Flavonoids and prenylhydroquinones from the prepared folium of Epimedium sagittatum Maxim. and their inhibition against phosphodiesterase5A.

An effort to identify novel active substances of the prepared folium of Epimedium sagittatum Maxim. (PFES) that was an important herb for male erectile dysfunction (ED) was taken. At present, phosphodiesterase-5A (PDE5A) is the most important target of new drugs for the treatment of ED. Therefore, the inhibition ingredients in PFES were systematically screened for the first time in this study. Eleven compounds, including eight new flavonoids and three prenylhydroquinones were isolated: sagittatosides DN (1-11), and their structures were elucidated by spectra and chemical analyses. Among them, a novel prenylflavonoid with oxyethyl group (1) was obtained and three prenylhydroquinones (9-11) were firstly isolated from Epimedium. All compounds were analyzed for the inhibition against PDE5A by molecular docking, and they all showed significant binding affinity as same as sildenafil. Their inhibitory activities were verified, and the results showed compound 6 had significant inhibition against PDE5A1. The isolation of new flavonoids and prenylhydroquinones with inhibitory activities of PDE5A from PFES implied that this herb might be a good source for the treatment of ED agents finding.

Discovery of novel piperonyl derivatives as diapophytoene desaturase inhibitors for the treatment of methicillin-, vancomycin- and linezolid-resistant Staphylococcus aureus infections.

Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.

Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease.

Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.

Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria.

Heterologous expression of the Drosophila melanogaster multi-substrate deoxyribonucleoside kinase (Dm-dNK) increases the sensitivity of cancer cells to several cytotoxic nucleoside analogs. Thus, it may be used as a suicide gene in combined gene/chemotherapy treatment of cancer. To further characterize this potential suicide gene, we constructed two retroviral vectors that enabled the expression of Dm-dNK in cancer cells. One vector harbored the wild­type enzyme that localized to the nucleus. The other vector harbored a mitochondrial localized mutant enzyme that was constructed by deleting the nuclear localization signal and fusing it to a mitochondrial import signal of cytochrome c oxidase. A thymidine kinase-deficient osteosarcoma cell line was transduced with the recombinant viruses. The sensitivity and bystander cell killing in the presence of pyrimidine nucleoside analogs (E)-5-(2-bromovinyl)­2'­deoxyuridine and 1-ß-D-arabinofuranosylthymine were investigated. Tanshinone IIA is a constituent of Danshen; a traditional Chinese medicine used in the treatment of cardiovascular diseases. This study also looked at the influence of Tanshinone IIA on the bystander effect and the underlying mechanisms. We showed that sensitivity of the osteosarcoma cell line to the nucleoside analogs and the efficiency of bystander cell killing were independent of the subcellular localization of Dm-dNK. The enhanced effect of tanshinone IIA on the bystander effect was related to the increased expression of Cx43 and Cx26.

The combined effect of survivin-targeted shRNA and emodin on the proliferation and invasion of ovarian cancer cells.

Survivin has been shown to be highly expressed in ovarian cancers, but not normal ovarian tissue, which makes it an attractive target for ovarian cancer treatment. Emodin is a traditional Chinese medicine that has been found to inhibit proliferation and induce apoptosis in ovarian cancer cells. Thus, in our study, we combined survivin-targeted shRNA (sur-shRNA) with emodin and tested the effects of this combination on ovarian cancer cells to identify more effective therapeutics against ovarian cancer. A sur-shRNA plasmid was constructed and transfected into the ovarian cancer cell lines SKOV3 and HO8910, and the cells were cultured for 24 h. The cells were then treated with emodin for specific time periods and assessed for viability and apoptosis using the MTT assay and flow cytometry, respectively. Cell invasion was also measured using a Matrigel invasion assay. The shRNA specific for survivin effectively reduced the expression of survivin at the mRNA and protein levels in SKOV3 and HO8910 cells. Both emodin and shRNA-mediated knockdown of survivin significantly inhibited cell proliferation, induced apoptosis, and suppressed invasion in SKOV3 and HO8910 cells (P<0.05). Moreover, the combination of the agents significantly enhanced these effects (P<0.05). We found that the combination of sur-shRNA and emodin could be effective in the treatment of ovarian cancer.

[Spatial pattern of soil fertility in Bashan tea garden: a prediction based on environmental auxiliary variables].

Taking topographic factors and NDVI as auxiliary variables, and by using regression-kriging method, the spatial variation pattern of soil fertility in Bashan tea garden in the hilly area of Fuyang City was explored. The spatial variability of the soil fertility was mainly attributed to the structural factors such as relative elevation and flat/vertical curvature. The lower the relative elevation, the worse the soil fertility was. The overall soil fertility level was relatively high, and the area with lower soil fertility only accounted for 5% of the total. By using regression-kriging method with relative elevation as auxiliary variable, the prediction accuracy of soil fertility was obviously higher than that by using ordinary kriging method, with the mean error and root mean square error being 0. 028 and 0. 108, respectively. It was suggested that the prediction method used in this paper could fully reflect the effects of environmental variables on soil fertility , improve the prediction accuracy about the spatial pattern of soil fertility, and provide scientific basis for the precise management of tea garden.