Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

NSAID, low-dose ASA use, and H. pylori infection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use and H. pylori infection, which may have implications for clinical practice in prevention strategies.

The purpose of this study was to investigate the effect of lipopolysaccharide (LPS) on spontaneous contractions and acetylcholine (ACh) induced contractions of rabbit intestinal segments in vitro, with two different protocols: intestinal segments isolated from LPS-treated rabbits and intestinal segments incubated with LPS. The frequency of spontaneous movements decreased significantly in LPS-treated rabbits at 2 microg kg-1 in the duodenum and 20 microg kg-1 in the duodenum, jejunum and ileum. LPS (0.2 microg kg-1) reduced significantly the ACh contractions (10-6 mol L-1) in the duodenum (61%), jejunum (48%) and ileum (21%). Indomethacin (1, 5 and 10 mg kg-1) administered 15 min before LPS (0.2 microg kg-1) antagonized the LPS effects on the ACh-induced contractions. Prostaglandin (PG)E2 (8 microg kg-1) inhibited significantly the frequency of spontaneous contractions in the ileum and reduced the ACh-induced contractions in the three segments, mimicking the LPS effects. The amplitude and frequency of contractions in rabbit intestinal segments previously incubated with LPS (0.03, 0.3, 3 and 30 microg mL-1) were not modified with respect to the control. The ACh-induced contractions (10-4 mol L-1) were significantly reduced after 90 min of incubation with LPS. The inhibition of LPS (0.3 microg mL-1) was 43% in the duodenum, 35% in the jejunum and 17% in the ileum. Indomethacin added before LPS blocked the effect of LPS on the ACh-induced contractions in the duodenum, jejunum and ileum. These results show that LPS decreases intestinal contractility in rabbits and suggest that PGs are implicated in these actions.

Lipopolysaccharide decreases the duodenal contractility in rabbits and increases the production of free radicals. p38 MAPK is a mediator of these effects.