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Wang H.,Ningxia Medical University | Sessions R.B.,University of Bristol | Prime S.S.,Bristol Dental Hospital | Shoemark D.K.,Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology | And 4 more authors.
Journal of Computer-Aided Molecular Design

Aberrant transforming growth factor-β (TGF-β) signalling has been associated with a number of disease pathologies, such as the development of fibrosis in the heart, lung and liver, cardiovascular disease and cancer, hence the TGF-β pathway represents a promising target for a variety of diseases. However, highly specific ways to inhibit TGF-β signalling need to be developed to prevent cross-talk with related receptors and minimise unwanted side effects. We have used used virtual screening and molecular docking to identify small molecule inhibitors of TGF-β binding to TßRII. The crystal structure of TGF-β3 in complex with the extracellular domain of the type II TGF-β receptor was taken as a starting point for molecular docking and we developed a structure-based pharmacophore model to identify compounds that competitively inhibit the binding of TGF-β to TβRII and antogonize TGF-β signalling. We have experimentally tested 67 molecules suggested by in silico screening and similarity searching for their ability to inhibit TGF-β signalling in TGF-β-dependent luciferase assays in vitro and the molecule with the strongest inhibition had an IC50 of 18 μM. These compounds were selected to bind to the SS1 subsite (composed of F30, C31, D32, I50, T51 S52, I53, C54 and E55) of TßRII and all share the general property of being aromatic and fairly flat. Molecular dynamics simulations confirmed that this was the most likely binding mode. The computational methods used and the hits identified in this study provide an excellent guide to medicinal chemistry efforts to design tighter binding molecules to disrupt the TGF-β/TßRII interaction. © 2013 Springer Science+Business Media Dordrecht. Source

Gardner M.P.,University of Bristol | Lightman S.L.,Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology | Gallacher J.,University of Cardiff | Hardy R.,University College London | And 4 more authors.
International Journal of Epidemiology

Background: Cross-sectional studies have suggested that elevated cortisol is associated with worse physical performance, a surrogate of ageing. We examined the relationship between repeat cortisol measures over 20 years and physical performance in later life. Methods: Middle-aged men (45-59 years) were recruited between 1979 and 1983 (Phase 1) from the Caerphilly Prospective Study (CaPS) and re-examined 20 years later at 65-83 years of age (Phase 5). Participants included 750 and 898 subjects with either Phase 1 and/or Phase 5 data on exposure and outcomes. Outcome measures were walking speed and balance time and exposures included morning fasting serum cortisol (Phase 1) and four salivary samples on 2 consecutive days (Phase 5). Results: Faster walking speed was associated with higher morning cortisol at Phase 1 [coefficient per standard deviation (SD) increase 0.68, 95% confidence interval (95% CI) 0.09-1.27; P = 0.02] though this was attenuated after adjustment for covariates (coefficient per SD increase 0.45; 95% CI -0.16 to 1.07; P = 0.15). Higher night-time cortisol at Phase 5 was associated with slower speed (coefficient per SD increase -1.06; 95% CI -1.60 to -0.52; P < 0.001) and poorer balance (odds ratio of top tertile vs bottom 2.49; 95% CI 1.63-3.81; P < 0.001). Worst performance was seen for men with a poor morning response (Phase 1) and less nocturnal decline (Phase 5). Conclusions: Dysregulation of the hypothalamic pituitary adrenal (HPA) axis is associated with worse physical performance in later life. This may reflect a causal effect of the HPA axis on ageing or that ageing itself is associated with reduced HPA reactivity. Published by Oxford University Press on behalf of the International Epidemiological Association. © The Author 2011; all rights reserved. Source

Gordon D.,University of Bristol | Pavlovska G.,University of Bristol | Uney J.B.,Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology | Wraith D.C.,University of Bristol | Scolding N.J.,University of Bristol
Journal of Neuropathology and Experimental Neurology

Mesenchymal stem cells (MSCs) can abrogate the animal model ofmultiple sclerosis, experimental autoimmune encephalomyelitis (EAE), but whether this therapeutic effect occurs entirely through systemic immune modulation and whether CNS infiltration occurs after peripheral delivery are uncertain. We studied the clinical and neuropathologic effects of intravenously administered human MSCs (hMSCs) in C57BL/6 mice with EAE. Human MSCs significantly reduced the clinical disease severity, particularly in later disease. Large numbers of hMSCs migrated into gray and white matter at all levels of the spinal cord in both naive mice and mice with EAE. In the latter, hMSCs accumulated over time in demyelinated areas. There were 2 distinct morphological appearances of the hMSCs in the tissue, that is, rounded and less numerous process-bearing forms; very few expressed neural markers. The number of spinal cord white matter lesions and areas of white matter demyelination were reduced after hMSC treatment compared with control treatment. These findings show that central nervous system infiltration occurs after peripheral delivery of hMSCs, that they accumulate where there is myelin damage, and that they are associated with a reduced extent ofdemyelination. These data support a potential role for hMSCs in autologous cell therapy in multiple sclerosis. © 2010 by the American Association of Neuropathologists, Inc. Source

Gardner M.P.,University of Bristol | Lightman S.,Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology | Sayer A.A.,University of Southampton | Cooper C.,University of Southampton | And 10 more authors.

The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50-92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from n=2146 for associations between morning Cortisol Awakening Response and balance to n=8448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.052, 95% confidence interval (CI) 0.029, 0.076, p<0.001; age and gender adjusted) and a quicker chair rise time (standardised coefficient per SD increase -0.075, 95% CI -0.116, -0.034, p<0.001; age and gender adjusted). There was little evidence of associations with balance or grip strength. Greater diurnal decline of the HPA axis is associated with better physical performance in later life. This may reflect a causal effect of the HPA axis on performance or that other ageing-related factors are associated with both reduced HPA reactivity and performance. © 2012 Elsevier Ltd. Source

Waite E.,UK National Institute for Medical Research | Waite E.,Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology | Lafont C.,CNRS Lyon Institute of Functional Genomics | Carmignac D.,UK National Institute for Medical Research | And 6 more authors.

We have generated transgenic mice with somatotroph-specific expression of a modified influenza virus ion channel, H37AM2, leading to ablation of GH cells with three levels of severity, dependent on transgene copy number. GH-M2low mice grow normally and have normal-size pituitaries but 40-50% reduction in pituitary GH content in adult animals. GH-M2med mice have male-specific transient growth retardation and a reduction in pituitary GH content by 75% at 42 d and 97% by 100 d. GH-M2high mice are severely dwarfed with undetectable pituitary GH. The GH secretory response of GH-M2low and GH-M2med mice to GH-releasing peptide-6 and GHRH was markedly attenuated. The content of other pituitary hormones was affected depending on transgene copy number: no effect in GH-M2low mice, prolactin and TSH reduced in GH-M2med mice, and all hormones reduced in GH-M2high mice. The effect on non-GH hormone content was associated with increased macrophage invasion of the pituitary. Somatotroph ablation affected GH cell network organization with limited disruption in GH-M2low mice but more severe disruption in GH-M2med mice. The remaining somatotrophs formed tight clusters after puberty, which contrasts with GHRH-M2 mice with a secondary reduction in somatotrophs that do not form clusters. A reduction in pituitary β-catenin staining was correlated with GH-M2 transgene copy number, suggesting M2 expression has an effect on cell-cell communication in somatotrophs and other pituitary cell types. GH-M2 transgenic mice demonstrate that differing degrees of somatotroph ablation lead to correlated secondary effects on cell populations and cellular network organization. Copyright © 2010 by The Endocrine Society. Source

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