Table of Content

    31 October 2020, Volume 29 Issue 10
    Original articles
    Evaluating reverse docking on general and selective inhibitors: a case study about glide
    Mingna Li, Xing Wu, Liangren Zhang, Zhenming Liu
    2020, 29(10):  679-688.  DOI: 10.5246/jcps.2020.10.063
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    As a powerful tool for target prediction, reverse docking remains largely unexplored. The objective evaluation of reversedocking software can help us know better about the strength and weakness of these tools, hence guiding us in target prediction. In the present study, we evaluated the target prediction power of Glide (SP) against general inhibitors and selective inhibitors. The results showed that the scoring tendency could be different for each ligand, and overall scoring sampling was necessary for a better understanding of the docking score for a certain protein-ligand pair. Besides, the input conformation of the binding pocket could affect the docking result. Glide (SP) showed a preferable performance on the target prediction of the general inhibitors. However, the accuracy of the target prediction of the selective inhibitors was relatively low, indicating that Glide (SP) might not be capable for this task. The case study about COVID-19 proved that coagulation factor Xa might be a potential target of chloroquine. Therefore, we recommend the further development of reverse docking tools and rectification of inter-target scoring bias. 
    Dopamine increases the anti-cancer efficacy of sunitinib in the treatment of pancreatic cancer
    Junsheng Xue, Siyuan Wang, Fangran Hao, Xiuyun Tian, Hong Su, Liang Yang, Qiming An, Chunyi Hao, Tianyan Zhou
    2020, 29(10):  689-700.  DOI: 10.5246/jcps.2020.10.064
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    Sunitinib (SUN) is a multi-targeted receptor tyrosine kinase inhibitor (TKI) that may lead to drug resistance and metastasis because of increased cancer stem-like cells (CSCs) due to the induction of hypoxia. Our group has proved that dopamine (DA) can specifically reduce CSC frequency and enhance the response of SUN in drug-resistant breast cancerand non-small cell lung cancer (NSCLC). In this study, DA and SUN combination therapy was investigated in the treatment of pancreatic cancer, a malignant tumor with high mortality rate and very limited therapies. The cytotoxicity assay, clone formation assay and wound healing assay in two pancreatic cancer cell line PANC-1 and SW1990 showed that DA could significantly increase the effect of SUN on cell survival, clone formation ability and migration ability. Besides, SW1990 cell-derived xenograft model and a pancreatic cancer patient-derived xenograft (PDX) model were constructed, further proving that DA could increase the in vivo anti-tumor efficacy of SUN, and could be reversed by SCH23390, a D1 dopamine receptor (D1DR) antagonist. Moreover, the CSC frequency of the combination groups was lower than the control groups or SUN monotherapy groups. In addition, the body weight, H&E staining and blood routine test results showed that the combination therapy was safe. In summary, DA and SUN combination therapy could be a promising strategy for the treatment of pancreatic cancer.  
    Co-delivery of paclitaxel and gemcitabine via folic acid-conjugated polymeric multi-drug nanoparticles (FA-PMDNPs) for the treatment of breast cancer
    Meng Lei, Xueyuan Wang, Hang Miao, Jia Wang, Sijia Sha, Jiang Zhu, Yongqiang Zhu
    2020, 29(10):  701-710.  DOI: 10.5246/jcps.2020.10.065
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    Multi-drug delivery focuses on different signaling pathways in cancer cells and has synergistic antiproliferative effects. In this manuscript, we developed folic acid (FA)-conjugated polymeric multi-drug nanoparticles (FA-PMDNPs) consisting of poly-L-lysine (PLL) and poly glutamic-conjugated PTX/GEM (PGA-PTX and PGA-GEM) for FA receptor-targeted synergistic breast cancer therapy. The carboxyl-rich structure of PGA provided plenty reaction sites and negative charge for drug loading. Transmission electron microscopy (TEM) results showed that FA-PMDNPs had uniform particle size and spherical morphology. The hemolysis study proved that FA-PMDNPs had good biocompatibility. In vitro cell viability and in vivo studies showed that FA-PMDNPs more effectively inhibited the proliferation of FA receptor (FR)-overexpressing breast cancer cells (4T1) than the pure drugs.Consequently, these results demonstrated that FA-PMDNPs could be effectively targeted at cancer cells compared with free drugs, indicating their strong potential as efficient multi-drug-carrying nano-platforms for cancer treatment. 
    The influence of B55γ on the neuroprotective effect of W026B in t-MCAO mice
    Kexiang Gao, Xiaoyan Liu, Yuanjun Zhu, Ye Liu, Yinye Wang
    2020, 29(10):  711-718.  DOI: 10.5246/jcps.2020.10.066
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    As a newly synthesized lignan derivative, W026B has been proved to be a neuroprotective agent, and it can significantly reduce cerebral infarct volume, improve behavioral scores and protect blood brain barrier in different models. However, its exact mechanism is still unclear. In the present study, a protein named B55γ, one of candidate targets of W026B screened by proteomic study, was investigated to explore its influence on the effect of W026B in t-MCAO mice. siRNA PPP2R2C was used to knockdown the expression of protein B55γ in t-MCAO mice. The results showed that the knockdown of B55γ significantly suppressed the neuroprotective effect of W026B. Further results showed that the knockdown of PPP2R2C, B55γ gene, abolished the effect of W026B on reducing the level of NF-κB p65 in ischemic brain tissue, and knockdownof PPP2R2C also reversed the effect of W026B on decreasing the activity of caspase-3 in ischemic brain tissue.In conclusion, protein B55γ might be an important mediator of the protective effect of W026B. B55γ actively participated in the brain protective effect of W026B by affecting the inflammatory response and apoptotic pathway during ischemia reperfusion. These results revealed a new mechanism underlying the neuroprotective effect of W026B.
    Protective effect of baicalin on experimental pulmonary arterial hypertension through inhibition of pulmonary vascular remodeling
    Wen Jiang, Chao Sun, Jue Wang, Qian Xin, Kailin Li, Tonggang Qi, Yun Luan
    2020, 29(10):  719-728.  DOI: 10.5246/jcps.2020.10.067
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    Previous studies have shown that baicalin can attenuate pulmonary arterial hypertension and right ventricular hypertrophy. However, the potential mechanism remains unexplored. Nuclear factor-κB (NF-κB) and bone morphogenetic protein (BMP) signaling pathway play an important role in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH). Therefore, we aimed to observe the regulation of baicalin on the NF-κB-BMP axis and the subsequent anti-proliferation in pulmonary vascular. Our results showed that baicalin could significantly decrease right ventricular systolic pressure (RVSP) and the RV/left ventricle plus septum ratio (P < 0.05), and attenuate vascular remodeling. Furthermore, the result of westen blot showed that the protein expression level of BMP receptor 2 (BMPR2) was significantly increased, while NF-κB p65, p-NF-κB p65, inhibitor of NF-κB (I-κBα) and the BMP antagonist, gremlin 1 were significantly down-regulated in the baicalin group (P < 0.05). On the other hand, the result of immunohistochemical staining in lung showed that the capillary density of pulmonary arterioles significantly increased in the baicalin group compared with the MCT group (P < 0.05). We concluded that baicalin exerted the protective effects against the lung and heart damage through inhibiting NF-κB-BMP signaling pathway, providing new mechanistic information about PAH and right ventricular hypertrophy.
    Pharmacological and clinical evaluation of a new anti-flu drug, baloxavir marboxil
    Jingjing Cao, Jun Sun, Shujuan Zhao, Peizhi Ma
    2020, 29(10):  729-733.  DOI: 10.5246/jcps.2020.10.068
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    Baloxavir marboxil is a polymerase acidic (PA) endonuclease inhibitor, which is approved by the U.S Food and Drug Administration (FDA) on October 25, 2018, for the treatment of uncomplicated influenza patients aged 12 years and older. In the present work, we reviewed the pharmacodynamics, pharmacokinetics, drug interactions, clinical trials and adverse reactions of baloxavir marboxil.
    A series of reviews on the “application of modern instruments and technologies in drug research”
    Applications of multiplexed immunohistochemistry/immunofluorescence and multispectral imaging technology in the field of tumor immunotherapy
    Wenzhe Li, Xia Yuan, Bo Xu, Shuxiang Song
    2020, 29(10):  734-747.  DOI: 10.5246/jcps.2020.10.069
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    Multiplexed immunohistochemistry/fluorescence (mIHC/IF) in combination with multispectral unmixing is a novelmultitarget histopathological staining and imaging technique. By simultaneously revealing expression level and spatial information for up to eight biomarkers in situ, in addition to a nuclear stain within a single formalin-fixed paraffin-embedded (FFPE) tissue section, this technology can analyze the phenotype, abundance, morphology and intercellular relationship of cells while providing statistically significant results. In recent years, technical improvements have brought new insight into mIHC/IF and multispectral imaging approaches, which have been successfully applied in the field of cancer immunotherapy, specifically in regard to tumor microenvironment research, immunotherapy drug discovery, and prognostic and metastatic risk evaluation. This reviewhighlights the principle, workflow, advantages and disadvantages of the technology, and discusses the latest applications of mIHC/IF-based imaging technology in the field ofTME-related research and immunotherapy drug discovery. 
    The others
    The group of Demin Zhou has made progress in the research on the regulation and universal chimeric antigen receptor T (CAR-T) autoimmune diseases and tumors
    School of Pharmaceutical Sciences, Peking University Health Science Center
    2020, 29(10):  748-749. 
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    The group of Demin Zhou has made progress in the research on the regulation and universal chimeric antigen receptor T (CAR-T) autoimmune diseases and tumors.
    The group of Suwei Dong has made progress in the research of glycopeptide self-assembly
    School of Pharmaceutical Sciences, Peking University Health Science Center
    2020, 29(10):  750-751. 
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    The group of Suwei Dong has made progress in the research of glycopeptide self-assembly.
    Special issue — Commemoration of the 100th Birthday of Academician Zhicen Lou will be published soon
    Journal of Chinese Pharmaceutical Sciences
    2020, 29(10):  752-752. 
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    Special issue — Commemoration of the 100th Birthday of Academician Zhicen Lou will be published soon.