Butyrate suppresses expression of neuropilin I in colorectal cell lines through inhibition of Sp1 transactivation

Background: Neuropilin is a transmembrane receptor for vascular endothelial growth factor (VEGF) and is expressed in normal endothelial cells and upregulated in cancer cells. Neuropilin-1 (NRP-1) has been shown to promote tumour cell migration and survival in colon cancer in response to VEGF binding. The expression profiles of neuropilins, associated co-receptors and known ligands have been mapped in three colorectal cell lines: Caco-2, HCT116 & HT29. We have previously shown that butyrate, a naturally occurring histone deacetylase inhibitor (HDACi) produced by fermentation of fibre in the colon, causes apoptosis of colon cancer cell lines. Results: Here we demonstrate that butyrate down-regulates NRP-1 and VEGF at the mRNA and protein level in colorectal cancer cell lines. NRP-1 is a known transcriptional target of Sp1, whose activity is regulated by acetylation. NRP-1 down-regulation by butyrate was associated with decreased binding affinity of Sp1 for canonical Sp-binding sites in the NRP-1 promoter. siRNA-mediated knock-down of Sp1 implied that Sp1 may have strong DNA binding activity but weak transactivation potential. Conclusion: The downregulation of the key apoptotic and angiogenesis regulator NRP-1 by butyrate suggests a novel contributory mechanism to the chemopreventive effect of dietary fibre

The role of diet and nutrition on mental health and wellbeing

Mental, neurological and substance-use disorders presently represent the greatest global burden of disease. Likewise, depression and other psychopathologies are elevated risk comorbidities of other health hazards, such as obesity. Nutrition has been implicated in behaviour, mood and in the pathology and treatment of mental illness. In this brief editorial, we aim to set the scale of the problem in context and overview advances and recent evidence linking nutrition to psychological outcomes. The purpose of the 2016 Nutrition Society Winter Meeting, 'Diet, nutrition and mental health and wellbeing' was to review where the evidence is strong, where there are unmet needs for research and to draw together the communities working in this area to share their findings. The papers presented demonstrated clear advancements that are being made in this field. The meeting illustrated compelling support for nutrition as a modifiable risk factor. The present research in the field and evidence presented at the 2016 Nutrition Society Winter Meeting lead us to postulate that even interventions with relatively modest effect sizes may plausibly and significantly curtail the disease burden of mental and neurological disease by food- and nutrient-based approaches

Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line

Butyrate, a known histone deacetylase inhibitor (HDACi) and product of fibre fermentation, is postulated to mediate the protective effect of dietary fibre against colon cancer. The transcription factor Sp1 is a target of acetylation and is known to be associated with class I HDACs, including HDAC1. Sp1 is a ubiquitous transcription factor and Sp1-regulated genes include those involved in cell cycle regulation, apoptosis and lipogenesis: all major pathways in cancer development. The only known acetylated residue of Sp1 is lysine703 which resides in the DNA binding domain. Here we show that acetylated Sp1 loses p21- and bak-promoter -binding function in vitro. Furthermore treatment with a panel of HDAC inhibitors showed clustering of activities for a subset of inhibitors, causing G2 cell cycle arrest, Sp1 acetylation, p21 and Bak over-expression, all with very similar EC50 concentrations. These HDACi activities were not distributed according to the molecular class of compound. In order to mimic loss of binding, an siRNA strategy was used to reduce Sp1 expression. This resulted in altered expression of multiple elements of the p53/p21 pathway. Taken together our data suggest a mechanistic model for the chemopreventive actions of butyrate in colon epithelial cells, and provide new insight into the differential activities some classes of HDAC inhibitors

Body mass index and age affect Three-Factor Eating Questionnaire scores in male subjects

This cross-sectional analysis evaluated the effect of age and body mass index (BMI) on Three-Factor Eating Questionnaire scores in males. Subjects (n = 60) were recruited according to BMI status. Each completed the 51-item Three-Factor Eating Questionnaire. The group was split at the median age to produce a "younger" and "older" group for statistical analysis. A 2-way between-groups analysis of variance revealed a significant main effect of BMI on disinhibition (P = .003) and hunger (P = .041) with higher levels found in overweight males compared to healthy-weight counterparts. A significant main effect of age on hunger (P = .046) demonstrated older males were less susceptible to hunger than younger males. These insights provide a better understanding of eating behavior across the male life cycle and may assist health professionals to better guide men in weight management in the light of rising overweight/obesity. (c) 2009 Elsevier Inc. All rights reserved

Post-Translational Control of Sp-Family Transcription Factors

Sp-family transcription factors are widely expressed in human tissues and involved in the regulation of many cellular processes and response to cellular microenvironment. These responses appear to be mediated by alterations in transcription factor affinity for DNA rather than altered protein level. How might such changes be effected? This review will identify the range of known post-translational modifications (PTMs) of Sp-factors and the sometimes conflicting literature about the roles of PTMs in regulating activity. We will speculate on the interaction between cell environment, chromatin microenvironment and the role of PTM in governing functionality of the proteins and the complexes to which they belong

An agent-based model of anoikis in the colon crypt displays novel emergent behaviour consistent with biological observations

Colorectal cancer (CRC) is a major cause of cancer mortality. Colon crypts are multi-cellular flask-shaped invaginations of the colonic epithelium, with stem cells at their base which support the continual turnover of the epithelium with loss of cells by anoikis from the flat mucosa. Mutations in these stem cells can become embedded in the crypts, a process that is strongly implicated in CRC initiation. We describe a computational model which includes novel features, including an accurate representation of the geometry of the crypt mouth. Model simulations yield previously unseen emergent phenomena, such as localization of cell death to a small region of the crypt mouth which corresponds with that observed in vivo. A mechanism emerges in the model for regulation of crypt cellularity in response to changes in either cell proliferation rates or membrane adhesion strengths. We show that cell shape assumptions influence this behaviour, with cylinders recapitulating biology better than spheres. Potential applications of the model include determination of roles of mutations in neoplasia and exploring factors for altered crypt morphodynamics

Rate of change of circulating 25-hydroxyvitamin D following sublingual and capsular vitamin D preparations

Background: Vitamin D is critical for skeletal health and is increasingly associated with other pathologies encompassing gastrointestinal, immunological, psychological effects. A significant proportion of the population exhibit suboptimal levels of vitamin D, particularly in Northern latitudes in winter. Supplementation is advocated, but few data are available on achievable or typical rates of change. There has been considerable interest in the potential use of sublingual sprays for delivery of nutrient supplements, but data on efficacy remains sparse. Methods: A randomised, placebo-controlled, 3-arm parallel design study was conducted in healthy volunteers (n=75) to compare the rate of change of vitamin D status in response to vitamin D3 (3000IU/day) supplementation in capsule and sublingual spray preparations over a six-week period between January and April 2017. Blood 25(OH)D concentrations were measured after day 0, 3, 7, 14, 21 and 42 days of supplementation with 3000IU per diem. Results: Baseline measurements show 25(OH)D deficiency (50mmol/l) in 14.9%, 44.6% and 40.5% of the participants respectively. There was a significant elevation in blood concentrations of 25(OH)D in both of the treatment arms (capsule p=0.003, spray p=0.001) compared to control. The capsule and spray were equally efficacious. The rate of change ranged from 0.69-3.93 (capsule) and 0.64-3.34 (spray) nmol/L day with average change in blood 25(OH)D levels of 2 nmol/l/day. Rates followed a simple normal distribution in the study population (ks= 0.94 and 0.82 for capsule and spray respectively). The data suggest that rates of change are higher in individuals with lower levels of 25(OH)D. Conclusions: A sublingual vitamin D spray is an effective mode of delivery for supplementation in a healthy population. The data provide reference values and ranges for the rate of change of 25(OH)D for nutrikinetic analyses

Alcohol-free and low-strength drinks: understanding their role in reducing alcohol-related harms.

This report examines the market for alcohol-free and low-strength beers, ciders, wines and spirits – “NoLo drinks” - in the UK. Key findings: • The market for NoLo drinks in the UK is seeing significant growth. • However, this growth is from a very low base and must be put into context. • Achieving a significant market share for NoLo drinks over the next decade would thus require consistent, strong sales growth. • The relatively small size of the NoLo drinks market thus needs to be taken into account when assessing the current health benefits from the use of such products at a population level