Table of Content

    31 August 2014, Volume 23 Issue 8
    Journal of Chinese Pharmaceutical Sciences
    2014, 23(8):  507-510. 
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    Original articles
    Differential signaling regulatory networks governing hormone refractory prostate cancers 
    Sujit Nair, Celine Liew, Tin Oo Khor, Li Cai, Ah-Ng Kong
    2014, 23(8):  511-524.  DOI: 10.5246/jcps.2014.08.067
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    To understand the organization of the biological networks that might potentially govern the pathogenesis of hormone refractory prostate cancer (HRPC), we investigated the transcriptional circuitry and signaling in androgen-dependent 22Rv1 and MDA PCa 2b cells, androgen- and estrogen-dependent LNCaP cells, and androgen-independent DU 145 and PC-3 prostate cancer (PCa) cell lines. We used microarray analyses, quantitative real-time PCR, pathway prediction analyses, and determination of Transcription Factor Binding Site (TFBS) signatures to dissect HRPC regulatory networks. We generated graphical representationsof global topology and local network motifs that might be important in prostate carcinogenesis. Many important putative biomarker ‘target hubs’ were identified in the current study including AP-1, NF-қB, EGFR, ERK1/2, JNK, p38 MAPK, TGF beta, VEGF, PDGF, CD44, Akt, PI3K, NOTCH1, CASP1, MMP2 and AR. Our results suggest that complex cellular events including autoregulation, feedback loops and cross-talk might govern progression from early lesion to clinically diagnosed PCa, as well as metastatic potential of pre-existent high-grade prostate intraepithelial neoplasia (HG-PIN) and/or advancement to HRPC. The identification of TFBS signatures for TCF/LEF, SOX9 and ELK1 in the regulatory elements suggests additional biomarkers for the potential development of chemopreventive/therapeutic strategies against PCa. Taken together, in this study, we have identified putative biomarker ‘target hubs’ in the architecture of PCa signaling networks, and investigated TFBS signatures that might enhance our understanding of key regulatory nodes in the progression and pathogenesis of HRPC.

    Isolation and characterization of cyclic lipopeptides from the marine-derived Bacillus licheniformis
    Du Gao, Li Tian, Jian Bai, Minjuan Xu, Lei Feng, Qingying Zhang, Wenhan Lin
    2014, 23(8):  525-532.  DOI: 10.5246/jcps.2014.08.068
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    Chromatographic separation of themarine-derived bacterium Bacillus licheniformis resulted in the isolation of two new cyclic lipopeptides named ai-C16 surfactin (1) and ai-C14 surfactin (2), together with iso-C15 surfactin and iso-C16 surfactin. The structures of the new cyclic lipopeptides were determined through extensive spectroscopic analysis. The sequences ofthe amino acids in cyclic nucleus were established by the ESI-MS/MS fragmentation, which provided an efficient method to detect lipopeptides from bacterium extracts without separation.

    Detection and quantification of cyclo-dopa amides in Portulaca oleracea L. by HPLC-DAD and HPLC-ESI-MS/MS
    Zezhao Jiao, Haina Wang, Peipei Wang, Hongxiang Sun, Su Yue, Lan Xiang
    2014, 23(8):  533-542.  DOI: 10.5246/jcps.2014.08.069
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    In the present study, we aimed to detect and quantify cyclo-dopa amides in Portulaca oleracea L. Together with four known ones (oleracein A–D), we further identified eight new cyclo-dopa amides, named oleracein H–O, using an HPLC-DAD combined with an improved HPLC-ESI-MS/MS method. A standardized HPLC fingerprint of cyclo-dopa amides was generated for the first time through analyzing 11 batches of P. oleracea. Simultaneously, the contents of two major amides, oleracein A (OA) and oleracein B (OB), and the total amides (TID) were determined. Our results showed that the contents of OA and OB of P. oleracea ranged from 35.00 to 151.93 mg/kg and from 40.00 to 150.44 mg/kg, respectively. Moreover, TID ranged from 314.16 to 928.60 mg/kg (calculated by OA), or from 475.83 to 1393.00 mg/kg (calculated by OB). Taken together, our newly developed method could be used for the quality assessment and quality control of this herb.

    Spectrophotometric studies on the interaction between chlorogenic acid, neochlorogenic acid, cryptochlorogenic acid and lysozyme
    Yuexiang Lan, Meixian Liu, Shizhong Chen, Hong Wang
    2014, 23(8):  543-547.  DOI: 10.5246/jcps.2014.08.070
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    The interactions of chlorogenic acid (CA), neochlorogenic acid (NCA) and cryptochlorogenic acid (CCA) with lysozyme (LYSO) were investigated in physiological buffer by fluorescence spectroscopy. The mechanism study indicated that CA, NCA and CCA could strongly quench the intrinsic fluorescence of LYSO through static quenching procedures withone binding site. Thermodynamic data show that the major force in the binding processes of CA to LYSO was hydrophobicinteractions; for NCA, it was the hydrogen bonds and van der Waals forces, as for the CCA system, the mainly force is electrostatic force.

    Population pharmacokinetic of losartan and its active metabolite E-3174 in five different ethnic populations of China
    Lu Yang, Lulu Sun, Tao Guo, Dongya Xia, Xipei Wang, Xingang Li, Wei Lu
    2014, 23(8):  548-557.  DOI: 10.5246/jcps.2014.08.071
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    The aim of this study was to develop a combined population pharmacokinetic (PPK) model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects (including Han, Mongolian, Korean, Hui and Uigur) using nonlinear mixed-effect modeling (NONMEM). From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokineticparameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume V1of losartan and also has a significant effect on the transit rate (Kt). A total of 925 out of 1000 iterations succeeded in minimization.The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.

    Preparation and characterization of sunitinib-loaded microspheres for arterial embolization
    Ziming Zhao, Jialin Li, Yongjie Yang, Daichao Cui, Xiaojing Lu, Tianyuan Fan
    2014, 23(8):  558-564.  DOI: 10.5246/jcps.2014.08.072
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    Drug-loaded microspheres have been caused much attention in embotherapy in recent years. In this study, polyvinyl alcohol/acrylic acid microspheres were prepared by inverse suspension polymerization method. Sunitinib malate (SU) was used as a model drug and loaded on microspheres through ion-exchange mechanism. We investigated the characterization of blank microspheres (B-Ms) and sunitinib-loaded microspheres (SU-Ms) in vitro, including morphology, size distribution, equilibrium water content (EWC), elasticity, drug loading and drug release. The result showed that both B-Ms and SU-Ms were spherical withsmooth surface. The particle size of B-Ms and SU-Ms were both suitable for embolization. Compared with that of B-Ms, the EWC of SU-Ms was decreased and the rigidity of SU-Ms was increased. Drug loading and entrapment efficiency ofmicrospheres were mainly affected by the concentration of sunitinib solution than by the size of microspheres. SU-Ms exhibited a sustained release in phosphate buffer solution (PBS). Thus, the SU-Ms may have potential application for arterial embolization.                    

    A new proteasome inhibitor YSY-01A induced autophagy in PC-3M cells
    Zhe Wang, Xia Yuan, Zemei Ge, Fuxiang Ran, Jun Wu, Runtao Li, Jingrong Cui
    2014, 23(8):  565-571.  DOI: 10.5246/jcps.2014.08.073
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    YSY-01A has shown proliferation inhibitory activity to certain types of tumor cells by inhibiting proteasome. However, its effect on autophagy, which is related with the ubiquitin proteasome pathway (UPP), remains unclear. Our study aimed to find out its effect on autophagy and possible molecular mechanisms. The results suggested that YSY-01A significantly (P<0.001) inhibited proliferation of PC-3M cells (IC50 was 287 nM for 48 h) in a concentration-dependent and time-dependent manner. YSY-01A (100 nM, 3 h) also induced autophagy in PC-3M cells through increasing the expression of P53 (P<0.001), Beclin-1 (P<0.001) and LC3 (P<0.001), and decreasingthe expression of p-mTOR (P<0.001) as compared with the negative control group. Autophagy stayed at a final stage in PC-3M cells after treated with YSY-01A(400 nM)for 12 h. Meanwhile inhibition of autophagy with chloroquine increased the sensitivity to YSY-01A in PC-3M cells. In conclusion, YSY-01A showed high proliferation inhibitory activity of PC-3M cells and it could induce autophagy in PC-3M cells. Inhibiting autophagy increased the cytotoxic activity of YSY-01A in PC-3M cells.

    Synthetic strategies for piperazine derivatives
    Yaya Zhai, Gang Yan, Wenjie Huang, Yan Niu, Fengrong Xu, Lei Liang, Chao Wang, Ping Xu
    2014, 23(8):  572-577.  DOI: 10.5246/jcps.2014.08.074
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    As important constitutes in many drugs, piperazine comprised compounds are of great interest for drug design. In this paper, two piperazine-based compounds were synthesized for the first time, with different strategies exploited. For one compound, a highly reactive intermediate of isothiocyanate was constructed to get the desired piperazinecarbothioa​mide. The synthesis of the other compound was completed sequentially through Friedel-Crafts acylation, coupling reaction and Michael addition. Both synthetic routes have short steps and acceptable yields, and such strategies can be applied to the synthesis of similar piperazine-containing compounds.

    Evaluation of the physicochemical properties and antioxidant activities of polysaccharides from Semen Euryales
    Rong Chen, Man Xue, Wei Chen, Qinan Wu
    2014, 23(8):  578-587.  DOI: 10.5246/jcps.2014.08.075
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    Polysaccharides were isolated from Semen Euryales by water extraction, alcohol precipitation and deproteinization. A refined polysaccharide, named EPJ, was separated into nine fractions by DEAE-52 cellulose chromatography and one of them was separated into two fractions by Sephadex G-100 column. The molecular weight of EPJ was determined to 15 367 Da and the monosaccharide composition was mainly glucose and rhamnose with the molar ratio of 5.46:1. The FT-IR spectra showed carbohydrate-related absorbance of polysaccharide functional groups. In vitro assay showed EPJ could significantly scavenge DPPH radical, superoxide anion, hydrogen peroxide and exhibited a strong reducing power. In vivo assay indicated that EPJ was effective in a D-galactose induced aging mice model. Results showed EPJ significantly inhibited formation of MDA and increased the activities of SOD, CAT, GSH-Px in a dose-dependent manner in mice tissues. The findings obtained from this study indicated that polysaccharides from Semen Euryales could be explored for a wide prospect of benefit.

    Editor profile
    Introduction of Professor Shao Li
    Journal of Chinese Pharmaceutical Sciences
    2014, 23(8):  588-590. 
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    Shao Li, born in Oct. 1973, received his B.S. degree from Beijing University of Chinese Medicine (1995), the M.S. from Wannan College of Medicine (1998) and the Ph.D. from Beijing University of Chinese Medicine (2001). Now he is a Professor (2009–present) at Tsinghua University and the Deputy Director of the Bioinformatics Division, Tsinghua National Laboratory for InformationScience and Technology (2006–present). He is also an Adjunct Professor of Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, and School of Life Sciences, Tsinghua University. Member of Editorial Boardof Journal of Chinese Pharmaceutical Sciences.