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Table of Content

    30 June 2019, Volume 28 Issue 6
    Original articles
    The spirocyclopiperazinium salt compound LXM-15 alleviates chronic inflammatory and neuropathic pain in mice and rats
    Ning Li, Yingying Liang, Qi Sun, Yimin Jiang, Runtao Li, Jia Ye
    2019, 28(6):  371-380.  DOI: 10.5246/jcps.2019.06.036
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    In the present study, we aimed to evaluate the effect of the spirocyclopiperazinium salt compound LXM-15 on chronic inflammatory pain and chronic neuropathic pain induced by complete Freund’s adjuvant (CFA) or chronic constriction injury (CCI) in mice and rats. The results showed that administration with LXM-15 significantly reduced paw edema and ankle swelling and increased the mechanical withdrawal threshold and paw withdrawal latency after CFA injection in mice. LXM-15 significantly alleviated the mechanical allodynia and thermal hyperalgesia in CCI rats. The effect was abolished by pretreatment with hexamethonium (a peripheral nAChR antagonist) or methyllycaconitine citrate (an α7 nAChR antagonist). Furthermore, LXM-15 significantly inhibited the phosphorylation of JAK2 and STAT3, and suppressed the expressions of TNF-α and c-fos in dorsal root ganglia of CCI rats. Collectively, we reported that LXM-15 relieved chronic inflammatory pain in CFA mice and chronic neuropathic pain in CCI rats. The underlying mechanism might be related to the activation of peripheral α7 nicotinic receptor, further inhibiting JAK2/STAT3 signaling pathway, and eventually suppressing the expressions of TNF-α and c-fos.
    The proteomic study and the target discovery of W026B, a new compound with brain protective effect
    Siyu Zhao, Xiaoyan Liu, Yuanjun Zhu, Ye Liu, Yinye Wang
    2019, 28(6):  381-392.  DOI: 10.5246/jcps.2019.06.037
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    W026B is a new compound that has a protective effect on cerebral ischemia reperfusion (I-R) injury in mice, while its specific mechanism is still unknown. In this study, proteomics was used to observe the effect of W026B on protein expression in brain I-R tissue, and to reveal its potential target. A total of 42 significantly altered proteins were identified in both brain I-R model and W026B treatment from 4852 proteins detected by proteomics, and most of these proteins were related to immunity and inflammation, metabolism, neuroprotection as well as cell proliferation and cell structure. Western blotting analysis showed that three out of five selected proteins showed consistent alteration with the proteomics. Regulator of G protein signaling 17 (RGS17) was selected for further study, and its knockdown by siRNA RGS17 aggravated brain injury and abolished the protective effect of W026B. W026B could bind with RGS17 (KD: 6.04×106 mol/L). The knockdown of RGS17 aggravated Neuro-2a cell damage induced by group I metabotropic glutamate receptors (mGluRs) agonist, and abolished the protective effect of W026B. In conclusion, W026B protected brain against I-R injury by affecting diverse proteins. RGS17 might be one of its targets and a potential therapeutic target of brain I-R injury. The upstream receptor of G protein, which was regulated by RGS17 and affected by W026B, might be group I mGluRs. This study provided useful evidence for the further R&D and the potential clinical application of W026B.
    Polymorphism analysis of Glutathione S-transferase A1 in patients with hematological diseases and its effect on GST enzyme activity
    Guangyi Yu, Qingshan Yang, Guoshun Zhang, Yin Xie, Lifeng Zhang
    2019, 28(6):  393-401.  DOI: 10.5246/jcps.2019.06.038
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    Glutathione S-transferases (GSTs) are important drug-metabolizing enzymes that catalyze the binding of glutathione (GSH) to electrophilic substances. GST has genetic polymorphism, and the enzyme activity of GST affects the metabolism of certain drugs in vivo. In the present day, we investigated the GST enzyme activity and GSTA1 gene polymorphism in 170 patients with hematological diseases and explored their relationship. The GSTA1 gene polymorphism of the patient was analyzed by PCR- restriction fragment length polymorphism (PCR-RFLP) technique, and the base sequences of the four mutation sites (-631, -567, -69, and -52) in the promoter region were determined by DNA-Sequencer. The patient's GST enzyme activity was calculated by measuring the rate at which it catalyzed the reaction between 1-chloro-2,4-dinitrobenzene (CDNB) and GSH. The average GST enzyme activities of males and females were 5.20±0.13 and 5.17±0.12 nmol/min/mL, respectively, and the difference was not significant (P = 0.91). The frequencies of genotypes GSTA1*A*A (wild genotype), GSTA1*A*B (heterozygous genotype), and GSTA1*B*B (homozygous mutant genotype) were 75.3%, 22.9%, and 1.8%, respectively. Alleles GSTA1*A and *B were distributed at 86.8% and 13.2%, respectively. The genotype frequency distribution between males and females was no significant difference by Pearson’s chi-square test (P = 0.743). The average GST activity of the heterozygous mutant genotype (4.83±0.76 nmol/min/mL) was lower than the wild genotype (5.34±1.26 nmol/min/mL, P = 0.018), and higher than that of the homozygous mutant genotype (3.32±0.07 nmol/min/mL, P = 0.022). These findings might help us improve the individualized treatment of patients with hematological diseases in the future and promote the development of precision medicine for blood diseases. 
    Improved synthesis of key intermediate of grayanotoxin III
    Weihao Ma, Zhi Huang, Yanxing Jia
    2019, 28(6):  402-407.  DOI: 10.5246/jcps.2019.06.039
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    A concise improved synthesis of the key intermediate for the synthesis of grayanotoxin III was realized in the present study, featuring a tandem reaction of Michael addition-esterification, Mukaiyama hydration and Mukaiyama dehydrogenaiton.
    Design, synthesis and biological evaluation of novel HDAC inhibitors: sulphur-containing zinc binding groups
    Wenwen Cheng, Dongmei Zhang, Qiang Zheng, Zhongjun Li, Xiangbao Meng
    2019, 28(6):  408-421.  DOI: 10.5246/jcps.2019.06.040
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    Zinc binding group (ZBG) is the crucial moiety in the chemical structure of any HDAC inhibitor. In the present study, a series of sulphur-containing ZBG were designed and synthesized in the novel HDAC inhibitors to replace the classical ZBGs of SAHA and BML-210,hydroxamic acids and benzamides, respectively. The HDAC inhibitory activity and the structure-activity relationships of these molecules were analyzed. A sulphur-rich group, diethylcarbamo (dithioperoxo)thioate, was finally identifiedas a novel potent ZBG. Among all the synthesized compounds, 4d was much more potent compared with BML-210, and it showed similar inhibitory effect of SAHA against HDAC isoforms 1 and 2. Therefore, it was chosen as a lead compound. 
    Synthesis and antibacterial studies of ciprofloxacin-metal complexes
    Najma Sultana, M. Saeed Arayne, Ahsan Zamir Siddiqi, Agha Zeeshan Mirza
    2019, 28(6):  422-429.  DOI: 10.5246/jcps.2019.06.041
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    Metal complexes of ciprofloxacin were synthesized to study the effect of the drug on the metals present in the body or metals co-administered as multivitamin therapy. These complexes were then characterized by IR, UV, 1H NMR, CHN and AA analyses. It was found that the metals coordinated through the β-keto carboxylic group, forming four coordinated complexes having square planar geometry. The effect of the antibacterial activity of these complexes with respect to parent drug was also studied against 14 different Gram+ve and Gramve organisms by the disk susceptibility technique. Some complexes showed improve activity as compared with the stated drug. 
    Drug administration and clinical pharmacy column
    Prevalence and influence factors of self-medication in Chinese middle-aged and elderly people: evidence from 2011, 2013 and 2015 CHARLS panel data
    Zhuangfei Wang, Xiaodong Guan, Yue Zhou, Sheng Han, Peng Yao, Luwen Shi
    2019, 28(6):  430-438.  DOI: 10.5246/jcps.2019.06.042
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    Self-medication is an increasingly frequent phenomenon worldwide and has an important influence on health. In this study, we analyzed the self-medication prevalence rate in Chinese middle-aged and elderly people, and explored the influence factors. The data from China Health and Retirement Longitudinal Study (CHARLS) in 2011, 2013 and 2015 were used. Self-medication prevalence was calculated as the number of whole people divided by the number of people taking self-medication. The influence factors of self-medication were analyzed by panel data random effect model. We excluded observations with missing values in our analysis, leaving 16 962, 17 876 and 19 572 observations in 2011, 2013 and 2015, respectively. The average 3-year self-medication prevalence was 45.52%. Moreover, 11.70% of respondents practiced self-medication with prescription medicine in 2011, 2013 and 2015. Respondents living in non-rural areas (P = 0.009) and western region (P = 0.000) took more self-medication. Self-medicationwas a common phenomenon among middle-aged and elderly population in China. The government should strengthen the guidance for the middle-aged and elderly people who took more self-medication, such as those living in urban and western region.
    Brief introduction for application of USA authorized generic drugs
    Dongsheng Yang, Lingyun Ma, Jianzhao Niu, Mingdi Xu
    2019, 28(6):  439-445.  DOI: 10.5246/jcps.2019.06.043
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    The authorized generic drugs (AGs) are drug products marketed in the USA with the permission of sponsor or holder of the approved brand name drug (usually refers to an innovator drug). Other than the fact that it does not have the brand name on its label, it is the exact same drug product as the brand name product. In China, for those published comparator products of generic drug products, the market availability is the first question to affect the smooth development and investigation for the process of the re-evaluation of the generic drugs. In the present paper, we systemically elaborated the definition, classification and relevant background of the AGs, as well as their differences to the generic drugs. At the same time, by taking drug products, which are adopted in the Chinese comparator product directories for generic medicinal products (first batch) and sourced from USA orange book, as examples, we introduced the searching process of the AGs with the integration of FDA listing of AGs, the USA orange book and the USA national drug code directory. It can facilitate the domestic and foreign pharmaceutical enterprises to search, identify and purchase the corresponding AGs of the designated comparator product when question emerges to its market availability.
    The others
    The team of Professor  Ning Jiao has made new progress in the field of halogenation modification of drug molecules
    State Key Laboratory of Natural and Biomimetic Drugs
    2019, 28(6):  446-447. 
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    The team of Professor  Ning Jiao has made new progress in the field of halogenation modification of drug molecules.

    The team of Professor Ning Jiao has made new progress in the field of small molecule activation
    State Key Laboratory of Natural and Biomimetic Drugs
    2019, 28(6):  447-448. 
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    The team of Professor Ning Jiao has made new progress in the field of small molecule activation.