Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modi®cation might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during in¯ammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-in¯amma-tory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor a or fecapentaene-12. Induction of COX2 by in¯ammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kB). Since curcumin inhibits NF-kB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kBsequestering protein, IkB. Recently components of this pathway, NF-kB-inducing kinase and IkB kinases, IKKa and b, which phosphorylate IkB to release NF-kB, have been characterised. Curcumin prevents phosphorylation of IkB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health e ects, makes curcumin an important candidate for consideration in colon cancer prevention.

A comparative analysis identified key cis-acting regulatory elements responsible for the temporal control of mosquito Defensin gene expression. The promoters of Anopheles gambiae Defensin 1 and two isoforms of Aedes aegypti Defensin A are up-regulated by immune challenge. This stimulated activity depends upon a cluster of three NF-kappaB binding sites and closely associated C/EBP-like motifs, which function as a unit for optimal promoter activity. Binding of NF-kappaB and C/EBP like transcription factors is confirmed by electrophoretic mobility shift assay, including supershifts with antibodies to C/EBP. KappaB-like motifs are abundant within antimicrobial peptide gene promoters and most are very closely associated with putative C/EBP binding sites. This novel association between NF-kappaB and C/EBP binding sites may, therefore, be of widespread significance.

The Stomoxys midgut defensin (Smd) family of genes are exclusively expressed in the anterior midgut of adult flies. Their putative function is protection of the stored bloodmeal from microbial attack. Smd genes are constitutively expressed, up-regulated in response to a bloodmeal and further up-regulated by immune stimulation per os but only in the presence of a bloodmeal not a sugar meal. Smd genes are down-regulated in response to a systemic immune challenge. Smd gene constructs transfected into l(2)mbn cells undertake constitutive expression but are not up-regulated by immune challenge. Electrophoretic mobility shift assays (EMSA) suggest the rel-like sites in the proximal promoter region of Smd genes do not bind midgut factors and so are non-functional.

The gut epithelium is an essential interface in insects that transmit parasites. We investigated the role that local innate immunity might have on vector competence, taking Stomoxys calcitrans as a model. S. calcitrans is sympatric with tsetse flies, feeds on many of the same vertebrate hosts, and is thus regularly exposed to the trypanosomes that cause African sleeping sickness and nagana. Despite this, S. calcitrans is not a cyclical vector of these trypanosomes. Trypanosomes develop exclusively in the lumen of digestive organs, and so epithelial immune mechanisms, and in particular antimicrobial peptides (AMPs), may be the prime determinants of the fate of an infection. To investigate why S. calcitrans is not a cyclical vector of trypanosomes, we have looked in its midgut for AMPs with trypanolytic activity. We have identified a new AMP of 42 amino acids, which we named stomoxyn, constitutively expressed and secreted exclusively in the anterior midgut of S. calcitrans. It displays an amphipathic helical structure and exhibits a broad activity spectrum affecting the growth of microorganisms. Interestingly, this AMP exhibits trypanolytic activity to Trypanosoma brucei rhodesiense. We argue that stomoxyn may help to explain why S. calcitrans is not a vector of trypanosomes causing African sleeping sickness and nagana.Epithelial intestinal innate immunity plays a major role in the control of infectious diseases in vertebrates (1, 2). In invertebrates, data are still fragmentary despite gut epithelium being an essential interface for parasites during their development in insect vectors. Understanding vector biology is a key element in the control of many parasitic diseases. In this context, the comparison of the trypanosome vector Glossina with the sympatric but non-vector Stomoxys calcitrans is particularly interesting. The tsetse fly Glossina spp. is the major vector of the range of trypanosomes that cause African sleeping sickness in humans and nagana in livestock. Stable flies, Stomoxys spp., feed on the same vertebrate hosts as tsetse flies and have a very similar digestive physiology and midgut anatomy. Although Stomoxys is constantly exposed to trypanosomes, it kills them in the midgut within 2-4 days of ingestion (3). So Stomoxys is not a cyclical vector of trypanosomes (although it can act as a mechanical vector, "flying pin"). Why Stomoxys is not a cyclical vector of trypanosomes is unknown. Recent studies have shown that the insect immune system plays a determinant role in the fate of trypanosome infections in tsetse flies (4, 5). Consequently, in this report, we address the possibility that the distinction in vectorial capacity between Glossina and Stomoxys may lie in differences in immune mechanisms.Trypanosoma vivax matures entirely in the mouthparts of Glossina. The other trypanosomes causing nagana and human disease are ingested into the fly midgut where they multiply first in the endoperitrophic space and later in the ectoperitrophic space tightly sandwiched between the peritrophic matrix and the ...