Liraglutide treatment improves endothelial function in the Ldlr−/− mouse model of atherosclerosis and affects genes involved in vascular remodelling and inflammation

Recent clinical intervention studies have shown that the GLP1 analogue liraglutide lowers cardiovascular risk, but the underlying mechanism has not yet been fully elucidated. This study investigated the effects of liraglutide on endothelial function in the Ldlr?/? mouse model. Mice (n = 12/group) were fed Western diet (WD) or chow for 12 weeks followed by 4 weeks of treatment with liraglutide (1 mg/kg/day) or vehicle subcutaneously. Weight loss, blood lipid content, plaque burden, vasomotor function of the aorta and gene expression pattern in aorta and brachiocephalic artery were monitored. Liraglutide treatment significantly induced weight loss (P < .0001), decreased blood triglycerides (P < .0001) and total cholesterol (P < .0001) in WD‐fed mice but did not decrease plaque burden. Liraglutide also improved endothelium‐mediated dilation of the distal thoracis aorta (P = .0067), but it did not affect phenylephrine or sodium nitroprusside responses. Fluidigm analyses of 96 genes showed significantly altered expression of seven genes related to inflammation, vascular smooth muscle cells and extracellular matrix composition in liraglutide‐treated animals. We conclude that treatment with liraglutide decreased endothelial dysfunction and that this could be linked to decreased inflammation or regulation of vascular remodelling.     

Parental characteristics in association with disordered eating in 11‐ to 12‐year‐olds: A study within the Danish National Birth Cohort

We examined the association between parental characteristics and disordered eating among 11‐ to 12‐year‐olds within the Danish National Birth Cohort. Frequency of fasting, purging, and binge eating was obtained by self‐report from 37,592 children and combined into a measure of disordered eating (no, monthly, and weekly). Information on parental characteristics was obtained during pregnancy, from the 7‐year follow‐up, and by linkage to population registers. Data were analysed using multinomial logistic regression models with robust standard errors. In total, 3.1% reported weekly and 4.1% reported monthly disordered eating. Parental young age, low educational level, and overweight/obesity were associated with disordered eating. The relative risk ratios for, respectively, weekly and monthly disordered eating according to maternal eating disorder were 1.01 [0.75, 1.37] and 1.09 [0.84, 1.42]. Disordered eating is common among children and is associated with several parental characteristics. We found social inequality in disordered eating, but our data did not support an association with maternal eating disorder.     

Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival

BACKGROUND:

Angiogenesis is pivotal in tumor development. Vascular endothelial growth factor‐A (VEGF‐A) is considered one of the most important angiogenic factors, but lately several microRNAs (miRs) have been associated with vascular development. miR‐126 has been related to tumor angiogenesis and in the regulation of VEGF‐A. The authors aimed to investigate the prognostic impact of miR‐126 and its co‐expression with VEGF‐A in nonsmall cell lung cancer (NSCLC) patients.

METHODS:

Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with 4 cores from each tumor specimen. VEGF‐A expression was evaluated by immunohistochemistry, and in situ hybridization was used to evaluate the expression of miR‐126.

RESULTS:

In the total material, miR‐126 was a significant negative prognostic factor in both univariate (P = .005) and multivariate analyses (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2‐2.8, P = .01). Stratified by histology, miR‐126 was only significant in squamous cell carcinomas (univariate: P < .001; multivariate: HR 3.1, CI 95% 1.7‐5.6, P<.001). Stratified by lymph node status, miR‐126 was significant only in the lymph node‐positive subgroup (univariate: P<.001; multivariate: HR 4.1, CI 95% 2.0‐8.4, P < .001). High miR‐126 expression correlated significantly with high VEGF‐A expression (P = .037). The co‐expression of miR‐126 and VEGF‐A had a significant prognostic impact (P = .002), with 5‐year survival rates of 68%, 51%, and 42% for low/low (n = 150), mixed combinations (n = 129), and high/high (n = 35) expression, respectively.

CONCLUSIONS:

miR‐126 is a strong and independent negative prognostic factor in NSCLC, and its prognostic impact appears related primarily to histology and nodal status. Cancer 2011. © 2011 American Cancer Society.     

Does brain slices from pentylenetetrazole-kindled mice provide a more predictive screening model for antiepileptic drugs?

The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive validity of this model as a screening model has been questioned as, e.g., carbamazepine has been reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from na?ve, saline-injected and PTZ-kindled mice. Our data suggest that the use of slices from PTZ-kindled mice in the cortical wedge does not increase the predictive validity of the model as an in vitro screening model for AEDs. Traditionally, the incidence of certain seizure types is widely used as a measure to characterize drug action in animal models of epilepsy. In our study, the anticonvulsant effect of the AEDs was investigated in vivo using several observational parameters (i.e., incidence and duration of convulsions, latency to clonic convulsions, and severity of convulsions). We found that including the observational parameter "severity" offered important additional information about the drug profile that would otherwise be lost if only a single parameter as "incidence" was used.     

Microfluidic device to study cell transmigration under physiological shear stress conditions

The development of new drug therapies relies on studies of cell transmigration in in vitro systems. Migration has traditionally been studied using two methods, the Boyden chamber and a shear flow chamber assay. Though, commonly applied in cell transmigration studies, they are far from imitating a natural migration process. Here we describe a novel in vitro cell transmigration microfluidic assay, which mimicks physiological shear flow conditions in blood vessels. The device was designed to incorporate the principles of both the Boyden chamber and the shear flow chamber assay, i.e. migration through the membrane under flow conditions. The 3D environment of migrating cells is imitated by injecting cell adhesion proteins to coat the membrane in the device. We tested the developed device with Jurkat cells migration towards medium supplemented with serum, and with chemokine induced lymphocytes migration. The applied continuous flow of cell suspension and chemoattractant ensures that the concentration gradient is maintained in time and space. The cell adhesion proteins used to enhance cell migration in the device were fibronectin and VCAM-1. We successfully observed a multistep transmigration process by means of the developed microfluidic migration assay. The presented device is inexpensive, easy to fabricate and disposable, having a potential to be applied in basic research as well as in the drug development process.