Research progress of ProTide technology and its application in the development of antiviral drugs / 药学学报

ProTide technology is a kind of prodrug design strategy invented by the team of Christopher McGuigan. ProTides are aryloxyphosphoramidates (or aryloxyphosphonamidates) which contain a phosphorus atom combined with an amino acid ester and an aryloxy group. These prodrugs can efficiently cross the cell membrane and escape from the first rate-limiting step of phosphorylation, which afford effective solutions to the drawbacks of current nucleoside analogues. At present, ProTide technology has been extensively applied in the field of antiviral research. It has been successful in providing a number of approved drugs and clinical candidates, such as sofosbuvir and so much more, highlighting the promising future in drug discovery. This review summarizes the brief history and characteristics of ProTide technology, as well as its application in the exploration of antiviral drugs.

Predictive analysis of quality markers of Coptidis Rhizoma based on network pharmacology and multivariate statistical analysis / 中国中药杂志

Coptidis Rhizoma, as a bulk medicinal material, is in great demand in clinical practice. Its quality is uneven in the market due to the mixture of genuine, counterfeit and adulterants. Therefore, it is particularly important to establish a quality control system for Coptidis Rhizoma. Based on the concept of Chinese medicine quality marker(Q-marker), the potential quality markers of Coptidis Rhizoma were analyzed and predicted from the perspective of chemistry and pharmacology. The sources of the Q-markers of Coptidis Rhizoma were identified by literature retrieval. The potential Q-markers were then screened through the visualization of the "components-targets-pathways" network. High performance liquid chromatography(HPLC) was used to establish a multi-indicator qualitative and quantitative control method featuring fingerprints for 10 batches of Coptidis Rhizoma. A supervised mode of orthogonality partial least squares method-discriminant analysis(OPLS-DA) was used to screen the main marker components that caused differences between groups. The literature review results showed that the alkaloids were the main source of Coptidis Rhizoma Q-markers.The fingerprints of 13 common peaks were successfully established, and berberine, palmatine, berberine and epiberberine were selected as Q-markers of Coptidis Rhizoma, and their contents were determined.Based on the concept of the Q-marker of traditional Chinese medicine, the four components can be selected as the Q-marker of Coptidis Rhizoma after comprehensive consideration. The results of this study are not only conducive to the quality evaluation of Coptidis Rhizoma on the market, but also provide a reference for the overall quality control of Coptidis Rhizoma and lay foundation for the future exploration of the mechanism of Coptidis Rhizoma.

Finite element analysis of maxillary anterior teeth retraction of posterior teeth with different alveolar bone absorption heights under orthodontic force / 华西口腔医学杂志

OBJECTIVE@#This study applied the direct orthodontic force system to explore the applicability of the finite element method in the simulation of alveolar bone absorption and analyze periodontal stress distribution and the overall displacement trend.@*METHODS@#The horizontal balanced alveolar bones of model 2, 3 and 4 were reduced by 2, 4, and 6 mm by deleting elements in reference to the established height of the normal alveolar bone model 1. Then, stress distribution on the posterior set of teeth and initial total tooth displacement under the simulated load of 1.47 N of orthodontic force were investigated.@*RESULTS@#The total displacement of posterior teeth increased and parodontium Von Mises stress gradually increased as the alveolar bone height decreased. The total displacement trend and parodontium stress drastically increased when alveolar bone absorp-tion reached the height of 4 mm.@*CONCLUSIONS@#When treating patients with alveolar bone loss, stress should be avoided or drasti-cally reduced to prevent irreversible damage to periodontal tissue and to improve the quality of medical treatment.

Effect of alisol A 24-acetate on proliferation of aorta smooth muscle cells in rats induced by ox-LDL / 中国中药杂志

Alisol A 24-acetate, a triterpenoid extracted from Alisma orientale, has shown anti-atherosclerotic actions and many studies have proved that oxidized low density lipoprotein (Ox-LDL) could promote proliferation of aorta smooth muscle cells (VSMCs) which are closely related to atherosclerosis (AS). The purpose of this study was to evaluate the effect of alisol A 24-acetate on the proliferation of VSMCs isolated from the thoracic aorta of rats induced by ox-LDL. VSMCs were induced by ox-LDL(50 mg·L⁻¹) to establish the proliferation model and intervened by alisol A 24-acetate (5, 10, 20 mg·L⁻¹) for 12, 24 and 48 h. Then the proliferation of VSMCs was detected by MTT assay; protein expression levels of VSMCs PCNA, cyclinD1, cyclinE, p21, p27 and VSMCs PCNA, p21and p27 mRNA expression levels were detected by Western blot and Real-time polymerase chain reaction (RT-PCR) respectively. The results showed that ox-LDL could induce the proliferation of VSMCs (<0.05), increase the protein expression levels of PCNA, cyclinD1 and cyclinE in the VSMCs (<0.05) and inhibit the protein and mRNA expression levels of p21 and p27 (<0.05). As compared with the model group, alisol A 24-acetate inhibited the proliferation of VSMCs in rats induced by ox-LDL and inhibited the protein expression of VSMCs PCNA, cyclinD1, cyclinE and enhanced the protein and mRNA p21 and p27 expression levels (<0.05). The effect was more obvious with the increase of concentration of alisol A 24-acetate. These data indicate that alisol A 24-acetate can inhibit the proliferation of VSMCs induced by ox-LDL and the mechanism may be associated with inhibiting expression of cyclin protein, including cyclinD1, cyclinE, p21, p27 and so on.

Impurity analysis and quality evaluation for commercial levofloxacin formulations using LC-MS/MS method / 药学学报

The study aims to develop a rapid, specific and sensitive method for quantitative analysis of trace impurities in levofloxacin formulation using LC-MS/MS. The quality of the different formulations from 19 plants was evaluated in the contents of the impurities. The results indicated that there were 5 impurities in the samples, and the content was different in the products with same formulation by different plants. The products of 3 plants were in good quality with impurities level under 0.01%. Levofloxacin N4'-methyl quaternary impurity was first reported as the formulation impurity. The impurities were tightly correlated to the reservation of drug, process control of formulation and storage during transportation. The results suggest that our method is sensitive and specific to detect the trace impurities in formulation, and can be used to monitor the quality of commercial drug product.

Establishment and application of a high-throughput drug screening model based on COL1A1 promoter for anti-liver fibrosis / 药学学报

For screening the potential drugs as anti-liver fibrosis candidates, we established a high- throughput drug screening cell model based on COL1A1 promoter. The activity of COL1A1 promoter and luciferase reporter gene can be elevated by TGF-β1, and inhibited by candidate drugs. We constructed a recombined plasmid with COL1A1 promoter and luciferase reporter gene pGL4.17, the activity of COL1A1 promoter was reflected by fluorescence intensity. COL1A1 promoter activity was detected by Dual-Luciferase Reporter Assay System, it came that the relative luciferase activity of COL1A1 promoter was 15.98 times higher than that of control group induced by TGF-β1, showing the recombined plasmid could be used in cell model. The recombined plasmid was transfected into human hepatic stellate cells LX2, detected the effect of potential drugs, and obtained a stable expression system through stable transfection and monoclonal cell culture. A sample which could reduce COL1A1 promoter activity signally by our cell model, decreased collagen I mRNA and protein expression detected by real-time RT-PCR and Western blotting. It indicates this novel cell model can be used in high-throughput drug screening of potential anti-liver fibrosis drugs.

Synthesis and antibacterial activity of 7-(3-amino-4-alkoxyimino-1 -piperidyl) -quinolones / 药学学报

To explore new agents of quinolone derivatives with high activity against Gram-positive and Gram-negative microorganisms, 7-(3-amino-4-alkoxyimino-1-piperidyl) quinolones were designed and synthesized, and their activity against Gram-positive and Gram- negative microorganisms were tested in vivo and in vitro. Twenty one target compounds were obtained. Their structures were established by 1H NMR, HRMS and X-ray crystallographic analysis. The target compounds possess different antimicrobial activities against both Gram-negative and Gram-positive microorganisms. Compounds 14a and 14m have broad spectral antibacterial activities. They show better antibacterial activities against 12 strains Gram-positive bacteria than three references. In particular, their activities against S. aureus and S. epidermidis (including MRSA and MRSE) were 4 - 16 times than that of gemifloxacin and balofloxacin, and 8 - 64 times than that of levofloxacin. The MIC values to S. aureus strains of compounds 14a and 14m were 0.25 - 1 mg x L(-1) and 0.125 - 1 mg x L(-1), to S. epidermidis strains were 0.5 - 4 mg x L(-1) and 1 - 8 mg x L(-1) respectively. The in vivo results showed that they have as good internal protection as gemifloxacin and moxifloxacin against systemic infection model in mice (P > 0.05).

Synthesis and antibacterial activity of dl-7-(4,4-dimethyl-3-aminomethylpyrrolidinyl) -quinolones / 药学学报

<p><b>AIM</b>To explore new agents of quinolone derivatives with high activity against Gram-positive organisms.</p><p><b>METHODS</b>dl-7-(4,4-Dimethyl-3- aminomethylpyrrolidinyl)-quinolones were designed and synthesized, and their activity against Gram-positive organisms was tested in vitro.</p><p><b>RESULTS</b>Ten target compounds were obtained. The structures of these compounds were confirmed by 1H NMR, MS. The target compounds with dl-4,4-dimethyl-3-( methyl) aminomethylpyrrolidine side chains had high activity against Gram-positive organisms. Especially the MIC values of compound 22 for 4 strains of Gram-positive resistant bacteria (two strains of MRSA and two of MRSE) were 0.015 -0.5 mg x L(-), which exhibited more potent activities than gatifloxacin (4 - 128 times). Its MIC value for Pseudomonas aeruginosa 03-5 (0.008 mg x L(-1)) was 4 times as that of gatifloxacin (0.03 mg x L(-1)).</p><p><b>CONCLUSION</b>The compound 22 showed high activity against Gram-positive organisms in vitro and it is worth of more investigation.</p>

Study on expression of genes in Tamarix androssowii under NaHCO3 stress using gene chip technology / 生物工程学报

Gene chip technology was employed to study gene expression in Tamarix androssowii under NaHCO3 stress. cDNAs from T. androssowii treated with NaHCO3 solution and that from control group were labeled with fluorescent dye CyS and Cy3 respectively. The two fluorescent cDNA probes were mixed and hybridized to gene chips containing T. androssowii genes, and the chips were scanned using biochip scanning system. Differential expression of genes was analyzed through calculation of the ratio of Cy5 to Cy3 signal intensities. Total of 89 genes differentially expressed were identified, among them, 27 showed down regulated expression and 62 showed up regulated expression. Blastx analysis showed that the function of the differentially expressed genes could be grouped into some categorizations such as photosynthesis, reactive oxygen species eliminated, regulation of osmotic potential, regulation of gene expression and signal transduction, metabolism, development, ribosomal protein, protein breakdown and recycling, transporter, water channel proteins and so on. Based on this research, some function-unknown or novel unreported genes that respond to salt stress were also identified, and these genes may have important functions in salt resistance of T. androssowii. Some important pathways of salt resistance in T. androssowii are revealed, and the gene expression profiling of T. androssowii under salt stress and without stress is obtained in this study.