Synthesis and anti-HCC activity of full 2ʹ-F/OMe-siRNA encapsulated with neutral cytidinyl/cationic lipid / 药学学报

A variety of full 2ʹ-F/OMe-modified siRNAs were designed and synthesized, and the activity against hepatocellular carcinoma Huh-7 and HepG2 cells was evaluated. K&A DNA/RNA H-8 synthesizer was used to synthesize siRNAs, and neutral cytidinyl lipid DNCA mixed with cationic lipid CLD were used to transfect siRNA. By RT-qPCR and CCK-8 assay, the target gene silence and the proliferation of Huh-7 and HepG2 cells were detected. The siRNAs loading into Ago2 protein was detected by RNA-binding protein immunoprecipitation. Drug uptake and cell apoptosis were detected by flow cytometry, and the expression of PLK1 protein was detected by Western blot. Partial full 2ʹ-F/OMe modified siRNAs, especial siPLK1A3, increased the uptake of Huh-7 cells, enhanced their binding to Ago2 and gene silencing activity, down-regulated PLK1 protein, as well as induced more Huh-7 cell apoptosis and proliferation inhibition activity. It provides important data for the development of novel siRNA modification patterns and anti-HCC formulations.

Treatment of triple negative breast cancer cells with combination of mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901 / 药学学报

MEK inhibition activates PI3K/AKT/mTOR pathway in triple negative breast cancer (TNBC) cell lines. Combination of PI3K inhibitor and MEK1/2 inhibitor is not appropriate for PI3K inhibitor insensitive TNBC cell lines. This study was designed to investigate the effects of dual treatments with mTOR1/2 inhibitor AZD8055 and MEK1/2 inhibitor PD0325901 in MDA-MB-435 cell line. MEK1/2 inhibition led to activation of AKT, which is the downstream signaling protein of PI3K pathway. The combination inhibited the phosphorylation of AKT and therefore abolished the feedback interaction of two pathways. Cell proliferation assay and DNA replication assay demonstrated that the dual treatments led to a significant synergistic inhibition of cell cycle progression and cell proliferation.

Design and synthesis of photoaffinity biotin labelled 2'-O-propargyl-guanosine / 药学学报

Photoaffinity labeling is widely applied to demonstrate targets of small molecule ligands. In this paper, biotin photoaffinity labeled molecule with propargyl group 1 has been designed and synthesized, followed it's labeling of N2-acetyl-2'-O-propargyl guanosine 9 by "click chemistry". This technology presents delight development potential in labeling of second messenger cyclic nucleotide, antisense oligonucleotide or siRNA.

Activity of cyclic diguanylate (c-di-GMP) in bacteria and the study of its derivatives / 药学学报

Cyclic diguanylate (c-di-GMP) is a ubiquitous second messenger present in a wide variety of bacteria, which is responsible for cell differentiation, biofilm formation, pathogenic factor generation, and so on. The level of c-di-GMP in bacteria is regulated by two opposing active domains, diguanylate cyclase (DGC) and phosphodiesterase (PDE), which are present in the same bifunctional protein, and in charge of the synthesis and the degradation of c-di-GMP, respectively. The target of c-di-GMP in the bacterial cell consists of PilZ domain and GEMM riboswitch, the only riboswitch that involved in signal transduction. This article gives an overview of c-di-GMP, focusing on its metabolic pathway, regulatory mechanism, biological function of c-di-GMP, and the synthesis of c-di-GMP analogues and their biological activity.

Design, synthesis and biological assay of novel tripeptidic tetrazoles as inhibitors of 20S proteasome / 药学学报

Ubiquitin-proteasome pathway (UPP) is one of the ways utilized for selective degradation of many proteins in cells, and the 20S proteasome takes the functional machinery where hydrolysis of targeted proteins takes place. Based on existing peptide inhibitors, a series of novel tripeptidic tetrazoles have been designed, synthesized, and the structures have been confirmed with 1H NMR, MS and elemental analysis. Among them, three compounds (6b, 6d and 6h) showed inhibitory activities of ChT-L of 20S proteasome.

Staurospolin promotes the apoptosis of multidrug resistance tumor cell lines induced by adriamycin / 肿瘤研究与临床

Objective To investigate whether the protein kinase C inhibitor can promote the apopto- sis of multidrug resistance tumor cell lines which are induced by chemotherapy drugs.Methods Choose the KB/S(oral squamous cancer cell line)and KB/VCR(its multidrug resistant cell line)to compare the Adri- amycin-induced apoptosis with or without staurospolin(protein kinase C inhibitor).The apoptosis is stained with acridine orange,tested by flow cytometry,and approved by electron microscope.Results 36 hours after the treatment with 0.04 ?g/ml adriamycin,apoptotic cells of KB/S are 96.68%,and after 48 hours,the apop- totic cells of KB/VCR are 64.99%.When the concentration of adriamycin are augmented to 0.4?g/ml and 2.0?g/ml,the apoptotic cells of KB/VCR are 69.74% and 37.18% respectively.When treated with stau- rospolin together,the apoptotic cells of KB/VCR increased to 72.58%(?~2=4.5,P0.05)respectively.These results were testified by electron microscope and acridine orange-stain.Conclu- sion The resistance to apoptosis may be one of the mechanisms of multidrug resistance and the protein ki- nase C inhibitor may reverse this resistance by promoting the apoptosis of multidrug resistance tumor cells.