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Table of Content

    27 September 2021, Volume 30 Issue 9
    Original articles
    Exploring the mechanism of Fu-Zi Decoction in treatment of chronic heart failure based on network pharmacology and molecular docking technology
    Taixiang Gao, Feng Zhao, Liyao Shi, Rui Wang
    2021, 30(9):  705-715.  DOI: 10.5246/jcps.2021.09.058
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    In the present study, we aimed to explore the mechanism of Fu-Zi Decoction in the treatment of chronic heart failure (CHF) using network pharmacology. SymMap database was used to analyze the modern medical (MM) symptoms of various medicines. The chemical components of Fu-Zi Decoction were obtained through TCMSP, ETCM database, and previous results. The targets of Fu-Zi Decoction were obtained through STITCH, SwissTargetPrediction, TargetNET database, and literature. The targets for the treatment of CHF were obtained from the DisGeNET, GEO, and DrugBank databases, and the common parts of the Fu-Zi Decoction targets were screened out to construct the PPI network. The PPI network was decomposed modularly, its functions were analyzed, and the KEGG pathway enrichment analysis was performed. The key target was verified by SwissDock for molecular docking. A total of 205 chemical components of Fu-Zi Decoction, 551 drug targets, and 521 disease targets were collected. Functional enrichment analysis revealed that it was mainly involved in biological processes, such as negative regulation of cell death, oxidative stress, and G protein-coupled receptor regulation. KEGG enrichment findings mainly involved fluid shear stress and atherosclerosis, IL-17 signaling pathway, and so on. The results of molecular docking showed that benzoylaconitine, aconitine, mesaconitine, paeoniflorin, and atractylodes III all had a strong affinity with the core target CXCL8, suggesting that Fu-Zi Decoction could negatively regulate cell apoptosis and oxidative stress through fluid shear stress and atherosclerosis, IL-17 signaling pathway, and so on. Collectively, our data showed that Fu-Zi Decoction had a good effect on the treatment of CHF.

    (–)-Epicatechin gallate serves as a novel new delhi metallo-β-lactamase-1 (NDM-1) inhibitor
    Qian Wang, Chennan Liu, Jiangxue Han, Sihan Liu, Chunling Xiao, Yan Guan, Xinghua Li, Ying Wang, Xiao Wang, Jianzhou Meng, Maoluo Gan, Yishuang Liu
    2021, 30(9):  716-724.  DOI: 10.5246/jcps.2021.09.059
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    The β-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health. We have previously screened out (–)-epicatechin gallate (ECG) as a potent NDM-1 inhibitor. We further discussed its inhibitory effect and action mode in the present study. According to our results, ECG reversibly inactivated NDM-1 in a non-competitive mode, with an IC50 value of 4.48 μM. ECG effectively recovered the activity of several β-lactam antibiotics against resistant strain harboring blaNDM-1. Especially, the effects on carbapenems were worth mentioning. The zinc supplement assay indicated a zinc-related mechanism of ECG. Different from traditional chelating agents, it showed low toxicity both in vivo and in vitro. In a word, our findings provided a promising NDM-1 inhibitor, ECG, which was able to assist carbapenems against NDM-1-producing strain.

    Transcriptome-wide identification of differentially expressed genes and long non-coding RNAs in nitroglycerin-tolerant rat aorta
    Chunya Cao, Kai He, Zhenhua Zeng, Jianxin Liu, Wei Cai, Weihua Wu
    2021, 30(9):  725-735.  DOI: 10.5246/jcps.2021.09.060
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    Tolerance to nitroglycerin (GTN) greatly limits its long-time application, and the underlying mechanism remains largely unexplored. In the present study, we aimed to investigate the comprehensive changes in the transcriptome of rat aorta tolerant to GTN by analyzing lncRNA expression. We employed the RNA sequencing (RNA-seq) technique to identify mRNAs and lncRNAs. Ingenuity pathway analysis (IPA) was used for pathway and functional analysis. RT-qPCR was used to validate the RNA-seq results. We identified 22 788 genes (reads per kilobase million [RPKM] > 0.1, 14 720 protein-coding genes and 4408 lncRNAs), including 115 differentially expressed (DE) mRNAs (65 up-regulated and 50 down-regulated) and 104 DE lncRNAs (56 up-regulated and 48 down-regulated), in GTN-tolerant aortas. IPA revealed the inhibition of a canonical pathway "Signaling by Rho Family GTPases" and alteration in six upstream regulators. Functional analysis showed that 11 genes were related to "disorder of blood pressure". We predicted the cis-target genes of DE lncRNAs by the analysis of their neighboring genes. The results revealed the 28 DE lncRNAs adjacent to the 26 protein-coding genes. Many DE mRNAs and cis-target genes of DE lncRNAs have been implicated in the regulation of blood pressure or cell contraction. These results suggested that the dysregulated mRNAs and lncRNAs contributed to the development of GTN tolerance and could serve as potential targets to prevent and reverse GTN tolerance.

    Preparation and evaluation of doxorubicin-luminespib co-loaded multivesicular liposomes
    Yajie Liu, Yu Wang, Jiajia Li, Xiaoqing Xu, Xinru Li
    2021, 30(9):  736-742.  DOI: 10.5246/jcps.2021.09.061
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    A combinational therapeutic system that simultaneously administrates various pathways is preferred for anti-cancer treatment. In the present study, we successfully constructed a co-delivery system, multivesicular liposomes (MVLs) co-encapsulating doxorubicin (DOX) and luminespib (AUY922). A simple and accurate dual-wavelength spectrophotometric method was established for the determination of DOX and AUY922 in liposomal formulation. MVL-loading drugs were prepared by a multi-emulsion solvent evaporation method, which exhibited excellent physicochemical properties, such as particle size of 3–8 μm and high entrapment efficiency above 95% for DOX and 73% for AUY922. The synergetic cytotoxic effect for these two drugs was evaluated in MDA-MB-231 cells. The in vitro antitumor studies demonstrated the superior anti-proliferation activity of DOX and AUY922 with a combination index of 0.43, indicating a great synergistic effect. The experimental data suggested that combinational use of DOX and AUY922 within liposomes could be an effective way to develop efficient treatments of cancers.

    Synthesis of a novel series of amino acid prodrugs based on tegafur and evaluation of their antitumor activity
    Shiqi Xu, Liyan Zhu, Chao Hao, Wenqian Liu, Chenglong Chen, Yongyi Chen, Aiqin Liu
    2021, 30(9):  743-753.  DOI: 10.5246/jcps.2021.09.062
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    As an oral chemotherapy prodrug, tegafur, can be converted to 5-fluorouracil, which is activated to kill tumor cells mainly by the inhibition of thymidylate synthase. In the present study, we synthesized 20 new tegafur derivatives containing amino acid ester groups by substitution, hydrolysis, and condensation. Their structures were confirmed by 1H NMR, 13C NMR, and H RMS, and their inhibitory effects on tumor cell growth were studied. The results showed that some of the compounds had good anti-tumor activity.

    Dropout reasons and associated factors with active dropout in Chinese healthy participants of bioequivalence studies
    Hengyi Yu, Yinian Fang, Kaifu Wang, Qian Chen, Aihua Du, Xiuhua Ren, Dong Liu
    2021, 30(9):  754-761.  DOI: 10.5246/jcps.2021.09.063
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    Maintaining participants in a trial ultimately without dropout helps keep a study on track, saving time, money, and resources. Since 2015, extensive bioequivalence (BE) studies have been carried out in China, while no research about dropout in healthy volunteers has been reported yet. In this retrospective study, 1078 healthy volunteers participating in 18 BE studies from March 2016 to February 2019 in one Chinese hospital were included. Information about the healthy participants and BE studies was recorded for analysis. In terms of the dropout reason, poor compliance, adverse event (AE), and loss of follow-up were found to be the three leading causes of dropout, accounting for 78.7% of all dropouts. In terms of associated factors with active dropout, smoking habit (OR = 5.790, P < 0.001) was significantly associated with increased risk of active dropout, while older age (OR = 0.940, P = 0.042) and AE except for SAE (OR = 0.321, P = 0.004) were significantly associated with a decreased risk of active dropout. Strengthening the education on younger participants and participants with a smoking habit, as well as emphasizing the possible adverse reactions and potential risks, might be strategies to reduce active dropout in healthy participants.

    Drug administration and clinical pharmacy column
    Association between CYP3A4 gene polymorphisms and clopidogrel response in patients with cardio-cerebrovascular diseases: a systematic review and Meta-analysis
    Sibei Qin, Tong Jia, Yu Fu, Junlei Li, Xinyi Zhang, Chunsu Zhu, Guangkai Liang, Xiaoyan Nie, Luwen Shi, Yimin Cui
    2021, 30(9):  762-772.  DOI: 10.5246/jcps.2021.09.064
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    CYP3A4 plays a critical role in clopidogrel activation in the liver. The polymorphism ofCYP3A4 may have an important effect on clopidogrel response in patients with cardio-cerebrovascular diseases. We conducted a systematic review and meta-analysis to evaluate the impact ofCYP3A4 polymorphism on platelet reactivity after clopidogrel treatment and the outcomes of patients. A systematic literature search (up to 7th October, 2019) was performed on the PubMed, EMBASE, Cochrane Library, clinicaltrials.gov, and Chinese databases, including China National Knowledge Infrastructure (CNKI) and Wan Fang Data. Cohort studies or case-control studies evaluated platelet reactivity and patients’ outcomes in different genotype patients. The Review Manager software was used for data analysis, and the NOS scale was used to assess the quality of included studies. A total of 18 articles were included in the Meta-analysis. The results showed the platelet reactivity after clopidogrel administration had no significant difference betweenCYP3A4 variant carriers and non-carriers. The occurrence of composite ischemic events or stent thrombosis had no significant difference betweenCYP3A4 variant carriers and non-carriers, either. In conclusion, there was no significant association betweenCYP3A4 polymorphism and clopidogrel response in patients with cardio-cerebrovascular diseases.

    Study on the factors of knowledge and willingness of online prescription drug purchases in Shanghai residents
    Weijie Yan, Lingxi Li, Yanran Li, Jie Min, Zhixuan Zhang, Yuliang Zhou, Jiaoling Huang, Li Zhang
    2021, 30(9):  773-777.  DOI: 10.5246/jcps.2021.09.065
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    In the present study, we aimed to survey whether Shanghai residents were willing to buy prescription drugs online. This study randomly surveyed the influence factors of Shanghai residents of different age, educational background, income, and occupation in the form of online questionnaires about whether they would buy prescription drugs online. Age had a significant effect on the awareness rate of online prescription drug purchases. There was no significant difference between the awareness rate of online prescription drug purchase and education, “whether the respondents are practitioners in pharmaceutical industry or not” and monthly income. Age and monthly income were related to the willingness of online prescription drug purchases. “Whether the respondents are practitioners in pharmaceutical industry or not” was not correlated with the willingness of online prescription drug purchases. It is necessary to strengthen the popularity of online drug stores and online prescription drug purchases and reduce consumers’ expenses on the above-mentioned drugs.

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