Virtual screening based on pharmacophore model for developing novel HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for herbicide design. A multilayered virtual screening workflow was constructed by combining two pharmacophore models based on ligand and crystal complexes, molecular docking, molecular dynamics (MD), and biological activity determination to identify novel small-molecule inhibitors of HPPD. About 110, 000 compounds of Bailingwei and traditional Chinese medicine databases were screened. Of these, 333 were analyzed through docking experiments. Five compounds were selected by analyzing the binding pattern of inhibitors with amino acid residues in the active pocket. All five compounds could produce stable coordination with cobalt ion, and form favorable π-π interactions. MD simulation demonstrated that Phe381 and Phe424 made large contributions to the strength of binding. The enzyme activity experiment verified that compound-139 displayed excellent potency against AtHPPD (IC50 = 0.742 µM), however, compound-5222 had inhibitory effect on human HPPD (IC50 = 6 nM). Compound-139 exhibited herbicidal activity to some extent on different gramineous weeds. This work provided a strong insight into the design and development of novel HPPD inhibitor using in silico techniques.

Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity.

Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.

The Efficacy of Brucea javanica Oil Emulsion Injection as Adjunctive Therapy for Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis.

Purpose. To evaluate the efficacy of Brucea javanica oil emulsion injection (BJOEI) in patients with advanced non-small-cell lung cancer (NSCLC) during chemotherapy. Method. Electronic database of EMBASE and PubMed and the conference proceeding of ASCO, CNKI, CBMdisc, VIP, and Wanfang database were searched to select RCTs comparing BJOEI plus chemotherapy with chemotherapy alone in the treatment of advanced NSCLC, until June 1, 2016. Two reviewers independently performed the analysis according to the inclusion and exclusion criteria. Review Manager 5.3 and STATA 12.0 were employed for data analysis. Result. Twenty-one studies including 2234 cases were included. The pooled result indicated that there were significant differences in ORR (RR = 1.25; 95% CI: 1.14-1.36; P < 0.00001), improvement of QOL (RR = 1.87; 95% CI: 1.63-2.15; P < 0.00001), nausea and vomiting (RR = 0.67; 95% CI: 0.46-0.98; P = 0.04), leukopenia (RR = 0.63; 95% CI: 0.52-0.75; P < 0.00001), but there was no difference in thrombocytopenia (RR = 0.78; 95% CI: 0.49-1.23; P = 0.29). Begg's funnel plot and Egger's test indicated that no publication bias was found. The sensitivity analysis suggested the stability of the pooled result. Conclusion. The addition of BJOEI can enhance efficacy, improve QOL, and decrease incidence of nausea and vomiting and leukopenia for advanced NSCLC patients. However, higher quality RCTs are needed to further confirm this finding.

Determination method for in vitro disintegrating time of oral disintegrating tablets of Chinese herbal drug / 第二军医大学学报

Objective: To develop methods for determining the disintegration time of oral disintegrating tablets (ODTs) of Chinese herbal drug, and to select the evaluation method with good reproducibility, resolving power, and in vivo and in vitro correlation. Methods: Several placebo ODTs and Chinese herbal drug ODTs were prepared. Their in vitro disintegration time was determined by self-developed method and routine methods, and the results were compared with the oral disintegration time. The reproducibility, resolving power, and the correlation between in vivo and in vitro of those methods were evaluated. Results = Different determination methods obtained different disintegration results of the same tablet. Graduated cylinder and improved disintegration apparatus both had shortcomings and their determination results were very different from that of the oral disintegration time. Our self-developed disintegration device could better determine the disintegration ability of the ODTs, and the result was closer to the oral disintegration time, with clear end point of disintegration and better reproducibility, resolving power, and the in vivo and in vitro correlation compared with other methods. Conclusion: Our self-developed device is suitable to determine in vitro disintegration time of ODTs, and may serve as a reference for quality control of ODTs.