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Abstract Background Nonsense mutations are at the origin of many cancers and inherited genetic diseases. The consequence of nonsense mutations is often the absence of mutant gene expression due to the activation of an mRNA surveillance mechanism called nonsense-mediated mRNA decay (NMD). Strategies to rescue the expression of nonsense-containing mRNAs have been developed such as NMD inhibition or nonsense mutation readthrough. Methods Using a dedicated screening system, we sought molecules capable to block NMD. Additionally, 3 cell lines derived from patient cells and harboring a nonsense mutation were used to study the effect of the selected molecule on the level of nonsense-containing mRNAs and the synthesis of proteins from these mutant mRNAs. Results We demonstrate here that amlexanox, a drug used for decades, not only induces an increase in nonsense-containing mRNAs amount in treated cells, but also leads to the synthesis of the full-length protein in an efficient manner. We also demonstrated that these full length proteins are functional. Conclusions As a result of this dual activity, amlexanox may be useful as a therapeutic approach for diseases caused by nonsense mutations.

Acute colonic diverticulitis (ACD) is an acute episode of severe and prolonged lower abdominal pain due to diverticular inflammation, usually associated with change in bowel movements, fever, and leukocytosis. Worldwide, computed tomography (CT) of the abdomen and pelvis with intravenous contrast is accepted as the best imaging method for evaluating the diverticular inflammation, serving the following functions: confirming the presence of ACD; evaluation of the disease severity and degree; therapy planning guide in presence of complications (such as abscess or intestinal perforation); diagnosis of other diseases that may simulate diverticular inflammation. In the literature, we found values of CT sensitivity for diverticular inflammation from 79% to 99%; CT is useful in differentiating other diseases, which may cause abdominal pain, when diverticular inflammation is not the cause, such as neoplasm, inflammatory bowel disease, appendix inflammations, epiploic appendix inflammation and colon ischemia. The trick to differentiate diverticulitis from other inflammatory diseases that involve the colon is the identification of diverticula in the pathological intestinal loop. In the last years, a radiological classification was created in order to guide the management of ACD in patients treated conservatively or with interventional procedures. The new classification system divides ACD into two groups: complicated and uncomplicated. Uncomplicated ACD is defined if only thickening of the intestinal wall is present, with increase of the perivisceral fat density. Complicated ACD is divided into 4 stages, depending on presence of microperforation without abscess and/or peritoneum involvement (stage 1 A), presence of abscess with diameter ≤4 cm (stage 1 B), presence of abscess with diameter >4 cm (stage 2 A), presence of distant air >5 cm from the pathological loop (stage 2 B), presence of diffuse fluid in at least two distant abdominal quadrants without distant free air (stage 3), presence of diffuse fluid and distant free air (stage 4). In this pictorial essay, we describe CT findings of the ACD and explain classification of the disease and its common and uncommon complications.

Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.