Acetylation: a critical factor in maintaining intestinal inflammation?

PhDIn inflammatory bowel disease (IBD), both chronic pro-inflammatory pathways and failure of anti-inflammatory (healing) mechanisms sustain disease. The two major anti-inflammatory gut cytokines are transforming growth factor (TGF)-β and interleukin (IL)-10. Acetylation of regulatory proteins may play a role in the activation of both pathways. In IBD there is excess production of pro-inflammatory cytokines such as IL-1β and under-expression of IL-10. Fibroblasts also over-produce matrix metalloproteinases (MMP), mediating tissue destruction. Curcumin, a component of the spice turmeric and a known inhibitor of acetylation, shows clinical benefit in IBD in early trials. Objectives: To assess the anti-inflammatory effects of curcumin in the gut of children and adults with IBD. Methods: Intestinal mucosal tissue biopsies, mononuclear cells and colonic myofibroblasts from children and adults with active IBD were cultured ex vivo with curcumin. p38 MAPK, NF-κB and MMP-3 were measured by immunoblotting. IL-1β, interferon (IFN)-γ and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA). Results: We have shown favourable modulation of the cytokine profile by curcumin, with enhanced IL-10 expression and decreased IL-1β, and we have demonstrated reduced p38 MAPK activation in intestinal mucosal tissue. We have also shown dose-dependent suppression of MMP-3 expression in colonic myofibroblasts (CMF) with curcumin, by a mechanism which appears to be acetylation-dependent. Conclusion: Curcumin, a naturally occurring food substance with no known human toxicity, holds promise as a novel therapy in IBD

The Influence of Microbial Metabolites in the Gastrointestinal Microenvironment on Anticancer Immunity

The gastrointestinal (GI) tumour microenvironment is characterised by its unique colonisation with bacteria that are estimated to match the total number of cells in our body. It is becoming increasingly clear that the microbiome and its metabolites are important orchestrators of local and systemic immune responses, anticancer immunity and the host response to cancer therapy. Apart from their role as an energy source, metabolites have been shown to modulate inflammation, immune cell function and cancer cell survival. The polarisation of immune cell subsets by microbial metabolites towards either pro- or antitumorigenic functions strongly affects cancer progression and outcomes. In this chapter, we will discuss the link between microbial metabolites in the GI tumour microenvironment, anticancer immune responses and cancer progression

Genetic Variations in Human Glutathione Transferase Enzymes: Significance for Pharmacology and Toxicology

Glutathione transferase enzymes (GSTs) catalyze reactions in which electrophiles are conjugated to the tripeptide thiol glutathione. While many GST-catalyzed transformations result in the detoxication of xenobiotics, a few substrates, such as dihaloalkanes, undergo bioactivation to reactive intermediates. Many molecular epidemiological studies have tested associations between polymorphisms (especially, deletions) of human GST genes and disease susceptibility or response to therapy. This review presents a discussion of the biochemistry of GSTs, the sources—both genetic and environmental—of interindividual variation in GST activities, and their implications for pharmaco- and toxicogenetics; particular attention is paid to the Theta class GSTs

Microbial Virulence Factors

Microbial virulence factors encompass a wide range of molecules produced by pathogenic microorganisms, enhancing their ability to evade their host defenses and cause disease. This broad definition comprises secreted products such as toxins, enzymes, exopolysaccharides, as well as cell surface structures such as capsules, lipopolysaccharides, glyco- and lipoproteins. Intracellular changes in metabolic regulatory networks, governed by protein sensors/regulators and non-coding regulatory RNAs, are also known to contribute to virulence. Furthermore, some secreted microbial products have the ability to enter the host cell and manipulate their machinery, contributing to the success of the infection. The knowledge, at the molecular level, of the biology of microbial pathogens and their virulence factors is central in the development of novel therapeutic molecules and strategies to combat microbial infections. The present collection comprises state of the art research and review papers on virulence factors and mechanisms of a wide range of bacterial and fungal pathogens for humans, animals, and plants, thus reflecting the impact of microorganisms in health and economic human activities, and the importance of the topic