The Toll-Like Receptor Signaling Molecule Myd88 Contributes to Pancreatic Beta-Cell Homeostasis in Response to Injury

Commensal flora and pathogenic microbes influence the incidence of diabetes in animal models yet little is known about the mechanistic basis of these interactions. We hypothesized that Myd88, an adaptor molecule in the Toll-like-receptor (TLR) pathway, regulates pancreatic β-cell function and homeostasis. We first examined β-cells histologically and found that Myd88−/− mice have smaller islets in comparison to C57Bl/6 controls. Myd88−/− mice were nonetheless normoglycemic both at rest and after an intra-peritoneal glucose tolerance test (IPGTT). In contrast, after low-dose streptozotocin (STZ) challenge, Myd88−/−mice had an abnormal IPGTT relative to WT controls. Furthermore, Myd88−/− mice suffer enhanced β-cell apoptosis and have enhanced hepatic damage with delayed recovery upon low-dose STZ treatment. Finally, we treated WT mice with broad-spectrum oral antibiotics to deplete their commensal flora. In WT mice, low dose oral lipopolysaccharide, but not lipotichoic acid or antibiotics alone, strongly promoted enhanced glycemic control. These data suggest that Myd88 signaling and certain TLR ligands mediate a homeostatic effect on β-cells primarily in the setting of injury

Tumour–stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness

Sporadic cases of colorectal cancer are primarily initiated by gene mutations in members of the canonical Wnt pathway, ultimately resulting in β-catenin stabilisation. Nevertheless, cells displaying nuclear β-catenin accumulation are nonrandomly distributed throughout the tumour mass and preferentially localise along the invasive front where parenchymal cells are in direct contact with the stromal microenvironment. Here, we discuss the putative role played by stromal cell types in regulating β-catenin intracellular accumulation in a paracrine fashion. As such, the tumour microenvironment is likely to maintain the cancer stem cell phenotype in a subset of cells, thus mediating invasion and metastasis

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Structural, functional and molecular analysis of the effects of aging in the small intestine and colon of C57BL/6J mice

Contains fulltext : 109613.pdf (publisher's version ) (Open Access)BACKGROUND: By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the functional decline associated with aging is still under debate. METHODS: Young (4 M) and old (21 M) male C57BL/6J mice were fed a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated and the small intestine was divided in three equal parts. Swiss rolls were prepared of each of the isolated segments for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q-PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. RESULTS: Digestible energy intake was similar between the two age groups on both the control and the high-fat diet. Microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a large number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. CONCLUSION: In 21-month old mice the most pronounced effects of aging were observed in the colon, whereas very few changes were observed in the small intestine