Biomedical subjects

John C Mathers

Publications and source records attributed to John C Mathers.

28 records · Page 2Linked to original sources

PubMed2004

Effecting dietary change.

A world epidemic of diet-related chronic disease is currently being faced. In the UK incidence of obesity alone has tripled in the last 20 years and this trend is predicted to continue. Consensus exists for the urgent need for a change in diet and other lifestyle factors and for the direction and targets for this change. The evidence for how this change can be achieved is less certain. It has been established that disease processes begin in childhood. Recent evidence indicates that dietary habits too are established in childhood but that these habits are amenable to change. While establishing a healthy lifestyle in childhood is paramount, interventions have the potential to promote positive change throughout the life course. Success in reversing current trends in diet-related disease will depend on commitment from legislators, health professionals, industry and individuals, and this collaboration must seek to address not only the food choices of the individual but also the environment that influences such choices. Recent public health policy development in England, if fully supported and implemented, is a positive move towards this goal. Evidence for effective strategies to promote dietary change at the individual level is emerging and three reviews of this evidence are discussed. In addition, three recent dietary intervention studies, in three different settings and with different methods and aims, are presented to illustrate methods of effecting dietary change. Further work is required on what factors influence the eating behaviour and physical activity of individuals. There is a need for further theory-based research on which to develop more effective strategies to enable individuals to adopt healthier lifestyles.

Chronic Disease↗

PubMed2004

Use of DNA from human stools to detect aberrant CpG island methylation of genes implicated in colorectal cancer.

Hypermethylation of cytosine residues in the CpG islands of tumor suppressor genes is a key mechanism of colorectal carcinogenesis. Detection and quantification of CpG island methylation in human DNA isolated from stools might provide a novel strategy for the detection and investigation of colorectal neoplasia. To explore the feasibility of this approach, colorectal biopsies and fecal samples were obtained from 32 patients attending for colonoscopy or surgery, who were found to have adenomatous polyps, colorectal cancer, or no evidence of neoplasia. A further 18 fecal samples were obtained from healthy volunteers, with no bowel symptoms. Isolated DNA was modified with sodium bisulfite and analyzed by methylation-specific PCR and combined bisulfite restriction analysis for CpG island methylation of ESR1, MGMT, HPP1, p16(INK4a), APC, and MLH1. CpG island methylation was readily detectable in both mucosal and fecal DNA with methylation-specific PCR. Using combined bisulfite restriction analysis, it was established that, in volunteers from whom biopsies were available, the levels of methylation at two CpG sites within ESR1 assayed using fecal DNA were significantly correlated with methylation in DNA from colorectal mucosa. Thus, noninvasive techniques can be used to obtain quantitative information about the level of CpG island methylation in human colorectal mucosa. The methods described here could be applied to a much expanded range of genes and may be valuable both for screening purposes and to provide greater insight into the functional consequences of epigenetic changes in the colorectal mucosa of free-living individuals.

Adenomatous Polyps↗

PubMed2003

Postprandial carbohydrate metabolism in healthy subjects and those with type 2 diabetes fed starches with slow and rapid hydrolysis rates determined in vitro.

The objective of the present study was to investigate the effects of starches with differing rates of hydrolysis on exposure to pancreatin in vitro on postprandial carbohydrate metabolism in healthy subjects and in subjects with type 2 diabetes. Two test starches, prepared from uncooked native granular starch products, and naturally enriched with 13C, were consumed in a randomized crossover design by eight healthy and thirteen type 2 diabetic subjects. One starch was characterized in vitro as being rapidly hydrolysed (R, 94% after 180 min), and the other was more slowly hydrolysed (S, 51% after 180 min). Each subject consumed 50 g of each test starch. In addition, the type 2 diabetic subjects consumed 89.7 g of the S starch on a separate occasion. Blood samples were taken at 10 min intervals for 3 h, and at 20 min intervals for a further 3 h during a 6 h postprandial period. Breath 13CO2 enrichment was measured at the same time points, and indirect calorimetry was performed for seven 20 min sessions immediately before and during the 6 h postprandial period. With the R starch, plasma glucose concentrations and serum insulin concentrations rose faster and the maximum glucose change was approximately 1.8 times that for the S starch, averaged across both subject groups. The areas under the curves for glucose and insulin were, respectively, 1.7 and 1.8 times higher for the R starch compared with the S starch, averaged across both subject groups. The rate of 13CO2 output and the proportion of 13C recovered in breath after consumption of the R starch was similar for both subject groups. The results provide evidence that starches which have different rates of hydrolysis in vitro result in different patterns of glycaemia and insulinaemia in both healthy adults and in diet-controlled type 2 diabetic subjects. Data from the hydrolysis of novel starch products in vitro, therefore, are useful in predicting glycaemic responses in vivo.

3-Hydroxybutyric Acid↗

PubMed2003

Anti-cancer effects of butyrate: use of micro-array technology to investigate mechanisms.

Epidemiological evidence suggests that a high intake of resistant starch and NSP protects against colo-rectal cancer. The mechanisms underlying this protection are thought to be mediated by the short-chain fatty acid butyrate, which is present in the colonic lumen in millimolar concentrations as a result of bacterial fermentation of carbohydrates that have resisted digestion in the small intestine. In vitro studies have shown that butyrate displays a host of chemo-preventative properties including increased apoptosis, reduced proliferation, down regulation of angiogenesis, enhanced immunosurveillance and anti-inflammatory effects in colo-rectal cancer cell lines. However, the molecular mechanisms underlying the apparent chemo-preventative actions of butyrate are largely unknown. The evidence supporting the role of butyrate as an anti-cancer agent is reviewed, with particular emphasis on those studies that have attempted to elucidate the mechanism of action of butyrate. Our understanding of the mechanistic action of butyrate and its role in cancer prevention is likely to advance considerably in this post-genomic era with the application of genomic and proteomic technologies. Studies are described that have used gene array and proteomic techniques to investigate the response of colo-rectal cancer cells to butyrate. These pioneering studies illustrate the potential of these technologies to help characterise the molecular responses of the cancer cell to butyrate, and to define the role of butyrate (and other nutrients) in the prevention of colo-rectal cancer.

Animals↗

PubMed2003

Can resistant starch and/or aspirin prevent the development of colonic neoplasia? The Concerted Action Polyp Prevention (CAPP) 1 Study.

Loss of function of the adenomatous polyposis coli (APC) tumour suppressor gene through truncating mutations or other means is an early event in most colo-rectal cancer (CRC). The APC gene encodes a large multifunctional protein that plays key roles in several cellular processes, including the wnt signalling pathway where an intact APC protein is essential for down regulation of beta-catenin. The APC protein also plays a role in regulation of cell proliferation, differentiation, apoptosis, cell-cell adhesion, cell migration and chromosomal stability during mitosis. Acquisition of a non-functional APC gene can occur by inheritance (in the disease familial adenomatous polyposis (FAP)) or by a sporadic event in a somatic cell. Whilst there is strong epidemiological evidence that variation in diet is a major determinant of variation in CRC incidence, conventional adenoma recurrence trials in sporadic cases of the disease have been relatively unsuccessful in identifying potentially protective food components. Since the genetic basis of CRC in FAP and in sporadic CRC is similar, intervention trials in FAP gene carriers provide an attractive strategy for investigation of potential chemo-preventive agents, since smaller numbers of subjects and shorter time frames are needed. The Concerted Action Polyp Prevention (CAPP) 1 Study is using a 2 x 2 factorial design to test the efficacy of resistant starch (30 g raw potato starch-Hylon VII (1:1, w/w)/d) and aspirin (600 mg/d) in suppressing colo-rectal adenoma formation in young subjects with FAP. Biopsies of macroscopically-normal rectal mucosa are also being collected for assay of putative biomarkers of CRC risk.

Adenomatous Polyposis Coli↗

PubMed2003

Nutrition and cancer prevention: diet-gene interactions.

Cancer is the major cause of death in the UK, and the Government has set a target to reduce death rate from cancer in individuals < 75 years by > or = 20% by 2010. Whilst earlier diagnosis and more effective treatments will contribute to meeting this target, there are considerable opportunities to prevent cancer by improving diet and other aspects of lifestyle. There is now a good understanding of the biological basis of carcinogenesis, which is providing the basis for mechanistic investigation of the chemo-preventive properties of certain foods and food components. It is becoming increasingly clear that there are important interactions between an individual's genotype (characterised by single nucleotide polymorphisms in particular genes) and habitual diet that modulate the risk of developing cancer. The technology to support this post-genomic revolution in nutrition research is now widely available, but brings with it considerable challenges in terms of study design and ethics. However, in the absence of a robust body of evidence on which dietary strategies will benefit which individuals, soundly based genetically-targeted nutrition advice to the public on cancer prevention is a little way in the future.

Chemoprevention↗

PubMed2002

A novel zinc-regulated human zinc transporter, hZTL1, is localized to the enterocyte apical membrane.

Zinc is essential to a wide range of cellular processes; therefore, it is important to elucidate the molecular mechanisms of zinc homeostasis. To date, no zinc transporters expressed at the enterocyte apical membrane, and so essential to mammalian zinc homeostasis, have been discovered. We identified hZTL1 as a human expressed sequence tag with homology to the basolateral enterocyte zinc transporter ZnT1 and deduced the full-length cDNA sequence by PCR. The protein of 523 amino acids belongs to the cation diffusion facilitator family of membrane transporters. Unusually, the predicted topology comprises 12 rather than 6 transmembrane domains. ZTL1 mRNA was detected by reverse transcription-PCR in a range of mouse tissues. A Myc-tagged hZTL1 clone was expressed in transiently transfected polarized human intestinal Caco-2 cells at the apical membrane. Expression of hZTL1 mRNA in Caco-2 cells increased with zinc supplementation of the nutrient medium; however, in the placental cell line JAR hZTL1 appeared not to be regulated by zinc. Heterologous expression of hZTL1 in Xenopus laevis oocytes increased zinc uptake across the plasma membrane. The localization, regulatory properties, and function of hZTL1 indicate a role in regulating the absorption of dietary zinc across the apical enterocyte membrane.

Acrodermatitis↗

PubMed2002

Pulses and carcinogenesis: potential for the prevention of colon, breast and other cancers.

Consumption of pulses as components of healthy diets is encouraged because it is believed that this is likely to help in reducing the risk of common non-communicable diseases, including cancers. However, the evidence base for the role of pulses in prevention of cancers is unconvincing because of the difficulties, using conventional epidemiological tools, in ascertaining the quantitative contribution made by pulses to cancer risk. Advances in understanding of the biological basis of cancer and of the mechanisms of action of cancer-preventing compounds offer new insights into the role of food-derived substances and of diet-gene interactions in modulating cancer risk. Pulses contain a rich variety of compounds which, if consumed in sufficient quantities, may help to reduce tumour risk.

Animals↗

PubMed2002

Degradation of transgenic DNA from genetically modified soya and maize in human intestinal simulations.

The inclusion of genetically modified (GM) foods in the human diet has caused considerable debate. There is concern that the transfer of plant-derived transgenes to the resident intestinal microflora could have safety implications. For these gene transfer events to occur, the nucleic acid would need to survive passage through the gastrointestinal tract. The aim of the present study was to evaluate the rate at which transgenes, contained within GM soya and maize, are degraded in gastric and small bowel simulations. The data showed that 80 % of the transgene in naked GM soya DNA was degraded in the gastric simulations, while no degradation of the transgenes contained within GM soya and maize were observed in these acidic conditions. In the small intestinal simulations, transgenes in naked soya DNA were degraded at a similar rate to the material in the soya protein. After incubation for 30 min, the transgenes remaining in soya protein and naked DNA were 52 (sem 13.1) % and 34 (sem 17.5) %, respectively, and at the completion of the experiment (3 h) these values were 5 % and 3 %, respectively. In contrast to the soya transgene, the maize nucleic acid was hydrolysed in the small intestinal simulations in a biphasic process in which approximately 85 % was rapidly degraded, while the rest of the DNA was cleaved at a rate similar to that in the soya material. Guar gum and tannic acid, molecules that are known to inhibit digestive enzymes, did not influence the rate of transgene degradation in soya protein. In contrast guar gum reduced the rate of transgene degradation in naked soya DNA in the initial stages, but the polysaccharide did not influence the amount of nucleic acid remaining at the end of the experiment. Tannic acid reduced the rate of DNA degradation throughout the small bowel simulations, with 21 (sem 5.4) % and 2 (sem 1.8) % of the naked soya DNA remaining in the presence and absence of the phenolic acid, respectively. These data indicate that some transgenes in GM foods may survive passage through the small intestine.

DNA, Plant↗

PubMed2002

Quantitative kinetics of glucose appearance and disposal following a 13C-labelled starch-rich meal: comparison of male and female subjects.

In the UK, starch contributes up to 25 % of energy intake in adults (). The present study investigated the acute response to a starchy meal on whole-body glucose metabolism and assessed insulin sensitivity in men compared with women. Low insulin sensitivity has been postulated to pre-dispose individuals to a cluster of associated abnormalities known to increase the risk of CHD. Metabolic responses to a 13C-labelled meal were determined in conjunction with a primed continuous infusion of d-[6,6-2H]glucose in groups of healthy age- and BMI-matched men and women. Peripheral plasma glucose disposal (Gd) was computed using non-steady state kinetics in a single compartment model, simultaneously with determination of whole-body net glucose oxidation by indirect calorimetry. Insulin sensitivity was derived using cumulative Gd as the dependent variable, and time and the integrated insulin concentration as independent variables. The female group had the higher fractional rate of glucose appearance in plasma from starch (P=0.019) immediately after ingestion. Females also had a higher rate of plasma Gd and a significantly higher insulin-dependent Gd (6.8 v. 5.6 microg glucose/(min.kg) per pmol insulin, P<0.05) compared with the males. A smaller absolute pool of endogenous glucose in females allowed the rate of exogenous 13CO2 production to be significantly higher in the females (P=0.007) corresponding also to a significantly higher (P<0.05) carbohydrate oxidation rate obtained by indirect calorimetry. The present study suggests that during the ingestion of a starchy meal, females exhibit higher glucose flux and greater whole-body insulin sensitivity than males.

Adult↗