Also relevant to NFκB activation and intestinal inflammation is the reported differential regulation of Toll-like receptors (TLRs) by fatty

acids with differing saturation states [54–56]. TLRs are single membrane-spanning proteins involved in the recognition of microbial-derived molecules harbouring pathogen-associated molecular patterns (PAMPs) and activation of various immune cell responses [57]. Upon activation, TLRs activate NFκB though a complex signalling network culminating with the activation of IKKα, followed by ubiquitination and subsequent degradation of IκBα and translocation of the P65 Rel A domain to the nucleus where it binds to and activates the expression of numerous Selleck FK506 pro-inflammatory genes [44]. Specifically, TLR4 has been shown to confer responsiveness to a number of lipids including lipid A, the primary biologically active component of LPS, and that in contrast to saturated fatty acids similar to those found in lipid A, unsaturated fatty acids inhibit NFκB activity through inhibition of TLR4 or other TLR-associated molecules [55, 56]. Therefore, it is possible that the anti-inflammatory effects associated with GTAs are being exerted through inhibition of TLRs upstream of NFκB. Further

work to investigate this hypothesis is warranted. NFκB, aging and gut microbiota A final point concerning NFκB and GTA metabolism is that both have age-related implications. We previously showed Venetoclax that in the general population, there is an inverse association between the circulating levels of GTA-446 and age, and that the rate of decline correlated precisely with the increase in CRC incidence with age [18]. As for NFκB, there is substantial literature regarding its various age-related facets [53, 58–63]. For example, it has been shown that NFκB protein levels, as well as several NFκB-targeted pro-inflammatory cytokines, are elevated in endothelial cells of old versus young subjects, which were also accompanied by decreased IκBα levels in the older group [60]. Microarray analysis further showed that the NFκB cis element is

the motif most strongly associated with aging [64] and that blockade of NFκB in the epidermis of chronologically aged mice resulted in the reversion of both tissue and gene expression characteristics to those of young mice [59]. These and numerous other reports clearly associate increased NFκB activity with multiple aspects of aging including Astemizole immunosenescence, antigenic stress, innate immunity, tissue atrophy, inflammation, cellular danger responses, apoptosis, DNA damage, oxidative stress and caloric restriction (see [62] for review). Left unchecked, therefore, NFκB activation is a probable driving force for many of these critical aging-related processes. Given the selectiveness of GTAs in human blood and their novel hydroxylated and unsaturated fatty acid structures, the possibility that human-specific gut microbial processes may be involved in the metabolism of GTAs from dietary sources cannot be excluded.