450
2,213.88
4.92
1,042

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    ABSTRACT: Androgens play an important role in regulation of body fat distribution in humans. They exert direct effects on adipocyte differentiation in a depot-specific manner, via the androgen receptor (AR), leading to modulation of adipocyte size and fat compartment expansion. Androgens also impact directly on key adipocyte functions including insulin signaling, lipid metabolism, fatty acid uptake and adipokine production. Androgen excess and deficiency have implications for metabolic health in both males and females, and these metabolic effects may be mediated through adipose tissue via effects on fat distribution, adipocyte function and lipolysis. Research into the field of androgen metabolism in human and animal adipose tissue has produced inconsistent results; it is important to take into account the sex-, depot- and organism-specific effects of androgens in fat. In general, studies point towards a stimulatory effect on lipolysis, with impairment of adipocyte differentiation, insulin signaling and adipokine generation. Observed effects are frequently gender-specific. Adipose tissue is an important organ of pre-receptor androgen metabolism, through which local androgen availability is rigorously controlled. Adipose androgen exposure is tightly controlled by isoenzymes of AKR1C, 5α-reductase and others, but regulation of the balance between generation and irreversible inactivation remains poorly understood. In particular, AKR1C2 and AKR1C3 are crucial in the regulation of local androgen bioavailability within adipose tissue. These isoforms control the balance between activation of androstenedione (A) to testosterone (T) by the 17β-hydroxysteroid dehydrogenase activity (17β-HSD) of AKR1C3, or inactivation of 5α-dihydrotestosterone (DHT) to 5α-androstane-3α,17β-diol by the 3α-hydroxysteroid dehydrogenase (3α-HSD) activity of AKR1C2. Most studies suggest that androgen inactivation is the predominant reaction in fat, particularly in the abdominal subcutaneous (SC) depot. Modulation of local adipose androgen availability may afford future therapeutic options to improve metabolic phenotype in disorders of androgen excess and deficiency.
    The Journal of steroid biochemistry and molecular biology 04/2014;
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    ABSTRACT: Adhesion of tumor cells to matrix components and endothelial cells is essential for tumor metastasis. Investigation of the adhesion molecules required and the signals which induce tumor cell adhesion and migration are crucial in order to increase our understanding of this process. This chapter describes protocols which may be used to study tumor cell adhesion to purified matrix elements and tissue sections. It also details methods used to investigate cell adhesion to endothelial cells, both under static and flow conditions. In addition, there is a section detailing the use of endothelial cell cultures on three-dimensional collagen gels which are useful when studying adhesion to endothelial cells and onward invasion through a protein matrix.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1070:57-75.
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    ABSTRACT: In the injured central nervous system (CNS), transforming growth factor (TGF)-β1/2-induced scarring and wound cavitation impede axon regeneration implying that a combination of both scar suppression and axogenic treatments is required to achieve functional recovery. After treating acute and chronic dorsal funicular spinal cord lesions (DFL) in adult rats with the pan-TGFβ1/2 antagonist Decorin, we report that in: (1), acute DFL, the development of all injury parameters was significantly retarded e.g., wound cavitation by 68%, encapsulation of the wound by a glia limitans accessoria (GLA) by 65%, GLA basal lamina thickness by 94%, fibronectin, NG2 and Sema-3A deposition by 87%, 48% and 48%, respectively, and both macrophage and reactive microglia accumulation by 60%; and (2), chronic DFL, all the above parameters were attenuated to a lesser extent e.g., wound cavitation by 11%, GLA encapsulation by 25%, GLA basal lamina thickness by 31%, extracellular fibronectin, NG2 and Sema-3A deposition by 58%, 22% and 29%, respectively, and macrophage and reactive microglia accumulation by 44%. Moreover, in acute and chronic DFL, levels of tissue plasminogen activator (tPA) were raised (by 236% and 482%, respectively), as were active-MMP-2 (by 64% and 91%, respectively) and active-MMP-9 (by 122% and 18%, respectively), while plasminogen activator inhibitor-1 (PAI-1) was suppressed (by 56% and 23%, respectively) and active-TIMP-and active TIMP-2 were both lower but only significantly suppressed in acute DFL (by 56 and 21%, respectively). These findings demonstrate that both scar tissue mass and cavitation are attenuated in acute and chronic spinal cord wounds by Decorin treatment and suggest that the dominant effect of Decorin during acute scarring is anti-fibrogenic through suppression of inflammatory fibrosis by neutralisation of TGFβ1/2 whereas, in chronic lesions, Decorin-induction of tPA and MMP (concomitant with reduced complimentary levels of TIMP and PAI-1) leads to dissolution of the mature established scar by fibrolysis. Decorin also promoted the regeneration of similar numbers of axons through acute and chronic wounds. Accordingly, intrathecal delivery of Decorin offers a potential translatable treatment for scar tissue attenuation in patients with spinal cord injury.
    Neurobiology of Disease 12/2013;
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    ABSTRACT: One of the key events in eukaryotic gene regulation and consequent transcription is the assembly of general transcription factors and RNA polymerase II into a functional pre-initiation complex at core promoters. An emerging view of complexity arising from a variety of promoter associated DNA motifs, their binding factors and recent discoveries in characterising promoter associated chromatin properties brings an old question back into the limelight: how is a promoter defined? In addition to position-dependent DNA sequence motifs, accumulating evidence suggests that several parallel acting mechanisms are involved in orchestrating a pattern marked by the state of chromatin and general transcription factor binding in preparation for defining transcription start sites. In this review we attempt to summarise these promoter features and discuss the available evidence pointing at their interactions in defining transcription initiation in developmental contexts. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development, edited by Dr. Peter Verrijzer and Dr. Elissa Lei.
    Biochimica et Biophysica Acta 11/2013;
  • Advanced drug delivery reviews 11/2013;
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    ABSTRACT: The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral TH receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology and sought to quantify changes in cortical MCT8 expression with IUGR. Firstly, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections from appropriately grown for gestational age (AGA) human fetuses between 19 weeks gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24-28 weeks gestation were objectively compared with gestationally-matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, epithelium of the choroid plexus and ependyma, and microvessel wall. When complicated by IUGR, fetuses showed a significant 5-fold reduction in the percentage area of cortical plate immunostained with MCT8 compared with AGA fetuses (p<0.05) but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression negatively correlated with the severity of IUGR indicated by brain:liver weight ratios (r2=0.28, p<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.
    Journal of Endocrinology 11/2013;
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    ABSTRACT: Immunesenescence is the functional deterioration of the immune system during natural aging. Despite increased susceptibility to bacterial infections in older adults age-associated changes to neutrophil responses are only partially understood and neutrophil migration has not been characterized in detail. Here we describe reduced chemotaxis but preserved chemokinesis towards a range of inflammatory stimuli in migrating neutrophils isolated from healthy older subjects. Cross-sectional data indicate that migratory behaviour changes in the sixth decade of life. Crucially, aberrant migration may increase "by-stander" tissue damage and heighten inflammation due to excess proteinase release during inaccurate chemotaxis, as well as reducing pathogen clearance. We show evidence of increased neutrophil proteinase activity in older adults, namely raised levels of neutrophil proteinase substrate-derived peptides and evidence of primary granule release, associated with increased systemic inflammation. Inaccurate migration was causally associated with increased constitutive Phosphoinositide 3-kinase (PI3K) signalling; untreated neutrophils from old donors demonstrated significant PI3K activation compared with cells from young donors. PI3K blocking strategies, specifically inhibition of PI3K γ or δ restored neutrophil migratory accuracy while SHIP1 inhibition worsened migratory flaws. Targeting PI3K signalling may therefore offer a new strategy in improving neutrophil functions during infections and reduce inappropriate inflammation in older patients.
    Blood 11/2013;
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    ABSTRACT: The complex process of oral drug absorption is influenced by a host of drug and formulation properties as well as their interaction with the gastrointestinal environment in terms of drug solubility, dissolution, permeability and pre-systemic metabolism. For adult dosage forms the use of biopharmaceutical tools to aid in the design and development of medicinal products is well documented. This review considers current literature evidence to guide development of bespoke paediatric biopharmaceutics tools and reviews current understanding surrounding extrapolation of adult methodology into a paediatric population. Clinical testing and the use of in silico models were also reviewed. The results demonstrate that further work is required to adequately characterise the paediatric gastrointestinal tract to ensure that biopharmaceutics tools are appropriate to predict performance within this population. The most vulnerable group was found to be neonates and infants up to 6months where differences from adults were greatest.
    Advanced drug delivery reviews 11/2013;
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    ABSTRACT: Carbon nanotubes (CNT) are increasingly been investigated for their use in biomedical applications and nanomedicine. An emergent need for the understanding of their in vivo biodistribution and pharmacokinetics is therefore needed to establish the essential properties and criteria for their further development as targeted CNT delivery systems to specific tissues for diagnostics and therapeutic purposes. Until their biodistribution and toxicoketic profiles are fully understood, their translation into the clinic will be hindered. This review will highlight the important factors affecting the biodistribution and pharmacokinetics of CNT and address their toxicokinetics following systemic, pulmonary and dermal exposure.
    Advanced drug delivery reviews 10/2013;
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    ABSTRACT: Stromal cells may regulate the recruitment and behaviour of leukocytes during an inflammatory response, potentially through interaction with the endothelial cells (EC) and the leukocytes themselves. Here we describe new in vitro methodologies to characterise the effects of stromal cells on the migration of lymphocytes through endothelium and its underlying matrix. Three-dimensional tissue-like constructs were created in which EC were cultured above a stromal layer incorporating fibroblasts either as a monolayer on a porous filter or dispersed within a matrix of collagen type 1. A major advantage of these constructs is that they enable each step in leukocyte migration to be analysed in sequence (migration through EC and then stroma), as would occur in vivo. Migrated cells can also be retrieved from the constructs to identify which subsets traffic more effectively and how their functional responses evolve during migration. We found that culture of EC with dermal fibroblasts promoted lymphocyte transendothelial migration but not onward transit through matrix. A critical factor influencing the effect of fibroblasts on recruitment proved to be their proximity to the EC, with direct contact tending to disrupt migration. Comparison of the different approaches indicates that choice of an appropriate 3-D model enables the steps in lymphocyte entry into tissue to be studied in sequence, the regulatory mechanism to be dissected, and the effects of changes in stroma to be investigated.
    Journal of immunological methods 10/2013;
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