SummaryThe IKK/NF-kB pathway is an essential signalling process initiated by the cell as a defence against viral infection like influenza virus. This pathway is therefore a prime target for viruses attempting to counteract the host response to infection. Here, we report that the influenza A virus NS1 protein specifically inhibits IKK-mediated NF-kB activation and production of the NF-kB induced antiviral genes by physically interacting with IKK through the C-terminal effector domain. The interaction between NS1 and IKKa/IKKb affects their phosphorylation function in both the cytoplasm and nucleus. In the cytoplasm, NS1 not only blocks IKKb-mediated phosphorylation and degradation of IkBa in the classical pathway but also suppresses IKKa-mediated processing of p100 to p52 in the alternative pathway, which leads to the inhibition of nuclear translocation of NF-kB and the subsequent expression of downstream NF-kB target genes. In the nucleus, NS1 impairs IKKmediated phosphorylation of histone H3 Ser 10 that is critical to induce rapid expression of NF-kB target genes. These results reveal a new mechanism by which influenza A virus NS1 protein counteracts host NF-kB-mediated antiviral response through the disruption of IKK function. In this way, NS1 diminishes antiviral responses to infection and, in turn, enhances viral pathogenesis.

Drug-induced cardiotoxicity seriously affects human health and drug development. However, many conventional detection indicators of cardiotoxicity exhibit significant changes only after the occurrence of severe heart injuries. Therefore, we investigated more sensitive and reliable indicators for the evaluation and prediction of cardiotoxicity. We created rat cardiotoxicity models in which the toxicity was caused by doxorubicin (20 mg/kg), isoproterenol (5 mg/kg), and 5-fluorouracil (125 mg/kg). We collected data from rat plasma samples based on metabolomics using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Following multivariate statistical and integration analyses, we selected 39 biomarker ions of cardiotoxicity that predict cardiotoxicity earlier than biochemical analysis and histopathological assessment. Because drugs with different toxicities may cause similar metabolic changes compared with other noncardiotoxic models (hepatotoxic and nephrotoxic models), we obtained 10 highly specific biomarkers of cardiotoxicity. We subsequently used a support vector machine (SVM) to develop a predictive model to verify and optimize the exclusive biomarkers. l-Carnitine, 19-hydroxydeoxycorticosterone, LPC (14:0), and LPC (20:2) exhibited the strongest specificities. The prediction rate of the SVM model is as high as 90.0%. This research provides a better understanding of drug-induced cardiotoxicity in drug safety evaluations and secondary development and demonstrates novel ideas for verification and optimization of biomarkers via metabolomics.

This manuscript introduces a one-pot fabrication procedure for the preparation of supramolecular hybrid hydrogels from low-cost commercially available natural products through a "green" strategy. In particular, the hybrid hydrogels, which are developed with Fmoc-Glu-OMe, silver nanoparticles and chitosan, exhibit outstanding antibacterial properties and can be regarded as excellent mouldable wound healing biomaterials.

MUC16/CA125 has been identified as a prominent cancer biomarker, especially for epithelial ovarian cancers, in clinical test for over three decades. Due to its huge mass, limited knowledge of MUC16 was acquired previously. By utilizing a well characterized self-made MUC16 monoclonal antibody, we identified the endogenous interaction between a C-terminal fragment of MUC16 (MUC16C) and β-catenin for the first time, and further elucidated that trans-activation domain of β-catenin is required for this interaction. Such interaction could activate the Wnt/β-catenin signaling pathway by facilitating cytosol-nucleus transportation of β-catenin, consequently induce cell proliferation and the migration, eventually lead to tumorigenesis and metastasis in nude mice. Consistently, knockdown of MUC16 significantly weakened the capabilities of cells for proliferation and migration. Based on our discovery, we suggest that MUC16 appears as an attractive target for the development of effective anticancer drugs.