No abstract

Autophagy, hallmarked by the formation of doublemembrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in earlystage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a prosurvival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cellfate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.

Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.

Cathelicidin is a pleiotropic host defense peptide secreted by epithelial and immune cells. Whether endogenous cathelicidin is protective against ulcerative colitis, however, is unclear. Here we sought to delineate the role of endogenous murine cathelicidin (mCRAMP) and the therapeutic efficacy of intrarectal administration of mCRAMP-encoding plasmid in ulcerative colitis using dextran sulfate sodium (DSS)-challenged cathelicidin-knockout (Cnlp(-/-)) mice as a model. Cnlp(-/-) mice had more severe symptoms and mucosal disruption than the wild-type mice in response to DSS challenge. The tissue levels of interleukin-1β and tumor necrosis factor-α, myeloperoxidase activity and the number of apoptotic cells were increased in the colon of DSS-challenged Cnlp(-/-) mice. Moreover, mucus secretion and mucin gene expression were impaired in Cnlp(-/-) mice. All these abnormalities were reversed by the intrarectal administration of mCRAMP or mCRAMP-encoding plasmid. Taken together, endogenous cathelicidin may protect against ulcerative colitis through modulation of inflammation and mucus secretion.

Background and purpose: Inhibition of proteasome has been emerging as a promising approach in pathway-directed cancer therapy. Bone morphogenetic protein (BMP) signalling, which is known to be regulated by the ubiquitin-proteasome pathway in osteoblasts, plays a crucial role in the suppression of gastrointestinal carcinogenesis. Here we sought to elucidate the antimitogenic effect of a proteasome inhibitor in relation to BMP signalling in colon cancer.

Adaptive cytoprotection is a concept to counteract against the gastric mucosal injury caused by stress, strong irritants and drugs such as non-steroidal anti-inflammatory drugs. The process is mediated through diverse mediators and mechanisms. Studies on adaptive cytoprotection began from the discovery of prostaglandin (PG)-dependent and PG-independent pathways, followed by the investigation on the types and concentrations of mild irritants to be used. Upon the confirmation on the importance of the vagus nerve and the vago-vagal pathway in regulating the mucosal protective actions of the mild irritants, individual participating mediators for the neuronal modulatory processes were explored, including peptide neurotransmitters such as calcitonin gene-related peptide and substance P. Further correlation with the sympathetic nervous system, the sensory afferent neurons and the enteric nervous system of the gastric mucosa had been made. A close working relationship between the hypothalamic-pituitary-adrenal axis, the autonomic nervous system and the enteric nervous system was then proposed, with concurrent regulation of PG, nitric oxide and sensory neuropeptides by different mild irritants. Apart from these conventional concepts, there are now contemporary ideas on newer forms of adaptive cytoprotection such as ischemic preconditioning and heat-shock proteins, which will cast new light to novel approaches in facilitating gastric mucosal protection.

Although propranolol has been shown to protect against ethanol and stress ulceration, the antiulcer mechanisms are still unclear. The present study examined the antiulcer mechanisms of propranolol in three different types of ulceration induced respectively by ethanol (60%), indomethacin (30 mg/kg) and stress (cold-restraint). Propranolol pretreatment in the highest dose (10 mg/kg) given either intraperitoneally (i.p.) or orally (p.o.) prevented gastric mucosal damage in these three ulcer models. The three doses of the drug (2.5, 5 or 10 mg/kg) dose-dependently decreased systemic blood pressure which was accompanied by a reduction of gastric mucosal blood flow. These findings suggest that the protection was unrelated to an improvement of local circulation in the stomach. However, propranolol preserved the mucus levels in the three types of ulcer models. The beta-adrenoceptor blocker also increased the basal gastric mucosal potential difference. These findings indicate that propranolol strengthens the mucosal barrier by the preservation of mucosal mucus and enhancement of the mucosal integrity in the stomach.

Adenosine is known for its modulatory effects on gastric secretory function and mucosal blood flow in rats. However, its action on gastric motility has not been defined. The influence of adenosine on gastric contractions provoked by cholinergic drugs and direct vagal stimulation have, therefore, been examined. Bethanechol (25, 50 or 100 µg/kg i.v.) and electrical vagal stimulation dose and voltage dependently increased the number and the amplitude of gastric contractions. An adenosine-A₁-receptor agonist, L-phenylisopropyladenosine (10 or 50 µg/kg s.c), given 30 min beforehand, did not affect the changes in gastric parameters but decreased the basal mean blood pressure and lessened the reduction in blood pressure evoked by bethanechol. The adenosine-A₂-receptor agonist N-ethylcarboxaminoadenosine (1 or 5 µg/kg s.c), 30 min beforehand, however, significantly increased the number but not the force of gastric contractions; a lower dose of this drug increased the basal blood pressure and potentiated the depressive action of bethanechol on systemic blood pressure. Adenosine administration (7.5 mg/kg s.c.) significantly increased its plasma levels at 30 and 60 min after injection; pretreatment with it (2.5, 7.5 or 12.5 mg/kg s.c), 30 min beforehand, did not affect the gastric and vascular actions of bethanechol. The highest dose of adenosine potentiated the contractile response of vagal stimulation. In the isolated fundus preparation, adenosine added to the organ bath (10^-6, 10^-4, 10^-2 M) also did not affect the contractions induced by acetylcholine. It is concluded that adenosine lacks an effect on the contractile cholinoceptors located on the smooth muscles of stomachs and blood vessels, but the nucleoside could have a presynaptic effect in potentiating the contractile action of direct vagal stimulation.