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Table of Content

    23 January 2014, Volume 23 Issue 1
    Contents
    Graphical contents list
    Journal of Chinese Pharmaceutical Sciences
    2014, 23(1):  1-4. 
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    Review
    Targeting voltage-gated Kv7/KCNQ/M-channel for therapeutic potential of neuropsychiatric disorders
    Xiling Bian, Kewei Wang*
    2014, 23(1):  5-15.  DOI: 10.5246/jcps.2014.01.001
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    M-type potassium current (IM) was initially isolated from sympathetic neurons in 1980 and named as it was inhibited by muscarine. In 1998, the molecular identity of M-current was revealed to be heterotetramers of KCNQ2 and KCNQ3 subunits, whose mutations cause neonatal epilepsy. Reduction of voltage-gated KCNQ2/3 K+ channel (M-channel) activity leads to neuronal hyperexcitability that defines the fundamental mechanism of neurological disorders such as epilepsy and pain. Thus, suppression of neuronal hyperexcitability by activation of KCNQ2/3 channels serves the basis for development of the channel openers for treatment of epilepsy and pain. The well-known KCNQ opener is retigabine (Potiga) that was approved by FDA as an antiepileptic drug in 2011. Recent studies also provide evidence that KCNQ2/3 channel openers are effective in animal models of bipolar disorder, anxiety and schizophrenia, whereas KCNQ2/3 inhibitors, on the other hand, are indicated for improvement of learning and memory in animal models. We recently designed and validated a novel series of pyrazolo [1,5-a]pyrimidin-7(4H)-ones (PPOs) that selectively activate KCNQ2/3 and show antiepileptic and analgesic activity in vivo. Up to date, all the progress made enforces the view that targeting voltage-gated KCNQ/M-channel may provide therapeutic potential for treatment of neuropsychiatric disorders. 

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    Dr. KeWei Wang is currently an endowed ChangJiangProfessor and Chair of the Department of Molecular and Cellular Pharmacology at Peking University School of Pharmaceutical Sciences, where his overall research in the lab is directed towards understanding structure and molecular mechanisms of ion channels, and to identify and validate ion channel targets that are helpful for proving therapeutic potential of channel modulators for treatment of neuropsychiatric disorders.Currently, two classes of ion channels, voltage-gated potassium (Kv) and ligand-gated TRP channels,are investigated for their role in modulation of neurological function and pathology in the brain using cutting-edge technologies such as patch clamping electrophysiology and confocal Ca2+/FRET imaging with combination of molecular biology and in vivo pharmacology. 
    Dr. Wang graduated with M.D. in medicine and obtained his Ph.D. in neurophysiology from Peking University Medical School in 1988. From 1988 to 1997, he went to the University of Cambridge and then Yale University for postgraduate studies/training in disciplines of pharmacology, biophysics and physiology. From 1997 to 2006, he as a principal scientist/team leader worked on ion channel target related drug discovery/research for pain and pain-related neurological disorders at Wyeth Neuroscience, Princeton, New Jersey. He published over 60 peer-reviewed articles in journals such as Neuron, Nature Neurosci, PNAS, Nature, JBC, and Biophysiol J. etc, and was granted for 7 patents. Since 2008, he serves a review editor for several journals including “Front. Neurosci” and “Pharm. Sin. B”, etc..  

     Dr. Xiling Bian is currently a Lecturer in the Department of Molecular and Cellular Pharmacology at Peking University School of Pharmaceutical Sciences, where she is trying to identify the ion channel-targets of natural medicine and explore neurological functions of ion channels. Dr. Bian received her Ph.D. in neuroscience from Chinese Academy of Sciences in 2008 with her research topic ‘Pheromone-Processing Circuits in the Medial Amygdala’. After that, Dr. Bian entered Peking University Health Science Center. She has published four first (co-first) authored research articles in scientific journals such as Nature Communications. She received three grants, including one grant from National Natural Science Foundation of China and another one from Beijing City Youth Talent Plan. She was honored as Model Teacher of Peking University Health Science Center in 2011. 

    Original articles
    DNA damaging effect of SLXM-2, a derivative of cyclophosphamide, on hepatocarcinoma H22 cells in vivo
    Mingming Chu, Xia Yuan, Xuan Jia, Ting Sun, Wei Guo, Xiao Jiang, Jingtao Liu, Runtao Li, Jingrong Cui
    2014, 23(1):  16-21.  DOI: 10.5246/jcps.2014.01.002
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    Compound SLXM-2, a derivative of cyclophosphamide (CTX), has shown potent growth-inhibitory effect on tumor cells with low toxicity in previous studies. However, the mechanism of its anti-tumor effect, especially on DNA damage, remains largely unclear. This study investigated the effect of SLXM-2 on the survival time of mice transplanted with the ascitic fluid-type hepatocarcinoma 22 (H22). We also evaluated the correlation between DNA damaging effect of SLXM-2 and its anti-tumor effect, and to probe the possible molecular mechanism for its effect on H22 cells. The results suggested that SLXM-2 significantly (P<0.05) prolonged the survival time of mice bearing the ascitic fluid-type H22. Furthermore, SLXM-2 induced DNA damage in a dose-dependent manner in H22 cells. Further investigation revealed that SLXM-2 significantly (P<0.05) up-regulated the expression levels of a series of DNA damage-related proteins, such as γH2AX (Ser139), p-Chk1 (Ser296), p-Chk2 (Thr68), p-p53 (Ser15), p-p53 (Ser20) and p21, and down-regulated the expression of p-ATR (Ser428) and p-ATM (Ser1981). In conclusion, SLXM-2 showed a remarkable anti-tumor activity on ascitic fluid-type H22 cells, and its molecular mechanism is related to its DNA damaging effect.

    rAcAP5: high-yield strain screening, expression, purification and thrombolytic effect evaluation in rat embolic middle cerebral artery occlusion model 
    Yanan Zhu, Yuanjun Zhu, Qixin Bu, Xiaoyan Liu, Yinye Wang*
    2014, 23(1):  22-27.  DOI: 10.5246/jcps.2014.01.003
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    Recombinant ancylostoma caninum anticoagulant peptide-5 (rAcAP5) has been reported to inhibit thrombin-activatable fibrinolysis inhibitor (TAFIa) activity and have thrombolytic effect. The present study was to screen a strain expressing high-yield of rAcAP5 and to assess its thrombolytic effect on embolic middle cerebral artery occlusion (MCAO) model in rats. Codons encoding for AcAP5 were optimized. Six expression plasmids and eleven E. coli strains with different characteristics were used, a total of 66 recombinant expression strains were generated and the one with the highest yield was selected to express rAcAP5, which was purified through anion- and cation-exchange chromatography. The purity of rAcAP5 and its molecular weight were determined by HPLC and mass spectrometry, respectively. The thrombolytic effect of rAcAP5 was evaluated on embolic MCAO model in rats; regional cerebral blood flow (rCBF) was monitored with a Laser-Doppler flowmetry to test the occlusion and recanalization of MCA. The highest yield recombinant strain was C2566H/pTYB1-rAcAP5. AcAP5 (28 mg) with 90% of purity was obtained from 1 L of cell culture. In rat embolic MCAO model, vehicle (normal saline) treatment did not change the rCBF, while treatment with rAcAP5 (50–200 µg/kg, i.v.) increased the rCBF in a dose-dependent manner. In conclusion, we prepared and characterized the rAcAP5 peptide and revealed its thrombolytic effect in embolic MCAO model and our results suggested that this peptide had the potential to be used as a thrombolytic agent.

    Effect of the Tang herb on the pharmacokinetics of lopinavir in rats
    Yamin Yao*, Jun Mu, Ji Sun, Lin Yin, Jun Chen, Hongzhou Lu, Lijun Zhang
    2014, 23(1):  28-32.  DOI: 10.5246/jcps.2014.01.004
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    This study was carried out in the Wistar rats to investigate the effect of Tang herb on the pharmacokinetics of the antiretroviral drug lopinavir (LPV) following single oral administration. Rats were randomly divided into LPV group (36 mg/kg) and LPV combining with Tang herb group (LPV: 36 mg/kg, Tang herb: 864 mg/kg). The blood concentrations of lopinavir at 0, 0.5, 1, 2, 4, 8, 10, 12, 14, 16, 22 h after administration were determined by HPLC and the pharmacokinetic parameters were investigated. The results showed that Tang herb significantly increased the Cmax and AUC (P<0.05) while slightly increased the t1/2z and Tmax of lopinavir (P>0.05). The present study suggests that Tang herb may delay the absorption, increase the time to reach the maximum concentration, and improve the bioavailability of LPV. Further evaluation of the possible interaction mechanism between Tang herb and LPV needs to be studied.
    Protective effects of 20-hydroxyecdysone on H2O2-induced cytotoxicity in human neuroblastoma SH-SY5Y cells
    Xia Si, Zhuo Ma, Yue Chen, Lin Huang, Wanyu Feng*
    2014, 23(1):  33-38.  DOI: 10.5246/jcps.2014.01.005
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    The aim of this study was to investigate the possible protective effects and mechanisms of 20-hydroxyecdysone, an insect steroid hormone, on H2O2-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Pretreatment with 20-hydroxyecdysone significantly elevated the cell viability and decreased LDH leakage in H2O2-treated SH-SY5Y cells. 20-Hydroxyecdysone also dramatically reduced malondialdehyde (MDA) contents and enhanced the superoxide dismutase (SOD) activities under oxidative stress conditions. Furthermore, 20-hydroxyecdysone pretreatment inhibited apoptosis by decreasing the Bax/Bcl-2 ratio and attenuating the activation of caspase-3. These results suggest that 20-hydroxyecdysone can protect SH-SY5Y cells against H2O2-induced cytotoxicity and might potentially be used to treat neurodegenerative diseases induced by oxidative stress and apoptosis.

    Upregulation of Nrf2-regulated gene expression by tBHQ alleviates cyclophosphamide-induced hematotoxicity in mice
    Linling Que, Xinzhu Wang, Pengzhan Qian, Baoshan Cao, Kui Wang, Siwang Yu*
    2014, 23(1):  39-45.  DOI: 10.5246/jcps.2014.01.006
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    Hematological toxicity (bone marrow suppression) is the most common dose-limiting adverse effect of chemotherapies. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal coordinator of cellular defensive responses against chemical insults in many tissues including bone marrow. In the present study, the effects of tert-butylhydroquinone (tBHQ) on the expression of Nrf2-regulated genes in peripheral blood cells and cyclophosphamide (CTX)-induced hematotoxicity in mice were investigated. CTX induced apoptosis of peripheral blood nucleated cells and leukopenia in mice, accompanied by mobilization of bone marrow hematopoietic cells. tBHQ treatment induced the expression of Nrf2-regulated genes such as heme oxygenase 1 (HO1) and glutamate-cysteine ligase catalytic subunit (GCLC) in RAW264.7 mouse macrophage cells and peripheral blood cells both in vitro and in vivo. Interestingly, pretreatment with tBHQ alleviated CTX-induced mouse peripheral blood cell apoptosis and leukopenia in vivo, indicating possible involvement of Nrf2 in the protection against CTX-induced hematotoxicity. This study provides new information on the chemotherapy-induced hematotoxicity, and suggests Nrf2 could serve as a target for the development of chemoprotectants against hematotoxicity.

    In vitro and in vivo antitumor efficacy of CLA-PTX on B16-F10 melanoma cells 
    Jiesi Li, KeYang, Xiyu Ke, Ruo Du, Xuan Zhang*, Qiang Zhang
    2014, 23(1):  46-53.  DOI: 10.5246/jcps.2014.01.007
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    The purpose of this study was to investigate the potential antitumor efficacy of conjugated linoleic acid-paclitaxel (CLA-PTX) on B16-F10 melanoma cell line in vitro and in vivo. The in vitro cytotoxicity, apoptosis and cell cycle of CLA-PTX were investigated. The in vitro cellular uptake of CLA-PTX in B16-F10 cells was also analyzed. The antitumor activity of CLA-PTX was also evaluated in B16-F10 tumor-bearing C57BL6/N mice in vivo. The in vitro cytotoxicity results showed that the IC50 of the CLA-PTX is (4.25±0.43) µM, compared with that of (6.70±0.80) µM in PTX treatment group (P<0.01). CLA-PTX increased the percentage of total apoptotic cells compared with that of control and PTX treatment groups (P<0.01). Compared with untreated cells, CLA-PTX arrested cell cycle progression at the S phase, whereas PTX caused accumulation of cell at G2-M phase both along with the reduction of the cellular fraction arrested at the G1 phase. The amount of cellular uptake of CLA-PTX was significantly higher than that of PTX (P<0.01). The in vivo antitumor activity of CLA-PTX was significantly higher than that of control and PTX treatment groups (P<0.01 or P<0.05). In conclusion, our study demonstrated that CLA-PTX has significant antitumor activity in B16-F10 cell line.

    Reactive oxygen species mediate ethaselen-induced rapid apoptosis in A549 cells
    Kun Xiong, Wei Xu, Huihui Zeng*
    2014, 23(1):  54-59.  DOI: 10.5246/jcps.2014.01.008
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    Thioredoxin reductase (TrxR) is an important enzyme responsible for the removal of excess reactive oxygen species (ROS) in mammalian cells. This study aimed to investigate the roles of ROS in the anti-tumor effects of ethaselen, a TrxR inhibitor. In a human lung cancer cell line A549, we observed rapidly elevated ROS levels, loss of mitochondrial potential, and cell death with the treatment of ethaselen. Such changes were prevented when cells were pre-incubated with of N-acetyl-cysteine (NAC), a ROS scavenger. The apoptosis study by Annexin V-PI assay and protein assay by Western blot suggested that mitochondrial pathway was involved in the initiation of apoptosis. In ethaselen-treated cells, cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pores (PTPs), inhibited the release of cytochrome c and reduced cell death in ethaselen-treated cells, while the protein levels of some Bcl-2 family proteins remained unchanged. These results suggest that ROS mediated the ethaselen-induced rapid apoptosis, at least, partially through the enhancement of mitochondrial membrane permeability, which may ultimately lead to the release of pro-apoptotic proteins. Our study, for the first time, demonstrated that the anti-tumor effects of ethaselen, including the early phase of cellular response, are associated with ROS. More studies are needed to confirm our conclusion, as well as to further explore the underlying mechanisms in the anti-tumor effects of ethaselen.

    Others
    Information for Authors
    Journal of Chinese Pharmaceutical Sciences
    2014, 23(1):  60-67. 
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    Journal of Chinese Pharmaceutical Sciences Stands out at the first National Forum on the Communication, Innovation and Development of Pharmaceutical Sciences
    Journal of Chinese Pharmaceutical Sciences
    2014, 23(1):  68-68. 
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    The first National Forum on the Communication, Innovation and Development of Pharmaceutical Sciences was held in Shanghai on November 17–18, 2013. This forum was sponsored by Chinese Pharmaceutical Association (CPA), and more than 100 professionals from editorial offices of pharmaceutical journals and newspapers attended. The participants discussed the various topics in the development of Chinese science and technology journals. Associate Prof. Heqing Huang, executive associate editor-in-chief of Journal of Chinese Pharmaceutical Sciences (JCPS) attended the forum, and delivered a speech on the experience of JCPS development.
    The forum announced the official news that JCPS and Chinese Journal of Natural Medicines (CJNM) were awarded with financial support from “the Chinese Science and Technology Journal Promotion Plan”. The forum also presented award for “the Best Article of CPA Journals”. Seven papers from three English CPA journals received the award and three of them were from JCPS. The award-winning papers are as follows.
    The 2nd “China Medical Development Forum”, A.K.A. the Seminar of Drug Quality and Market Access
    Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
    2014, 23(1):  69-70. 
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          In December 27, 2013, the 2nd “China Medical Development Forum”, A.K.A. the Seminar of Drug Quality and Market Access, jointly managed by Peking University International Research Center of Medicinal Administration(IRCMA) and Center for Research and Development of Medications (CRDM) was ceremoniously held in Peking University Health Science Center (PHUSC). Prof. Mingli Shao, the original director of State Food and Drug Administration (SFDA) and Prof. Yang Ke, associated president of university, government managers, university scholars, hospital pharmacists, and experts of IRCMA and CRDM attended the forum. 
          At the start of the forum, Prof. Yang Ke delivered a speech on behalf of PHUSC. She pointed out that drug quality and market access have a close contact with healthcare reform, experts and scholars’ participation will contribute a lot to the reform of drug safety. She emphasized that the quality of drug depended on the quality of design, which made drug safety related to multiple steps, more and more practice proved that multidiscipline and a combination of natural and social sciences could indeed solve problems related to medical, healthcare system, and human health. Finally, she put forward the hope of long-term development of the forum. Prof. Mingli Shao also delivered a speech representing academic advisers of IRCMA, highly praised the efforts and achievements the IRCMA had made on ensuring drug safety, rational use of medications, and promoting the healthy development of pharmaceutical industry. He thanked the support from PUHSC to IRCMA.