Lastly, an important new study in the next review period, highlighted only briefly here, has shown that the T4SS, independently of CagA signalling,

upregulates the cancer-related miRNA, miR-155. miR-155 has reported antiapoptotic effects in immune cells, and therefore, modulation of its expression by the T4SS as revealed by Koch et al. may have direct influence on the regulation of apoptosis BVD-523 order during H. pylori infection [42]. Considering the role of dysregulated protein kinase C (PKC) signalling in gastric cancer, a recent study has shown that H. pylori induces phosphorylation of PKC isoforms and their substrates [43]. Interestingly, H. pylori-mediated PKC activation upregulated matrix metalloproteinase-1 (MMP-1) expression. In turn, this increased the invasion of AGS cells suggesting a mechanism by which PKC activation promotes remodelling and destruction of gastric tissue in response to H. pylori infection independently of CagA signalling. Promotion of cell invasion is also indicated to occur via calpain protease-mediated disruption of adherens junctions in response to TLR2 stimulation by an as yet unidentified H. pylori outer membrane protein [44]. Other work Sorafenib nmr examining the secreted

HtrA protease has demonstrated functional conservation of its E-cadherin cleavage activity among a range of other gastrointestinal pathogens [45]. Cleavage specificity was shown to be a function of structural conservation within the active site of the protein, indicating that HtrA-mediated E-cadherin cleavage is a conserved mechanism underlying different pathogenic strategies. A virtual screening approach has also been successful in identifying several small

molecule inhibitors of H. pylori HtrA activity [46]. The vacuolating cytotoxin, VacA, is a major virulence factor of H. pylori and has pleiotropic effects in target host cells. Of these, the involvement of VacA in various mechanisms of programmed cell death including apoptosis and necrosis has attracted particular attention. Investigating VacA-targeting of mitochondria, Jain et al. show that VacA induces apoptosis through disruption of selleck chemicals llc mitochondrial morphological dynamics by inducing the activation of dynamin-related protein 1 (Drp1) [47]. Drp1 regulates mitochondrial fission and, once activated, locates to the mitochondrial outer membrane. VacA increases Drp1 localization indicating that the previously observed VacA-dependent fragmentation of the mitochondrial network involves the cellular fission machinery. The membrane channel activity of VacA was found to be important in this respect. VacA-induced cell death may therefore proceed via a mechanism of enhanced Drp1-dependent fission promoting activation of the proapoptotic Bcl-2 effector Bax and mitochondrial outer membrane permeabilization [47]. Examining morphological and biochemical markers of both necrotic and apoptotic cell death, Radin et al.