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Table of Content

    24 October 2021, Volume 30 Issue 10
    Review
    High-throughput screening technologies for ion channel drug discovery
    Guifang Duan, Bo Xu, Xia Yuan, Shuxiang Song
    2021, 30(10):  785-793.  DOI: 10.5246/jcps.2021.10.066
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    Ion channels are attractive targets for drug discovery as an increasing number of new ion channel targets have been uncovered in diseases, such as pain, cardiovascular disease, and neurological disorders. Despite their relevance in diseases and the variety of physiological functions they are involved in, ion channels still remain underexploited as drug targets. This, to a large extent, is attributed to the absence of screening technologies that ensure both the quality and the throughput of data. However, an increasing number of assays and technologies have evolved rapidly in the past decades. In this review, we summarized the currently available high-throughput screening technologies in ion channel drug discovery.

    Original articles
    A stochastic population pharmacodynamic model of QAP14 in the treatment of lung metastases of 4T1 breast cancer
    Mengyi Han, Ling Yong, Yuchen Guo, Xiaoxue Yan, Guoshu Chen, Daming Kong, Tianyan Zhou
    2021, 30(10):  794-805.  DOI: 10.5246/jcps.2021.10.067
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    Cancer metastasis is a process with multi-step complexity and apparent randomness. In this study, we aimed to establish a stochastic mathematical model to describe the random process of cancer metastasis and predict the drug effect of QAP14 on metastasis in a mouse model. The data of lung metastases on the 22nd day after cancer cell implantation with or without the treatment of QAP14, a new chemical compound, were collected in 4T1 breast cancer BALB/c mice. Based on the exponential growth of the primary tumor and metastatic loci, a joint distribution model of metastasis size and number was developed. Disease progression of metastasis and preclinical efficacy of QAP14 were modeled. Parameters M and m representing maximum and minimum of metastasis volume were 3.24 and 0.0184 mm3, respectively. The metastasis growth rate γ and metastasis promotion time ρ were estimated and fixed to be 0.0216 d–1 and 7.8 d, respectively. The efficacy of QAP14 acted on metastasis promotion time and metastasis growth rate constant in an exponential term, and the effect parameter Effectρ and Effectγ were 16.6 and 0.327 g/mg, respectively. In the present study, we comprehensively characterized the random process of lung metastasis and efficacy of QAP14 in 4T1 breast cancer mice, which might provide a useful reference for the establishment of a clinical population model of cancer metastasis.

    Virtual screening and high-throughput testing of L1 metallo-β-lactamase inhibitor
    Chennan Liu, Qian Wang, Jiangxue Han, Sihan Liu, Chunling Xiao, Yan Guan, Xinghua Li, Ying Wang, Xiao Wang, Jianzhou Meng, Maoluo Gan, Yishuang Liu
    2021, 30(10):  806-812.  DOI: 10.5246/jcps.2021.10.068
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    As a zinc-dependent enzyme, metal-β-lactamase L1 contributes to the development of β-lactam antibiotic resistance. The metal-β-lactamase inhibitor can restore the efficacy of β-lactam antibiotics, and its development has attracted much attention. In the present study, we used four widely-used virtual screening programs to screen 7035 small molecules to identify potential L1 inhibitors, and a high-throughput experimental model of L1 inhibitors was established. In this high-throughput testing model, the inhibition rate of 163 compounds on L1 exceeded 40%. The results of virtual screening of 7035 small molecules using the following four programs showed that among the top 1.35% of the compounds, their hit rates were ranked as Schr?dinger’s (5.26%), DS (1.05%), and Sybyl-x 2.0 (1.05%), and Smina (2.11%).

    Discussion on the mechanism of Salvia miltiorrhiza in treating pathological scars based on network pharmacology
    Hongzhuang Zhang, Zhiwei Yang, Jianghe Zhang, Yiming Zhang, Shike Hou, Zhenguo Wang, Li Yan, Dongli Fan
    2021, 30(10):  813-821.  DOI: 10.5246/jcps.2021.10.069
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    In the present study, we aimed to explore the mechanism of Salvia miltiorrhiza in the treatment of pathological scars (PS) by network pharmacology. The active ingredients and drug targets of Salvia miltiorrhiza were screened out through TCMSP database, the disease targets of PS in GeneCards database were obtained, and Venn diagram analysis on drug targets and disease targets was performed, and the intersection was used as the target of Salvia miltiorrhiza for the treatment of PS. Cytoscape software was used to construct a drug-ingredient-target-disease network diagram. A protein-protein interaction network was constructed through String website, its key protein modules and hub genes were screened with Cytoscape software, and GO and KEGG enrichment analyses were performed in DAVID database. Fifty-nine active ingredients, 138 drug targets, and 90 targets of Salvia miltiorrhiza for the treatment of PS were screened out. Core ingredients, such as luteolin and tanshinone IIA, were obtained. The hub genes, such as VEGFA, TP53, JUN, STAT3, AKT1, MAPK1, and PTGS2, and signaling pathways, such as HIF-1, TNF, MAPK, PI3K-Akt, and Jak-STAT, were screened out. Salvia miltiorrhiza might improve PS hypoxia, inflammation, and balance of proliferation and apoptosis of fibroblasts by regulating HIF-1, TNF, MAPK, PI3K-Akt, and Jak-STAT signaling pathways. Moreover, it had the characteristics of multiple centers, multiple targets, and multiple pathways.

    Quantification of flupirtine and its active metabolite D-13223 in human plasma by LC-MS/MS: application to a clinical trial of flupirtine maleate capsules in healthy male Chinese volunteers
    Yanfang Liu, Jiashan Zhang, Yunbiao Tang, Hua Huo
    2021, 30(10):  822-830.  DOI: 10.5246/jcps.2021.10.070
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    In the present study, we developed a simple, sensitive, precise, and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) method and validated such approach for simultaneous determination of flupirtine and its active metabolite D-13223 in human plasma. The flupirtine, D-13223, and stable isotope internal standard (IS) were extracted from plasma samples by liquid-liquid extraction and chromatographed on a C18 column with a mobile phase consisting of acetonitrile–water–ammonia (55:45:0.1, v/v/v) at a flow rate of 0.25 mL/min. Detection was performed on a triple quadrupole tandem mass spectrometer with an electrospray ionization source (ESI) by multiple reaction monitoring (MRM) in positive ion mode. The linear calibration curves were obtained within the concentration range of 10.00–2000.00 ng/mL for flupirtine and 2.00–400.00 ng/mL for D-13223. The intra- and inter-run RSD, calculated from quality control (QC) samples, was less than 9.26% for flupirtine and D-13223. The accuracy was –5.80%–3.31% for flupirtine and D-13223. The extraction recoveries of flupirtine, D-13223, and their IS were all between 88.3%–97.2%. The method was successfully applied to investigate the pharmacokinetic profiles of flupirtine and its active metabolite D-13223 in human plasma following peroral administration of 100 mg flupirtine maleate capsules in healthy male Chinese volunteers.

    Facile extraction of high-purity mangiferin from mango industrial wastes
    Chaohai Pang, Hai Tian, Xiaojie Guo, Pan Wang, Bingjun Han, Xinfeng Yang
    2021, 30(10):  831-837.  DOI: 10.5246/jcps.2021.10.071
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    In the present study, we described a novel, simple, and scalable method for isolating and purifying natural mangiferin from fresh mango leaves. An ultrasonic-assisted method was used to extract mangiferin from mango leaves using methanol as the solvent. The yields of the mangiferin crude extract and purified mangiferin recrystallized from a mixture of methanol and trichloromethane (10:1, v/v) were 1.41% (purity 86.5%) and 0.75% (purity > 99.6%), respectively. The purity of mangiferin was assessed by UV spectroscopy and HPLC. The structure of the purified compound was confirmed spectroscopically by UV, IR, Q-TOF/MS, 1H NMR, and 13C NMR. The method described herein to isolate mangiferin was simple, inexpensive, rapid, and efficient. Moreover, we, for the first time, obtained mangiferin with a purity of more than 99.6% using this method.

    Preparation and antibacterial activities of metal complexes of norfloxacin
    Ahsan Zamir Siddiqi, Muneeba Akhtar, Agha Zeeshan Mirza
    2021, 30(10):  838-844.  DOI: 10.5246/jcps.2021.10.072
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    The metal complexes of norfloxacin were prepared, and their structures were characterized using spectroscopic techniques like IR, 1H NMR, UV, atomic absorption, and CHN analysis. The solubility, melting point, and conductance measurements were also performed. These studies suggested that norfloxacin formed complexes with the metals utilizing carbonyl oxygen atom of the ring and carboxylic group oxygen atom. The antibacterial activities of these metal complexes against 14 different Gram-positive and Gram-negative microorganisms were studied by the disk susceptibility method. It was observed that the complexes of norfloxacin with magnesium, calcium, cobalt, nickel, and copper showed improved activity compared with the stated drug.

    Drug administration and clinical pharmacy column
    Analysis of reimbursement policy for outpatient chronic diseases in basic medical insurance for urban residents in China provincial capitals
    Ningtai Luo, Yajuan Xiong, Li Liu, Bin Jiang, Jianying Yue
    2021, 30(10):  845-850.  DOI: 10.5246/jcps.2021.10.073
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    Reimbursement policy for outpatient chronic diseases is an important part of the basic medical insurance scheme in China. The reimbursement policy for outpatient chronic diseases in basic medical insurance for urban residents of provincial capitals in China were analyzed from the perspectives of disease types, benefits package, qualification and health service access. Proposals to improve policy design, establish standardized disease inclusion criteria and set reasonable benefits package, strengthen management and complete supporting policy, strengthen policy coordination were put forward according the existing problems such as fragmented policy, great difference in disease types and benefit package, supervision difficulty, incomplete policy framework and lack of policy coordination.

    News
    The group of Professor Wanliang Lu has made progress in targeted gene editing systems against metastatic breast cancer
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(10):  851-852. 
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    The group of Professor Wanliang Lu has made progress in targeted gene editing systems against metastatic breast cancer.
    The group of Professor Tao Liu reported Cas12a efficient gene editing system in Molecular Cell
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(10):  853-854. 
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    The group of Professor Tao Liu reported Cas12a efficient gene editing system in Molecular Cell.
    The group of Professor Xinjing Tang has made progress in the study of cyclic antisense oligonucleotides as microRNA inhibitors
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(10):  855-856. 
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    The group of Professor Xinjing Tang has made progress in the study of cyclic antisense oligonucleotides as microRNA inhibitors.
    The group of Professor Qiang Zhang and Bing He has made important progress in nanodrug transport mechanism
    State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center
    2021, 30(10):  857-858. 
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    The group of Professor Qiang Zhang and Bing He has made important progress in nanodrug transport mechanism.