Table of Content

31 October 2017, Volume 26 Issue 10

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Review

Endogenous antioxidant DJ-1: A potential target for asthenozoospermia

Yupeng Wang, Yi Sun, Xiaoping Pu

2017, 26(10):  697-708.  DOI: 10.5246/jcps.2017.10.079

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Asthenozoospermia is a common cause of male infertility and is characterized by reduced forward motility of spermatozoa. The pathogenesis of asthenozoospermia remains unclear. DJ-1 is a  ubiquitous protein, widely expressed in the liver, skeletal muscle, kidney, brain and testis. It has been found correlated with many diseases including male infertility. This review presents the novel concept that the endogenous antioxidant properties of DJ-1 in sperm is associated with asthenozoospermia. Thus, DJ-1 is likely a new target for the treatment of asthenozoospermia.



Original articles

Nrf2/ARE signaling protects against oxaliplatin-induced hepatotoxicity in mice

Liu He, Jiangli Xu, Limei Guo, Linling Que, Wencheng Yin, Baoshan Cao, Siwang Yu

2017, 26(10):  709-718.  DOI: 10.5246/jcps.2017.10.080

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Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the expression of a wide array of antioxidant response element (ARE)-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts (MEFs) and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2^–/–mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-inducedhepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.



Transfection of 3′,3′′-bis-peptide-siRNA conjugate by cationic lipoplexes mixed with a neutral cytosin-1-yl-lipid

Mengyi Yang, Jing Sun, Chao Wang, Yanfen Zhang, Lihe Zhang, Zhenjun Yang

2017, 26(10):  719-726.  DOI: 10.5246/jcps.2017.10.081

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Cationic lipids have been applied to siRNA delivery for tumor therapeutics. However, the excess positive charges of these nanoplexes may lead to high cytotoxicity and nonnegligible immunogenicity both in vitro and in vivo, which limited the applications of gene drugs. We constructed multi-component lipoplex to delivery 3′,3′′-bis-peptide-siRNA conjugate (pp-siRNA) by the treatment of melanoma. Based on the previous studies that the gemini lipid (CLD) encapsulated pp-siRNA, a novel neutral cytosin-1-yl-lipid (DNCA) was considered to replace a certain ration of CLD by hydrogen bonds and π-π stacking for reducing the cytotoxicity. It similarly retained in both the loading efficiency and targeted mRNA inhibition when DNCA was accounted for 40% in the lipoplex, with lower toxicity. Moreover, CLD/DNCA/pp-siRNA nanoplex could be uptake in A375 cells and internalized mainly by macropinocytosis and caveolin-mediated endocytosis. Besides, 90%CLD/DNCA/pp-siRNA nanoplexes presented the highest efficient knockdown for the mutant B-RAF mRNA (~80%). All the results demonstrated that the mixed cationic and neutral lipids could efficiently realize the delivery of pp-siRNA and had potential application for cancer therapy.



Design, synthesis and anti-tumor activities of cyclic phosphoramidate mustard-quinazoline conjugates

Jiabei Chen, Yufen Zheng, Weiqi Kong, Xin Li, Laichun Luo, Yanjun Han, Songwen Lin, Qi Sun, Zemei Ge, Runtao Li

2017, 26(10):  727-736.  DOI: 10.5246/jcps.2017.10.082

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A series of new cyclic phosphoramidate mustard-quinazolineconjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC₅₀ = 0.6 μM(8-fold of EMB-3) on BT474breast tumor cells. Compound 6d inhibited epidermal growth factor receptor (EGFR, biomarker for NSCLC) and human epidermal growth factor 2 (HER2, biomarker for breast cancer) with IC₅₀ of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os (PO) administration of 6d in rat model (10 mg/kg) resulted in a moderate t_1/2of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.



Discovery of thiazostatin siderphores from Streptomyces sp. HMU0027 with a genomic DNA-based PCR assay targeting nonribosomal peptide synthetase

Fawang Liu, Mengjie Zhou, Jing Jin, Xiaoyan Yang, Yingtao Zhang, Ming Ma, Donghui Yang

2017, 26(10):  737-746.  DOI: 10.5246/jcps.2017.10.083

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Nonribosomal peptides (NRPs) represent a large family of natural products with great diversities of chemical structures and biological activities. The peptide backbones of NRPs are synthesized by nonribosomal peptide synthetases (NRPSs) that minimally consist of one adenylation (A) domain, one peptidyl carrier protein (PCP) and one condensation (C) domain. In this study, we carried out a PCR screening and identified 21 “positive” strains from 100 actinomycete strains with the degenerate primers designed from the conserved sequences of A domains of NRPSs. One of the 21 “positive” strains, Streptomyces sp. HMU0027, was selected for large-scale fermentation (9 L) based on HPLC analysis, and subsequent isolation and structural elucidation afforded seven NRPS-synthesized thiazostatin siderophore analogues (1–7).Compound 1 was a new compound containing an unusual linkage between a phenolate siderophore and a sugar moiety. These results laid the foundation for further biosynthetic research of these thiazostatin analogues and highlighted the power of genome mining technologies based on biosynthetic knowledge in NRP discovery.



Determination of 8,2′-diprenylquercetin 3-methyl ether in plasma by UPLC-MS-MS and its pharmacokinetic application in rats

Huan Liu, Shanshan Fan, Wen Zhang, Yifan Zhang, Teng Li, Mingying Shang, Guangxue Liu, Feng Xu, Shaoqing Cai

2017, 26(10):  747-753.  DOI: 10.5246/jcps.2017.10.084

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8,2′-Diprenylquercetin 3-methyl ether with significant anti-breast cancer activityis the main constituent of Tibetan medicine Sinopodophylli Fructus. In the present study, we developed and validated a rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of 8,2′-diprenylquercetin 3-methyl etherin rat plasma. 8-Prenylkaempferol was used as the internal standard. The separation was carried out using Waters ACQUITY UPLC BEH C₁₈ column (2.1 mm×100 mm, 1.7 µm) with a mobile phase consisting of acetonitrile and 0.1% formic acid in water on a gradient program at a flow rate of 0.4 mL·min^–1 and temperature of 30 ºC. Triple quadrupole mass spectrometric detection in negative ion mode was used for multiple-reaction monitoring of the transitions at m/z 451.30→177.25 and m/z 353.25→298.15 for 8,2′-diprenylquercetin 3-methyl ether and 8-prenylkaempferol, respectively. The calibration curves were linear within the concentration range 0.1–2000 ng/mL (r = 0.9954). The recoveries were 103%–115%, and the results were consistent across low, middle and high concentration levels. The intra- and inter-day precisions were within 15%, and the bias was between –6%~15%. This method was simple, rapid and sensitive, which could be applied to the determination of 8,2′-diprenylquercetin 3-methyl ether in plasma and pharmacokinetic study in rats. Pharmacokinetic test indicated that the peak plasma concentration occurred in 2 h after the female rats were intragastrically administered with 8,2′-diprenylquercetin 3-methyl ether at the dose of 100 mg/kg, and the biological half-life was 6.79 h. The blood drug concentration maintained equal amount for 20 h, which was conducive to the in vivo effects of drugs.



Chemical constituents from the red alga Symphyocladia latiuscula

Weijie Guo, Guoliang Li, Yuxue Hou, Rongrong Wang, Yang Liu, Xiaohong Liu, Hua Gao, Wei Wang

2017, 26(10):  754-762.  DOI: 10.5246/jcps.2017.10.085

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The extraction and solvent fractionation of red alga Symphyocladia latiuscula, and repeated column chromatography led to isolation of 17 compounds: cholesterol (1), 3β,5β-dihydroxy-B-norcholestan-6β-carboxaldehyde(2),6β-hydroxy-cholest-4-ene-3-one(3), 1-O-myristoyl-3-O-(6′-sulfo-α-D-quinovopyranosyl)glycerol (4), 1-O-palmitoyl-3-O-(6′-sulfo-α-D-quinovopyranosyl)glycerol (5), 1-O-palmitoyl-3-O-[α–D-galactopyranosyl(1→6)β-D-galactopyranosyl] glycerol(6), 1-O-palmitoyl-3-O-β-D-galactopyranosylglycerol (7), methyl hexadecanoate (8), methyl stearate(9), hexadecanoic acid (10), γ-n-butyl cis-aconiate (11), α-n-Butyl cis-aconiate (12), phenethylamine (13),3,5-dibromo-L-tyrosine (14), 3-methylbutylamine (15),methyl pyroglutamate (16),n-butyl pyroglutamate (17).The structures of these compounds were identified by NMR spectroscopy and mass spectrometry, and compared with those reported in the literature. All the compounds were isolated from Symphyocladia genus for the first time.These compounds were investigated for their inhibitory effects on human recombinant aldose reductase in vitro. Of the compounds, 1-O-palmitoyl-3-O-β-D-galactopyranosylglycerol (7) demonstrated moderate enzyme inhibition.



Drug administration and clinical pharmacy column

Meta-analysis of gemcitabine at 30 min standard-dose infusion versus prolonged low-dose infusion for advanced non-small cell lung cancer

Dehua Zhao, Mingming Chu, Jing Chen, Jisheng Wang

2017, 26(10):  763-770.  DOI: 10.5246/jcps.2017.10.086

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To evaluate the efficacy and safety of gemcitabine (GEM) at 30 min standard-dose infusion (30 min-SDI) compared with prolonged low-dose infusion(P-LDI) in patients withadvanced non-small-cell lung cancer (NSCLC). Electronic databases including Pubmed, EMbase, Cochrane Library, CNKI, CBM, and VIP were searched using keywords “GEM”,“P-LDI”, and “NSCLC”. Review Manager 5.3 was used to perform the meta-analysis. Primary endpoints were overall response rate (ORR) and 1-year survival rate (1-year SR). Secondary endpoints were grade 3/4 hematotoxicity and nausea/vomiting. Six randomized controlled trials (RCTs) with a total of 637 patients were included.The results showed that P-LDIwas superior in ORR (OR = 1.50, 95% CI: 1.08–2.10, P = 0.02), but had an equal 1-year SR (OR = 1.27, 95 % CI: 0.90–1.79, P = 0.18) as compared with 30 min-SDI.For grade 3/4 adverse events, there was no significant difference in anemia (OR = 1.84, 95% CI: 0.61–5.57, P = 0.28) and nausea/vomiting (OR = 1.15, 95% CI: 0.63–2.12, P = 0.64) between thetwo treatments. However, patients with P-LDI experiencedless leukopenia (OR = 0.64, 95% CI: 0.43–0.97, P = 0.04)and thrombocytopenia (OR = 0.37, 95% CI: 0.17–0.80, P = 0.01). P-LDI was superior in terms of ORR, experienced less grade 3/4thrombocytopenia and leukopenia compared with 30 min-SDI, and could be a viable treatment option for advanced NSCLC.



Short communication

Establishment of the 8th National Standard of Endotoxin

Tong Cai, Yusheng Pei, Guolai Zhang, Chen Chen, Hua Gao

2017, 26(10):  771-774.  DOI: 10.5246/jcps.2017.10.087

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In the present study, we aimed to establish the 8^th National Standard of Endotoxin using three batches of proposedNational Standard of Endotoxin. We co-calibrated the potency of the proposed preparations against the 3^rd International Standard (10/178) using the gel-clot method, kinetic-turbidimetric test and kinetic-chromogenic test. A total of 14 laboratories participated in this collaborative study. By comparing precision of three approved candidates’ calibrationresults and analyzing the differences among the three results from different methods, we ultimately selected one of candidates as 8^th National Standard of Endotoxin, and its potency is 9000 EU/ampoule and lot is 150801-201601.