Table of Content

18 September 2015, Volume 24 Issue 9

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Original articles

Efficacy and mechanism of a compound epirubicin plus quinine injection for the treatment of drug-resistant breast cancer

Lei Liu, Ruijun Ju, Hongjun Xie, Fan Zeng, Chengjiang Zhang, Weiyu Zhao, Wanliang Lu

2015, 24(9):  563-571.  DOI: 10.5246/jcps.2015.09.072

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A single drug chemotherapy fails to eliminate residual cancer cells due to the existence of the multidrug resistance (MDR). In the present study, we aimed to develop a compound epirubicin plus quinine injection, to characterize the efficacy in treatment of the drug-resistant breast cancer, and to reveal the involved mechanisms. The HPLC-UV methods were developed for quantifications, and the evaluations were performed on the drug-resistant human breast cancer MCF-7/adr cells using a high content screening system. Results demonstrated that the compound epirubicin plus quinine injection was able to effectively block the drug efflux, exhibiting an evidently overall efficacy in treatment of the resistant breast cancer cells by direct killing effect and by apoptosis-inducing effect. In the formulation, quinine played multiple roles in blocking drug efflux and in inducing the apoptosis of the resistant breast cancer cells. The apoptosis signaling pathways were associated with a cascade of reactions by activating Caspase family and by inhibiting Bcl-2 family. In conclusion, the present study preliminarily revealed the efficacy and mechanism of the compound epirubicin plus quinine formulation in treatment of the drug-resistant breast cancer, and offered a potential strategy to overcome drug resistance in cancer treatments.



Comparison and discovery of potential non-covalent CD38 inhibitors by virtual screening strategy based on natural substrates and known inhibitors

Xiwen Xue, Wenjie Zhu, Liangren Zhang, Yongjuan Zhao, Zhenming Liu

2015, 24(9):  572-580.  DOI: 10.5246/jcps.2015.09.073

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As a type II or III transmembrane glycoprotein, human CD38 is ubiquitously expressed in all mammalian tissues. CD38 is a multi-functional enzyme and a member of the ADP-ribosyl cyclase family, and it catalyzes nicotinamide adenine dinucleotide (NAD⁺) and nicotinamide adenine dinucleotide phosphate (NADP⁺) to two distinct Ca²⁺ messengers as follows: cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), respectively. Moreover, both cADPR and NAADP mediate mobilization of intracellular Ca²⁺ targeting endoplasmic stores and the lysosomes, respectively. In this study, we combined ligand-based and structure-based virtual screening strategies to compare the inhibitor discovery efficacy based on natural substrates and the known inhibitors. The similarity queries towards SPECS database were carried out using ROCS and EON modules of OpenEye software. The hits were further docked to CD38 using AutoDock 4.05 program. In addition, ADME studies were also processed considering solubility in water and membrane permeability. Finally, we identified 17 compounds-based on natural substrates and 10 compounds based on known inhibitor models. The results showed that the known inhibitor H2-based model was more efficient in virtual screening of CD38 non-covalent inhibitors.



On-line HPLC-DAD coupled with ESI-IT-TOF-MS and fluorescence detection to identify DNA-binding compounds from Lithospermum erythrorhizon using acridine orange as the fluorescence probe

Wenfang Huang, Cangman Zhang, Sensen Li, Yi Liang, Hong Wang, Shizhong Chen

2015, 24(9):  581-590.  DOI: 10.5246/jcps.2015.09.074

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We have developed an on-line detection method using acridine orange as the fluorescence probe and applied this method to rapidly identify active compounds in herbal medicines. This on-line method was equipped with a high-performance liquid chromatography tandem diode array detector, electrospray ionization-ion-trap time-of-flight mass spectrometry and DNA-acridine orange fluorescence detection (HPLC-DAD-MSⁿ-DNA-AO-FLD). A large amount of information could be simultaneouslyobtained during one run, which included HPLC fingerprint, ultraviolet spectra, total ion chromatograms, MSⁿ data of high-resolution mass spectrometry and activity profile of each compound binding with DNA. The method also provided information on structure-activity relationships and mechanism of interaction. We used this on-line method to identify five DNA-binding activity components from Lithospermum erythrorhizon sample for the first time. The result showed that the parent nucleus of shikonin derivatives could bind with DNA. The structure-activity relationship showed that the parent nucleus of shikonin derivatives plays a major role in DNA binding, not the carboxyl group on the side chain. This simple, rapid, high precision and good stability on-line method should be useful for compound separation, structural identification and screening of DNA-binding compounds in herbal medicines.



Quantification of seven phenylpropanoid compounds in Chinese Cinnamomi Cortex and Ramulus by HPLC

Pengfei Yuan, Yajing Ma, Dan Su, Mingying Shang, Feng Xu, Guangxue Liu, Niloufar Iranmanesh, Lanfang Li, Tingliang Jiang, Shaoqing Cai

2015, 24(9):  591-599.  DOI: 10.5246/jcps.2015.09.075

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In the present study, we developed and validated a high-performance liquid chromatography method for the simultaneousdetermination of seven phenylpropanoid compounds (2-hydroxyl cinnamaldehyde, coumarin, cinnamyl alcohol, cinnamic acid, 2-methoxy cinnamic acid, cinnamaldehyde and 2-methoxy cinnamaldehyde) in Cinnamomi Cortex and Cinnamomi Ramulus. The levels of seven phenylpropanoid compounds in Cinnamomi Cortex and Cinnamomi Ramulus were compared using this method. A total of 48 samples (27 Cinnamomi Cortex and 21 Cinnamomi Ramulus) were purchased in China and analyzed. Quantities of seven phenylpropanoid compounds ranged from 17.5 to 61.6 mg/g in Cinnamomi Cortex and ranged from 9.91 to 23.4 mg/g in Cinnamomi Ramulus. The level of 2-methoxy cinnamic acid in the Cinnamomi Cortex samples was below the LOD, whereas it ranged from 0 to 0.119 mg/g in the Cinnamomi Ramulus samples. The (cinnamyl alcohol+cinnamic acid)/cinnamaldehyde ratios (R₃₄₆) of Cinnamomi Cortex and Cinnamomi Ramulus ranged from 0.0121 to 0.0467 and 0.0598 to 0.182, respectively. This ratio could be used to discriminate Cinnamomi Cortex (<0.05) and Cinnamomi Ramulus (>0.05). The extraction rates (D_n) of seven compounds in boiling water were different, with the lowest dissolution for cinnamaldehyde (<3%) and the highest for cinnamic acid (about 60%).



Chemical constituents from the fruit calyx of Physalis alkekengi var. francheti

Xifeng Peng, Qiong Wu, Chun Gao, Chunyan Gai, Dan Yuan, Hongzheng Fu

2015, 24(9):  600-606.  DOI: 10.5246/jcps.2015.09.076

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In the present study, in order to investigate the chemical constituents of Physalis alkekengi L. var. franchetii (Mast.) Makino, the isolation of ingredients was performed by repeated chromatography on silica gel, Sephadex LH-20 and preparative HPLC. Their structures were identified based on 1D, 2D NMR, and mass spectral analysis. A total of 14 compounds were obtained, and their structures were identified as physalin P (1), 4,7-didehydroneophysalin B (2), physalin D (3), 5α-hydroxy-25,27-dihydro-7-dehydro-7-deoxyneophysalin A(4), 4,7-didehydrophysalin B (5), ursolic acid (6), wogonin (7), blumenol A (8), nobiletin (9), liquiritigenin (10), schizandrin (11), 5-hydroxymethylfurfural (12), 5-(hydroxymethyl)-2-(dimethoxymethyl)furan (13), 1-O-[3-O-2-methyl-5-(2,3,4-trimethyl)phenyl-2,3-pentanediol]-β-D-xylopyranosyl-(1→6)-β-D-galactopyranoside(14). Among them,  compound 14 is a new compound. Compounds 7–11, 13 are isolated from Physalis alkekengi L. var. franchetii (Mast.) Makino for the first time.



Effects and mechanism of proteasome inhibitor YSY01-A alone or in combination with cisplatin against A549 cells in vitro

Ting Sun, Xia Yuan, Wei Huang, Wei Guo, Zemei Ge, Runtao Li, Jingrong Cui

2015, 24(9):  607-616.  DOI: 10.5246/jcps.2015.09.077

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YSY01-A, as a novel proteasome inhibitor, has shown remarkable proliferation inhibitory effect on certain types of tumor cells. However, few studies have reported its effect on non-small cell lung cancer (NSCLC), and its underlying mechanism remains unknown. In our present study, we aimed to figure out the inhibitory effects as well as the mechanism of proteasome inhibitor YSY01-A against A549 cells both individually and in combination with cisplatin. A549 cell proliferation inhibition was assessed by SRB assay. Its related protein expression levels were determined by western blot assay. Moreover, the change of intracellular cisplatin accumulation was examined by ICP-MS assay. The results suggested that YSY01-A significantly (P<0.001) inhibited the proliferation of A549 cells (IC₅₀ was 36.2 nM for 72 h) in a concentration-dependent and time-dependent manner. Compared with the negative control group, YSY01-A (60 nM, 48 h) down-regulated PI3K/Akt pathway in A549 cells by increasing the expression level of PTEN (P<0.01), and decreasing the expression level of PI3K (P<0.001) and p-Akt/Akt (P<0.001). When combined with cisplatin, YSY01-A of different concentrations (5, 10, 20 nM) could significantly increase the inhibition effects on A549 cells compared with the cisplatin alone treatment, showing a synergistic effect. At the same time, YSY01-A could remarkably block the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increase cisplatin uptake from 2.01 to 2.47 fold (P<0.001). In conclusion, compound YSY01-A could significantly inhibit proliferation of NSCLC A549 cells, showing a strong synergistic effect when combined with cisplatin. Down-regulation of PI3K/Akt pathway might be the mechanism of inhibitory effect of YSY01-A, and the combination with cisplatin might increase the expression of CTR1 and intracellular cisplatin accumulation.



Impact of clinical pharmacist intervention on rational use of surgical antibiotic prophylaxis in thyroid surgery

Yuanchao Zhu, Yongfang Hu, Liping Yang, Xin Hu

2015, 24(9):  617-624.  DOI: 10.5246/jcps.2015.09.078

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In the present study, we aimed to evaluate the intervention effect of prophylactic antibiotic use in thyroid surgery in a largehospital. From 2004 to 2012, 70 patients who underwent thyroid surgery were randomly selected each year. The quality of surgical antibiotic prophylaxis (SAP) was assessed each year in terms of antibiotic ratio, choice, duration, timing, combination, route of administration and so on. The result showed that the SAP ratio was 100% from 2004 to 2010. With our intervention, this SAP ratio was decreased to 45.7% in 2011, and it reached 2.9% in 2012. The AUD was consistently greater than 38 before 2010, while it rapidly declined to 1 in 2012. The number of DDDs per 100 operations was decreased from 431 to 3 after the intervention. The average cost of antibiotic drugs per patient was RMB 350.65 in 2010, whereas it was decreased to RMB 18.51 in 2012. The average duration of hospitalization showed no difference during the intervention. This study indicated that implementation of a multi-disciplinary protocol and clinical pharmacist interventions could improve the rational use of SAP.



Rapid screening of anti-HIV ingredients in Artemisia rupestris L. extracts interacting with V3 loop region of HIV-1 gp120 and reverse transcriptase by affinity capillary electrophoresis and capillary zone electrophoresis

Yiran Zhao, Zhongjie Li, Yong Jiang, Xiaodan Zhang, Xiaomei Ling

2015, 24(9):  625-629.  DOI: 10.5246/jcps.2015.09.079

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HIV-1 gains entry into target cells by sequentially interacting with cellular receptors and co-receptors. Both the receptorand co-receptor are recognized by HIV-1 envelope protein gp120, which plays a key role in the entry process of HIV-1 into cells. The development of new inhibitors is essential since the viral enzyme reverse transcriptase (RT) is one of the first targets of antiretroviral therapy. It has been reported that a variety of natural plants, such as Artemisia rupestris L., have anti-viral pharmacological activity, and they might be the potential inhibitors of RT or V3 loop of gp120 against HIV-1. RIQRGPGRAFVTIGK (R15K), the relatively conserved region of V3 loop, can be used for binding research. In this work, we analyzed the interactions between different extracts from Artemisia rupestris L. and R15K by affinity capillary electrophoresis (ACE). Moreover, we analyzed the interactions betweendifferent extracts from Artemisia rupestris L. and RT by capillary zone electrophoresis (CZE). Our data showed that the chloroform extract of Artemisia rupestris L. was active among the different plant extracts, which was consistent with previous studies. Taken together, our study provided a rapid screening method to seek anti-HIV ingredients in natural plants’ extracts.



Short communication

Analgesic components of Dahurian Angelica root in the serum of a rat model

Qiubing Cui, Yaohui You, Bi Wang

2015, 24(9):  630-634.  DOI: 10.5246/jcps.2015.09.080

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In the present study, we aimed to determine the major components responsible for the analgesic effects of Dahurian Angelica root. The rats were administered with either the volatile oil or decoction of Dahurian Angelica root. Formalin plantar injection test was employed as the pain model. The rats were observed for nociception, after which their blood was collected fromthe abdominal aorta. High-performance liquid chromatography (HPLC) fingerprints of serum were performed. The results demonstrated that no remarkable analgesic effect was observed from the low-dose decoction group, whereas the other doses showed pain-relieving effects in the rat model. The components of the rat sera in the different treatments were determined by HPLC. Common chromatographicpeaks were observed at 24.941, 25.755, 29.854, 32.761 and 33.928 min, representing the major constituents of the decoction and volatile oil of Dahurian Angelica root. The analgesic components of Dahurian Angelica root obtained from the rat serum mainly peaked at 24.941, 25.755, 29.854, 32.761 and 33.928 min, suggesting trace components and metabolites.