Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of multi-drug resistance (MDR). In the present study, we demonstrated the discovery of a novel inhibitor for Notch activating/cleaving enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of NOTCH protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of HCC cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. ZLDI-8 treatment enhanced the effect of Sorafenib on inhibiting tumor growth in nude HCC-bearing mice model. These results suggest that ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib's anti-tumor effect and to overcome the MDR of HCC patients.

Pregnane X receptor mediates sorafenib resistance in advanced hepatocellular carcinoma.

BACKGROUND: Kinase inhibitor sorafenib is the most widely used drug for advanced HCC clinical treatment nowadays. However, sorafenib administration is only effective for a small portion of HCC patients, and the majority develop sorafenib-resistance during treatment. Thus, it is urgent to discover the endogenous mechanism and identify new pharmaceutical targets of sorafenib-resistance. METHODS: Pregnane X receptor (PXR) was detected by immunohistochemistry and quantitative PCR. GST-pull down and LC-MS/MS was used to detect the interaction of PXR and Sorafenib. To test the properties of HCC tumor growth and metastasis, in vivo tumor explant model, FACS, trans-well assay, cell-survival inhibitory assay and Western blot were performed. In terms of mechanistic study, additional assays such as ChIP and luciferase reporter gene assay were applied. RESULTS: In the present work, we found high PXR level in clinical specimens is related to the poor prognosis of Sorafenib treated patients. By the mechanistic studies, we show that sorafenib binds to PXR and activates PXR pathway, and by which HCC cells develop sorafenib-resistance via activating. Moreover, PXR overexpression helps HCC cells to persist to sorafenib treatment. CONCLUSION: This study reports the endogenous sorafenib-resistance mechanism in HCC cells, which offers an opportunity to design new therapeutic approaches for HCC treatment. GENERAL SIGNIFICANCE: PXR mediates sorafenib-resistance in HCC cells and targeting PXR can be a useful approach to facilitate HCC treatment.

Can music improve sleep quality in adults with primary insomnia? A systematic review and network meta-analysis.

BACKGROUND: Primary insomnia is one of the most common issues for adults. However, whether to use music intervention as a non-pharmacological method of treatment, as well as which treatment should be preferred, is still a matter of controversy. Therefore, we aimed to compare and rank music interventions and no-music controls for primary insomnia patients. METHODS: A network meta-analysis was used to identify evidence from relevant clinical trials. We searched PubMed, Embase, the Cochrane Library, and the China National Knowledge Infrastructure Library for publications up to May 2017, pertaining to music intervention for primary insomnia patients. The prespecified primary outcome was sleep quality (scored by the PSQI and overall), and the secondary outcomes were sleep onset latency and sleep efficiency. We did pairwise meta-analyses using the random-effects model, later completing the random-effects network meta-analyses. The study was registered with PROSPERO, number CRD42017064750. RESULTS: We deemed 20 trials to be eligible, involving 1339 patients and 12 intervention arms. For PSQI scores, all intervention arms were statistically more effective than the usual care, with patients ranking listening to music as the best means of intervention (SMD: -0.61, 95%CrI: -1.01 to -0.20). For overall sleep quality, only music-associated relaxation was statistically more effective than the patients' usual care (-0.28, -0.48 to -0.08). In terms of sleep onset latency, music-associated relaxation and listening to music had significant advantages (-0.26, -0.64 to -0.09, and -0.28, -0.53 to -0.02); listening to music and music with exercise displayed a tendency to improve sleep efficiency. CONCLUSIONS: When considering the efficacy, music intervention seemed to offer clear advantages for adults with primary insomnia. Listening to music and music-associated relaxation are probably the best options to consider in the application of music intervention.