Non-Destructively Shattered Mesoporous Silica for Protein Drug Delivery.

Non-destructively shattered mesoporous silica for protein drug delivery.

Microporous Mesoporous Mater. 2013 Jul 15; 175: 157-160
Lei C, Chen B, Li X, Qi W, Liu J

Mesoporous silicas have been extensively used for entrapping small chemical molecules and biomacromolecules for drug delivery. We hypothesize that the loading density of biomacromlecules such as proteins in mesoporous silicas could be limited due to disordering in the pore structure and long diffusion time in the pore channels. We shattered mesoporous silicas non-destructively resulting in improved intramesoporous structures and reduced particle sizes in aqueous solutions by a powerful sonication, where the mesoporous structures were still well maintained. The sonication-shattered mesoporous silica can increase the protein loading density to nearly 2.7 times as high as that of the non-shattered one, demonstrating that significantly more mesopore space of the silica could be accessible by the protein molecules, which may result in more sustained protein drug delivery. HubMed – drug

Novel oral anticoagulants for stroke prevention in atrial fibrillation: a focus on the older patient.

Int J Gen Med. 2013; 6: 167-180
Yates SW

Atrial fibrillation (AF) is a common arrhythmia that is associated with an increased risk of stroke, particularly in the elderly. Traditionally, a vitamin K antagonist such as warfarin is prescribed for stroke prevention. Warfarin is effective at lowering stroke risk but has several limitations due to food restrictions, drug interactions, and a narrow therapeutic window. Various novel oral anticoagulants (NOACs) are available or under development to provide alternative treatment options. This article reviews the efficacy and safety of three NOACs (dabigatran etexilate, rivaroxaban, and apixaban) in addition to warfarin and aspirin, for prevention of stroke in patients with AF, focusing on the elderly population. Results of clinical trials demonstrate that the efficacy of NOACs for stroke prevention in patients with AF is as good as or better than that of warfarin. The NOACs are also associated with an equivalent or lower risk of bleeding. Regardless of the medication chosen, older patients with AF must be treated cautiously due to an increased risk of stroke and bleeding, as well as potential challenges related to drug interactions and monitoring requirements. NOACs may be suitable alternatives to warfarin for stroke prevention in older patients due to several advantages, including a faster onset of action, few drug or food interactions, and no requirement for regular monitoring. However, dose adjustments may be required for certain patients, such as those with severe renal impairment or in the setting of drug interactions. HubMed – drug

Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma.

World J Gastroenterol. 2013 May 14; 19(18): 2772-2780
Chan D, Tsoi MY, Liu CD, Chan SH, Law SY, Chan KW, Chan YP, Gopalan V, Lam AK, Tang JC

AIM: To identify the downstream regulated genes of GAEC1 oncogene in esophageal squamous cell carcinoma and their clinicopathological significance. METHODS: The anti-proliferative effect of knocking down the expression of GAEC1 oncogene was studied by using the RNA interference (RNAi) approach through transfecting the GAEC1-overexpressed esophageal carcinoma cell line KYSE150 with the pSilencer vector cloned with a GAEC1-targeted sequence, followed by MTS cell proliferation assay and cell cycle analysis using flow cytometry. RNA was then extracted from the parental, pSilencer-GAEC1-targeted sequence transfected and pSilencer negative control vector transfected KYSE150 cells for further analysis of different patterns in gene expression. Genes differentially expressed with suppressed GAEC1 expression were then determined using Human Genome U133 Plus 2.0 cDNA microarray analysis by comparing with the parental cells and normalized with the pSilencer negative control vector transfected cells. The most prominently regulated genes were then studied by immunohistochemical staining using tissue microarrays to determine their clinicopathological correlations in esophageal squamous cell carcinoma by statistical analyses. RESULTS: The RNAi approach of knocking down gene expression showed the effective suppression of GAEC1 expression in esophageal squamous cell carcinoma cell line KYSE150 that resulted in the inhibition of cell proliferation and increase of apoptotic population. cDNA microarray analysis for identifying differentially expressed genes detected the greatest levels of downregulation of calpain 10 (CAPN10) and upregulation of trinucleotide repeat containing 6C (TNRC6C) transcripts when GAEC1 expression was suppressed. At the tissue level, the high level expression of calpain 10 protein was significantly associated with longer patient survival (month) of esophageal squamous cell carcinoma compared to the patients with low level of calpain 10 expression (37.73 ± 16.33 vs 12.62 ± 12.44, P = 0.032). No significant correction was observed among the TNRC6C protein expression level and the clinocopathologcial features of esophageal squamous cell carcinoma. CONCLUSION: GAEC1 regulates the expression of CAPN10 and TNRC6C downstream. Calpain 10 expression is a potential prognostic marker in patients with esophageal squamous cell carcinoma. HubMed – drug

The Effect of Surface Tension on the Gravity-driven Thin Film Flow of Newtonian and Power-law Fluids.

Comput Fluids. 2012 Jul 15; 64(15): 83-90
Hu B, Kieweg SL

Gravity-driven thin film flow is of importance in many fields, as well as for the design of polymeric drug delivery vehicles, such as anti-HIV topical microbicides. There have been many prior works on gravity-driven thin films. However, the incorporation of surface tension effect has not been well studied for non-Newtonian fluids. After surface tension effect was incorporated into our 2D (i.e. 1D spreading) power-law model, we found that surface tension effect not only impacted the spreading speed of the microbicide gel, but also had an influence on the shape of the 2D spreading profile. We observed a capillary ridge at the front of the fluid bolus. Previous literature shows that the emergence of a capillary ridge is strongly related to the contact line fingering instability. Fingering instabilities during epithelial coating may change the microbicide gel distribution and therefore impact how well it can protect the epithelium. In this study, we focused on the capillary ridge in 2D flow and performed a series of simulations and showed how the capillary ridge height varies with other parameters, such as surface tension coefficient, inclination angle, initial thickness, and power-law parameters. As shown in our results, we found that capillary ridge height increased with higher surface tension, steeper inclination angle, bigger initial thickness, and more Newtonian fluids. This study provides the initial insights of how to optimize the flow and prevent the appearance of a capillary ridge and fingering instability. HubMed – drug

A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function.

J Cell Sci. 2013 May 17;
Trebble PJ, Woolven JM, Saunders KA, Simpson KD, Farrow SN, Matthews LC, Ray DW

The ubiquitously expressed glucocorticoid receptor (GR) is a major drug target for inflammatory disease, but issues of specificity, and target tissue sensitivity remain. We now identify high potency, non-steroidal GR ligands, GSK47867A and GSK47869A, which induce a novel conformation of the GR ligand binding domain (LBD) and augment the efficacy of cellular action. Despite their high potency GSK47867A and GSK47869A both induce surprisingly slow GR nuclear translocation, followed by prolonged nuclear GR retention, and transcriptional activity following washout. We reveal that GSK47867A and GSK47869A specifically alter the GR LBD structure at the HSP90 binding site. The alteration in HSP90 binding site was accompanied by resistance to HSP90 antagonism, with persisting transactivation seen after geldanamycin treatment. Taken together, our studies reveal a novel mechanism governing GR intracellular trafficking regulated by ligand binding, which relies on a specific surface charge patch within the LBD. This conformational change permits extended GR action, likely due to altered GR-HSP90 interaction. This chemical series may offer anti-inflammatory drugs with prolonged duration of action due to altered pharmacodynamics rather than altered pharmacokinetics. HubMed – drug