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991.
The aim of this article was to construct a T–ϕ phase diagram for a model drug (FD) and amorphous polymer (Eudragit® EPO) and to use this information to understand the impact of how temperature–composition coordinates influenced the final properties of the extrudate. Defining process boundaries and understanding drug solubility in polymeric carriers is of utmost importance and will help in the successful manufacture of new delivery platforms for BCS class II drugs. Physically mixed felodipine (FD)–Eudragit® EPO (EPO) binary mixtures with pre-determined weight fractions were analysed using DSC to measure the endset of melting and glass transition temperature. Extrudates of 10 wt% FD–EPO were processed using temperatures (110°C, 126°C, 140°C and 150°C) selected from the temperature–composition (T–ϕ) phase diagrams and processing screw speed of 20, 100 and 200rpm. Extrudates were characterised using powder X-ray diffraction (PXRD), optical, polarised light and Raman microscopy. To ensure formation of a binary amorphous drug dispersion (ADD) at a specific composition, HME processing temperatures should at least be equal to, or exceed, the corresponding temperature value on the liquid–solid curve in a F–H T–ϕ phase diagram. If extruded between the spinodal and liquid–solid curve, the lack of thermodynamic forces to attain complete drug amorphisation may be compensated for through the use of an increased screw speed. Constructing F–H T–ϕ phase diagrams are valuable not only in the understanding drug–polymer miscibility behaviour but also in rationalising the selection of important processing parameters for HME to ensure miscibility of drug and polymer.KEY WORDS: DSC, Flory–Huggins theory, hot-melt extrusion, thermal processing 相似文献
992.
Ketaki Ganti Paola Massimi Joaquin Manzo-Merino Vjekoslav Tomai? David Pim Martin P. Playford Marcela Lizano Sally Roberts Christian Kranjec John Doorbar Lawrence Banks 《PLoS pathogens》2016,12(9)
A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways. This interaction is highly conserved across E6 proteins from multiple high-risk HPV types and is mediated by a classical PBM-PDZ interaction but unlike many E6 targets, SNX27 is not targeted for degradation by E6. Rather, in HPV-18 positive cell lines the association of SNX27 with components of the retromer complex and the endocytic transport machinery is altered in an E6 PBM-dependent manner. Analysis of a SNX27 cargo, the glucose transporter GLUT1, reveals an E6-dependent maintenance of GLUT1 expression and alteration in its association with components of the endocytic transport machinery. Furthermore, knockdown of E6 in HPV-18 positive cervical cancer cells phenocopies the loss of SNX27, both in terms of GLUT1 expression levels and its vesicular localization, with a concomitant marked reduction in glucose uptake, whilst loss of SNX27 results in slower cell proliferation in low nutrient conditions. These results demonstrate that E6 interaction with SNX27 can alter the recycling of cargo molecules, one consequence of which is modulation of nutrient availability in HPV transformed tumour cells. 相似文献
993.
Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology 总被引:1,自引:0,他引:1
Marcela Montes de Oca Rajiv Kumar Fabian de Labastida Rivera Fiona H Amante Meru Sheel Rebecca J. Faleiro Patrick T. Bunn Shannon E. Best Lynette Beattie Susanna S. Ng Chelsea L. Edwards Werner Muller Erika Cretney Stephen L. Nutt Mark J. Smyth Ashraful Haque Geoffrey R. Hill Shyam Sundar Axel Kallies Christian R. Engwerda 《PLoS pathogens》2016,12(1)
Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation. 相似文献
994.
Lu Fang Piyushkumar A. Mundra Fenling Fan Abby Galvin Jacquelyn M. Weir Gerard Wong Jaye Chin-Dusting Flavia Cicuttini Peter Meikle Anthony Michael Dart 《Metabolomics : Official journal of the Metabolomic Society》2016,12(8):136
Introduction
Rheumatoid arthritis (RA) is linked to increased cardiovascular morbidity and mortality, not completely explained by traditional risk factors. Importantly, the increased risk occurs despite lower levels of total and low-density lipoprotein cholesterol. Whilst systemic inflammation may be a factor, it is possible that changes in individual lipid species contribute to the increased cardiovascular risk.Objectives
In the present study, we characterized plasma lipidomic profiles in patients with RA in comparison with healthy controls.Methods
Patients with RA (n = 32) and age- and gender-matched healthy volunteers (n = 84) were recruited. Fasting plasma lipid profiles were measured using electrospray-ionisation tandem mass spectrometry. 24 lipid classes and subclasses were measured.Results
Patients with RA had normal total, low-density lipoprotein and high-density lipoprotein cholesterol, but higher triglycerides than controls. Five lipid classes (dihydroceramides, alkylphosphatidylethanolamine, alkenylphosphatidylethanolamine, lysophosphatidylinositol, phosphatidylserine) differed between patients with RA and controls. Then we measured 36 lipid species within these 5 classes and found that 11 lipid species were different between patients with RA and controls. Three lipid classes (dihydroceramides, lysophosphatidylinositol, phosphatidylserine) and 10 lipid species remained significantly associated with RA after adjusting for age, sex, body mass index, current smoking, systolic blood pressure and anti-hypertensive treatment in a binary logistic regression model.Conclusion
This study has identified lipid alterations in RA. These alterations of lipids warrant further investigation as they may be associated with accelerated atherosclerosis and joint inflammation in patient with RA.995.
Discovery of A-type procyanidin dimers in yellow raspberries by untargeted metabolomics and correlation based data analysis 总被引:1,自引:0,他引:1
Elisabete Carvalho Pietro Franceschi Antje Feller Lorena Herrera Luisa Palmieri Panagiotis Arapitsas Samantha Riccadonna Stefan Martens 《Metabolomics : Official journal of the Metabolomic Society》2016,12(9):144
Introduction
Raspberries are becoming increasingly popular due to their reported health beneficial properties. Despite the presence of only trace amounts of anthocyanins, yellow varieties seems to show similar or better effects in comparison to conventional raspberries.Objectives
The aim of this work is to characterize the metabolic differences between red and yellow berries, focussing on the compounds showing a higher concentration in yellow varieties.Methods
The metabolomic profile of 13 red and 12 yellow raspberries (of different varieties, locations and collection dates) was determined by UPLC–TOF-MS. A novel approach based on Pearson correlation on the extracted ion chromatograms was implemented to extract the pseudospectra of the most relevant biomarkers from high energy LC–MS runs. The raw data will be made publicly available on MetaboLights (MTBLS333).Results
Among the metabolites showing higher concentration in yellow raspberries it was possible to identify a series of compounds showing a pseudospectrum similar to that of A-type procyanidin polymers. The annotation of this group of compounds was confirmed by specific MS/MS experiments and performing standard injections.Conclusions
In berries lacking anthocyanins the polyphenol metabolism might be shifted to the formation of a novel class of A-type procyanidin polymers.996.
Andrei Prodan Sultan Imangaliyev Henk S. Brand Martijn N. A. Rosema Evgeni Levin Wim Crielaard Bart J. F. Keijser Enno C. I. Veerman 《Metabolomics : Official journal of the Metabolomic Society》2016,12(9):147
Introduction
Understanding the changes occurring in the oral ecosystem during development of gingivitis could help improve prevention and treatment strategies for oral health. Erythritol is a non-caloric polyol proposed to have beneficial effects on oral health.Objectives
To examine the effect of experimental gingivitis and the effect of erythritol on the salivary metabolome and salivary functional biochemistry.Methods
In a two-week experimental gingivitis challenge intervention study, non-targeted, mass spectrometry-based metabolomic profiling was performed on saliva samples from 61 healthy adults, collected at five time-points. The effect of erythritol was studied in a randomized, controlled trial setting. Fourteen salivary biochemistry variables were measured with antibody- or enzymatic activity-based assays.Results
Bacterial amino acid catabolites (cadaverine, N-acetylcadaverine, and α-hydroxyisovalerate) and end-products of bacterial alkali-producing pathways (N-α-acetylornithine and γ-aminobutyrate) increased significantly during the experimental gingivitis. Significant changes were found in a set of 13 salivary metabolite ratios composed of host cell membrane lipids involved in cell signaling, host responses to bacteria, and defense against free radicals. An increase in mevalonate was also observed. There were no significant effects of erythritol. No significant changes were found in functional salivary biochemistry.Conclusions
The findings underline a dynamic interaction between the host and the oral microbial biofilm during an experimental induction of gingivitis.997.
Lifang Zou Guihua Tu Wei Xie Shiyao Wen Qiuyu Xie Shuangmei Liu Guilin Li Yun Gao Hong Xu Shouyu Wang Yun Xue Bing Wu Qiulan Lv Mofeng Ying Xi Zhang Shangdong Liang 《Purinergic signalling》2016,12(1):127-137
Adenosine triphosphate (ATP) acts on P2X receptors to initiate signal transmission. P2X7 receptors play a role in the pathophysiological process of myocardial ischemic injury. Long noncoding RNAs (lncRNAs) participate in numerous biological functions independent of protein translation. LncRNAs are implicated in nervous system diseases. This study investigated the effects of NONRATT021972 small interference RNA (siRNA) on the pathophysiologic processes mediated by P2X7 receptors in stellate ganglia (SG) after myocardial ischemic injury. Our results demonstrated that the expression of NONRATT021972 in SG was significantly higher in the myocardial ischemic (MI) group than in the control group. Treatment of MI rats with NONRATT021972 siRNA, the P2X7 antagonist brilliant blue G (BBG), or P2X7 siRNA improved the histology of injured ischemic cardiac tissues and decreased the elevated concentrations of serum myocardial enzymes, creatine kinase (CK), CK isoform MB (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) compared to the MI rats. NONRATT021972 siRNA, BBG, or P2X7 siRNA treatment in MI rats decreased the expression levels of P2X7 immunoreactivity, P2X7 messenger RNA (mRNA), and P2X7 protein, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) in the SG compared to MI rats. NONRATT021972 siRNA treatment prevented the pathophysiologic processes mediated by P2X7 receptors in the SG after myocardial ischemic injury. 相似文献
998.
Melanie Kaiser Anja Penk Heike Franke Ute Krügel Wolfgang Nörenberg Daniel Huster Michael Schaefer 《Purinergic signalling》2016,12(3):453-463
Effective therapeutic measures against the development of brain edema, a life-threatening complication of cerebral ischemia, are necessary to improve the functional outcome for the patient. Here, we identified a beneficial role of purinergic receptor P2X7 activation in acute ischemic stroke. Involvement of P2X7 in the development of neurological deficits, infarct size, brain edema, and glial responses after ischemic cerebral infarction has been analyzed. Neurologic evaluation, magnetic resonance imaging, and immunofluorescence assays were used to characterize the receptor’s effect on the disease progress during 72 h after transient middle cerebral artery occlusion (tMCAO). Sham-operated animals were included in all experiments for control purposes. We found P2X7-deficient mice to develop a more prominent brain edema with a trend towards more severe neurological deficits 24 h after tMCAO. Infarct sizes, T2 times, and apparent diffusion coefficients did not differ significantly between wild-type and P2X7?/? animals. Our results show a characteristic spatial distribution of reactive glia cells with strongly attenuated microglia activation in P2X7?/? mice 72 h after tMCAO. Our data indicate that P2X7 exerts a role in limiting the early edema formation, possibly by modulating glial responses, and supports later microglia activation. 相似文献
999.
1000.
Carola Ledderose Marco M. Hefti Yu Chen Yi Bao Thomas Seier Linglin Li Tobias Woehrle Jingping Zhang Wolfgang G. Junger 《Purinergic signalling》2016,12(4):673-685
In neutrophils, adenosine triphosphate (ATP) release and autocrine purinergic signaling regulate coordinated cell motility during chemotaxis. Here, we studied whether similar mechanisms regulate the motility of breast cancer cells. While neutrophils and benign human mammary epithelial cells (HMEC) form a single leading edge, MDA-MB-231 breast cancer cells possess multiple leading edges enriched with A3 adenosine receptors. Compared to HMEC, MDA-MB-231 cells overexpress the ectonucleotidases ENPP1 and CD73, which convert extracellular ATP released by the cells to adenosine that stimulates A3 receptors and promotes cell migration with frequent directional changes. However, exogenous adenosine added to breast cancer cells or the A3 receptor agonist IB-MECA dose-dependently arrested cell motility by simultaneous stimulation of multiple leading edges, doubling cell surface areas and significantly reducing migration velocity by up to 75 %. We conclude that MDA-MB-231 cells, HMEC, and neutrophils differ in the purinergic signaling mechanisms that regulate their motility patterns and that the subcellular distribution of A3 adenosine receptors in MDA-MB-231 breast cancer cells contributes to dysfunctional cell motility. These findings imply that purinergic signaling mechanisms may be potential therapeutic targets to interfere with the motility of breast cancer cells in order to reduce the spread of cancer cells and the risk of metastasis. 相似文献