane (RBCm)‐derived coating is adopted as “outer shell”. This glucose‐responsive nanoplatform can steadily circulate in the blood at normalglycemia. While under hyperglycemic condition, the glucose internalized by the anchored GLUTs is catalytically converted into gluconic acid with the aid of GOx and CAT and subsequently triggers acid degradation of RBCm‐Ace‐DEX NPs to secrete insulin.
Inflammation plays a key role in the pathogenesis of acute lung injury (ALI). Soluble epoxide hydrolase (sEH) is suggested as a vital pharmacologic target for inflammation. In this study, we ...determined whether a sEH inhibitor, AUDA, exerts lung protection in lipopolysaccharide (LPS)-induced ALI in mice.
Male BALB/c mice were randomized to receive AUDA or vehicle intraperitoneal injection 4 h after LPS or phosphate buffered saline (PBS) intratracheal instillation. Samples were harvested 24 h post LPS or PBS administration.
AUDA administration decreased the pulmonary levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α. Improvement of oxygenation and lung edema were observed in AUDA treated group. AUDA significantly inhibited sEH activity, and elevated epoxyeicosatrienoic acids (EETs) levels in lung tissues. Moreover, LPS induced the activation of nuclear factor (NF)-κB was markedly dampened in AUDA treated group.
Administration of AUDA after the onset of LPS-induced ALI increased pulmonary levels of EETs, and ameliorated lung injury. sEH is a potential pharmacologic target for ALI.
Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer’s disease (AD). However, the underlying ...mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of β-amyloid protein (Aβ) but also induced Aβ efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aβ. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aβ production and clearing Aβ from the brains of AD mice.
Excessive risk-taking behaviors have been implicated as a potential endophenotype for substance use disorders and psychopathological gambling. However, the genetic and environmental influences on ...risk taking and the risk-related brain activations remain unclear. This study investigated the heritability of risk taking and the genetic influence on individual variation in risk-related brain activation. The Balloon Analogue Risk Task was used to assess individuals’ risk-taking behavior. In a sample of 244 pairs of young adult twins, we found that there was a moderate heritability (41%) of risk taking. Using voxel-level analysis, we found a moderate genetic influence on risk-related brain activation. We also found a moderate genetic correlation between risk-taking behavior and risk-related brain activation in the left insula, right striatum, and right superior parietal lobule in the active-choice condition. The present study provides important evidence for the genetic correlation between risk-taking behavior and risk-related brain activation.
To develop a method for systematic classification of gallbladder stones, analyze the clinical characteristics of each type of stone and provide a theoretical basis for the study of the formation ...mechanism of different types of gallbladder stones.
A total of 807 consecutive patients with gallbladder stones were enrolled and their gallstones were studied. The material composition of gallbladder stones was analyzed using Fourier Transform Infrared spectroscopy and the distribution and microstructure of material components was observed with Scanning Electron Microscopy. The composition and distribution of elements were analyzed by an X-ray energy spectrometer. Gallbladder stones were classified accordingly, and then, gender, age, medical history and BMI of patients with each type of stone were analyzed.
Gallbladder stones were classified into 8 types and more than ten subtypes, including cholesterol stones (297), pigment stones (217), calcium carbonate stones (139), phosphate stones (12), calcium stearate stones (9), protein stones (3), cystine stones (1) and mixed stones (129). Mixed stones were those stones with two or more than two kinds of material components and the content of each component was similar. A total of 11 subtypes of mixed stones were found in this study. Patients with cholesterol stones were mainly female between the ages of 30 and 50, with higher BMI and shorter medical history than patients with pigment stones (P<0.05), however, patients with pigment, calcium carbonate, phosphate stones were mainly male between the ages of 40 and 60.
The systematic classification of gallbladder stones indicates that different types of stones have different characteristics in terms of the microstructure, elemental composition and distribution, providing an important basis for the mechanistic study of gallbladder stones.
α‐Oxo gold carbenoids generated by the oxidation of N‐arylynamides can be trapped intramolecularly at the ortho position of the aryl ring to give functionalized oxindoles under mild reaction ...conditions. Pyridine N‐oxide works as the oxidant, ligand, and base in this transformation.
A mild and convenient gold‐catalyzed method to synthesize functionalized oxindoles by using N‐arylynamides has been developed. A gold carbenoid was proven to be the key intermediate, which underwent a Friedel–Crafts‐type reaction to afford the oxindoles.
Background & objectives: The treatment of unruptured intracranial aneurysms (IAs) remains controversial; the ability to predict the risk of rupture for an aneurysm would be of clinical value. The aim ...of this study was to determine and evaluate the predictive value of the risk factors of IA rupture.
Methods: This retrospective study involved 379 consecutive patients with 441 aneurysms between August 2011 and July 2014. Based on clinical data and computed tomography angiography findings, the potential of risk factors to predict the aneurysmal rupture was assessed using statistical methods.
Results: Age, hypertension, heart disease, diabetes mellitus, cerebral atherosclerosis, aneurysms located at the internal carotid artery (ICA) and neck width (N) correlated negatively with rupture risk. Aneurysms located at the anterior communicating artery, bifurcation, irregularity, with a daughter sac, aneurysm height, maximum size, aspect ratio (AR), height-to-width ratio and bottleneck factor were significantly and positively correlated with rupture risk. The multivariate logistic regression model revealed that bifurcation aneurysm, irregular aneurysm and high AR increased the rupture risk, while cerebral atherosclerosis, aneurysm located on the ICA and greater N decreased the risk. Receiver operating characteristic analysis of AR curve values differed according to circumstances.
Interpretation & conclusions: Cerebral atherosclerosis, location in the ICA and larger N were the protective factors against aneurysm rupture, and IAs located at bifurcations, irregular shape and increased AR indicated a greater rupture risk.
A series of 1‐azaaurone derivatives were designed and synthesized from 3,5‐dimethoxyaniline and 2‐chloroacetonitrile. Their structures were characterized by melting point, 1H NMR, IR, and elemental ...analysis, as well as 13C NMR. The target compounds were evaluated for antitumor activities against human hepatocellular liver carcinoma cell line (HepG‐2) and human cervix carcinoma cell line (Hela) using methyl thiazolyl tetrazolium method. The results revealed that several 1‐azaaurones exhibited strong proliferation inhibition efficacy against HepG‐2 and Hela with an IC50 range of 5.6–8.8 μg/mL without damaging normal cell.
To investigate the performance of multi-parametric magnetic resonance imaging (MRI) for glioma grading.
Seventy consecutive patients with histopathologically confirmed glioma were retrospectively ...evaluated by conventional MRI, dynamic susceptibility-weighted contrast-enhanced, multiple diffusion-weighted imaging signal models including mono-exponential, bi-exponential, stretched exponential, and diffusion kurtosis imaging. One-way analysis of variance and independent-samples t test were used to compare the MR parameter values between low and high grades as well as among all grades of glioma. Receiver operating characteristic analysis, Spearman's correlation analysis, and binary logistic regression analysis were used to assess their diagnostic performance.
The diagnostic performance (the optimal thresholds, area under the receiver operating characteristic curve, sensitivity, and specificity) was achieved with normalized relative cerebral blood flow (rCBV) (2.240 ml/100 g, 0.844, 87.8%, and 75.9%, respectively), mean kurtosis (MK) (0.471, 0.873, 92.7%, and 79.3%), and water molecular diffusion heterogeneity index (α) (1.064, 0.847, 79.3% and 78.0%) for glioma grading. There were positive correlations between rCBV and MK and the tumor grades and negative correlations between α and the tumor grades (p < 0.01). The parameter of α yielded a diagnostic accuracy of 85.3%, the combination of MK and α yielded a diagnostic accuracy of 89.7%, while the combination of rCBV, MK, and α were more accurate (94.2%) in predicting tumor grade.
The most accurate parameters were rCBV, MK, and α in dynamic susceptibility-weighted contrast, diffusion kurtosis imaging, and Multi-b diffusion-weighted imaging for glioma grading, respectively. Multiparametric MRI can increase the accuracy of glioma grading.
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