Nanjing, China

China Pharmaceutical University is a university in Nanjing, China that specializes in the pharmaceutical science. Wikipedia.

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Guo R.,CAS Shanghai Institute of Organic Chemistry | Guo R.,University of Chinese Academy of Sciences | Zheng X.,China Pharmaceutical University | Zhang D.,China Pharmaceutical University | And 2 more authors.
Chemical Science | Year: 2017

An efficient and convenient synthesis of highly functionalized dihydropyrans has been achieved through rhodium(i)-catalysed tandem C(sp3)-C(sp3) bond cleavage and annulation of oxetanols with alkynes. An enantioselective version was enabled using a Binaphine ligand. Excellent site-selectivity and remarkable enantioretention are obtained for 2-substituted oxetanols. © The Royal Society of Chemistry.

Yin T.,China Pharmaceutical University | Liu J.,Shanghai University | Zhao Z.,China Pharmaceutical University | Zhao Y.,China Pharmaceutical University | And 4 more authors.
Advanced Functional Materials | Year: 2017

Nanocarriers capable of circumventing various biological barriers between the site of administration and the therapeutic target hold great potential for cancer treatment. Herein, a redox-sensitive, hyaluronic acid-decorated graphene oxide nanosheet (HSG) is developed for tumor cytoplasm-specific rapid delivery using near-infrared (NIR) irradiation controlled endo/lysosome disruption and redox-triggered cytoplasmic drug release. Hyaluronic acid (HA) modification through redox-sensitive linkages permits HSG a range of advantages over the standard graphene oxide, including high biological stability, enhanced drug-loading capacity for aromatic molecules, HA receptor-mediated active tumor targeting, greater NIR absorption and thermal energy translation, and a sharp redox-dependent response for accelerated cargo release. Results of in vivo and in vitro testing indicate a high loading of doxorubicin (DOX) onto HSG. Selective delivery to HA-receptor overexpressing tumors is achieved through passive and active targeting with minimized unfavorable interactions with blood components. Cytoplasm-specific DOX delivery is then achieved through NIR controlled endo/lysosome disruption along with redox-triggered release of DOX in glutathione rich areas. HSG's specificity is resulted in enhanced cytotoxicity of chemotherapeutics with minimal collateral damage to healthy tissues in a xenograft animal tumor model. HSG is validated the programmed delivery of therapeutic agents in a spatiotemporally controlled manner to overcome multiple biological barriers results in specific and enhanced cancer treatment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Jiang Y.,Nanjing Forestry University | Liu F.-J.,China Pharmaceutical University | Wang Y.-M.,China Pharmaceutical University | Li H.-J.,China Pharmaceutical University
Journal of Pharmaceutical and Biomedical Analysis | Year: 2017

Although natural products (NPs) from ethnomedical plants have played a vital role in modern drug discovery, separation and purification of bioactive compounds from plant extract is still challenging. In this study, a dereplication strategy using HPLC–QTOF-MS was employed to rapidly discover and highly targeted isolate the novel hepatoprotective triterpenoid saponins from the methanol extract of Celosiae Semen. Firstly, four known saponins, i.e. celosin H, celosin I, celosin J, and pseudoginsenoside RT1 were selected as model compounds, and their fragmentation patterns in ESI-QTOF-MS/MS were characterized. Secondly, an HPLC–QTOF-MS/MS method was applied to chemically screen the saponins of interest, and thereby to guide the subsequent fraction and isolation procedure. Thirdly, the targeted isolation of desired compounds afforded two new triterpenoid saponins namely celosin K (1) and celosin L (2), which were structurally elucidated by combination of extensive NMR spectroscopic and chemical analyses. Finally, the protective effects of compounds 1 and 2 against APAP-induced hepatotoxicity in HepG2 cells were evaluated. These results indicate that the HPLC–QTOF-MS-guided isolation is an efficient methodology for isolating new NPs from medicinal plants through improving selectivity in separation and purification process. © 2016 Elsevier B.V.

Shi F.,Zunyi Medical University | Li X.,Shenyang University | Pan H.,Zunyi Medical University | Ding L.,China Pharmaceutical University
Journal of Pharmaceutical and Biomedical Analysis | Year: 2017

Rifampicin (RIF) is used in regimens for infections caused by Mycobacteria accompanied by serious adverse reactions. Rifampicin-quinone (RIF-Q) is a major autoxidation product of RIF. It is not clear whether RIF-Q plays a role in RIF induced adverse reactions. Investigation of the systemic exposure of RIF-Q is helpful to better understand the role of RIF-Q in RIF induced adverse reactions. In this study, a simple and reproducible high performance liquid chromatography-mass spectrometry (LC–MS) method involving a procedure to prevent the RIF from oxidation for simultaneous quantification of RIF and RIF-Q in rat plasma has been developed and validated, and applied to elucidate the systemic exposure of RIF-Q in rats. The pharmacokinetics data showed that the systemic exposure of RIF-Q was very low (0.67% of RIF, AUC0-24) in rats after oral administration of RIF. However, RIF-Q may undergo the redox cycle in vivo by the evidence that the majority of RIF-Q was reduced to RIF after an oral dose of RIF-Q. Pretreatment with the NAD(P)H: quinone oxidoreductase 1 (NQO1) specific inhibitor dicoumarol and/or cytochrome P450 reductase (CPR) inhibitor diphenyleneiodonium suppressed the redox cycle and significantly increased the systemic exposure of RIF-Q. The inhibitors also attenuated the redox cycle induced reactive oxygen species formation and cytotoxicity in RIF-Q-treated HepG2 cells. These results indicate that NQO1 and CPR play an important role in redox cycle of RIF-Q and may thus contribute to RIF-induced adverse reactions. © 2016 Elsevier B.V.

Liu Q.,University of Science and Technology of China | Wu Z.,University of Science and Technology of China | Wu Y.,CAS Lanzhou Institute of Chemical Physics | Gao T.,China Pharmaceutical University | Yao J.,University of Science and Technology of China
ACS Sustainable Chemistry and Engineering | Year: 2017

We report a novel composite absorbent prepared by the simple method that catechol-amine resin coats the hydrocellulose based on the adhesion property like polydopamine. The composite which contains many chelating groups on its surface was characterized by scanning electron microscopy (SEM), infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), etc. The obtained adsorbents were investigated to remove Methyl Orange (MO) and Alizarin Red S (AR) from pH-unregulated aqueous system by batch experiments, including the affected factors of adsorbent dosage, contact time, initial concentration, and temperature. Results showed the adsorption processes belonged to the chemisorption and exhibited a spontaneous and endothermic nature. Besides, the removal performances fitted with the Langmuir isotherm model and pseudo-second order kinetic model very well. The maximum adsorption amounts of MO and AR were 189.39 and 284.09 mg/g at 303 K, respectively. The difference about adsorption amounts may be caused by the strong effect of π-π conjugation and hydrogen bonding between adsorbent and AR. Furthermore, the adsorption processes exhibited a spontaneous and endothermic nature. The recycling test indicated that the adsorbent stayed stable for the removal of both dyes by desorbed three times. Accordingly, the adsorbent with high adsorption capacity and rapid removal rate should be a promising material for the removal of anionic dyes from sewage. © 2016 American Chemical Society.

LI J.,China Pharmaceutical University | Larregieu C.A.,University of California at San Francisco | Benet L.Z.,University of California at San Francisco
Chinese Journal of Natural Medicines | Year: 2016

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products. © 2016 China Pharmaceutical University

Sun D.-Y.,CAS Shanghai Institute of Materia Medica | Sun D.-Y.,China Pharmaceutical University | Han G.-Y.,Renmin University of China | Gong J.-X.,CAS Shanghai Institute of Materia Medica | And 3 more authors.
Organic Letters | Year: 2017

The first total synthesis of a marine derived polyacetylene, distaminolyne A, and its enantiomer were achieved from the commercially available undec-10-en-1-ol. A key proline-catalyzed asymmetric α-aminooxylation of an aldehyde intermediate was used to introduce the chiral center en route to the enantiomerically pure 1,2-amino alcohols. The absolute configuration of both synthesized enantiomers of distaminolyne A was confirmed by using chiral derivatizing agents, leading to revision of the natural product absolute configuration from 2S to 2R. Antibacterial, pancreatic lipase (PL) inhibitory, and protein-tyrosine phosphatase 1B (PTP1B) inhibitory activities were evaluated. © 2017 American Chemical Society.

Dong S.,China Pharmaceutical University | Yan Z.,China Pharmaceutical University | Yang H.,Jiangsu Deyuan Pharmaceutical Co. | Long Z.,Thermo Fisher Scientific
Analytical Sciences | Year: 2017

A sensitive non-derivatization method for the determination of the highly polar compound 3-aminopiperidine was developed using a mixed-mode column combined with a charged aerosol detector (CAD). Chromatographic conditions, including the type of detector, separation mode, and mobile phase composition, were optimized to achieve high sensitivity towards and sufficient retention of 3-aminopiperidine. Compared to the precolumn derivatization UV method, the current method showed higher recovery and greater simplicify. High sensitivity (LOQ < 2.73 μg mL-1) and good precision (RSD of peak area < 2%) were also observed in the current method. Furthermore, the parameters such as buffer solution and column bleed that affected the sensitivity of the CAD were investigated. Finally, the current method was applied for the determination of 3-aminopiperidine in linagliptin samples. This is a new non-derivative for the determination of 3-aminopiperidine, and constitutes a novel application of the CAD for the quantitative analysis of highly polar basic compounds. © 2017, The Japan Society for Analytical Chemistry.

Hou G.-X.,Sun Yat Sen University | Liu P.,Sun Yat Sen University | Yang J.,Sun Yat Sen University | Wen S.,Sun Yat Sen University | Wen S.,China Pharmaceutical University
PLoS ONE | Year: 2017

DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan-Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients. © 2017 Hou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Gu Y.,China Pharmaceutical University | Lu M.,China Pharmaceutical University | Wang Z.,China Pharmaceutical University | Wu X.,China Pharmaceutical University | Chen Y.,China Pharmaceutical University
Chemistry - A European Journal | Year: 2017

Glycosaminoglycans (GAG) lyases are useful biocatalysts for the preparation of oligosaccharides, but their substrate spectra are limited to the same family. Thus, the degradation activity across families of GAG lyases is advantageous and desirable for various applications. In this study, residue Lys130 at the substrate entrance of monomeric heparinaseIII from Pedobacter heparinus ATCC 13125 was replaced by cysteine, and the resulting mutant K130C showed novel catalytic activity in degrading hyaluronic acid without affecting its native activity toward heparin and heparan sulfate. The broadened catalytic promiscuity by mutant K130C was the result of dimerization through a disulfide bond to expand the substrate binding pocket. This bifunctional enzyme is potentially valuable in the degradation of different types of GAGs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Yuan X.,China Pharmaceutical University | Dou Y.,China Pharmaceutical University | Wu X.,China Pharmaceutical University | Wei Z.,China Pharmaceutical University | Dai Y.,China Pharmaceutical University
Journal of Cellular and Molecular Medicine | Year: 2017

Tetrandrine, a bisbenzylisoquinoline alkaloid constituent of the root of Stephania tetrandra S. Moore, was previously shown to suppress the differentiation of T helper 17 (Th17) cells and consequently ameliorate the collagen-induced arthritis (CIA) in mice by activating the aryl hydrocarbon receptor (AhR), but its underlying mechanism is incompletely understood. Here, we investigated how tetrandrine suppressed Th17 cell differentiation through the AhR pathway. The naïve CD4+ T cells were stimulated with anti-CD3/CD28 for 72 hrs in the presence or absence of tetrandrine under the Th17-polarizing condition. Tetrandrine inhibited the phosphorylation of signal transducer and activator of transcription-3 (STAT3) and boosted the phosphorylation of STAT5, while it did not alter the expression levels of phospho-Janus kinase-1 (p-JAK1), p-JAK2, p-JAK3, and suppressor of cytokine signalling-3 (SOCS3). The tetrandrine-mediated inhibition of the Th17 cell differentiation could be diminished by the activator of STAT3 and the inhibitor of STAT5. Meanwhile, the effect of tetrandrine on the either STAT3 or STAT5 phosphorylation was almost completely reversed by the AhR antagonist CH223191 and the AhR knockdown. In CIA mice, tetrandrine decreased p-STAT3 levels and increased p-STAT5 levels, which could also be reversed by the AhR antagonist resveratrol administration. Furthermore, tetrandrine promoted the AhR binding to the STAT5, but not to the STAT3. The tetrandrine-induced inhibition of the STAT3 phosphorylation was diminished by the inhibitor of STAT5. Taken together, tetrandrine suppressed Th17 cell differentiation by reciprocally modulating the activities of STAT3 and STAT5 in an AhR-dependent manner. © 2017 Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Xu Y.,China Pharmaceutical University | Hong T.,China Pharmaceutical University | Chen X.,China Pharmaceutical University | Ji Y.,China Pharmaceutical University
Electrophoresis | Year: 2017

Baseline separation of omeprazole (OME) enantiomers was achieved by affinity capillary electrophoresis (ACE), using human serum albumin (HSA) as the chiral selector. The influence of several experimental variables such as HSA concentration, the type and content of organic modifiers, applied voltage and running buffer concentration on the separation was evaluated. The binding of esomeprazole (S-omeprazole, S-OME) and its R-enantiomer (R-omeprazole, R-OME) to HSA under simulated physiological conditions was studied by ACE and fluorescence spectroscopy which was considered as a reference method. ACE studies demonstrated that the binding constants of the two enantiomers and HSA were 3.18 × 103 M-1 and 5.36 × 103 M-1, respectively. The binding properties including the fluorescence quenching mechanisms, binding constants, binding sites and the number of binding sites were obtained by fluorescence spectroscopy. Though the ACE method could not get enough data when compared with the fluorescence spectrum method, the separation and binding studies of chiral drugs could be achieved simultaneously via this method. This study is of great significance for the investigation and clinical application of chiral drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Li Z.,China Pharmaceutical University | Xu X.,China Pharmaceutical University | Huang W.,China Pharmaceutical University | Qian H.,China Pharmaceutical University
Medicinal Research Reviews | Year: 2017

The free fatty acid receptor 1 (FFAR1/GPR40) amplifies glucose-dependent insulin secretion; therefore, it has attracted widespread attention as a promising antidiabetic target. Current clinical proof of concept also indicates that FFAR1 agonists achieve the initially therapeutic endpoint for the treatment of type 2 diabetes mellitus (T2DM) without the hypoglycemic risk. Thus, many pharmaceutical companies and academic institutes are competing to develop FFAR1 agonists. However, several candidates have been discontinued in clinical trials, often without reporting the underlying reasons. Herein, we review the challenges and corresponding strategies chosen by different medicinal chemistry teams to improve the physicochemical properties, potency, pharmacokinetics, and safety profiles of FFAR1 agonists, with a brief introduction to the biology and pharmacology of related targets. © 2017 Wiley Periodicals, Inc.

Yuan C.,North University of China | Du B.,Sichuan University | Xun M.-M.,North University of China | Liu B.,China Pharmaceutical University
Tetrahedron | Year: 2017

A series of hydroxamic acids, involving aliphatic, aromatic and cyclic substrates, were transformed to the corresponding carboxylic acids through NaIO4-mediated oxidative cleavage in mild conditions. Esterification of these acids with TMSCHN2 could result in formation of the corresponding methyl ester. This methodology makes good compensation for the existing methods transforming amides to esters. Our results also pave the way to harness hydroxamic acids as useful synthetic building blocks. © 2017 Elsevier Ltd.

Xu G.,Changzhou University | Liu K.,Changzhou University | Dai Z.,China Pharmaceutical University | Sun J.,Changzhou University
Organic and Biomolecular Chemistry | Year: 2017

An unprecedented regioselective metallo-vinylcarbene insertion into O-H bonds has been achieved with vinyldiazoacetates and 2-pyridones/benzyl alcohols as ideal substrates, which displayed distinct regioselectivity by employing gold and silver catalytic systems. © The Royal Society of Chemistry.

Xie J.,China Pharmaceutical University | Wang Y.-W.,China Pharmaceutical University | Qi L.-W.,China Pharmaceutical University | Zhang B.,China Pharmaceutical University
Organic Letters | Year: 2017

A copper-catalyzed aminooxygenation of unactivated alkenes with various O-nucleophiles is described. This novel methodology uses commercially available N-fluorobenzenesulfonimide as an amination reagent and provides a simple and efficient approach to a wide range of aminated saturated oxygen heterocycles in moderate to good yields. The reaction features mild reaction conditions, operational simplicity, and a broad substrate scope. © 2017 American Chemical Society.

Shu X.,China Pharmaceutical University | Ai D.-G.,China Pharmaceutical University | Zhao H.-P.,China Pharmaceutical University
Chinese Journal of New Drugs | Year: 2017

Firstly, this paper collected all the patent data of the blockbuster new drugs Praluent and Repatha by using multiple database search. After cleansing, I established a database by SQL. Using the database, polynomial regression analysis, trended line fitted patent application, given Praluent/Repatha patent status of the network layout. Meanwhile, through data mining clustering analysis, set Praluent for the training set, built a patent map in the United States on Repatha. Finally, the paper carried out the dimension combination, drew lots of patent graphs of two drugs through statistical analysis, and further interpretation of the status and trends of Praluent and Repatha's patent layout. The results of the study provided precious information for other inhibitors drugs and generic imitation planning and development process regulation. © 2017, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Cao Y.,China Pharmaceutical University | Yan Y.,China Pharmaceutical University
Chinese Journal of New Drugs | Year: 2017

In this paper, the effects of innovation inputs on innovation output were studied. First, entropy method was used to evaluate the status quo of the innovation performance of pharmaceutical industry in Jiangsu province. By using Almon polynomial distribution lag model, the influencing factors on pharmaceutical industry innovation output in Jiangsu province were empirically tested. The results show that the innovation investment is growing faster than output in recent years, and the growth rate and industry innovation performance need to be improved. At the same time, estimation using the polynomial distribution lag model shows that R&D personnel full-time equivalent and R&D capital investment promote income of new product sales, and the effect appears in 2, 3 and 5 years, respectively, after the investment; while the capital investment to new product development always has a positive impact. R&D capital and capital investment to develop new products have an effect in the first three and two years, respectively, on the number of patent applications. R&D personnel full-time equivalent always has its positive effects. © 2017, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Ling J.,Jiangsu University | Wang F.,China Pharmaceutical University | Yan F.-R.,China Pharmaceutical University
Chinese Journal of New Drugs | Year: 2017

Objective: To propose a new strategy for dose-finding in clinical trials when both efficacy and toxicity responses are count data with dependence. Methods: A bivariate count responses model was established using Archimedean Copula, and a dose decision rule was developed based on the joint probability of both efficacy and toxicity. Results and Conclusion: Significant gains can be achieved when using Archimedean Copula joint model. Firstly, the correlation between efficacy and toxicity can be estimated. Secondly, the regression parameters in Archimedean Copula for both efficacy and toxicity are meaningful. Thirdly, Archimedean Copula has no restrictions on the probability distribution of response. The simulation study showed that the new joint model based on Archimedean Copula can enable physicians to evaluate the efficacy and toxicity simultaneously and select the optimal dose successfully. © 2017, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Cao Y.,China Pharmaceutical University | Qin C.-M.,China Pharmaceutical University
Chinese Journal of New Drugs | Year: 2017

Based on logistic regression analysis, this paper analyzed the internal and external environment factors that affecting the technological innovation intention of pharmaceutical industry, aiming to provide the basis for the government to draw up relevant policies to stimulate the intrinsic motivation of pharmaceutical industry for technological innovation. The analysis showed that the internal factors which could strengthen the willing of enterprises for technological innovation were their own technological innovation ability and R&D personnel investment. The significant external factors were patent protection and market entry barriers. It was suggested that the pharmaceutical enterprises allocate resources rationally and improve their own technological innovation ability. The government should complete patent protection policy and protect R&D results of pharmaceutical enterprises. Also the government should create a favorable market environment and improve market access system of new drugs. © 2017, Chinese Journal of New Drugs Co. Ltd. All right reserved.

Xu M.,China Pharmaceutical University | Zou H.,China Pharmaceutical University | Gao J.,Beijing Institute of Pharmacology and Toxicology
Academic Journal of Second Military Medical University | Year: 2017

Objective To prepare the paclitaxel-loaded poly(2-oxazolyl) nano-micelles and to investigate the morphological changes of nano-micelles after changing drug dosage, so as to establish a novel block copolymer micelles delivery system with high loading capacity. Methods The paclitaxel-loaded poly(2-oxazolyl) nano-micelles were prepared using filming-rehydration method. The physical and chemical properties of the prepared nano-micelles, including particle size, encapsulation efficiency and drug loading efficiency, were characterized. The in vitro release characteristics of the prepared nano-micelles were investigated by membrane dialysis method, and the cytotoxicity was determined by CCK-8 method. Results The morphology of micelles gradually extended from spherical to worm-like when the mass ratio of paclitaxel and poly(2-oxazoline) increased from 80: 100 to 110: 100. The particle size, encapsulation efficiency and drug loading efficiency of spherical micelles were (43. 17 + 0. 95) nm, (88. 81 + 2. 93) % and (40. 49 + 2. 03)%, respectively, while those of worm-like micelles were (107. 83 + 1. 51) nm, (77. 08 + 0. 97)% and (40. 34 + 0. 51) %, respectively. The 24 h cumulative release rates of spherical micelles and worm-like micelles in PBS were (76. 58 + 3. 07)% and (77. 66 + 1. 00)%, respectively; meanwhile, those in PBS with 2% bovine serum albumin were up to (100. 31 + 1. 80)% and (99. 73 + 2. 56)%, respectively. The IC50 values of sphere micelles and worm-like micelles on human lung adenocarcinoma cell line A549 were 0. 336 μg/mL and 0. 342 μg/mL, respectively. Conclusion Paclitaxel-loaded spherical micelles and worm-like micelles with high loading capacity have been successfully prepared. In vitro cytotoxicity results have found that both micelles have anti-tumor activities. © 2017, Second Military Medical University Press. All rights reserved.

Huang J.,China Pharmaceutical University | Li N.,China Pharmaceutical University | Wang Q.,China Pharmaceutical University | Gu Y.,China Pharmaceutical University | Wang P.,China Pharmaceutical University
Sensors and Actuators, B: Chemical | Year: 2017

The early diagnosis of ovarian cancer plays an important role in the treatment of ovarian cancer. β-Galactosidase (β-gal) which is an overexpressed enzyme in primary ovarian cancer can be employed as a valuable biomarker of ovarian cancer. A fluorescent probe for β-gal detection and imaging is of important significance for the diagnosis of primary ovarian cancer. Toward this goal, we have rationally designed and synthesized a novel two-photon fluorescence probe FC-βgal for monitoring endogenous β-gal in lysosome. The probe FC-βgal showed apparently fluorescence changes from blue to green in response to β-gal by the cleavage of glycosidic bond. 4-Propylmorpholine group endowed the probe with the property of lysosomal targeting. We confirmed that the probe FC-βgal exhibited rapid response, high sensitivity, excellent biocompatibility and favorable performances to β-gal even in the interfering of other biologic substances. In addition, single photon and two-photon confocal imaging experiments indicated that probe FC-βgal displayed a desirable cellular imaging for endogenous β-gal in human ovarian cancer SKOV-3 cells with low cytotoxicity. Moreover, the probe had satisfactory ability to accumulate into lysosomes compared with LysoTracker. © 2017 Elsevier B.V.

Wang Y.,China Pharmaceutical University | Wang Y.,Yunnan Academy of Agricultural Sciences | Liu E.,China Pharmaceutical University | Li P.,China Pharmaceutical University
Journal of Pharmaceutical and Biomedical Analysis | Year: 2017

Paris species, which contain steroid saponins, have been used as herb folk medicines in Asia. In the present study, a comprehensive strategy based on liquid chromatography-tandem mass spectrometry (LC–MS/MS) and Fourier transform infrared (FT-IR) spectroscopy was firstly proposed to evaluate the chemotaxonomic relationships of nine Paris species sampled from different geographical regions in China. Principle component analysis (PCA) based on FT-IR data revealed chemical similarities in term of the nine species and geographical regions, indicating the accumulation of metabolites affected by the combination of geographical factors and species. The chemotaxonomic relationships of four species supported the morphological taxonomy and implied ancestry from P. polyphylla. After high-efficiency chromatographic separation, ions trap/time-of-flight mass spectrometry (IT-TOFMS) and triple quadrupole mass spectrometry (QQQ-MS) were used to identify unknown metabolites and simultaneously determine six key compounds (polyphyllin I, II, V, VI, VII and gracillin) in Paris species, respectively. The tentative identification of 22 steroid saponins was indicative of a common biosynthetic pathway in Paris species. Phytoecdysones, gracillin and open-chain steroid saponins were considered as key precursors. According to Pearson's correlation analysis, an insignificant correlation was found between diosgenin-type and pennogenin-type saponins belonging to the same biosynthetic pathways in the current stage. Our results could provide a reasonable foundation for chemotaxonomy or further studies of Paris species. © 2017 Elsevier B.V.

Zheng X.,China Pharmaceutical University | Wang G.-J.,China Pharmaceutical University | Hao H.-P.,China Pharmaceutical University
Yaoxue Xuebao | Year: 2017

Traditional anti-depressant therapy based on the regulation of monoamine neurotransmitters has shown certain limitations. Recently, accumulating clinical and preclinical studies have reported the tantalizing link between immune dysregulation, inflammatory process and the initiation and exacerbation of major depressive disorder (MDD). With a deepening understanding of neural-immune-metabolic interactions, an immunometabolism driven disease network has attracted huge interests in understanding neuronal inflammation and dysfunction underlying MDD pathogenesis and intervention. This review describes recent data uncovering immunometabolic dysregulation as a key factor in MDD network, with a focus on the recent appreciation of immune-metabolic actions of several anti-depressant compounds. The implications for the discovery of novel antidepressant drugs and clinical management of MDD are discussed.

Wang H.-S.,Nanjing University | Wang H.-S.,China Pharmaceutical University | Li J.,Nanjing University | Li J.-Y.,Nanjing University | And 3 more authors.
NPG Asia Materials | Year: 2017

Two-dimensional (2D) materials have attracted tremendous interest as fluorescence quenchers of dye-labeled biomolecules for application in biosensing. Metal-organic framework (MOF) nanosheets, as a new type of 2D material, have rarely been studied as bioanalytical platforms. Herein, we synthesize a series of ultrathin lanthanide-based MOF (MOF-Ln) nanosheets as a dye-labeled aptamer platform. The fluorescence quenching or recovery on the MOF-Ln nanosheets is determined by the charge properties (positive or negative) of the labeled fluorophores. The negatively charged fluorophores experience a fluorescence 'turn-down followed by turn-down' process, whereas the positively charged fluorophores experience a fluorescence 'turn-down followed by turn-up' process. The interesting fluorescence quenching properties of the MOF-Ln nanosheets make them an excellent two-color sensing platform for the intracellular detection of biomolecules. © The Author(s) 2017.

Wang F.,China Pharmaceutical University | Cao F.,China Pharmaceutical University | Li C.,China Pharmaceutical University
Nanoscience and Nanotechnology Letters | Year: 2017

Heck coupling reaction catalysed directly by ligand-free nickel nanoparticles (NPs) has been reported in heterogeneous processes. The nickel NPs with 25 nm in size showed good results in the arylation of olefins with iodoarenes in the presence of K2CO3 and n-Bu4NCl in DMF solvent at high temperature (130 °C). Bromobenzene showed low conversion (<14%) during the Heck reaction. Electron-donating group-substituted iodoarenes exhibited better performance in the Heck reaction compared with the non-reactive electron-withdrawing group-substituted iodoarenes. Supported nickel NPs on metal oxide and activated carbon exhibited simple work-up and good reusability at least five runs without dramatically decreasing their catalytic reactivity. Copyright © 2017 American Scientific Publishers.

Wang P.,China Pharmaceutical University | Wang P.,Institute for Chemical Drug Control | Huang J.,China Pharmaceutical University | Gu Y.,China Pharmaceutical University
Sensors and Actuators, B: Chemical | Year: 2017

Biothiol compounds, commonly involving cysteine (Cys), homocysteine (Hcy), and glutathione (GSH) are of wide range in mammalian cells for maintaining the stability of their internal environments. Due to their special significance in physiology and pathology for human, development of fluorescence probes for selective and sensitive detection of thiols under physiological conditions has attracted great interest. Compared to conventional fluorescent probes, near-infrared (NIR) fluorescent probes possess unique advantages for tracing molecular processes in vitro and in vivo. In this report, we designed and synthesized a novel NIR fluorescent probe DCM-NBD, which employed dicyanomethylene-4H-pyran (DCM) derivatives as the NIR fluorophore and nitrobenzoxadiazole (NBD) as the response group via ether linkage. It exhibited satisfactory selectivity and sensitivity to differentiate between Cys/Hcy and GSH by dual fluorescence signals. Moreover, the probe DCM-NBD showed admirable imaging capability in living cells and animals with low cytotoxicity. © 2017 Elsevier B.V.

Xu J.,China Pharmaceutical University | Zhao P.,China Pharmaceutical University | Zhang Y.,China Pharmaceutical University
Journal of Biomaterials Science, Polymer Edition | Year: 2017

Swollen hydrogels with extended iodine release kinetics is highly desirable for burn and scald treatment. In this paper semi-interpenetrating poly (HEMA–PVP) hydrogels were prepared by radical polymerization followed by thermo-treatment to crosslink its PVP component. Incorporation of PVP component endows the hydrogels responsive to loaded iodine undergoing a reversible shrunken/swollen volume transition. This resulted in a self-regulating iodine release model, in which shrunken hydrogel at high iodine loading decreased drug diffusion thereby reducing burst release, and then gradually swollen hydrogel as drug release ensures rapid release of dissociated drug from strong affinity sites on hydrogel backbone, achieving a burst-free extended release. The hydrogels demonstrated 11.5-fold higher iodine loading than pure pHEMA hydrogel and showed a highest 40% volume shrink. Initial burst release of iodine was efficiently decreased from 12,894 μg/day of pure pHEMA hydrogel to 2570 μg/day of pHEMA/PVP hydrogel with 37% PVP content. Iodine-loaded hydrogels showed zero-order release at three time periods of 0–15 h, 15 h–3.5 days and 3.5–23.5 days corresponding to release rate of 2570, 776 and 493 μg/day. The work gained a new insight into swollen hydrogel drug delivery system with burst-free extended drug release kinetics. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Yan Z.-Y.,China Pharmaceutical University | Du Q.-Q.,China Pharmaceutical University | Qian J.,China Pharmaceutical University | Wan D.-Y.,China Pharmaceutical University | Wu S.-M.,China Pharmaceutical University
Enzyme and Microbial Technology | Year: 2017

In the paper, a green and efficient biosynthetical technique was reported for preparing cadmium sulfide (CdS) quantum dots, in which Escherichia coli (E. coli) was chosen as a biomatrix. Fluorescence emission spectra and fluorescent microscopic photographs revealed that as-produced CdS quantum dots had an optimum fluorescence emission peak located at 470 nm and emitted a blue-green fluorescence under ultraviolet excitation. After extracted from bacterial cells and located the nanocrystals’ foci in vivo, the CdS quantum dots showed a uniform size distribution by transmission electron microscope. Through the systematical investigation of the biosynthetic conditions, including culture medium replacement, input time point of cadmium source, working concentrations of raw inorganic ions, and co-cultured time spans of bacteria and metal ions in the bio-manufacture, the results revealed that CdS quantum dots with the strongest fluorescence emission were successfully prepared when E. coli cells were in stationary phase, with the replacement of culture medium and following the incubation with 1.0 × 10−3 mol/L cadmium source for 2 days. Results of antimicrobial susceptibility testing indicated that the sensitivities to eight types of antibiotics of E. coli were barely changed before and after CdS quantum dots were prepared in the mild temperature environment, though a slight fall of antibiotic resistance could be observed, suggesting hinted the proposed technique of producing quantum dots is a promising environmentally low-risk protocol. © 2016 Elsevier Inc.

Cao Y.,CNRS Interdisciplinary Nanoscience Centre of Marseille | Liu X.,China Pharmaceutical University | Peng L.,CNRS Interdisciplinary Nanoscience Centre of Marseille
Frontiers of Chemical Science and Engineering | Year: 2017

Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined molecular architecture and multivalent cooperativity. However, the clinical translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of dendrimers that are of high quality to meet good manufacturing practice standard. In this context, we have developed small amphiphilic dendrimers that self-assemble into supramolecular structures, which mimic high-generation dendrimers synthesized with covalent construction, yet are easy to produce in large amount and superior quality. Indeed, the concept of supramolecular dendrimers has proved to be very promising, and has opened up a new avenue for dendrimer-mediated siRNA delivery. A series of self-assembling supramolecular dendrimers have consequently been established, some of them out-performing the currently available nonviral vectors in delivering siRNA to various cell types in vitro and in vivo, including human primary cells and stem cells. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible dendrimers for siRNA delivery. We then highlight our efforts in creating selfassembling amphiphilic dendrimers to construct supramolecular dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramolecular dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications. [Figure not available: see fulltext.] © 2017 Higher Education Press and Springer-Verlag Berlin Heidelberg

Yan Z.,China Pharmaceutical University | Tian C.,China Pharmaceutical University | Qu X.,China Pharmaceutical University | Shen W.,China Pharmaceutical University | Ye B.,China Pharmaceutical University
Colloids and Surfaces B: Biointerfaces | Year: 2017

A novel type of suspension array for multiplex detection of heavy metal ions with photonic crystal hydrogel microspheres was reported. The photonic crystal hydrogel microspheres have close-packed photonic crystal particles as their encoding units and ssDNA-functionalized hydrogel as the sensing units. The developed microspheres were successfully applied in multiplex detection of heavy metal ions. © 2017 Elsevier B.V.

Chi H.,China Pharmaceutical University | Chi H.,Tianjin Institute of Pharmaceutical Research | Gu Y.,China Pharmaceutical University | Xu T.,China Pharmaceutical University | Cao F.,China Pharmaceutical University
International Journal of Nanomedicine | Year: 2017

To study the cellular uptake mechanism of multifunctional organic-inorganic hybrid nanoparticles and nanosheets, new chitosan-glutathione-valine-valine-layered double hydroxide (CG-VV-LDH) nanosheets with active targeting to peptide transporter-1 (PepT-1) were prepared, characterized and further compared with CG-VV-LDH nanoparticles. Both organic-inorganic hybrid nanoparticles and nanosheets showed a sustained release in vitro and prolonged precorneal retention time in vivo, but CG-VV-LDH nanoparticles showed superior permeability in the isolated cornea of rabbits than CG-VV-LDH nanosheets. Furthermore, results of cellular uptake on human corneal epithelial primary cells (HCEpiC) and retinal pigment epithelial (ARPE-19) cells indicated that both clathrin-mediated endocytosis and active transport of PepT-1 are involved in the internalization of CG-VV-LDH nanoparticles and CG-VV-LDH nanosheets. In summary, the CG-VV-LDH nanoparticle may be a promising carrier as a topical ocular drug delivery system for the treatment of ocular diseases of mid-posterior segments, while the CG-VV-LDH nanosheet may be suitable for the treatment of ocular surface diseases. © 2017 Chi et al.

Li X.,China Pharmaceutical University | Li X.,Shanghai University | Cao Y.,China Pharmaceutical University | Gong X.,China Pharmaceutical University | Li H.,Shanghai University
Oncotarget | Year: 2017

Head and neck cancers (HNCs) include a series of malignant tumors arising in epithelial tissues, typically oral cancer, laryngeal cancer, nasopharynx cancer and thyroid cancer. HNCs are important contributors to cancer incidence and mortality, leading to approximately 225,100 new patients and 77,500 deaths in China every year. Determination of the mechanisms of HNC carcinogenesis and progression is an urgent priority in HNC treatment. Long noncoding RNAs (lncRNAs) are noncoding RNAs longer than 200 bps. lncRNAs have been reported to participate in a broad scope of biological processes, and lncRNA dysregulation leads to diverse human diseases, including cancer. In this review, we focus on lncRNAs that are dysregulated in HNCs, summarize the latest findings regarding the function and molecular mechanisms of lncRNAs in HNC carcinogenesis and progression, and discuss the clinical application of lncRNAs in HNC diagnosis, prognosis and therapy.

Liu Y.,China Pharmaceutical University | Liu Y.,Shandong University | Wan W.-Z.,China Pharmaceutical University | Li Y.,China Pharmaceutical University | And 2 more authors.
Oncotarget | Year: 2017

Phosphatidylinostitol-3-kinase (PI3K) is the potential anticancer target in the PI3K/Akt/ mTOR pathway. Here we reviewed the ATP-competitive small molecule PI3K inhibitors in the past few years, including the pan Class I PI3K inhibitors, the isoform-specific PI3K inhibitors and/or the PI3K/mTOR dual inhibitors.

Yuan Z.,China Pharmaceutical University | Gai K.,China Pharmaceutical University | Wu Y.,China Pharmaceutical University | Wu J.,China Pharmaceutical University | And 2 more authors.
Chemical Communications | Year: 2017

A tandem 1,6-addition/cyclization/vinylcyclopropane rearrangement reaction (VCPR) of vinylogous para-quinone methides at low temperature under metal-free conditions has been disclosed for the first time. This method provides an efficient strategy for the construction of a range of spiro[4.5]cyclohexadienones in good yield, exhibiting good functional group tolerance as well as gram-scale capacity. © The Royal Society of Chemistry.

Zhu G.,Sichuan University | Liu B.,Sichuan University | Liu B.,China Pharmaceutical University
Tetrahedron | Year: 2017

Derivatives of podocarpane-type diterpenoids, including cassane-type, abietane-type and totarane-type diterpenoids, are either widely distributed natural products or common intermediates in synthetic and medicinal chemistry. Although unmasked ortho-benzoquinone has been used in [4+2] cycloadditions in sparse cases due to its multiple reactivity as diene, dienophile, heterodiene and heterodienophile, applications of this motif in cycloadditions of complex molecules are very rare. We report herein that this [4+2] process can be successfully extended to various polycyclic substrates, followed by a photo-decarbonylation, to generate versatile derivatives of podocarpane-type diterpenoids. Racemic synthesis of isolophanthins A & B and abietatrien-3. β-ol was accomplished on the basis of this methodology. © 2017 Elsevier Ltd.

Pu Z.,Dalian Medical University | Pu Z.,China Pharmaceutical University | Wu G.-Z.,Dalian Medical University | Wang Q.,Dalian Medical University
Oncotarget | Year: 2017

Background: In recent years, survivin expression had been investigated as a prognostic biomarker for renal cell carcinoma (RCC), however, the results were conflicting. This study was aimed to explore the association between survivin expression and clinicalpathological features and the prognostic value for cancerspecific survival (CSS) and overall survival (OS) in RCC. Results: Eleven studies with 1,697 subjects were included in this meta-analysis. The results showed that survivin expression was associated with higher tumor grade (OR=4.25, 95%CI: 3.04-5.95, p < 0.001), advanced tumor stage (OR=3.83, 95%CI: 2.01-7.3, p < 0.001) and lymph node metastasis (OR=4.19, 95%CI: 2.34-7.52, p < 0.001), but had no association with age, gender or distant metastasis. In addition, survivin expression was also correlated with poor CSS (HR=2.08, 95%CI: 1.07-4.05, p=0.032) and poor OS (HR=2.28, 95%CI: 1.57-3.33, p < 0.001). Materials and Methods: Literature was searched by PubMed, Embase and Web of Science. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were extracted from eligible studies. Fixed or random effects model were used to calculate pooled HRs and 95%CIs according to heterogeneity. Conclusions: This study demonstrated that survivin expression was associated with more aggressive clinical features and predicted poor CSS and OS in patients with RCC.

Li X.,China Pharmaceutical University | Yang L.,China Pharmaceutical University | Yang Y.,China Pharmaceutical University | Shao M.,China Pharmaceutical University | Liu Y.,China Pharmaceutical University
Monoclonal Antibodies in Immunodiagnosis and Immunotherapy | Year: 2017

Human transferrin receptor (hTfR1), a type II homodimeric transmembrane protein, is extensively expressed at low levels in most normal human tissues. However, the expression level of hTfR1 in some tumor tissues and the blood-brain barrier (BBB) is comparatively higher. Therefore, we developed an hTfR1 monoclonal antibody 2C9, which may be utilized to deliver drugs across the BBB through receptor-mediated endocytosis in the future. 2C9 was obtained by hybridoma cells fused by the SP2/0-Ag14 cell line and splenic B cells from hTfR1-immunized BALB/c mice. In this study, we used indirect ELISA, Western blot, and immunofluorescence to explore the characterization and application of MAb 2C9. The results showed that the affinity constant (Kaff) of the MAb 2C9 produced from ascites was 2.85 × 10-8 M and its isotype is IgG2a (Kappa chain). Above all, this report provides a more comprehensive protocol to produce monoclonal antibodies against the extracellular domain of hTfR1. © Copyright 2017, Mary Ann Liebert, Inc. 2017.

Fang X.,China Pharmaceutical University | Tong Y.,China Pharmaceutical University | Tian H.,China Pharmaceutical University | Ning H.,China Pharmaceutical University | And 2 more authors.
Experimental Cell Research | Year: 2017

In vitro immunization with antigens and cytokines triggers specific human B-cell response in short periods and is therefore superior to conventional in vivo immunization for antibody development. However, this new technology is limited by low efficiency, poor reproducibility, and requirement of pre-immunized lymphocytes. In this study, we demonstrate a novel method for de novo inducing antigen-specific human B cells in vitro. Unlike previous in vitro immunization of unfractionated PBMCs, we firstly optimized the conditions for inducing monocyte-derived dendritic cells (DCs) to efficiently capture, process, and present antigens. Instead of using the conventional method to activate Th2 cells for in vitro immunization, we succeeded to differentiate naïve CD4+ T cells into T follicular helper (Tfh) cells using antigen-sensitized DCs and cytokine cocktail. We discovered the differentiated T cells expressed ICOS, PD-1, BCL-6, and IL-21 at high levels. After 12 days of T-B co-culture, we observed induced T cells efficiently promoted naïve B cells to differentiate into plasmablasts secreting antigen-specific antibodies, with expression of Blimp-1 and AID related to affinity maturation and class switching. Thus, we established a new co-culture system with naïve lymphocyte populations for de novo acquisition of specifically in vitro immunized B cells potentially for development of therapeutic antibodies, which also provides novel insights into understanding the complex interactions among immune cells in lymph nodes. © 2017 Elsevier Inc.

Wang L.,China Pharmaceutical University | Du J.,China Pharmaceutical University | Zhou Y.,China Pharmaceutical University | Wang Y.,China Pharmaceutical University
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2017

Nanosuspension technology is currently undergoing dramatic expansion in pharmaceutical science research and development. However, most of the research efforts generally focus on formulation and potential beneficial description, while the research into potential toxicological effects and implications (i.e., in vivo safety and health effects) is lacking. This review identifies some of the key factors for studying nanosuspension safety and the potential undesired effects related to nanosuspension exposure. The key factors for discussion herein include particle characterization, preparation approach, composition, and excipients of the formulation and sterilization methods. A few comments on the primary and required safety aspects of each administration route are also reviewed. © 2016 Elsevier Inc.

RATIONALE:: Endothelial progenitor cells (EPCs) respond to SDF-1 through receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes induced EPCs dysfunction remains unknown. OBJECTIVE:: To determine the role of SDF-1 receptors in diabetic EPCs dysfunction. METHODS AND RESULTS:: CXCR7 expression, but not CXCR4 was reduced in EPCs from db/db mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, while up-regulation of CXCR7 rescued angiogenic function of EPCs from db/db mice. In normal EPCs treated with oxidized low-density lipoprotein (ox-LDL) or high glucose (HG) also reduced CXCR7 expression, impaired tube formation and increased oxidative stress and apoptosis. The damaging effects of ox-LDL or HG were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus (CXCR7-EPCs) but not in EPCs transduced with control lentivirus (Null-EPCs). Most importantly, CXCR7-EPCs were superior to Null-EPCs for therapy of ischemic limbs in db/db mice. Mechanistic studies demonstrated that ox-LDL or HG inhibited Akt and GSK-3β phosphorylation, nuclear export of Fyn and nuclear localization of Nrf2, blunting Nrf2 downstream target genes HO-1, NQO-1 and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in CXCR7-EPCs. Furthermore, inhibition of PI3K/Akt prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo. CONCLUSIONS:: Elevated expression of CXCR7 enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by an Akt/GSK-3β/Fyn pathway via increased activity of Nrf2. © 2017 American Heart Association, Inc.

Gao Y.,Zhejiang University of Technology | Zhang C.,Zhejiang University of Technology | Peng S.,China Pharmaceutical University | Chen H.,China Pharmaceutical University
Sensors and Actuators, B: Chemical | Year: 2017

A new Schiff-base fluorescence probe CS containing benzimidazole and coumarin fluorophores was synthesized and characterized by NMR, IR and ESI-MS. Fluorescence and absorption spectra show the unique changes in the presence of Hg2+ and Cu2+. Hg2+ induces a remarkable fluorescence enhancement and results in mercury-promoted hydrolysis of a mercury-CS complex to convert the imine group to the aldehyde group. Cu2+ leads to a colorimetric change from colorless to pale yellow and causes formation of a copper-CS complex. Thus, CS can act as a fluorescent chemodosimeter for Hg2+ and a naked-eye chemosensor Cu2+. The cell imaging experiments for Hg2+ show a slow enhancement of a bright blue fluorescence with increasing incubation time, while Cu2+ instantly quenches the fluorescence and then the fluorescence intensity has no further change by extending the incubation time. Therefore, the probe CS shows its potential application for simultaneous differential detection of Hg2+ and Cu2+ in living cells based on the fluorescence response time. © 2016 Elsevier B.V.

Wang Y.,Center for Drug Delivery and Nanomedicine | Wang Y.,China Pharmaceutical University | Xie Y.,Center for Drug Delivery and Nanomedicine | Li J.,Center for Drug Delivery and Nanomedicine | And 5 more authors.
ACS Nano | Year: 2017

Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells that are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the codelivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of codelivering ICG and TPZ in a single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy. © 2017 American Chemical Society.

Liu Z.,China Pharmaceutical University | Sun Q.,China Pharmaceutical University | Wang X.,China Pharmaceutical University
Translational Oncology | Year: 2017

Polo-like kinase 1 (PLK1) plays an important role in the initiation, maintenance, and completion of mitosis. Dysfunction of PLK1 may promote cancerous transformation and drive its progression. PLK1 overexpression has been found in a variety of human cancers and was associated with poor prognoses in cancers. Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis. Thus, PLK1 is expected to be a potential target for cancer therapy. In this article, we examined PLK1’s structuralcharacteristics,its regulatory roles in cell mitosis, PLK1 expression, and its association with survival prognoses of cancer patients in a wide variety of cancer types, PLK1 interaction networks, and PLK1 inhibitors under investigation. Finally, we discussed the key issues in the development of PLK1-targeted cancer therapy. © 2016 The Authors. Published by Elsevier Inc.

Guerram M.,China Pharmaceutical University | Hamdi A.M.,China Pharmaceutical University | Zhang L.-Y.,China Pharmaceutical University | Jiang Z.,China Pharmaceutical University
Current Cancer Drug Targets | Year: 2017

The evolution of genomic research enabled the genetic and molecular profiling of breast cancer and revealed the profound complexity and heterogeneity of this disease. Subtypes of breast cancer characterized by mutations and/or amplifications of some proto-oncogenes are associated with an increased rate of recurrence and poor prognosis. They represent a challenge in the clinic with limited arsenal to attack them. Nowadays, metabolic reprogramming is firmly established as a hallmark of cancer. An increased rate of lipid and protein syntheses in cancerous tissues, a direct consequence of alterations in key metabolic enzymes involved in these pathways, is now recognized as an important aspect of the rewired metabolism of neoplastic cells. Over the past several years, accumulating evidence has revealed that mutations or amplifications of some proto-oncogenes are primarily involved in this metabolic dysregulation. It is thus critically important to dissect the molecular mechanisms tumors use to link metabolic reprogramming with upstream altered signaling. In this article, we review the recent findings that support the importance of lipid and protein biosyntheses in breast tumorigenesis, discuss the crosstalk between growth factor signal transduction and key metabolic enzymes involved in these processes, and point out the potentials of developing new strategies and therapeutics to target these key parameters in order to help breast cancer patients by providing new therapeutic opportunities. © 2017 Bentham Science Publishers.

Wang C.,China Pharmaceutical University | Nie X.-G.,China Pharmaceutical University
Chemistry - A European Journal | Year: 2017

Enzyme mimics have been widely used as alternatives to natural enzymes. However, the catalytic performances of enzyme mimics are often decreased due to different spatial structures or absence of functional groups compared to natural enzymes. Here, we report a highly efficient enzyme-like catalytic performance of gold nanoparticles (AuNPs) by visible-light stimulation. The enzyme-like reaction is evaluated by the catalytic reaction of AuNPs oxidizing a typical chromogenic substrate 3,3′,5,5′-tetramethylbenzydine (TMB) with hydrogen peroxide as an oxidant. From investigations of the wavelength-dependent reaction rate, radical capture, hole-donor addition, and dark-field scattering spectroscopy experiments, it is revealed that the strong plasmonic absorption of AuNPs facilitates generation of hot electrons, which are transfered from AuNPs to the adsorbed reactant molecule, greatly promoting the catalytic performance of the enzyme-like catalytic reaction. The present work provides a simple method for improving the performance of enzyme mimics, which is expected to find further application in the field of plasmon-enhanced biocatalysis and biosensors. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Li Q.,China Pharmaceutical University | Yang H.,China Pharmaceutical University | Chen Y.,Nanjing University | Sun H.,China Pharmaceutical University
European Journal of Medicinal Chemistry | Year: 2017

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders with notable factor of dysfunction in cholinergic system. Low ACh level can be observed in the pathogenesis of AD. Several AChE inhibitors have already been used for clinical treatments. However, other than normal conditions, ACh is mostly hydrolyzed by BuChE in progressed AD. Account for an increased level of BuChE and decreased level of AChE in the late stage of AD, development of selective BuChE inhibitor is of vital importance. Up till now, compounds with various scaffolds have been discovered to selectively inhibit BuChE. Different effective anti-BuChE molecules are concluded in this review. © 2017

Li D.-J.,Shanghai University | Li D.-J.,China Pharmaceutical University | Evans R.G.,Monash University | Yang Z.-W.,Shanghai University | And 7 more authors.
Hypertension | Year: 2011

Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the α7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. We tested the hypothesis that α7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the α7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and α7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor κB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in α7nAChR-/- mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension. © 2011 American Heart Association. All rights reserved.

Ling J.,China Pharmaceutical University | Wei B.,China Pharmaceutical University | Lv G.,University of Macau | Ji H.,China Pharmaceutical University | Li S.,University of Macau
Food Chemistry | Year: 2012

This study was to evaluate the anti-hyperlipidaemic and antioxidant effects of turmeric oil (TO), the supercritical fluid extract from turmeric, in hyperlipidaemic rats induced by a high-fat diet. TO significantly decreased (p < 0.05) the levels of serum total cholesterol, low-density lipoprotein cholesterol, triglyceride, and free fatty acid and increased (p < 0.05) that of high-density lipoprotein cholesterol in this model. It also markedly elevated (p < 0.05) the activities of superoxide dismutase and glutathione peroxidase and lowered (p < 0.05) maleic dialdehyde activity, to suppress oxidative reactions. Besides, histological morphology examination showed that TO prevented the damage of liver tissues induced by high-fat diet. Thus, the findings indicate that TO might provide protection against cardiovascular diseases. © 2011 Elsevier Ltd. All rights reserved.

Tu Z.,Nanjing University of Posts and Telecommunications | Ma Y.,China Pharmaceutical University | Akers W.,Washington University in St. Louis | Achilefu S.,Washington University in St. Louis | Gu Y.,China Pharmaceutical University
Journal of Cancer Research and Clinical Oncology | Year: 2014

Introduction: Our preliminary study on repressing colorectal tumors by recombinant adenoviruses (Ads) delivering the human ERβ gene (Ad-ERβ) has achieved positive result. Methods: In this study, hydrophobic fluorescent dyes ICG-Der-01 was entrapped into the N-succinyl-N′-octyl chitosan (SOC) micelles to form the near infrared absorbing dyes SOC-ICG-Der-01 and SOC-ICG-Der-01 mediated near infrared laser (SOC-ICG-Der-01/NIR) thermotherapy was combined with Ad-ERβ gene therapy to regress colon cancer in vivo. Results: Firstly, the antitumor efficacies of SOC-ICG-Der-01/NIR thermotherapy were investigated on S180 ascites tumor-bearing mice. Results indicated that, the average tumor volume of SOC-ICG-Der-01/NIR group was the smallest among the three treatment groups. Then, thermotherapy with SOC-ICG-Der-01/NIR combined with Ad-ERβ gene therapy to treat HCT-116 colon cancer xenograft model was investigated. Further results demonstrated that, SOC-ICG-Der-01/NIR thermotherapy showed the significantly inhibitory efficiency compared with control group and Ad-ERβ enhanced the therapeutic effect of SOC-ICG-Der-01/NIR. Conclusion: These findings demonstrated that combined administration of Ad-ERβ with SOC-ICG-Der-01/NIR thermotherapy represents a promising colon cancer therapeutic strategy. © 2014 Springer-Verlag.

Liu W.,Free University of Berlin | Liu W.,China Pharmaceutical University | Gust R.,University of Innsbruck
Coordination Chemistry Reviews | Year: 2016

The clinical success of platinum-based chemotherapeutic agents was of enormous impact on the discovery of novel metal N-heterocyclic carbene (NHC) complexes as potential anti-cancer drugs. During the last years, the research on cytotoxic transition metal (e.g. Ag, Au, Pt, Pd, Cu, Hg, Ru, Os, Rh and Ir) NHC complexes was successful and the results are remarkable. In this review, we provide an update on the recent advances in this direction, which reflects new discoveries since the publication of our previous review. The anti-tumor properties along with the mechanisms of action for these complexes as well as possible structure–activity relationships are discussed. © 2016 Elsevier B.V.

Chen G.-T.,China Pharmaceutical University | Ma X.-M.,China Pharmaceutical University | Liu S.-T.,China Pharmaceutical University | Liao Y.-L.,China Pharmaceutical University
Carbohydrate Polymers | Year: 2012

The crude polysaccharides (GFP) were isolated from the fruiting bodies of Grifola frondosa and purified by DEAE cellulose-52 chromatography and Sephadex G-100 size-exclusion chromatography in that order. Three main fractions, GFP-1, GFP-2 and GFP-3, were obtained through the isolation and purification steps. Then the antioxidant activities of these three fractions were investigated in vitro. The results showed that GFP-1, GFP-2 and GFP-3 possessed significant inhibitory effects on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, hydroxyl radical and superoxide radical; their reducing power, ferrous ions chelating effect and the inhibition ability of the rat liver lipid oxidation where also strong. These results suggest that G. frondosa polysaccharides could be a suitable natural antioxidant and may be the functional foods for humans. © 2012 Elsevier Ltd. All rights reserved.

Geng J.,National University of Singapore | Zhu Z.,China Pharmaceutical University | Qin W.,Hong Kong University of Science and Technology | Ma L.,Nanyang Technological University | And 6 more authors.
Nanoscale | Year: 2014

Near-infrared (NIR) fluorescence signals are highly desirable to achieve high resolution in biological imaging. To obtain NIR emission with high brightness, fluorescent nanoparticles (NPs) are synthesized by co-encapsulation of 2,3-bis(4-(phenyl(4-(1,2,2-triphenylvinyl)phenylamino)phenyl)fumaronitrile (TPETPAFN), a luminogen with aggregation-induced emission (AIE) characteristics, and a NIR fluorogen of silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) (NIR775) using 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] as the encapsulation matrix. The good spectral overlap between the emission of TPETPAFN and the absorption of NIR775 leads to efficient energy transfer, resulting in a 47-fold enhancement of the NIR775 emission intensity upon excitation of TPETPAFN at 510 nm as compared to that upon direct excitation of NIR775 at 760 nm. The obtained fluorescent NPs show sharp NIR emission with a band width of 20 nm, a large Stokes shift of 275 nm, good photostability and low cytotoxicity. In vivo imaging study reveals that the synthesized NPs are able to provide high fluorescence contrast in live animals. The Förster resonance energy transfer strategy overcomes the intrinsic limitation of broad emission spectra for AIE NPs, which opens new opportunities to synthesize organic NPs with high brightness and narrow emission for potential applications in multiplex sensing and imaging. © 2013 The Royal Society of Chemistry.

Sun Y.,China Pharmaceutical University | Li J.,China Pharmaceutical University | Xiao N.,China Pharmaceutical University | Wang M.,University of Macau | And 5 more authors.
Pharmacological Research | Year: 2014

Adipose and endothelial dysfunction is tightly associated with cardiovascular diseases in obesity and insulin resistance. Because perivascular adipose tissue (PVAT) surrounds vessels directly and influences vessel functions through paracrine effect, and AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) show similarities in modulation of metabolic pathway, we hypothesized that activation of AMPK and SIRT1 in PVAT might regulate the endothelial function in pathological settings. Thus, in this study, we focused on the regulation of AMPK and SIRT1 activities implicated in adipocytokine expression and endothelial homeostasis under inflammatory conditions by using salicylate, metformin, AICA riboside (AICAR) and resveratrol as AMPK activating agents. We prepared conditioned medium (CM) by stimulating PVAT with palmitic acid (PA) and observed the effects of AMPK activating agents on adipocytokine expression and vessel vasodilation in rats. Moreover, we explored the effects of resveratrol and metformin in fructose-fed rats. We observed that PA stimulation induced inflammation and dysregulation of adipocytokine expression accompanied with reduced AMPK activity and SIRT1 abundance in PVAT. AMPK activating agents inhibited NF-κB p65 phosphorylation and suppressed gene expression of pro-inflammatory adipocytokines, and upregulated adiponectin and PPARγ expression in PVAT in an AMPK/SIRT1-interdependent manner. Meanwhile, CM stimulation impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Pretreatment of CM with AMPK-activating agents enhanced eNOS phosphorylation in the aorta and restored the loss of endothelium-dependent vasodilation, whereas this action was abolished by co-treatment with AMPK inhibitor compound C or SIRT1 inhibitor nicotinamide. Long-term fructose-feeding in rats induced dysregulation of adipocytokine expression in PVAT and the loss of endothelium-dependent vasodilation, whereas these alterations were reversed by oral administration of resveratrol and metformin. Altogether, pharmacological activation of AMPK beneficially regulated adipocytokine expression in PVAT and thus ameliorated endothelial dysfunction against inflammatory insult in an AMPK/SIRT1-interdependent manner. © 2014 Elsevier Ltd.

Gao C.,Peking University | Gao C.,Novo Nordisk AS | Xu F.,Peking University | Xu F.,China Pharmaceutical University | Liu G.G.,Peking University
Social Science and Medicine | Year: 2014

This paper is intended to assess the primary effects on cost, utilization and quality of care from payment reform of capitation and open enrollment in Changde city, Hunan Province of China. Open enrollment policy was introduced to deal with possible cream skimming associated with capitation. Based on the longitudinal Urban Resident Basic Medical Insurance (URBMI) Household Survey, this study analyses the URBMI data through a set of regression models. The original data included over five thousand inpatient admissions during the study period between 2008 and 2010. The study finds the payment reform to reduce its inpatient out-of-pocket cost by 19.7%, out-of-pocket ratio by 9.5%, and length of stay by 17.7%. However, the total inpatient cost, drug cost ratio, treatment effect, and patient satisfaction showed little difference between Fee-For-Service and capitation models. We conclude that the payment reform in Changde did not reduce overall inpatient expenditure, but it decreased the financial risk and length of stay of inpatient patients without compromising quality of care. The findings would contribute to the health care payment literatures from developing countries and open further research tracks on the ability of open enrollment to compensate for capitation drawbacks. © 2014 Elsevier Ltd.

Chen G.,Flinders University | Liu G.G.,Peking University | Xu F.,China Pharmaceutical University
PharmacoEconomics | Year: 2014

Background: The Urban Resident Basic Medical Insurance (URBMI), launched in 2007 by the State Council, aims to cover around 420 million urban residents in China. Objective: This study aimed to assess the impact of URBMI on health services access (especially inpatient utilisation) in urban China. Methods: Data was drawn from the recent four-wave URBMI Survey (2008-2011). Probit and recursive bivariate probit models have been adopted to handle the possible endogeneity of medical insurance in the utilisation equations. Results: Based on the preferred results from the unbalanced four-wave panel data, we found that the URBMI had significantly increased the likelihood of receiving inpatient treatment in the past year. However, the insurance effect on reducing the refused hospitalisation was insignificant. Finally, the URBMI had also increased the probability of using outpatient services in the past 2 weeks, although the insurance reimburses mainly against critical outpatient care. Conclusions: Given that it is still early days for the URBMI scheme, the positive effect on health services utilisation is appreciable. © 2013 Springer International Publishing.

Zhang Q.,China Pharmaceutical University | Du Y.,China Pharmaceutical University | Du S.,Peking University
Journal of Chromatography A | Year: 2014

Nanoparticles (NPs) and ionic liquids (ILs) have been extensively studied and have aroused considerable interest in separation science; however, the employment of ILs-dispersed NPs as buffer modifiers for CE chiral separation has not been previously studied. In this work, we describe a new CE method using ILs dispersed multi-walled carbon nanotubes (ILs-MWNTs) as a modifier for enantioseparation with a polysaccharide, chondroitin sulfate E (CSE), as the chiral selector. As observed, significantly improved separations, including better enantioselectivity and improved peak shapes, were obtained in the ILs-MWNTs modified separation system for all drug enantiomers compared to the single CSE system. Several parameters affecting the enantioseparation, such as the choice of ILs and carbon nanoparticles, ILs-MWNTs concentration, chiral selector concentration, buffer pH and applied voltage, were systematically investigated. Satisfactory separations were achieved when 2.4μg/mL ILs-MWNTs were introduced into the 20mM Tris/H3PO4 buffer solution containing 2.5% CSE at pH 2.8-3.4 with a 15kV applied voltage. A brief mechanism of the enhanced enantioseparation capability of the ILs-MWNTs modified chiral separation system was also discussed. © 2014 Elsevier B.V.

Ding L.,Yancheng Institute of Technology | Qiu J.,Yancheng Institute of Technology | Wei J.,Yancheng Institute of Technology | Zhu Z.,China Pharmaceutical University | Zhu Z.,National University of Singapore
Polymer Chemistry | Year: 2014

A novel divergent approach was developed for the first time for the synthesis of linear-dendritic polyphosphoester (PPE) structures using an acrylated poly(ethylene glycol) methyl ether as a linear macromolecular chain stopper by acyclic diene metathesis (ADMET) polymerization of phosphoester functional asymmetric α,ω-diene monomers. This synthesis is remarkable, because unlike all others, each low-generation linear-dendron copolymer could be readily converted, by thiol-Michael addition click reaction and esterification, to a new selective macromolecular chain stopper by subsequent ADMET polymerization to synthesize high-generation linear-dendron block PPEs, and it requires no means of purification other than a simple precipitation. The prepared linear-dendritic PPEs can self-assemble spontaneously in a selective solvent to form polymeric nanoparticles, which were characterized in detail by DLS, AFM, and TEM analyses. To the best of our knowledge, this is the first report that describes the synthesis of linear-dendron-like block PPEs via ADMET polymerization. Consequently, this provides a versatile strategy not only for the synthesis of biodegradable and amphiphilic block PPEs with linear-dendron-like architecture but also for the fabrication of biocompatible nanoparticles with a suitable size for biomedical applications. © 2014 the Partner Organisations.

Zhong W.,China Pharmaceutical University | Zhang C.,China Pharmaceutical University | Li H.,Nanjing University
Microchimica Acta | Year: 2012

Multicolor and water-soluble CdTe quantum dots (QDs) were synthesized with thioglycolic acid (TGA) as stabilizer. These QDs have a good size distribution, display high fluorescence quantum yield, and can be applied to the ultrasensitive detection of Pb(II) ion by virtue of their quenching effect. The size of the QDs exerts a strong effect on sensitivity, and quenching of luminescence is most effective for the smallest particles. The quenching mechanism is discussed. Fairly selective detection was accomplished by utilizing QDs with a diameter of 1. 6 nm which resulted in a detection limit of 4. 7 nmol L -1 concentration of Pb(II). The method was successfully applied to the determination of Pb(II) in spinach and citrus leaves, and the results are in good agreement with those obtained with atomic absorption spectrometry. © 2011 Springer-Verlag.

Ding L.,Yancheng Institute of Technology | Qiu J.,Yancheng Institute of Technology | Wei J.,Yancheng Institute of Technology | Zhu Z.,China Pharmaceutical University | Zhu Z.,National University of Singapore
Macromolecular Rapid Communications | Year: 2014

Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA)-based brush poly(phosphoamidate)s are successfully synthesized by a combination of ring-opening metathesis polymerization (ROMP) and atom transfer radical polymerization (ATRP) following either a commutative two-step procedure or a straightforward one-pot process using Grubbs ruthenium-based catalysts for tandem catalysis. Compared with the traditional polymerization method, combining ROMP and ATRP in a one-pot process allows the preparation of brush copolymers characterized by a relatively moderate molecular weight distribution and quantitative conversion of monomer. Moreover, the surface morphologies and aggregation behaviors of these polymers are studied by AFM and TEM measurements. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hou L.,China Pharmaceutical University | Fan Y.,China Pharmaceutical University | Yao J.,China Pharmaceutical University | Zhou J.,China Pharmaceutical University | And 3 more authors.
Carbohydrate Polymers | Year: 2011

As a novel nanocarrier for simultaneous delivery of multiple anticancer drugs, low molecular weight heparin-all-trans-retinoid acid (ATRA) (LHR) conjugate was developed. Amphiphilic LHR conjugate had markedly lower anticoagulant activity, and could self-assemble to form nanoparticles for loading hydrophobic drugs. The critical aggregation concentrations of LHR conjugates were varied from 407 to 40 mg/L. Paclitaxel (PTX)-loaded LHR nanoparticles were prepared by the dialysis method, with particle sizes in the range of 228.0-108.9 nm. The maximum drug-loading was as much as 33.1% with an entrapment efficiency of 93.1%. They displayed enhanced PTX-induced cytotoxicity to HepG2 cells compared to PTX solution. Hemolysis and cytotoxicity studies showed that LHR conjugate was a safe material for intravenous administration. Moreover, the pharmacokinetic profiles indicated that PTX-loaded LHR nanoparticles contributed to an extended circulation of PTX and ATRA. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising anticancer drug delivery system for combination chemotherapy. © 2011 Elsevier Ltd. All rights reserved.

Zhu H.-J.,University of Florida | Wang X.,China Pharmaceutical University | Markowitz J.S.,University of Florida
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Clopidogrel pharmacotherapy is associated with substantial interindividual variability in clinical response, which can translate into an increased risk of adverse outcomes. Clopidogrel, a recognized substrate of hepatic carboxylesterase 1 (CES1), undergoes extensive hydrolytic metabolism in the liver. Significant interindividual variability in the expression and activity of CES1 exists, which is attributed to both genetic and environmental factors. We determined whether CES1 inhibition and CES1 genetic polymorphisms would significantly influence the biotransformation of clopidogrel and alter the formation of the active metabolite. Coincubation of clopidogrel with the CES1 inhibitor bis(4-nitrophenyl) phosphate in human liver s9 fractions significantly increased the concentrations of clopidogrel, 2-oxo-clopidogrel, and clopidogrel active metabolite, while the concentrations of all formed carboxylate metabolites were significantly decreased. As anticipated, clopidogrel and 2-oxoclopidogrel were efficiently hydrolyzed by the cell s9 fractions prepared from wild-type CES1 transfected cells. The enzymatic activity of the CES1 variants G143E and D260fs were completely impaired in terms of catalyzing the hydrolysis of clopidogrel and 2-oxo-clopidogrel. However, the natural variants G18V, S82L, and A269S failed to produce any significant effect on CES1- mediated hydrolysis of clopidogrel or 2-oxo-clopidogrel. In summary, deficient CES1 catalytic activity resulting from CES1 inhibition or CES1 genetic variation may be associated with higher plasma concentrations of clopidogrel-active metabolite, and hence may enhance antiplatelet activity. Additionally, CES1 genetic variants have the potential to serve as a biomarker to predict clopidogrel response and individualize clopidogrel dosing regimens in clinical practice. © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Xie W.,CAS Shanghai Institute of Organic Chemistry | Jiang G.,China Pharmaceutical University | Liu H.,China Pharmaceutical University | Hu J.,China Pharmaceutical University | And 5 more authors.
Angewandte Chemie - International Edition | Year: 2013

A shorter path: A highly enantioselective bromocyclization of tryptamine has been developed using an anionic chiral phase-transfer catalyst. This method provides a direct approach for preparing chiral 3-bromopyrroloindoline from tryptamine, which enables a four-step enantioselective synthesis of (-)-chimonanthine. PG=protecting group. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chen S.,China Pharmaceutical University | An F.-M.,China Pharmaceutical University | Yin L.,China Pharmaceutical University | Liu A.-R.,Nanjing Southeast University | And 2 more authors.
Neuroscience | Year: 2014

We have previously demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist ameliorated neurodegenerative changes in rat models of diabetes-related Alzheimer's disease (AD), and protected neurons from glucose toxicity in vitro. Herein, we investigated the effects of GLP-1 receptor mediates on cell toxicity and tau hyperphosphorylation induced by advanced glycation end products (AGEs), which are associated with glucose toxicity, and the molecular mechanism in PC12 cells and the primary hippocampal neurons. Our study demonstrated that the similar protection effects of GLP-1 existed in PC12 cells treated with glucose-bovine serum albumin (BSA) in hyperglycemic conditions or with glycoaldehyde-BSA alone. Additionally, glucose-BSA alone did not induce significant cytotoxicity in PC12 cells, but resulted in tau hyperphosphorylation in primary hippocampal neurons in 24. h. And we found that GLP-1 could reduce cell tau phosphorylation induced by high glucose or glucose-BSA. Furthermore, our data in the present study suggested that GLP-1 regulated tau phosphorylation induced by AGEs through a signaling pathway involving glycogen synthase kinase 3β (GSK-3β), similarly to the GSK-3β inhibitor, lithium chloride. Our findings suggest that GLP-1 can protect neurons from diabetes-associated AGE insults in vitro, and provide new evidence for a potential therapeutic value of GLP-1 receptor agonist in the treatment of AD especially diabetes-related AD. © 2013 IBRO.

Deng D.,China Pharmaceutical University | Gu Y.,China Pharmaceutical University
Langmuir | Year: 2013

In this paper, we report on the versatile self-assembly of water-soluble thiol-capped CdTe quantum dots (QDs), nanoparticles (NPs), or nanocrystals induced by l-cysteine (l-Cys). Major efforts are focused on the control of the self-organization of QDs into nanosheets (NSs), for example, by altering the solution pH and the QD size. The as-prepared nanosheets exhibit bright photoluminescence (PL) and retain the size-quantized properties of initial CdTe QDs, since they are actually formed by a 2D network of assembled QDs. By optical techniques, TEM, EDX, powder XRD, etc., it is found that the unique l-Cys-induced external destabilization is responsible for the template-free self-organization process, with the further assistance of the specific NP-NP interactions. And the internal chemical stability of initial CdTe QDs also is proven for the first time to play an important role. These results help to enhance the current understanding about the mechanism for the destabilization of colloidal NPs and their self-assembly behavior. © 2013 American Chemical Society.

Li G.-F.,Shanghai University | Li G.-F.,China Pharmaceutical University | Wang K.,Shanghai University | Chen R.,China Pharmaceutical University | And 3 more authors.
Acta Pharmacologica Sinica | Year: 2012

Aim: To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. Methods: Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB-PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients. Results: The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C max, and T max) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles. Conclusion: The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency. © 2012 CPS and SIMM All rights reserved.

Ho W.E.,National University of Singapore | Ho W.E.,Massachusetts Institute of Technology | Xu Y.-J.,National University of Singapore | Xu F.,China Pharmaceutical University | And 5 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2013

Metabolomics refers to the comprehensive analysis of metabolites in biological systems, and has been employed to study patients with asthma based on their urinary metabolite profile. We hypothesize that airway allergic asthma would affect metabolism in the lungs, and could be detected in bronchoalveolar lavage (BAL) fluid (BALF) using a combined liquid chromatography- and gas chromatographymass spectrometry (MS) platform. The objective of this study was to investigate changes of lung metabolism in allergic asthma by metabolomic analysis of BALF. BALB/c mice were sensitized and challenged with ovalbumin to develop experimental asthma. Dexamethasone was administered to study the effects of corticosteroids on lung metabolism. Metabolites in BALF were measured using liquid chromatography-MS and gas chromatography-MS, and multivariate statistical analysis was performed by orthogonal projections to latent structures discriminant analysis. Metabolomic analysis of BALF from ovalbumin-challenged mice revealed novel changes in metabolic pathways in the lungs as compared with control animals. Thesemetabolite changes suggest alterations of energy metabolism in asthmatic lungs, with increases of lactate, malate, and creatinine and reductions in carbohydrates, such as mannose, galactose, and arabinose. Lipid and sterol metabolism were affected with significant decreases in phosphatidylcholines, diglycerides, triglycerides, cholesterol, cortol, and cholic acid. Dexamethasone treatment effectively reversed many key metabolite changes, but was ineffective in repressing lactate, malate, and creatinine, and induced additional metabolite changes. Metabolomic analysis of BALF offers a promising approach to investigating allergic asthma. Our overall findings revealed considerable pathway changes in lung metabolismin asthmatic lungs, including energy, amino acids, and lipid metabolism. Copyright © 2013 by the American Thoracic Society.

Zhuang J.,China Pharmaceutical University | Ping Q.,China Pharmaceutical University | Song Y.,University of South Australia | Qi J.,China Pharmaceutical University | Cui Z.,Peking University
International Journal of Nanomedicine | Year: 2010

The objective of this work was to evaluate the physical properties and in vivo circulation of chitosan (CH)-coated liposomes of mitoxantrone (MTO). Changes in particle size and zeta potential confirmed the existence of a coating layer on the surface of liposomes. The in vitro release of adsorbed CH from the liposomes was significantly slower than CH solution, indicating the stable interaction between CH and liposomes. The physical stability of the CH-coated liposomes was evaluated by measuring the change in particle size before and after freeze-drying and rehydration. The smallest change was observed when saturated adsorption of CH occurred (0.3%). The sustained release in vitro of MTO from CH-coated liposomes confirmed the increased stability of liposomes. Systemic circulation of CH-coated MTO liposomes was examined. The 0.3% CH-coated liposomes showed the longest circulation time. It could be concluded that the prolonged retention time of the liposomes was closely related with CH coating and its stability effect. © 2010 Zhuang et al, publisher and licensee Dove Medical Press Ltd.

Xu F.,National University of Singapore | Li Z.,Singapore MIT Alliance for Research and Technology | Liu Y.,National University of Singapore | Zhang Z.,China Pharmaceutical University | And 2 more authors.
Mass Spectrometry Reviews | Year: 2011

The integration of liquid chromatography-mass spectrometry (LC-MS) with derivatization is a relatively new and unique strategy that could add value and could enhance the capabilities of LC-MS-based technologies. The derivatization process could be carried out in various analytical steps, for example, sampling, storage, sample preparation, HPLC separation, and MS detection. This review presents an overview of derivatization-based LC-MS strategy over the past 10 years and covers both the general principles and applications in the fields of pharmaceutical and biomedical analysis, biomarker and metabolomic research, environmental analysis, and foodsafety evaluation. The underlying mechanisms and theories for derivative reagent selection are summarized and highlighted to guide future studies. © 2011 Wiley Periodicals, Inc.

Ding Y.,China Pharmaceutical University | Wang W.,China Pharmaceutical University | Feng M.,Shanghai University | Wang Y.,Nanjing Medical University | And 6 more authors.
Biomaterials | Year: 2012

RNA interference holds tremendous potential as a therapeutic approach of malignant tumors. However, safe and efficient nanovectors are extremely lack for systemic delivery of small interfering RNA (siRNA). The study aimed to develop a biomimetic nanovector, reconstituted high density lipoprotein (rHDL), mediating targeted cholesterol-conjugated siRNA (Chol-siRNA) delivery for Pokemon gene silencing therapy. Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were prepared using thin-film dispersion method and their characteristics were investigated in detail. RHDL/Chol-siRNA complexes at the optimal volume ratio (lipid: Chol-siRNA) exhibited high Chol-siRNA-loading efficiency (∼99%), desirable nanoparticle size and excellent stability in serum. In addition, by analyzing Chol-siRNA release profile, rHDL/Chol-siRNA complexes displayed sustained-release characteristic and storage stability. Observations from FACS and confocal microscopic analyses revealed that rHDL-mediated carboxyfluorescein tagged Chol-siRNA (FAM-Chol-siRNA) transfection resulted in highly efficient uptake and specific cytoplasmic delivery of FAM-Chol-siRNA into human hepatocellular carcinoma cell line HepG2 via HDL-receptor mediated mechanism. In vitro cytotoxicity, apoptosis and Western-blot analyses revealed significant cellular growth inhibition and decrease of Pokemon and Bcl-2 protein expression in HepG2 cells treated with Chol-siRNA-Pokemon-loaded rHDL nanoparticles (rHDL/Chol-siRNA-Pokemon complexes), respectively. In in vivo studies, the near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-siRNA complexes) obviously accumulated in tumor of nude mice after i.v. administration as compared with Cy5-Chol-siRNA-loaded lipoplexes (Lipos/Cy5-Chol-siRNA complexes). Morover, rHDL/Chol-siRNA-Pokemon complexes demonstrated great tumor growth inhibition and significant decrease of Pokemon and Bcl-2 protein expression in vivo. These results suggested that rHDL should be an ideal non-viral tumor-targeting vector for Chol-siRNA transfer, and rHDL-mediated Chol-siRNA-Pokemon delivery might be a promising new strategy for gene therapy in hepatocellular carcinoma. © 2012 Elsevier Ltd.

Jiang T.,China Pharmaceutical University | Zhang Z.,Jiangsu Province Academy of Traditional Chinese Medicine | Zhang Y.,China Pharmaceutical University | Lv H.,China Pharmaceutical University | And 4 more authors.
Biomaterials | Year: 2012

Dual-functional liposomes with pH-responsive cell-penetrating peptide (CPP) and active targeting hyaluronic acid (HA) were fabricated for tumor-targeted drug delivery. A series of synthetic tumor pH-triggered CPPs rich in arginines and histidines were screened by comparing tumor cellular uptake efficiency at pH 6.4 with at pH 7.4, and R6H4 (RRRRRRHHHH) was obtained with the optimal pH-response. To construct R6H4-modified liposomes (R6H4-L), stearyl R6H4 was anchored into liposomes due to hydrophobic interaction. HA was utilized to shield positive charge of R6H4-L to assemble HA-coated R6H4-L (HA-R6H4-L) by electrostatic effect for protecting the liposomes from the attack of plasma proteins. The rapid degradation of HA by hyaluronidase (HAase) was demonstrated by the viscosity and zeta potential detection, allowing the R6H4 exposure of HA-R6H4-L at HAase-rich tumor microenvironment as the protection by HA switches off and cell-penetrating ability of R6H4 turns on. After HAase treatment, paclitaxel-loaded HA-R6H4-L (PTX/HA-R6H4-L) presented a remarkably stronger cytotoxicity toward the hepatic cancer (HepG2) cells at pH 6.4 relative to at pH 7.4, and additionally coumarin 6-loaded HA-R6H4-L (C6/HA-R6H4-L) showed efficient intracellular trafficking including endosomal/lysosomal escape and cytoplasmic liberation by confocal laser scanning microscopy (CLSM). In vivo imaging suggested the reduced accumulation of near infrared dye 15 (NIRD15)-loaded HA-R6H4-L (NIRD/HA-R6H4-L) at the tumor site, when mice were pre-treated with an excess of free HA, indicating the active tumor targeting of HA. Indeed, PTX/HA-R6H4-L had the strongest antitumor efficacy against murine hepatic carcinoma (Heps) tumor xenograft models in vivo. These findings demonstrate the feasibility of using tumor pH-sensitive CPPs and active targeting HA to extend the applications of liposomal nanocarriers to efficient anticancer drug delivery. © 2012 Elsevier Ltd.

Yao J.,China Pharmaceutical University | Zhang L.,China Pharmaceutical University | Zhang L.,Community Pharmacy | Zhou J.,China Pharmaceutical University | And 2 more authors.
Molecular Pharmaceutics | Year: 2013

An amphiphilic hyaluronic acid (HA)-g-all-trans retinoid acid (HRA) conjugate was successfully developed as a tumor-targeting nanocarrier for potentially synergistic combination chemotherapy of all-trans retinoid acid (ATRA) and paclitaxel (PTX). The HRA conjugate was synthesized by an imine reaction between HA-COOH and ATRA-NH2. PTX-loaded HRA nanoparticles possessed a high loading capacity, nanoscale particle sizes, and good biocompatible characteristics. Cell viability assays indicated that PTX-loaded HRA nanoparticles exhibited concentration- and time-dependent cytotoxicity. Moreover, they displayed obvious superiority in inducing the apoptosis of tumor cells. Cellular uptake analysis suggested that HRA nanoparticles could be efficiently taken up by cells via endocytic pathway and transport into the nucleus, contributing to HA receptor-mediated endocytosis and ATRA-induced nuclear translocation, respectively. Moreover, in vivo imaging analysis indicated that the accumulation of DiR-loaded HRA nanoparticles in tumor was increased obviously after intravenous administration as compared to free DiR solution, which confirmed that the HRA nanoparticles could assist the drugs targeting to the tumor. Furthermore, PTX-loaded HRA nanoparticles exhibited greater tumor growth inhibition effect in vivo with reducing the toxicity. Therefore, HRA nanoparticles can be considered as a promising targeted codelivery system for combination cancer chemotherapy. © 2013 American Chemical Society.

Cao Z.,University of California at Davis | Cao Z.,China Pharmaceutical University | Cui Y.,University of California at Davis | Nguyen H.M.,University of California at Davis | And 3 more authors.
Molecular Pharmacology | Year: 2014

Bifenthrin, a relatively stable type I pyrethroid that causes tremors and impairs motor activity in rodents, is broadly used. We investigated whether nanomolar bifenthrin alters synchronous Ca2+ oscillations (SCOs) necessary for activity-dependent dendritic development. Primary mouse cortical neurons were cultured 8 or 9 days in vitro (DIV), loaded with the Ca2+ indicator Fluo-4, and imaged using a Fluorescence Imaging Plate Reader Tetra. Acute exposure to bifenthrin rapidly increased the frequency of SCOs by 2.7-fold (EC50 = 58 nM) and decreased SCO amplitude by 36%. Changes in SCO properties were independent of modifications in voltage-gated sodium channels since 100 nM bifenthrin had no effect on the whole-cell Na+ current, nor did it influence neuronal resting membrane potential. The L-type Ca 2+ channel blocker nifedipine failed to ameliorate bifenthrin-triggered SCO activity. By contrast, the metabotropic glutamate receptor (mGluR)5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine] normalized bifenthrin-triggered increase in SCO frequency without altering baseline SCO activity, indicating that bifenthrin amplifies mGluR5 signaling independent of Na+ channel modification. Competitive [AP-5; (-)-2-amino-5-phosphonopentanoic acid] and noncompetitive (dizocilpine, or MK-801 [(5S, 10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10- imine maleate]) N-methyl-D-aspartate antagonists partially decreased both basal and bifenthrin-triggered SCO frequency increase. Bifenthrin-modified SCO rapidly enhanced the phosphorylation of cAMP response element-binding protein (CREB). Subacute (48 hours) exposure to bifenthrin commencing 2 DIV-enhanced neurite outgrowth and persistently increased SCO frequency and reduced SCO amplitude. Bifenthrin-stimulated neurite outgrowth and CREB phosphorylation were dependent on mGluR5 activity since MPEP normalized both responses. Collectively these data identify a new mechanism by which bifenthrin potently alters Ca2+ dynamics and Ca2+-dependent signaling in cortical neurons that have long term impacts on activity driven neuronal plasticity.

Zhang J.,Beijing Normal University | Zhang J.,China Pharmaceutical University | He M.,Beijing Normal University
Journal of Hazardous Materials | Year: 2010

Sorption and desorption isotherms of phenanthrene (PHE) on sediment organic matter (SOM) prepared at different combustion temperature were studied to examine the impact of SOM structure on sorption and desorption. With the increase of combustion temperature from 0 to 400°C, the aromatic groups (-CC) in SOM samples increased, while the aliphatic groups (-CH, -CH 2) and polar structures (-C-O, -OH) decreased. When the combustion temperature increased to 500°C, aliphatic structures, polar structures and most aromatic structures were burnt out, and the mineral materials were dominant in the sample. The increase of combustion temperature decrease the sorption isotherm nonlinearity index n value, and enhanced the adsorption capacity and desorption hysteresis for PHE on SOM. However, higher n value, lower sorption capacity and sorption irreversibility were presented in the sample treated at 500°C (T500). Positive correlations between single-point organic carbon-normalized distribution coefficient logK oc values and aromatic carbon (p<0.01) and negative correlations between logK oc values and aliphaticity or H/C ratios (p<0.05) were observed. There was a negative relation between hysteresis index (HI) value and aromatic carbon (p<0.01) and a negative trend of the sorption isotherm nonlinearity index n values and aromatic carbon (p<0.01). The above results indicated the dominance of aromatic structures in the sorption nonlinearity, sorption capacity and desorption hysteresis of PHE on SOM. © 2010 Elsevier B.V.

Jia L.-H.,China Pharmaceutical University | Liu Y.,Peking University | Li Y.-Z.,Peking University
Journal of Pharmaceutical Analysis | Year: 2011

An inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma atomic emission spectrometry (ICP-AES) was developed to determine 19 elements in safflower, a traditional Chinese medicinal herb from Xinjiang Autonomous Region and Henan Province of China. Totally 19 elements in safflower included heavy metals, i.e. As, Cd, Cu, Hg and Pb, and wholesome elements, i.e. Al, Ca, Co, Cr, Fe, Mg, Mn, Mo, Ni, P, Se, Sr, V and Zn. The results showed that the concentrations of heavy metals in safflower samples were both low, all of which met the national hygiene standards except for Pb in Xinjiang sample. Meanwhile, the distribution tendency of elements in the two samples was similar, which indicated that the plant might absorb given elements in a proportional way. The method can be used for the quality control of elements in safflower, and it provides a way for the determination of the contents of safflower from Xinjiang and Henan.

Hou L.,China Pharmaceutical University | Hou L.,Zhengzhou University | Yao J.,China Pharmaceutical University | Zhou J.,China Pharmaceutical University | Zhang Q.,Peking University
Biomaterials | Year: 2012

Amphiphilic low molecular weight heparin-all-trans-retinoid acid (LHR) conjugate, as a drug carrier for cancer therapy, was found to have markedly low toxicity and to form self-assembled nanoparticles for simultaneous delivery of paclitaxel (PTX) and all-trans-retinoid acid (ATRA) in our previous study. In the present study, PTX-loaded LHR nanoparticles were prepared and demonstrated a spherical shape with particle size of 108.9 nm. Cellular uptake analysis suggested rapid internalization and nuclear transport of LHR nanoparticles. In order to investigate the dynamic behaviors and targeting ability of LHR nanoparticles on tumor-bearing mice, near-infrared fluorescent (NIFR) dye DiR was encapsulated into the nanoparticles for ex vivo optical imaging. The results indicated that LHR nanoparticles could enhance the targeting and residence time in tumor site. Furthermore, in vivo biodistribution study also showed that the area under the plasma concentration time curve (AUC (0→inf)) values of PTX and ATRA for PTX-loaded LHR nanoparticles in tumor were 1.56 and 1.62-fold higher than those for PTX plus ATRA solution. Finally, PTX-loaded LHR nanoparticles demonstrated greater tumor growth inhibition effect in vivo without unexpected side effects, compared to PTX solution and PTX plus ATRA solution. These results suggest that PTX-loaded LHR nanoparticles can be considered as promising targeted delivery system for combination cancer chemotherapy to improve therapeutic efficacy and minimize adverse effects. © 2012 Elsevier Ltd.

Li Q.,Shanghai University | Chen J.,Shanghai University | Xiao Y.,Shanghai University | Xiao Y.,Shanghai University of Traditional Chinese Medicine | And 3 more authors.
BMC Genomics | Year: 2014

Background: Isatis indigotica Fort. is one of the most commonly used traditional Chinese medicines. Its antiviral compound is a kind of lignan, which is formed with the action of dirigent proteins (DIR). DIR proteins are members of a large family of proteins which impart stereoselectivity on the phenoxy radical-coupling reaction, yielding optically active lignans from two molecules of E-coniferyl alcohol. They exist in almost every vascular plant. However, the DIR and DIR-like protein gene family in I. indigotica has not been analyzed in detail yet. This study focuses on discovery and analysis of this protein gene family in I. indigotica for the first time.Results: Analysis of transcription profiling database from I. indigotica revealed a family of 19 full-length unique DIR and DIR-like proteins. Sequence analysis found that I. indigotica DIR and DIR-like proteins (IiDIR) were all-beta strand proteins, with a signal peptide at the N-terminus. Phylogenetic analysis of the 19 proteins indicated that the IiDIR genes cluster into three distinct subfamilies, DIR-a, DIR-b/d, and DIR-e, of a larger plant DIR and DIR-like gene family. Gene-specific primers were designed for 19 unique IiDIRs and were used to evaluate patterns of constitutive expression in different organs. It showed that most IiDIR genes were expressed comparatively higher in roots and flowers than stems and leaves.Conclusions: New DIR and DIR-like proteins were discovered from the transcription profiling database of I. indigotica through bioinformatics methods for the first time. Sequence characteristics and transcript abundance of these new genes were analyzed. This study will provide basic data necessary for further studies. © 2014 Li et al.; licensee BioMed Central Ltd.

Zhang Z.-F.,Peking University | Guo Y.,China Pharmaceutical University | Zhang J.-B.,Inner Mongolia University of Technology | Wei X.-H.,Peking University
Archives of Pharmacal Research | Year: 2011

The objective of this study was to evaluate the antitumor activity of chelerythrine chloride (CHE) and investigate its potential apoptotic induction mechanism in SMMC-7721 cells. Our results suggested that the proliferation of SMMC-7721 cells was inhibited by CHE in a time and dose dependent manner, with a significant accumulation in S phase, and the cells exhibited typical apoptotic features. Moreover, CHE remarkably induced apoptosis by disruption of the mitochondrial membrane potential, release of Cyt-c, activation of caspase-3, and cleavage of poly-ADP-ribose polymerase in a dose dependent manner. Furthermore, the expression of Bcl-xl was downregulated while Bax and Bid expression was upregulated, and no variation was found for Bcl-2. These results indicated that CHE may play an important role in suppression of tumor growth by inducing apoptosis in human hepatoma cells via the activation of a mitochondrial pathway and regulating the expression of Bcl-2 family proteins. © 2011 The Pharmaceutical Society of Korea and Springer Netherlands.

Xiong Y.,China Pharmaceutical University | Shen Y.,China Pharmaceutical University | Li H.,Chinese Pharmacopoeia Commission | Sun C.,China Pharmaceutical University | And 2 more authors.
Biomaterials | Year: 2012

A cisplatin-loaded nanoconjugate, poly(γ, l-glutamic acid)-citric acid-cisplatin [γ-PGA-CA-CDDP], as a tumor-targeted drug delivery system with sustained release capacity was successfully synthesized and characterized, and its antitumor activity was evaluated. The particle size (107 ± 6.3 nm) and average molecular weight (66 kDa) were determined by dynamic light scattering (DLS) and gel permeation chromatography (GPC), respectively. The nanoconjugate delivery system released platinum in a sustained manner in PBS at 37 °C with an initial burst release during the first 8 h and 50% cumulative release within 48 h. Both in-vitro and in-vivo studies showed that the toxicity of γ-PGA-CA-CDDP nanoconjugate significantly decreased by comparison to that of unconjugated CDDP. The maximum tolerated dose (MTD) of γ-PGA-CA-CDDP nanoconjugate was about 38 mg/kg versus 8 mg/kg for CDDP. No apathy or acute adverse reactions were observed in γ-PGA-CA-CDDP nanoconjugate groups while mice expressed apathy at all dose levels with CDDP treatment. In ICR mice, the area under the curve and total body clearance values for γ-PGA-CA-CDDP nanoconjugate were 9-fold and one-twentieth of the values for CDDP, respectively. With the aid of near-infrared fluorescence (NIRF) imaging system, it was demonstrated that γ-PGA-CA-CDDP nanoconjugate gradually accumulated at the tumor site within 15 min postinjection and exhibited prolonged retention for more than 8 h. In H22-implanted mice, γ-PGA-CA-CDDP showed a significantly higher antitumor activity versus CDDP. These results reveal that γ-PGA-CA-CDDP nanoconjugate with improved stability, reduced toxicity and prolonged in-vivo retention time holds great potential in terms of clinical application to cancer therapy. © 2012 Elsevier Ltd.

Chen J.,Shanghai University | Dong X.,Shanghai University | Li Q.,Shanghai University | Zhou X.,Shanghai University | And 5 more authors.
BMC Genomics | Year: 2013

Backgroud: Isatis indigotica is a widely used herb for the clinical treatment of colds, fever, and influenza in Traditional Chinese Medicine (TCM). Various structural classes of compounds have been identified as effective ingredients. However, little is known at genetics level about these active metabolites. In the present study, we performed de novo transcriptome sequencing for the first time to produce a comprehensive dataset of I. indigotica.Results: A database of 36,367 unigenes (average length = 1,115.67 bases) was generated by performing transcriptome sequencing. Based on the gene annotation of the transcriptome, 104 unigenes were identified covering most of the catalytic steps in the general biosynthetic pathways of indole, terpenoid, and phenylpropanoid. Subsequently, the organ-specific expression patterns of the genes involved in these pathways, and their responses to methyl jasmonate (MeJA) induction, were investigated. Metabolites profile of effective phenylpropanoid showed accumulation pattern of secondary metabolites were mostly correlated with the transcription of their biosynthetic genes. According to the analysis of UDP-dependent glycosyltransferases (UGT) family, several flavonoids were indicated to exist in I. indigotica and further identified by metabolic profile using UPLC/Q-TOF. Moreover, applying transcriptome co-expression analysis, nine new, putative UGTs were suggested as flavonol glycosyltransferases and lignan glycosyltransferases.Conclusions: This database provides a pool of candidate genes involved in biosynthesis of effective metabolites in I. indigotica. Furthermore, the comprehensive analysis and characterization of the significant pathways are expected to give a better insight regarding the diversity of chemical composition, synthetic characteristics, and the regulatory mechanism which operate in this medical herb. © 2013 Chen et al.; licensee BioMed Central Ltd.

Huang S.-M.,National University of Singapore | Xu F.,National University of Singapore | Xu F.,China Pharmaceutical University | Lam S.H.,National University of Singapore | And 2 more authors.
Molecular BioSystems | Year: 2013

Zebrafish embryogenesis is a rapid process driven by a myriad of gene products and small molecules. As previous studies have detailed the relevant transcriptional and proteomics changes, here we assess the metabolomic changes that occur at different stages of embryogenesis (4, 8, 12, 24 and 48 hours post fertilization). Metabolite levels were detected using GC-MS and LC-MS, following which multivariate analysis (OPLS-DA) was applied to identify metabolites that were differentially regulated throughout embryogenesis. From the two robust OPLS-DA models that were generated (Q2(cum) = 0.940 and Q 2(cum) = 0.894), a total of 60 detected metabolites (20 from GC-MS, 40 from LC-MS) were identified and found to be important in discriminating between developmental stages. Hierarchical clustering analysis was applied to the dataset and metabolite classes such as amino acids and lipids were shown to be differentially regulated. Biologically relevant transcriptomic and proteomic data were associated with metabolites to provide a more holistic systems perspective of embryogenesis. In summary, the metabolic profiles of different developmental stages highlight the dynamic changes occurring during embryogenesis. These data could serve as a basis for future toxicological or developmental studies. © 2013 The Royal Society of Chemistry.

Ding L.,Yancheng Institute of Technology | An J.,Yancheng Institute of Technology | Zhu Z.,China Pharmaceutical University | Zhu Z.,National University of Singapore
Polymer Chemistry | Year: 2014

The click chemistry strategy was successfully applied for the preparation of long-chain highly branched ring-opening metathesis polymers (LCHBPs). The hydroxyl-functionalized monotelechelic polymers with various molecular weights were synthesized first via ring-opening metathesis polymerization of N-azidopentyl oxanorbornene imide in the presence of a symmetrical functional terminating agent, and then transformed into alkynyl-monotelechelic polymers, which acted as ABn-type macromonomers for subsequent click reaction to finally produce LCHBPs as the reaction time prolonged. All intermediates, macromonomer, and the resultant LCHBPs were characterized in detail by mass spectroscopy, elemental analysis, FTIR, GPC, and NMR measurements. The experimental results showed that polymerization has a two-step feature, that is, a fast and a slow increase of the average degree of polymerization at the initial and the subsequent stages, respectively. The final LCHBPs have high molecular weight up to Mn,NMR = 210600, and relatively moderate molecular weight distributions (Mw/Mn = 2.12-1.67). This journal is © 2014 The Royal Society of Chemistry.

Zhou Z.-B.,China Pharmaceutical University | Zhou Z.-B.,Tarim University | Zhang Y.-M.,China Pharmaceutical University | Pan K.,China Pharmaceutical University | And 2 more authors.
Fitoterapia | Year: 2014

Six new polycyclic polyprenylated acylphloroglucinols, attenuatumiones A-F (1-6), together with twelve known analogs (7-18) were isolated from the whole plant of Hypericum attenuatum. Their structures were elucidated by spectroscopic methods, and the absolute configuration of C-13 in attenuatumione C (3) was deduced via the circular dichroism datum of the in situ formed [Rh 2(OCOCF3)4] complexes. All isolates were evaluated for the cytotoxic activities on three human cancer cell lines. Compound 3 showed moderate cytotoxic activities with IC50 values of 10.12 and 10.56 μM against SMMC7721 and U2OS, respectively. © 2014 Elsevier B.V.

Chu J.,University of Macau | Li S.-L.,University of Macau | Yin Z.-Q.,China Pharmaceutical University | Ye W.-C.,Jinan University | Zhang Q.-W.,University of Macau
Journal of Pharmaceutical and Biomedical Analysis | Year: 2012

A high performance liquid chromatography coupled with diode array detector (HPLC-DAD) method was developed for simultaneous quantification of eleven major bioactive components including six coumarins, three flavonoids and two limonoids in Fructus Citri Sarcodactylis. The analysis was performed on a Cosmosil 5 C 18-MS-II column (4.6mm×250mm, 5μm) with water-acetonitrile gradient elution. The method was validated in terms of linearity, sensitivity, precision, stability and accuracy. It was found that the calibration curves for all analytes showed good linearity (R 2>0.9993) within the test ranges. The overall limit of detection (LOD) and limit of quantification (LOQ) were less than 3.0 and 10.2ng. The relative standard deviations (RSDs) for intra- and inter-day repeatability were not more than 4.99% and 4.92%, respectively. The sample was stable for at least 48h. The spike recoveries of eleven components were 95.1-104.9%. The established method was successfully applied to determine eleven components in three samples from different locations. The results showed that the newly developed HPLC-DAD method was linear, sensitive, precise and accurate, and could be used for quality control of Fructus Citri Sarcodactylis. © 2012 Elsevier B.V.

Liu H.,China Pharmaceutical University | Jiang G.,China Pharmaceutical University | Pan X.,Shanghai University | Wan X.,CAS Shanghai Institute of Organic Chemistry | And 3 more authors.
Organic Letters | Year: 2014

Highly asymmetric bromocyclization of tryptophol by using chiral anionic phase-transfer catalyst and DABCO-derived brominating reagent is described. Optimization of the reaction conditions revealed that the reaction rate was accelerated together with improvement of enantioselectivity by addition of catalytic DABCO-derived brominating reagent. From tryptophol, 3-bromofuroindoline could be directly obtained in excellent enantioselectivities by employing this novel methodology. © 2014 American Chemical Society.

Yin Z.,China Pharmaceutical University | Yin Z.,University of Wollongong | Song Y.,Shanghai University | Rehse P.H.,Shanghai Medicilon Inc.
ACS Chemical Biology | Year: 2013

Phosphorylation-dependent protein-protein interaction has rarely been targeted in medicinal chemistry. Thymoquinone, a naturally occurring antitumor agent, disrupts prephosphorylated substrate recognition by the polo-box domain of polo-like kinase 1, a key mitotic regulator responsible for various carcinogenesis when overexpressed. Here, crystallographic studies reveal that the phosphoserine/phosphothreonine recognition site of the polo-box domain is the binding pocket for thymoquinone and its analogue poloxime. Both small molecules displace phosphopeptides bound with the polo-box domain in a slow but noncovalent binding mode. A conserved water bridge and a cation-π interaction were found as their competition strategy against the phosphate group. This mechanism sheds light on small-molecule intervention of phospho-recognition by the polo-box domain of polo-like kinase 1 and other phospho-binding proteins in general. © 2012 American Chemical Society.

Zhang X.,China Pharmaceutical University | Zhang X.,Virginia Commonwealth University | Wang G.,China Pharmaceutical University | Gurley E.C.,Virginia Commonwealth University | And 3 more authors.
PLoS ONE | Year: 2014

Background: Apigenin is a non-toxic natural flavonoid that is abundantly present in common fruits and vegetables. It has been reported that apigenin has various beneficial health effects such as anti-inflammation and chemoprevention. Multiple studies have shown that inflammation is an important risk factor for atherosclerosis, diabetes, sepsis, various liver diseases, and other metabolic diseases. Although it has been long realized that apigenin has anti-inflammatory activities, the underlying functional mechanisms are still not fully understood.Methodology and Principal Findings: In the present study, we examined the effect of apigenin on LPS-induced inflammatory response and further elucidated the potential underlying mechanisms in human THP-1-induced macrophages and mouse J774A.1 macrophages. By using the PrimePCR array, we were able to identify the major target genes regulated by apigenin in LPS-mediated immune response. The results indicated that apigenin significantly inhibited LPS-induced production of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α through modulating multiple intracellular signaling pathways in macrophages. Apigenin inhibited LPS-induced IL-1β production by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly. Apigenin also prevented LPS-induced IL-6 and IL-1β production by reducing the mRNA stability via inhibiting ERK1/2 activation. In addition, apigenin significantly inhibited TNF-α and IL-1β-induced activation of NF-κB.Conclusion and Significance: Apigenin Inhibits LPS-induced Inflammatory Response through multiple mechanisms in macrophages. These results provided important scientific evidences for the potential application of apigenin as a therapeutic agent for inflammatory diseases. © 2014 PLOS ONE.

Chu X.-M.,Jinling Hospital | Zhang L.-F.,China Pharmaceutical University | Wang G.-J.,China Pharmaceutical University | Zhang S.-N.,Jinling Hospital | And 2 more authors.
European Journal of Clinical Pharmacology | Year: 2012

Purpose The aim of this study was to investigate the genetic polymorphisms of UGT1A3, UGT1A6, and UGT2B7 in Chinese epilepsy patients and their potential influence on the pharmacokinetics of valproic acid (VPA). Methods The genetic architectures of UGT1A3, UGT1A6, and UGT2B7 in 242 epilepsy patients were detected by DNA sequencing and PCR-restriction fragment length polymorphism. Steady-state plasma concentrations of VPA in 225 patients who had received VPA (approx. 250- 1,000 mg/day) for at least 2 weeks were determined and associated with UGT polymorphisms. Results The allelic distribution of UGT1A3 in our Chinese epilepsy patients was significantly different from that in healthy subjects based on reference data. The standardized trough plasma concentration (CS) of VPA was much lower in our patients with the UGT1A3*5 variant than in the wild type carriers (3.24±1.05 vs. 4.68±1.24 μg/kg/mL-1/mg-1, P<0.01). UGT polymorphisms had no influence on the pharmacokinetic interactions between carbamazepine and VPA. Conclusion Our results suggest that UGT1A3*5 may be an important determinant of individual variability in the pharmacokinetics of VPA and that it may be necessary to increase VPA dose for UGT1A3*5 carriers to ensure its therapeutic range of 50-100 μg/mL. © Springer-Verlag 2012.

Huang H.-L.,Guangdong Medical College | Wang Y.-J.,China Pharmaceutical University | Zhang Q.-Y.,Guangdong Medical College | Liu B.,Guangdong Medical College | And 3 more authors.
World Journal of Gastroenterology | Year: 2012

AIM: To investigate the hepatoprotective effect of baicalein against carbon tetrachloride (CCl4)-induced liver damage in mice. METHODS: Mice were orally administered with baicalein after CCl4 injection, and therapeutic baicalein was given twice a day for 4 d. The anti-inflammation effects of baicalein were assessed directly by hepatic histology and serum alanine aminotranferease and aspartate aminotransferase measurement. Proliferating cell nuclear antigen was used to evaluate the effect of baicalein in promoting hepatocyte proliferation. Serum interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay and liver IL-6, TNF-α, transforming growth factor-α (TGF-α), hepatocyte growth factor (HGF) and epidermal growth factor (EGF) genes expression were determined by quantitative real-time polymerase chain reaction. RESULTS: CCl4-induced acute liver failure model offers a survival benefit in baicalein-treated mice. The data indicated that the mRNA levels of IL-6 and TNF-α significantly increased within 12 h after CCl4 treatment in baicalein administration groups, but at 24, 48 and 72 h, the expression of IL-6 and TNF-α was kept at lower levels compared with the control. The expression of TGF-α, HGF and EGF was enhanced dramatically in baicalein administration group at 12, 24, 48 and 72 h. Furthermore, we found that baicalein significantly elevated the serum level of TNF-α and IL-6 at the early phase, which indicated that baicalein could facilitate the initiating events in liver regeneration. CONCLUSION: Baicalein may be a therapeutic candidate for acute liver injury. Baicalein accelerates liver regeneration by regulating TNF-α and IL-6 mediated pathways. © 2012 Baishideng. All rights reserved.

Dai J.,Jiangnan University | Wu Y.,Shanghai JiaoTong University | Chen S.-W.,Jiangnan University | Zhu S.,Jiangnan University | And 3 more authors.
Carbohydrate Polymers | Year: 2010

A modified high-performance liquid chromatography method of pre-column derivatization with 1-phenyl-3-methyl-5-pyrazolone (PMP) has been established for high resolution separation and high sensitivity determination of ten monosaccharides simultaneously, which frequently occur in algae polysaccharides. The effects of volume proportion of acetonitrile and pH value of mobile phase (0.1 M phosphate buffer-acetonitrile) on retention and separation of the monosaccharide derivatives were investigated with Eclipse XPB-C18 column screened out. The hydrolyzation condition of polysaccharides and derivatization procedure of hydrolysates were also optimized. The modified analysis method was used for the determination of monosaccharide compositions in five polysaccharide fractions isolated from Duanaliella salina. The results showed that PD1 and PD4a were acidic heteropolysaccharide mainly containing glucose and galactose respectively, and PD4a contained sulfated groups; PD2 and PD3 all were a glucan; while PD4b was a complex of polysaccharide linked with nucleic acids by covalent bonds. © 2010 Elsevier Ltd. All rights reserved.

Ding L.,Yancheng Institute of Technology | Qiu J.,Yancheng Institute of Technology | Zhu Z.,China Pharmaceutical University
Macromolecular Rapid Communications | Year: 2013

The synthesis of thiol-functionalized long-chain highly branched polymers (LCHBPs) has been accomplished in combination of ring-opening metathesis polymerization (ROMP) and thiol-Michael addition click reaction. A monotelechelic polymer with a terminal acrylate and many pendent thiol groups is first prepared through adding an internal cis-olefin terminating agent to the reaction mixture immediately after the completion of the living ROMP, and then utilized as an ABn-type macromonomer in subsequent thiol-ene reaction between acrylate and thiol, yielding LCHBPs as the reaction time prolonged. Au nanoparticles are then covalently conjugated onto the surface of thiol-functionalized LCHBP to fabricate novel hybrid nanostructures, which is shown as one interesting application of such functionalized metathesis polymers. This facile approach can be extended toward the fabrication of novel nanomaterials with sophisticated structures and tunable multifunctionalities. Branched ring-opening metathesis polymerization (ROMP)-polymer architecture is successfully constructed employing ABn-type macromonomer that carries several thiol groups along the polymer chain and one acrylate group at the chain end. A thiol-Michael addition click reaction between these functional groups yields long-chain highly branched polymer. The coating of gold nanoparticles is shown as one interesting application of such functionalized metathesis polymers. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gong P.,China Pharmaceutical University | Cui N.,China Pharmaceutical University | Wu L.,China Pharmaceutical University | Liang Y.,China Pharmaceutical University | And 5 more authors.
Analytical Chemistry | Year: 2012

Global metabolite identification of complex compound mixtures in biological systems is a very challenging task. Herein, we developed and validated a chemicalome to metabolome matching approach by taking herbal medicine as an example to delineate the metabolic networks of complex systems. This approach consists of five steps of data processing including raw data output, endogenous background subtraction, parent compound and metabolite differentiation, chemicalome to metabolome correlation, and the final validation via manual fragment comparison. Chemicalome to metabolome correlation, the core step of this approach, was performed based on matching the accurate mass differences of pseudomolecular ions between them with the accurate mass changes of known metabolic pathways and validating the matches by validation ions. A step-forward approach that confers a gradual identification of metabolites generated from different steps (1-4) and types (degradation, phase I/II, or mixed) of metabolic reactions was further proposed for chemicalome to metabolome matching. This approach was validated to be very useful and powerful for the metabolite identification of a single compound, a homologous compound mixture, and a complex herbal system. Using this approach, all metabolites (162) detected from urine samples of rats treated with Mai-Luo-Ning injection could be linked to their respective parent compounds, and 143 of them were supported by the final validation via manual fragment analysis. In most cases, more than 80% of the automatic matching results could be supported by the manual fragment validations. A complex metabolic network showing all the possible links between precursors and metabolites was successfully constructed. This study provides a generally applicable approach to global metabolite identification of complex compound mixtures in complex matrixes. © 2012 American Chemical Society.

Deqiu Z.,Shanghai JiaoTong University | Deqiu Z.,Tongji University | Kang L.,China Pharmaceutical University | Jiali Y.,China Pharmaceutical University | And 2 more authors.
Biochimie | Year: 2011

Endothelial insulin resistance is tightly associated with diabetic cardiovascular complication, and it is well known that inflammation plays an important role in the development of insulin resistance. Luteolin, a flavonoid abundant in some medical and eatable plants, is a potent inhibitor of inflammation. It is also reported that luteolin exhibited some chemoprotection capability to the endothelial integrity. This study aims to clarify whether the anti-inflammatory potency of luteolin contributes to amelioration of insulin resistance in the endothelium. Palmitate (PA) stimulation markedly reduced insulin-mediated endothelium-dependent relaxation in rat aorta, while luteolin pretreatment effectively reversed the effects of palmitate in a concentration-dependent manner. PA stimulation also evoked inflammatory response in endothelial cells. When the cells were pretreated with luteolin, IKKβ phosphorylation were reduced, which, in turn, blocked the NF-κB activation through attenuating P65 phosphorylation. At the same time, it was also found that the gene over-expressions for TNF-α and IL-6 were also reduced by luteolin pretreatment. When endothelial cells were stimulated with PA, the insulin signaling cascades were impaired with reduced insulin-dependent production of NO. Again, pretreatment of luteolin could effectively reverse the effects of PA. Luteolin modulated the Ser/Thr phosphorylation of insulin receptor substrates-1 and restored downstream Akt/eNOS activation, resulting in increased NO production in the presence of insulin. In conclusion, these results suggested that luteolin ameliorated inflammation related endothelial insulin resistance in an IKKβ/IRS-1/Akt/eNOS-dependent pathway. © 2010 Elsevier Masson SAS. All rights reserved.

Chang J.S.,Pennington Biomedical Research Center | Huypens P.,Pennington Biomedical Research Center | Zhang Y.,Pennington Biomedical Research Center | Zhang Y.,China Pharmaceutical University | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

Peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) plays a central role in the regulation of cellular energy metabolism and metabolic adaptation to environmental and nutritional stimuli. We recently described a novel, biologically active splice variant of PGC-1α (NT-PGC-1α, amino acids 1-270) that retains the ability to interact with and transactivate nuclear hormone receptors through its N-terminal transactivation domain. Whereas PGC-1α is an unstable nuclear protein sensitive to ubiquitin-mediated targeting to the proteasome, NT-PGC-1α is relatively stable and predominantly cytoplasmic, suggesting that its ability to interact with and activate nuclear receptors and transcription factors is dependent upon regulated access to the nucleus. We provide evidence that NT-PGC-1α interacts with the nuclear exportin, CRM1, through a specific leucine-rich domain (nuclear export sequence) that regulates its export to the cytoplasm. The nuclear export of NT-PGC-1α is inhibited by protein kinase A-dependent phosphorylation of Ser-194, Ser-241, and Thr-256 on NT-PGC-1α, which effectively increases its nuclear concentration. Using site-directed mutagenesis to prevent or mimic phosphorylation at these sites, we show that the transcriptional activity of NT-PGC-1α is regulated in part through regulation of its subcellular localization. These findings suggest that the function of NT-PGC-1α as a transcriptional co-activator is regulated by protein kinase A-dependent inhibition of CRM1-mediated export from the nucleus. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Li T.,China Pharmaceutical University | Li T.,CAS Shanghai Institute of Materia Medica | Zhou S.,CAS Shanghai Institute of Materia Medica | Wang J.,CAS Shanghai Institute of Materia Medica | And 5 more authors.
Chemical Communications | Year: 2015

We report herein that the NaOMe-catalyzed reactions between the chiral glycine Schiff base (S)-4 with 2-cyanobenzaldehyde 3a provide for a convenient preparation of the novel α-(1-oxoisoindolin-3-yl)glycine 1 of high pharmaceutical potential. The reactions involve at least eight synthetic steps and can mechanistically be realized only with application of Ni(II) complexes described in this study. © The Royal Society of Chemistry 2015.

Wang X.-Y.,PLA Fourth Military Medical University | Chen X.-L.,PLA Fourth Military Medical University | Tang H.-F.,PLA Fourth Military Medical University | Gao H.,No309 Hospital Of Chinese Pla | And 2 more authors.
Planta Medica | Year: 2011

Two new oleanane-type triterpenoid saponins, 1 and 2, and a new natural product, 3, together with five known saponins, 48, were isolated from the rhizomes of Anemone taipaiensis. Their structures were elucidated by extensive spectroscopic analysis and chemical evidences. Six saponins, 1, 2, 47, which possessed a free carboxylic group at C-28, exhibited significant cytotoxicity against human leukemia HL-60 cells and human hepatocellular carcinoma Hep-G2 cells with ICvalues in the range of 1.3110.12M. © Georg Thieme Verlag KG Stuttgart - New York.

Yin R.,Nantong University | Wang R.,Shanghai JiaoTong University | Guo L.,Ningxia Medical University | Zhang W.,Nantong University | Lu Y.,China Pharmaceutical University
Journal of Vascular Research | Year: 2013

MicroRNAs (miRs) are endogenously expressed small noncoding RNAs that regulate gene expression at the posttranscriptional level. Previous works indicated that the miR-17-92 cluster could regulate endothelial cell (EC) functions involved in angiogenesis. miR-17-3p, a component of the miR-17-92 cluster, could control the angiogenic activity of human umbilical vein ECs in a cell-autonomous manner in vitro. A 21-bp fragment from the Flk-1 3′-untranslated region containing miR-17-3p targeting sites was required for the rapid downregulation of Flk-1 expression by in silico and experimental analysis. Subsequently, the downstream cell growth pathway was inhibited by forced upregulation of miR-17-3p. Based on these data, we conclude that miR-17-3p is a negative regulator of the angiogenic phenotype of ECs through its ability to modulate the expression of Flk-1, which is implicated in the pleiotropic effects of miR-17-92 in angiogenesis. © 2012 S. Karger AG, Basel.

Song X.,Linyi Normal University | Xu S.,Linyi Normal University | Chen L.,CAS Yantai Institute of Coastal Zone Research | Wei Y.,China Pharmaceutical University | Xiong H.,Nanchang University
Journal of Applied Polymer Science | Year: 2014

Food security as a world issue has received increasing concern, and therefore, effective analytical methods and technologies have been continuously developed. However, the matrix complexity of food samples and the trace/ultratrace presence of targeted analytes require highly efficient cleanup and enrichment materials and procedures. Molecularly imprinted polymers (MIPs) with specific recognition abilities as versatile materials are being increasingly developed for diverse species in various fields, especially in food analysis. In this review, we mainly summarize the recent advances in MIPs used for food matrices over the last 5 years. We focus on toxic and harmful substances, such as pesticide/drug residues, heavy metals, microbial toxins, and additives. Some relatively new preparation methods involving surface imprinting, composites, and stimuli responsiveness are reviewed. Different MIPs as solid-phase adsorbents in solid-phase extraction, solid-phase microextraction, matrix solid-phase dispersion, stirring bar sorptive extraction, and magnetic material extraction and as stationary phases in chromatographic separation for foodstuff have been comprehensively summarized. MIP-based biomimetic sensing and enzymelike catalysis receive special attention. Moreover, some limitations and comparisons related to MIPs performances are also discussed. Finally, some significant attempts to further promote MIP properties and applications to ensure food safety are discussed. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40766. © 2014 Wiley Periodicals, Inc.

Fang L.,Nanjing Southeast University | Fang L.,China Pharmaceutical University | Wang M.,China Pharmaceutical University | Gou S.,Nanjing Southeast University | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2014

By taking advantage of the cytotoxic effect of nitric oxide (NO) and PepT1 for molecule-targeted drug delivery, a series of amino acid/dipeptide diester prodrugs of NO-donating oleanolic acid derivatives were designed and synthesized. Two prodrugs 6a and 8a showed potent cytotoxcity, which is probably due to their high PepT1 affinity and NO-releasing ability. Furthermore, the aqueous solubility of the prodrugs was also significantly enhanced because of the hydrophilic amino acid/dipeptide promoiety. © 2014 American Chemical Society.

Wang Q.Z.,CAS Institute of Botany | Liang J.Y.,China Pharmaceutical University | Feng X.,CAS Institute of Botany
Chinese Chemical Letters | Year: 2010

Two new indole alkaloids, evodiagenine 1 and dievodiamine 2 were isolated from the fruits of Evodia rutaecarpa (Juss.) Benth. The structure of compounds 1 and 2 were elucidated by comprehensive spectroscopic analysis and compound 1 was confirmed by X-ray crystallographic analysis. © 2009 Xu Feng.

Liu A.-R.,Nanjing Southeast University | Liu L.,Nanjing Southeast University | Chen S.,China Pharmaceutical University | Yang Y.,Nanjing Southeast University | And 4 more authors.
Journal of Cellular Physiology | Year: 2013

The differentiation of mesenchymal stem cells (MSCs) into type II alveolar epithelial (AT II) cells in vivo and in vitro, is critical for reepithelization and recovery in acute lung injury (ALI), but the mechanisms responsible for differentiation are unclear. In the present study, we investigated the role of the canonical wnt pathway in the differentiation of mouse bone marrow-derived MSCs (mMSCs) into AT II cells. Using a modified co-culture system with murine lung epithelial-12 (MLE-12) cells and small airway growth media (SAGM) to efficiently drive mMSCs differentiation, we found that GSK 3β and β-catenin in the canonical wnt pathway were up-regulated during differentiation. The levels of surfactant protein (SP) C, SPB, and SPD, the specific markers of AT II cells, correspondingly increased in mMSCs when Wnt3a or LiCl was added to the co-culture system to activate wnt/β-catenin signaling. The expression of these factors was depressed to some extent by inhibiting the pathway with the addition of DKK 1. The differentiation rate of mMSCs also depends on their abilities to accumulate and survive in inflammatory tissue. Our results suggested that the activation of wnt/β-catenin signaling promoted mMSCs migration towards ALI mouse-derived lung tissue in a Transwell assay, and ameliorated the cell death and the reduction of Bcl-2/Bax induced by H2O2, which simultaneously caused reduced GSK 3β and β-catenin in mMSCs. These data supports a potential mechanism for the differentiation of mMSCs into AT II cells involving canonical wnt pathway activation, which may be significant to their application in ALI. © 2012 Wiley Periodicals, Inc.

Ye B.,Nanjing Southeast University | Ye B.,China Pharmaceutical University | Rong F.,Nanjing Southeast University | Rong F.,Suzhou University | And 7 more authors.
Chemical Communications | Year: 2013

An angle-independent photonic crystal (PhC) colorimetric sensor was developed by using a stimuli-response hydrogel to replicate the template arrays of isotropic photonic crystal beads (PCBs) for the detection of Hg2+. This journal is © The Royal Society of Chemistry 2013.

Ding Z.-Q.,China Pharmaceutical University | Ge J.-P.,Beihang University | Wu X.-M.,China Pharmaceutical University | Zheng X.-N.,China Pharmaceutical University
Scientometrics | Year: 2013

Pharmacology/pharmacy is an important scientific field and plays a pivotal role in new drug research and development. China has steadily increased investment in drug development. This study aimed to evaluate the productivity of China in the field pharmacology/pharmacy in the past decade in relation to ten representative countries. The publications in the field pharmacology/pharmacy of China and ten representative countries in the past decade (2001-2010) were retrieved from Web of Science database, and studies were conducted on the immediacy index of articles published in 2011. Multiple bibliometric indicators were obtained from the "InCites" analysis. Most of the bibliometric indicators for the developed countries including the USA and the European countries remained stable in the past decade. The number of publications by the Asian countries, especially China, increased dramatically in the past decade year by year; however, the Asian countries improved little in the indicators assessing the scientific quality of publications including the citation behaviors and the impact relative to either country and subject area. It may need a long time to fill in the gap, in terms of the scientific quality, between the developing countries and the developed countries. In view of the dramatic increase in the financial investment, our findings suggest that the development of the field pharmacology/pharmacy worldwide is not optimistic, which may partially explain the decreased R&D productivity of pharmaceutical industry since the last decade. © 2013 Akadémiai Kiadó, Budapest, Hungary.

Bai Y.,Peking Union Medical College | Bai Y.,Chinese PLA General Hospital | Sun L.,Peking Union Medical College | Du L.,Peking Union Medical College | And 5 more authors.
Ageing Research Reviews | Year: 2013

Background: Epidemiologic investigations have linked the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), to carotid intima-media thickness (IMT). However, these studies result in various extent of relation between ADMA and IMT, the conclusions were inconsistent, and the precise relationship is therefore under debate. The objective of this systematic review and meta-analysis is to provide an overview of the relevant studies evaluating the association of levels of ADMA with carotid IMT and to gain more robust estimate of the relationship. Methods: Studies were identified through PubMed, Cochrane Library, Embase, reviews, and reference lists of relevant papers. Weighted means of the correlation coefficient (R) and partial correlation coefficient (PR) were calculated for relations by using random-effect models. Results: 22 studies with a total of 6168 subjects were included in our meta-analysis. In an overall pooled estimate of correlation coefficient (R), levels of ADMA were significantly related to carotid IMT (pooled R: 0.29; 95% confidence interval [CI]: 0.20-0.38, P<0.001). Pooled estimate of partial correlation coefficient (PR) also resulted in a significant association of ADMA with carotid IMT (pooled PR: 0.21; 95% CI: 0.14-0.29; P<0.001). Furthermore, subgroup analysis found that the relation between ADMA and IMT was stronger in patients with chronic kidney diseases (CKDs) than that in subject with normal renal function. Conclusions: Circulating levels of ADMA were positively related to carotid IMT, especially in patients with CKDs. The findings need confirmation in longitudinal and interventional studies. © 2012 Elsevier B.V.

Chen S.,China Pharmaceutical University | Liu A.-R.,Nanjing Southeast University | An F.-M.,China Pharmaceutical University | Yao W.-B.,China Pharmaceutical University | Gao X.-D.,China Pharmaceutical University
Age | Year: 2012

Growing evidence suggests that type 2 diabetes mellitus (DM) is associated with agedependent Alzheimer's disease (AD), the latter of which has even been considered as type 3 diabetes. Several physiopathological features including hyperglycemia, oxidative stress, and dysfunctional insulin signaling relate DM to AD. In this study, high glucose-, oxidative stress-induced neuronal injury and intracerebroventricular-streptozotocin (ICV-STZ) animals as the possible models for diabetes-related AD were employed to investigate the effects of exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, on diabetes-associated Alzheimer-like changes as well as the molecular mechanisms involved. Our study demonstrated that GLP-1/Ex-4 could exert a protective effect against reduced viability of PC12 cells caused by high glucose and that this protective effect was mediated via the PI3-kinase pathway. In addition, GLP-1/Ex-4 ameliorated oxidative stress-induced injury in PC12 cells. In rat models, bilateral ICV-STZ administration was used to produce impaired insulin signaling in the brain. Fourteen days following ICV-STZ injection, rats treated with twice-daily Ex-4 had better learning and memory performance in the Morris water maze test compared with rats treated with saline. Additionally, histopathological evaluation confirmed the protective effects of Ex-4 treatment on hippocampal neurons against degeneration. Furthermore, we demonstrated that Ex-4 reversed ICV-STZ-induced tau hyperphosphorylation through downregulation of GSK-3β activity, a key kinase in both DM and AD. Our findings suggests that Ex-4 can protect neurons from diabetes-associated glucose metabolic dysregulation insults in vitro and from ICV-STZ insult in vivo, and that Ex-4 may prove of therapeutic value in the treatment of AD especially DM-related AD. © American Aging Association 2011.

Yan L.,Nanjing Medical University | Zhao L.,Nanjing Medical University | Long Y.,China Pharmaceutical University | Zou P.,Nanjing Medical University | And 3 more authors.
PLoS ONE | Year: 2012

Background: Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs. Methods: An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis. Results: A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis (TT versus CC: OR = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls. Conclusion: The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted. © 2012 Yan et al.

Senthilkumar R.,Nanjing Southeast University | Chen B.-A.,Nanjing Southeast University | Cai X.-H.,Nanjing Southeast University | Fu R.,China Pharmaceutical University
Chinese Journal of Natural Medicines | Year: 2014

Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds. © 2014 China Pharmaceutical University.

Zhang D.,Nanjing Southeast University | Yang M.,China Pharmaceutical University | Dong S.,Nanjing Southeast University
Journal of Physical Chemistry C | Year: 2015

Hydroxylation of the rutile TiO2(110) surface has attracted much attention as the excess unpaired electrons introduced by hydroxyls play a critical role in surface chemistry and photocatalysis process of this material. In this work, based on density functional theory calculations with the Hubbard U correction, the electronic structures of the hydroxylated TiO2(110) surfaces have been studied. One interesting effect is found that the hydroxylation can elevate band edges of TiO2 and thus can enhance its reducing power for photocatalysis. The underlying physical mechanism for such shifts of the band edges are associated with the electric dipoles arising from the hydroxyl groups on the surface. © 2014 American Chemical Society.

Ye B.,Nanjing Southeast University | Ye B.,China Pharmaceutical University | Ding H.,Nanjing Southeast University | Cheng Y.,Nanjing Southeast University | And 7 more authors.
Advanced Materials | Year: 2014

A novel suspension array, which possesses the joint advantages of photonic crystal encoded technology, bioresponsive hydrogels, and photonic crystal sensors with capability of full multiplexing label-free detection is developed. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Yin R.,Nanjing Southeast University | Yin R.,China Pharmaceutical University | Bao W.,China Pharmaceutical University | Xing Y.,China Pharmaceutical University | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

MicroRNAs are endogenously expressed small, non-coding RNAs that modulate biological processes by recognizing specific gene transcripts, leading to translational repression or degradation. Previous work showed that the miR-17-92 cluster is highly expressed in human endothelial cells that participate in angiogenesis. In this study we showed that miR-19b-1, a component of this cluster, controls the intrinsic angiogenic activity of human umbilical vein endothelial cells (HUVECs) in vitro. In silico and in vitro analyses have suggested that miR-19b-1 targets mRNA corresponding to the pro-angiogenic protein, FGFR2, and blocks the cell cycle from the S phase to the G2/M phase transition by controlling the expression of cyclin D1. Thus, miR-19b-1 may serve as a valuable therapeutic agent in the context of tumor angiogenesis. © 2011.

He Y.,Shanghai University of Traditional Chinese Medicine | He Y.,China Pharmaceutical University | Du M.,CAS Institut Pasteur of Shanghai | Gao Y.,Shanghai University of Traditional Chinese Medicine | And 4 more authors.
PLoS ONE | Year: 2013

Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease found mostly in young adults in the western world. Oxidative stress induced neuronal apoptosis plays an important role in the pathogenesis of MS. In current study, astragaloside IV (ASI), a natural saponin molecule isolated from Astragalus membranceus, given at 20 mg/kg daily attenuated the severity of experimental autoimmune encephalomyelitis (EAE) in mice significantly. Further studies disclosed that ASI treatment inhibited the increase of ROS and pro-inflammatory cytokine levels, down-regulation of SOD and GSH-Px activities, and elevation of iNOS, p53 and phosphorylated tau in central nervous system (CNS) as well as the leakage of BBB of EAE mice. Meanwhile, the decreased ratio of Bcl-2/Bax was reversed by ASI. Moreover, ASI regulated T-cell differentiation and infiltration into CNS. In neuroblast SH-SY5Y cells, ASI dose-dependently reduced cellular ROS level and phosphorylation of tau in response to hydrogen peroxide challenge by modulation of Bcl-2/Bax ratio. ASI also inhibited activation of microglia both in vivo and in vitro. iNOS up-regulation induced by IFNγ stimulation was abolished by ASI dose-dependently in BV-2 cells. In summary, ASI prevented the severity of EAE progression possibly by counterbalancing oxidative stress and its effects via reduction of cellular ROS level, enhancement of antioxidant defense system, increase of anti-apoptotic and anti-inflammatory pathways, as well as modulation of T-cell differentiation and infiltration into CNS. The study suggested ASI may be effective for clinical therapy/prevention of MS. © 2013 He et al.

Zhang X.,Harvard University | Zhang X.,China Pharmaceutical University | Kuo C.,Perkin Elmer Corporation | Moore A.,Harvard University | Ran C.,Harvard University
PLoS ONE | Year: 2013

Objective:Brown adipose tissue (BAT), a specialized tissue for thermogenesis, plays important roles for metabolism and energy expenditure. Recent studies validated BAT's presence in human adults, making it an important re-emerging target for various pathologies. During this validation, PET images with 18F-FDG showed significant uptake of 18F-FDG by BAT under certain conditions. Here, we demonstrated that Cerenkov luminescence imaging (CLI) using 18F-FDG could be utilized for in vivo optical imaging of BAT in mice.Methods:Mice were injected with 18F-FDG and imaged 60 minutes later with open filter and 2 minute acquisition. In vivo activation of BAT was performed by norepinephrine and cold treatment under isoflurane or ketamine anesthesia. Spectral unmixing and 3D imaging reconstruction were conducted with multiple-filter CLI images.Results:1) It was feasible to use CLI with 18F-FDG to image interscapular BAT in mice, with the majority of the signal (>85%) at the interscapular site originating from BAT; 2) The method was reliable because excellent correlations between in vivo CLI, ex vivo CLI, and ex vivo radioactivity were observed; 3) CLI could be used for monitoring BAT activation under different conditions; 4) CLI signals from the group under short-term isoflurane anesthesia were significantly higher than that from the group under long-term anesthesia; 5) The CLI spectrum of 18F-FDG with a peak at 640 nm in BAT after spectral unmixing reflected the actual context of BAT; 6) Finally 3D reconstruction images showed excellent correlation between the source of the light signal and the location and physical shape of BAT.Conclusion:CLI with 18F-FDG is a feasible and reliable method for imaging BAT in mice. Compared to PET imaging, CLI is significantly cheaper, faster for 2D planar imaging and easier to use. We believe that this method could be used as an important tool for researchers investigating BAT. © 2013 Zhang et al.

Xu J.,Sichuan University | Liu B.,Sichuan University | Liu B.,China Pharmaceutical University
Chinese Chemical Letters | Year: 2015

First total synthesis of norleucosceptroids F and G has been achieved through key steps of Michael-Aldol cascade, oxa-Michael cyclization-dehydration-deprotection cascade and cross metathesis (CM), this work developed a general and concise method to the synthesis of leucosceptroid and norleucosceptroid. © 2015 Bo Liu.

Su C.,China Pharmaceutical University | Ji H.,China Pharmaceutical University | Su Y.,Ordos Center Hospital
Pharmacoepidemiology and Drug Safety | Year: 2010

Purpose: This study was designed to investigate the knowledge and opinions of hospital pharmacists about the spontaneous reporting of adverse drug reactions (ADRs) in Inner Mongolia, a northern region of China. Methods: A face-to-face questionnaire survey of hospital pharmacists was conducted in five tertiary general hospitals in Inner Mongolia between July and December 2007. The structured questionnaire consisted of questions about the demographic details of the pharmacists, their knowledge of pharmacovigilance and their opinions on pharmacists' involvement in ADR reporting. Results: Of the 288 pharmacists visited, 246 responded giving a total response rate of 85.4%. An amount of 70% of the pharmacists could define ADR correctly and 78.0% knew how to report ADRs. However, only one-third were clear as to what should be reported. The majority of pharmacists (92.7%) considered ADR reporting to be a professional obligation. However, only 36 (14.6%) claimed to have reported an ADR in their career, 25 of these 36 pharmacists (69.4%) were clinical pharmacists. Younger pharmacists and those who had received ADR training were more likely to report an ADR. The three major reasons for not reporting were: uncertain association (81.9%), insufficient clinical knowledge (68.6%) and lack of time (45.7%). The most frequently mentioned suggestion for improvement included more education on ADR reporting (66.7%), participation in ward rounds (43.9%) and encouragement from the pharmacy department (32.9%). Conclusion: Our investigation showed hospital pharmacists in a northern region of China had a reasonable knowledge of and positive attitudes towards pharmacovigilance. However, the majority of pharmacists had never reported an ADR in their career. Pharmacists' ADR education and increasing involvement in patient care would be important in improving ADR reporting in hospitals. Copyright © 2009 John Wiley & Sons, Ltd.

Ye B.-F.,Nanjing Southeast University | Ye B.-F.,China Pharmaceutical University | Zhao Y.-J.,Nanjing Southeast University | Zhao Y.-J.,Suzhou University | And 6 more authors.
Nanoscale | Year: 2012

We have developed a robust method for the visual detection of heavy metal ions (such as Hg2+ and Pb2+) by using aptamer- functionalized colloidal photonic crystal hydrogel (CPCH) films. The CPCHs were derived from a colloidal crystal array of monodisperse silica nanoparticles, which were polymerized within the polyacrylamide hydrogel. The heavy metal ion-responsive aptamers were then cross-linked in the hydrogel network. During detection, the specific binding of heavy metal ions and cross-linked single-stranded aptamers in the hydrogel network caused the hydrogel to shrink, which was detected as a corresponding blue shift in the Bragg diffraction peak position of the CPCHs. The shift value could be used to estimate, quantitatively, the amount of the target ion. It was demonstrated that our CPCH aptasensor could screen a wide concentration range of heavy metal ions with high selectivity and reversibility. In addition, these aptasensors could be rehydrated from dried gels for storage and aptamer protection. It is anticipated that our technology may also be used in the screening of a broad range of metal ions in food, drugs and the environment. This journal is © 2012 The Royal Society of Chemistry.

Mo R.,China Pharmaceutical University | Sun Q.,China Pharmaceutical University | Xue J.,China Pharmaceutical University | Li N.,China Pharmaceutical University | And 3 more authors.
Advanced Materials | Year: 2012

Zwitterionic oligopeptide liposomes (HHG2C 18-L) containing a smart lipid (1,5-dioctadecyl-L-glutamyl 2-histidyl-hexahydrobenzoic acid, HHG2C 18) are developed to overcome the barriers faced by anticancer drugs on the route from the site of injection into the body to the final antitumor target within transport steps with multiple physiological and biological barriers. HHG2C 18-L show the multistage pH-responsive to the tumor cell (the mitochondria in this case). Their multistage pH response leads to more effective entry of the tumor cell, improved escape from the endolysosomes, and accumulation at the mitochondria (see picture). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Long Y.,China Pharmaceutical University | Wang Y.,Nanjing Medical University | Ji G.,Nanjing Institute of Environmental Sciences | Yan L.,Nanjing Medical University | And 2 more authors.
PLoS ONE | Year: 2013

Perfluorooctane sulfonate (PFOS) is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA) and 3,4-dihydrophenylacetic acid (DOPAC) in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase), Herc5 (hect domain and RLD 5 isoform 2) and Tyro3 (TYRO3 protein tyrosine kinase 3) were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit), Gzma (Isoform HF1 of Granzyme A precursor), Plau (Urokinase-type plasminogen activator precursor) and Lig4 (DNA ligase 4) were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i) increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii) the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice. © 2013 Long et al.

Song L.,Sichuan University | Zhu G.,Sichuan University | Liu Y.,Sichuan University | Liu B.,Sichuan University | And 2 more authors.
Journal of the American Chemical Society | Year: 2015

Few examples of [4 + 2] cycloaddition with unmasked ortho-benzoquinones (UMOBs) as carbodiene have been reported in complex molecule synthesis. Herein we report that this cycloaddition with podocarpane-type UMOB was developed and applied to construct fully functionalized bicyclo[2.2.2]octanes. Based on this methodology, divergent total syntheses of atisane-type diterpenoids, including (±)-crotobarin, crotogoudin, atisane-3β,16α-diol, and 16S,17-dihydroxy-atisan-3-one, were accomplished in 14, 14, 12, and 16 steps, respectively. Key elements in these total syntheses include: (1) FeCl3-catalyzed cationic cascade cyclization to construct podocarpane-type skeleton; (2) Mn(III)/Co(II)-catalyzed radical hydroxylation of alkene with high regio-, diastereo-, and chemoselectivities; (3) and a ketal-deprotection/lactone-opening/deprotonation/lactonization cascade. Additionally, the synthetic utility of the fully functionalized bicyclo[2.2.2]octane framework was further elucidated by applying ring distortion strategy to afford different skeleton-rearranged natural product-like compounds. © 2015 American Chemical Society.

Wang Q.-H.,China Pharmaceutical University | Wang Q.-H.,Heilongjiang University of Chinese Medicine | Kuang H.-X.,Heilongjiang University of Chinese Medicine | Yang B.-Y.,Heilongjiang University of Chinese Medicine | And 3 more authors.
Journal of Natural Products | Year: 2011

Eight new sesquiterpene lactones (chlorajapolides A-E, 1-5, chlorajaposide, 6, chlorajaponol, 7, and chloraeudolide, 8) were isolated from an ethyl acetate-soluble partition of the ethanol extract of the whole plants of Chloranthus japonicus. The structures and relative configurations of 1-8 were established on the basis of spectroscopic data analysis. All isolates obtained were evaluated for their cytotoxic activity against a small panel of cancer cell lines. © 2011 American Chemical Society and American Society of Pharmacognosy.

Wu Q.,Nanjing Southeast University | Nouara A.,Nanjing Southeast University | Li Y.,Nanjing Southeast University | Zhang M.,Nanjing Southeast University | And 6 more authors.
Chemosphere | Year: 2013

Nematode Caenorhabditis elegans has been developed in a variety of environmental studies to address adverse effects of a wide range of toxicants. In the present study, we compared the toxicities of three metal oxide nanoparticles (NPs) including TiO2-NPs, ZnO-NPs, and SiO2-NPs with the same nanosize (30nm) after prolonged exposure from L1-larvae to adult at environmental relevant concentrations. Our data indicated that the adverse effects were detected in nematodes exposed to TiO2-NPs and ZnO-NPs at concentrations more than 0.05μg/L and SiO2-NPs at concentrations more than 5μg/L with locomotion behavior and ROS production as endpoints. With growth, locomotion behavior, reproduction, and ROS production as endpoints, toxicity order for the examined metal oxide NPs was: ZnO-NPs>TiO2-NPs>SiO2-NPs. In nematodes exposed to the examined metal oxide NPs, ROS production was significantly correlated with lethality, growth, reproduction, and locomotion behavior. Moreover, treatment with antioxidants of ascorbate or NAC effectively inhibited the formation of oxidative stress and retrieved the adverse effects of TiO2-NPs, ZnO-NPs, and SiO2-NPs on survival, growth, reproduction and locomotion behaviors in nematodes. Our data demonstrated the subtle toxicity differences of different NPs exposure at environmental relevant concentrations in C. elegans. © 2012 Elsevier Ltd.

Huo M.,China Pharmaceutical University | Zou A.,China Pharmaceutical University | Yao C.,China Pharmaceutical University | Zhang Y.,Jiangsu Chia Tai Tianqing Pharmacy Co. | And 5 more authors.
Biomaterials | Year: 2012

In this study, a ligand-PEG-lipid conjugate, octreotide-polyethene glycol-deoxycholic acid (OCT(Phe)-PEG-DOCA, or OPD) was successfully synthesized and used as a targeting molecule for N-deoxycholic acid-O, N-hydroxyethylation chitosan (DAHC) micelles for efficient cancer therapy. DAHC micelles exhibited good loading capacities for doxorubicin (DOX), a model anti-cancer drug, and the modification of OPD showed no significant effect on drug load while slightly increasing the particle size and partly shielding the positive charges on the surface of micelles. Accelerated release rate of DOX from micelles were also observed after OPD modification and the release profile exhibited pH-sensitive properties. Compared with DAHC-DOX micelles, OPD-DAHC-DOX micelles exhibited significantly stronger cytotoxicity to MCF-7 cells (SSTRs overexpression) but with hardly any difference from WI-38 cells (no SSTRs expression). The results of flow cytometry and confocal laser scanning microscopy further revealed that OPD-DAHC-DOX micelles could be selectively taken into tumor cells by SSTRs-mediated endocytosis. In vivo investigation of micelles on nude mice bearing MCF-7 cancer xenografts confirmed that OPD-DAHC micelles possessed much higher tumor-targeting capacity than the DAHC control and exhibited enhanced anti-tumor efficacy and decreased systemic toxicity. These results suggest that OPD-DAHC micelles might be a promising anti-cancer drug delivery carrier for targeted cancer therapy. © 2012 Elsevier Ltd.

Hu B.,China Pharmaceutical University | Li Y.,China Pharmaceutical University | Li Y.,Peking Union Medical College | Li Z.,China Pharmaceutical University | Meng X.,China Pharmaceutical University
Organic and Biomolecular Chemistry | Year: 2013

A metal-free and 4-methyl aniline mediated method for the oxidative C-C bond cleavage has been developed. The reaction proceeds in air using molecular oxygen as the oxidant, affording one-carbon shortened esters in moderate to good yields within a short time. Moreover, it provides a model reaction for the highly enantioselective synthesis of (d)-serine esters by combining with a l-proline catalyzed Mannich reaction. © 2013 The Royal Society of Chemistry.

Li J.,China Pharmaceutical University | Huo M.,China Pharmaceutical University | Wang J.,China Pharmaceutical University | Zhou J.,China Pharmaceutical University | And 6 more authors.
Biomaterials | Year: 2012

A targeted intracellular delivery system of paclitaxel (PTX) was successfully developed based on redox-sensitive hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates. The conjugates self-assembled into nano-size micelles in aqueous media and exhibited excellent drug-loading capacities (34.1%) and entrapment efficiency (93.2%) for PTX. HA-ss-DOCA micelles were sufficiently stable at simulated normal physiologic condition but fast disassembled in the presence of 20m. m reducing agent, glutathione. Invitro drug release studies showed that the PTX-loaded HA-ss-DOCA micelles accomplished rapid drug release under reducing condition. Intracellular release of fluorescent probe nile red indicated that HA-ss-DOCA micelles provide an effective approach for rapid transport of cargo into the cytoplasm. Enhanced cytotoxicity of PTX-loaded HA-ss-DOCA micelles further confirmed that the sensitive micelles are more potent for intracellular drug delivery as compared to the insensitive control. Based on flow cytometry and confocal microscopic analyses, observations revealed that HA-ss-DOCA micelles were taken up to human breast adenocarcinoma cells (MDA-MB-231) via HA-receptor mediated endocytosis. Invivo investigation of micelles in tumor-bearing mice confirmed that HA-ss-DOCA micelles possessed much higher tumor targeting capacity than the insensitive control. These results suggest that redox-sensitive HA-ss-DOCA micelles hold great potential as targeted intracellular delivery carriers of lipophilic anticancer drugs. © 2011.

Cao F.,China Pharmaceutical University | Gao Y.,China Pharmaceutical University | Wang M.,China Pharmaceutical University | Fang L.,China Pharmaceutical University | And 2 more authors.
Molecular Pharmaceutics | Year: 2013

In our previous studies, ethylene glycol-linked amino acid diester prodrugs of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug, designed to target peptide transporter 1 (PepT1) have been synthesized and evaluated. Unlike ethylene glycol, propylene glycol is of very low toxicity in vivo. In this study, propylene glycol was used as a linker to further compare the effect of the type of linker on the stability, permeability, affinity, and bioavailability of the prodrugs of OA. Seven diester prodrugs with amino acid/dipeptide promoieties containing l-Val ester (7a), l-Phe ester (7b), l-Ile ester (7c), d-Val-l-Val ester (9a), l-Val-l-Val ester (9b), l-Ala-l-Val ester (9c), and l-Ala-l-Ile ester (9d) were designed and successfully synthesized. In situ rat single-pass intestinal perfusion (SPIP) model was performed to screen the effective permeability (Peff) of the prodrugs. Peff of 7a, 7b, 7c, 9a, 9b, 9c, and 9d (6.7-fold, 2.4-fold, 1.24-fold, 1.22-fold, 4.15-fold, 2.2-fold, and 1.4-fold, respectively) in 2-(N-morpholino) ethanesulfonic acid buffer (MES) with pH 6.0 showed significant increase compared to that of OA (p < 0.01). In hydroxyethyl piperazine ethanesulfonic acid buffer (HEPES) of pH 7.4, except for 7c, 9a, and 9d, Peff of the other prodrugs containing 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (1.7-fold) exhibited significantly higher values than that of OA (p < 0.01). In inhibition studies with glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1), Peff of 7a (5.2-fold), 7b (2.0-fold), 9b (3.1-fold), and 9c (2.3-fold) had significantly reduced values (p < 0.01). Compared to the apparent permeability coefficient (Papp) of OA with Caco-2 cell monolayer, significant enhancement of the Papp of 7a (5.27-fold), 9b (3.31-fold), 9a (2.26-fold), 7b (2.10-fold), 7c (2.03-fold), 9c (1.87-fold), and 9d (1.39-fold) was also observed (p < 0.01). Inhibition studies with Gly-Sar (1 mM) showed that Papp of 7a, 9b, and 9c significantly reduced by 1.3-fold, 1.6-fold, and 1.4-fold (p < 0.01), respectively. These results may be attributed to PepT1-mediated transport and their differential affinity toward PepT1. According to the permeability and affinity, 7a and 9b were selected in the pharmacokinetic studies in rats. Compared with group OA, Cmax for group 7a and 9b was enhanced to 3.04-fold (p < 0.01) and 2.62-fold (p < 0.01), respectively. AUC0→24 was improved to 3.55-fold (p < 0.01) and 3.39-fold (p < 0.01), respectively. Compared to the ethylene glycol-linked amino acid diester prodrugs of OA in our previous work, results from this study revealed that part of the propylene glycol-linked amino acid/dipeptide diester prodrugs showed better stability, permeability, affinity, and bioavailability. In conclusion, propylene glycol-linked amino acid/dipeptide diester prodrugs of OA may be suitable for PepT1-targeted prodrugs of OA to improve the oral bioavailability of OA. © 2013 American Chemical Society.

Wu Q.,Nanjing Southeast University | Wang W.,Nanjing Southeast University | Li Y.,Nanjing Southeast University | Ye B.,China Pharmaceutical University | And 2 more authors.
Journal of Hazardous Materials | Year: 2012

In Caenorhabditis elegans, although acute toxicity of TiO2 nanoparticles (TiO2-NPs) at high concentrations has been investigated, we still know little about chronic toxicity of TiO2-NPs. Our data here showed that acute TiO2-NPs exposure in the range of μg/L had no obviously adverse effects on nematodes, but the chronic toxicities of large sizes (60nm and 90nm) of TiO2-NPs in the range of μg/L were detected in nematodes in a modified chronic toxicity assay system. Moreover, chronic toxicities of small sizes (4nm and 10nm) of TiO2-NPs in the range of ng/L were observed in nematodes with locomotion behavior and ROS production as endpoints. In nematodes chronically exposed to small sizes of TiO2-NPs at predicted environmental relevant concentrations, locomotion behavior was significantly (P<0.01) correlated with ROS production. Furthermore, treatment with antioxidants (ascorbate and N-acetyl-l-cysteine) inhibited both the induction of ROS production and the decrease of locomotion behaviors observed in nematodes chronically exposed to small sizes of TiO2-NPs at predicted environmental relevant concentrations. Therefore, chronic exposure to small sizes of TiO2-NPs at predicted environmental relevant concentrations can cause adverse effects on nematodes, and formation of such adverse effects may be largely due to the induction of oxidative stress. © 2012 Elsevier B.V.

Chen Y.,China Pharmaceutical University | Chen Y.,Nanjing Southeast University | Meng L.,China Pharmaceutical University | Shao H.,Nanjing Southeast University | Yu F.,China Pharmaceutical University
Hypertension Research | Year: 2013

To investigate the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs and placebo in patients with hypertension, a meta-analysis was performed of studies published between 1950 and 2012. A systematic literature search of MEDLINE and the Cochrane Library was conducted for randomized controlled trials. Weighted mean differences and relative risk with 95% confidence intervals were calculated for continuous and dichotomous data, respectively. In all, 14 studies with 6741 participants were included in the present meta-analysis. Nine studies included trial arms with placebo, four included angiotensin (Ang) AT1 receptor blockers (ARBs), three included Ang-converting enzyme inhibitors (ACEIs), two included calcium channel blockers (CCBs), one included a β-blocker, and one included hydrochlorothiazide (HCTZ). We found that aliskiren, which lowered blood pressure (BP) effectively in patients with mild-to-moderate hypertension, was similar to HCTZ but inferior to CCBs in BP reduction, response rates and control rates. Furthermore, aliskiren was superior to ACEIs in lowering diastolic BP (DBP), while it had similar effects to ACEIs on systolic BP (SBP) reduction, response rates and control rates. Additionally, the present meta-analysis showed the superiority of atenolol over aliskiren in DBP reduction and BP response but showed that atenolol was inferior in SBP reduction and BP control. No difference was found in the rates of therapeutic response between aliskiren and ARBs, while more patients achieved BP control with aliskiren. Further studies will be needed to determine the antihypertensive effects and tolerability of aliskiren in comparison with other antihypertensive drugs. © 2013 The Japanese Society of Hypertension All rights reserved.

Pan C.,Nanjing Southeast University | Wang J.,Jintan Hospital | Liu W.,China Pharmaceutical University | Liu L.,Nanjing Southeast University | And 3 more authors.
Respiratory Research | Year: 2012

Background: Sepsis could induce indirect acute lung injury(ALI), and pulmonary vasomotor dysfunction. While low tidal volume is advocated for treatment of ALI patients. However, there is no evidence for low tidal volume that it could mitigate pulmonary vasomotor dysfunction in indirect ALI. Our study is to evaluate whether low tidal volume ventilation could protect the pulmonary vascular function in indirect lipopolysaccharide (LPS) induced acute lung injury rats.Methods: An indirect ALI rat model was induced by intravenous infusion of LPS. Thirty rats (n = 6 in each group) were randomly divided into (1)Control group; (2) ALI group; (3) LV group (tidal volume of 6mL/kg); (4) MV group (tidal volume of 12mL/kg); (5)VLV group (tidal volume of 3mL/kg). Mean arterial pressure and blood gas analysis were monitored every 2 hours throughout the experiment. Lung tissues and pulmonary artery rings were immediately harvested after the rats were bled to be killed to detect the contents of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) and TNF-α. Acetylcholine (Ache)-induced endothelium-dependent and sodium nitroprusside (SNP)-induced endothelium-independent relaxation of isolated pulmonary artery rings were measured by tensiometry.Results: There was no difference within groups concerning blood pressure, PaCO2 and SNP-induced endothelium-independent relaxation of pulmonary artery rings. Compared with MV group, LV group significantly reduced LPS-induced expression of ET-1 level (113.79 ± 7.33pg/mL vs. 152.52 ± 12.75pg/mL, P < 0.05) and TNF-α (3305.09 ± 334.29pg/mL vs.4144.07 ± 608.21pg/mL, P < 0.05), increased the expression of eNOS (IOD: 15032.05 ± 5925.07 vs. 11454.32 ± 6035.47, P < 0.05). While Ache (10-7mol/L-10-4mol/L)-induced vasodilatation was ameliorated 30% more in LV group than in MV group.Conclusions: Low tidal volume could protect the pulmonary vasodilative function during indirect ALI by decreasing vasoconstrictor factors, increasing expressions of vasodilator factors in pulmonary endothelial cells, and inhibiting inflammation injuries. © 2012 Pan et al.; licensee BioMed Central Ltd.

Wu P.,China Pharmaceutical University | Liu N.,Nanjing Southeast University
Patient Preference and Adherence | Year: 2016

Purpose: The objective of this study was to identify, using the theory of planned behavior (TPB), patients’ beliefs about taking oral antidiabetic drugs (OADs) as prescribed, and to measure the correlations between beliefs and medication adherence. Patients and methods: We performed a cross-sectional study of type 2 diabetic patients using structured questionnaires in a Chinese tertiary hospital. A total of 130 patients were enrolled to be interviewed about TPB variables (behavioral, normative, and control beliefs) relevant to medication adherence. Medication adherence was assessed using the eight-item Morisky Medication Adherence Scale (MMAS-8). Spearman’s rank correlation was used to assess the association between TPB and MMAS-8. Logistic regression analysis was performed to examine the relationship between different variables and MMAS-8, with statistical significance determined at P<0.05. Results: From 130 eligible Chinese patients with an average age of 60.6 years and a male proportion of 50.8%, a nonsignificant relationship between behavioral, normative, and the most facilitating control beliefs and OAD adherence was found in our study. Having the OADs on hand (P=0.037) was the only facilitating control belief associated with adherence behavior. Being away from home or eating out (P=0.000), not accepting the disease (P=0.000), ignorance of life-long drug adherence (P=0.038), being busy (P=0.001), or poor memory (P=0.008) were control belief barriers found to be correlated with poor adherence. TPB is the only important determinant influencing OAD adherence among all the factors (P=0.011). Conclusion: The results indicate that the TPB model could be used to examine adherence to OADs. One facilitating control belief, and most of the barrier control beliefs of TPB were related to medication adherence among Chinese type 2 diabetes inpatients. It will be helpful to understand patients’ self-medication and provide methods to develop instruments for identifying factors that influence OAD adherence. © 2016 Wu and Liu.

Ouyang L.,University of Sichuan | Shi Z.,Sichuan University | Shi Z.,Guizhou Normal University | Zhao S.,Sichuan University | And 5 more authors.
Cell Proliferation | Year: 2012

Programmed cell death (PCD), referring to apoptosis, autophagy and programmed necrosis, is proposed to be death of a cell in any pathological format, when mediated by an intracellular program. These three forms of PCD may jointly decide the fate of cells of malignant neoplasms; apoptosis and programmed necrosis invariably contribute to cell death, whereas autophagy can play either pro-survival or pro-death roles. Recent bulk of accumulating evidence has contributed to a wealth of knowledge facilitating better understanding of cancer initiation and progression with the three distinctive types of cell death. To be able to decipher PCD signalling pathways may aid development of new targeted anti-cancer therapeutic strategies. Thus in this review, we present a brief outline of apoptosis, autophagy and programmed necrosis pathways and apoptosis-related microRNA regulation, in cancer. Taken together, understanding PCD and the complex interplay between apoptosis, autophagy and programmed necrosis may ultimately allow scientists and clinicians to harness the three types of PCD for discovery of further novel drug targets, in the future cancer treatment. © 2012 Blackwell Publishing Ltd.

Fang X.,Nanjing Southeast University | Fang L.,Nanjing Southeast University | Fang L.,China Pharmaceutical University | Gou S.,Nanjing Southeast University | Cheng L.,Nanjing Southeast University
Bioorganic and Medicinal Chemistry Letters | Year: 2013

A series of dimethylaminomethyl-substituted curcumin derivatives/analogues were designed and synthesized. All compounds effectively inhibited HepG2, SGC-7901, A549 and HCT-116 tumor cell lines proliferation in MTT assay. Particularly, compounds 2a and 3d showed much better activity than curcumin against all of the four tumor cell lines. Antioxidant test revealed that these compounds had higher free radical scavenging activity than curcumin towards both DPPH and galvinoxyl radicals. Furthermore, the aqueous solubility and stability of the target compounds were also significantly improved compared with curcumin. © 2012 Elsevier Ltd. All rights reserved.

Zheng X.,Nanjing University | Zheng X.,Nanjing Southeast University | Zhang X.,Nanjing Southeast University | Wang G.,China Pharmaceutical University | Hao H.,China Pharmaceutical University
Drug Discovery Today | Year: 2015

The limited medication for major depressive disorder (MDD) against an ever-rising disease burden presents an urgent need for therapeutic innovations. During recent years, studies looking at the systems regulation of mental health and disease have shown a remarkably powerful control of MDD by systemic signals. Meanwhile, the identification of a host of targets outside the brain opens the way to treat MDD by targeting systemic signals. We examine these emerging findings and consider the implications for current thinking regarding MDD pathogenesis and treatment. We highlight the opportunities and challenges of a periphery-targeting strategy and propose its incorporation into a holistic approach. © 2015 Elsevier Ltd. All rights reserved.

Zhang D.,Nanjing Southeast University | Yang M.,China Pharmaceutical University
Physical Chemistry Chemical Physics | Year: 2013

The advantages of one-dimensional nanostructures, such as excellent charge separation and charge transport, low charge carrier recombination losses and so on, render them the photocatalysts of choice for many applications that exploit solar energy. In this work, based on very recently synthesized ultrathin anatase TiO2 nanowires, we explore the possibility of these wires as photocatalysts for photoelectrochemical water-splitting via the mono-doping (C, N, V, and Cr) and n-p codoping (C&V, C&Cr, N&V, and N&Cr) schemes. Our first-principles calculations predict that the C&Cr and C&V codoped ANWs may be strong candidates for photoelectrochemical water-splitting, because they have a substantially reduced band gap of 2.49 eV, appropriate band edge positions, no carrier recombination centers, and enhanced optical absorption in the visible light region. © 2013 the Owner Societies.

Shi L.,China Pharmaceutical University | Wu T.-T.,China Pharmaceutical University | Wang Z.,China Pharmaceutical University | Xue J.-Y.,CAS Institute of Botany | Xu Y.-G.,China Pharmaceutical University
European Journal of Medicinal Chemistry | Year: 2014

Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. In this work, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinolin-4-amine derivatives were designed and identified as potent inhibitors of VEGFR-2 (KDR) kinase. These compounds with quinoline scaffold and benzimidazole moiety were synthesized and their biological activities against VEGFR-2 and two human cancer cell lines were evaluated. Among them, compound 7s exhibited the most potent inhibitory activity against VEGFR-2 with IC50 of 0.03 μM and it also showed the highest anticancer activity against the tested cancer cell lines with IC50 of 1.2 μM against MCF-7 and 13.3 μM against Hep-G2. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of VEGFR-2, which demonstrates that compound 7s is a potential agent for cancer therapy deserving further researching. © 2014 Elsevier Masson SAS. All rights reserved.

Li S.,Nanjing Southeast University | Wang Z.,Nanjing University | Wei Y.,China Pharmaceutical University | Wu C.,Nanjing Southeast University | And 5 more authors.
Biomaterials | Year: 2013

Multidrug resistance (MDR) of bacteria is still an unsolved serious problem to threaten the health of human beings. Developing new antibacterial agents, therefore, are urgently needed. Herein, we have explored the possibility to design and synthesize some novel antibacterial agents including ferrocene-substituted carborane derivative (Fc2SBCp1) and have evaluated the relevant antibacterial action against two clinical common MDR pathogens (i.e., Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa) in vitro and in vivo. The results demonstrate that in vitro antimicrobial activity of Fc2SBCp1 could be gradually transformed into a bactericidal effect from a bacteriostatic effect with the increasing concentration of the active carborane derivative, which can also prevent biofilm formation at concentrations below MIC (i.e., minimal inhibitory concentration). Biocompatibility studies indicate that there exists no/or little toxic effect of Fc2SBCp1 on normal cells/tissues and leads to little hemolysis. In vivo studies illustrate that the new carborane derivative Fc2SBCp1 is highly effective in treating bacteremia caused by S. aureus and P. aeruginosa as well as interstitial pneumonia caused by S. aureus. This raises the possibility for the potential utilization of the new ferrocene-substituted carborane derivatives as promising antibacterial therapeutic agents against MDR bacterial infections in future clinical applications. © 2012 Elsevier Ltd.

Li Y.,Nanjing Southeast University | Wang W.,Nanjing Southeast University | Wang W.,China Pharmaceutical University | Wu Q.,Nanjing Southeast University | And 3 more authors.
PLoS ONE | Year: 2012

With growing concerns of the safety of nanotechnology, the in vivo toxicity of nanoparticles (NPs) at environmental relevant concentrations has drawn increasing attentions. We investigated the possible molecular mechanisms of titanium nanoparticles (Ti-NPs) in the induction of toxicity at predicted environmental relevant concentrations. In nematodes, small sizes (4 nm and 10 nm) of TiO2-NPs induced more severe toxicities than large sizes (60 nm and 90 nm) of TiO2-NPs on animals using lethality, growth, reproduction, locomotion behavior, intestinal autofluorescence, and reactive oxygen species (ROS) production as endpoints. Locomotion behaviors could be significantly decreased by exposure to 4-nm and 10-nm TiO2-NPs at concentration of 1 ng/L in nematodes. Among genes required for the control of oxidative stress, only the expression patterns of sod-2 and sod-3 genes encoding Mn-SODs in animals exposed to small sizes of TiO2-NPs were significantly different from those in animals exposed to large sizes of TiO2-NPs. sod-2 and sod-3 gene expressions were closely correlated with lethality, growth, reproduction, locomotion behavior, intestinal autofluorescence, and ROS production in TiO2-NPs-exposed animals. Ectopically expression of human and nematode Mn-SODs genes effectively prevented the induction of ROS production and the development of toxicity of TiO2-NPs. Therefore, the altered expression patterns of Mn-SODs may explain the toxicity formation for different sizes of TiO2-NPs at predicted environmental relevant concentrations. In addition, we demonstrated here a strategy to investigate the toxicological effects of exposure to NPs upon humans by generating transgenic strains in nematodes for specific human genes. © 2012 Li et al.

Li J.,China Pharmaceutical University | Liu Y.,Kaifeng University | Liu L.,Changzhou University
Letters in Organic Chemistry | Year: 2012

New surfactant-type bifunctional thiourea organocatalysts 3 were synthesized. It was found that in the presence of 10 mol% PhCOOH, bifunctional thiourea bearing a long chain 3b in 10 mol% loading could smoothly catalyze the asymmetric Michael reaction of nitroalkenes 4 with cyclohexanone at room temperature in the presence of water, giving the desired adducts 5a-i in good yields (80 - 93%) with high diastereoselectivities (syn/anti = 95/5 - > 99/1) and enantioselectivities (up to 92% ee). © 2012 Bentham Science Publishers.

Zhang X.,Harvard University | Zhang X.,China Pharmaceutical University | Zhang X.,Nanjing Southeast University | Tian Y.,Harvard University | And 9 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

.1073/pnas.1505420112 Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.

Senyilmaz D.,German Cancer Research Center | Virtue S.,University of Cambridge | Xu X.,German Cancer Research Center | Xu X.,China Pharmaceutical University | And 6 more authors.
Nature | Year: 2015

Mitochondria are involved in a variety of cellular functions, including ATP production, amino acid and lipid biogenesis and breakdown, signalling and apoptosis. Mitochondrial dysfunction has been linked to neurodegenerative diseases, cancer and ageing. Although transcriptional mechanisms that regulate mitochondrial abundance are known, comparatively little is known about how mitochondrial function is regulated. Here we identify the metabolite stearic acid (C18:0) and human transferrin receptor 1 (TFR1; also known as TFRC) as mitochondrial regulators. We elucidate a signalling pathway whereby C18:0 stearoylates TFR1, thereby inhibiting its activation of JNK signalling. This leads to reduced ubiquitination of mitofusin via HUWE1, thereby promoting mitochondrial fusion and function. We find that animal cells are poised to respond to both increases and decreases in C18:0 levels, with increased C18:0 dietary intake boosting mitochondrial fusion in vivo. Intriguingly, dietary C18:0 supplementation can counteract the mitochondrial dysfunction caused by genetic defects such as loss of the Parkinson's disease genes Pink or Parkin in Drosophila. This work identifies the metabolite C18:0 as a signalling molecule regulating mitochondrial function in response to diet. © 2015 Macmillan Publishers Limited.

Liu D.,Hubei University of Chinese Medicine | Liu Y.-W.,Hubei University of Chinese Medicine | Guan F.-Q.,CAS Institute of Botany | Liang J.-Y.,China Pharmaceutical University
Fitoterapia | Year: 2014

Two new dimeric diarylheptanoids, named Alpinin C (1) and D (2), a new natural product of diarylheptanoid (3) along with three known diarylheptanoids (4-6) were isolated from the rhizomes of Alpinia officinarum Hance. Their structures were elucidated based on extensive spectroscopic analyses (1D and 2D NMR, HRTOFMS, IR). The isolated compounds were evaluated for their cytotoxicity against human tumor cell lines HepG2, MCF-7, T98G and B16-F10. Compound 1 showed selective cytotoxicity against cell lines of MCF-7 and T98G, while compound 6 showed significant cytotoxicity to the all tested tumor cell lines with IC 50 in the range from 8.46 to 22.68 μmol/L. © 2014 Elsevier B.V.

Ye B.,China Pharmaceutical University | Ye B.,Nanjing Southeast University | Rui Q.,Nanjing Southeast University | Rui Q.,Nanjing Agricultural University | And 2 more authors.
PLoS ONE | Year: 2010

Metallothioneins (MTs) are small, cysteine-rich polypeptides, but the role of MTs in inducing the formation of adaptive response is still largely unknown. We investigated the roles of metallothionein genes (mtl-1 and mtl-2) in the formation of cross-adaptation response to neurobehavioral toxicity from metal exposure in Caenorhabditis elegans. Pre-treatment with mild heat-shock at L2-larva stage effectively prevented the formation of the neurobehavioral defects and the activation of severe stress response in metal exposed nematodes at concentrations of 50 and 100 μM, but pre-treatment with mild heatshock did not prevent the formation of neurobehavioral defects in 200 μ M of metal exposed nematodes. During the formation of cross-adaptation response, the induction of mtl-1 and mtl-2 promoter activity and subsequent GFP gene expression were sharply increased in 50 μM or 100 μM of metal exposed Pmtl-1::GFP and Pmtl-2::GFP transgenic adult animals after mild heat-shock treatment compared with those treated with mild heat-shock or metal exposure alone. Moreover, after pre-treatment with mild heat-shock, no noticeable increase of locomotion behaviors could be observed in metal exposed mtl-1 or mtl-2 mutant nematodes compared to those without mild heat-shock pre-treatment. The defects of adaptive response to neurobehavioral toxicity induced by metal exposure formed in mtl-1 and mtl-2 mutants could be completely rescued by the expression of mtl-1 and mtl-2 with the aid of their native promoters. Furthermore, overexpression of MTL-1 and MTL-2 at the L2-larval stage significantly suppressed the toxicity on locomotion behaviors from metal exposure at all examined concentrations. Therefore, the normal formation of cross-adaptation response to neurobehavioral toxicity induced by metal exposure may need the enough accumulation of MTs protein in animal tissues. © 2010 Ye et al.

Song M.,China Pharmaceutical University | Zhang S.,China Pharmaceutical University | Xu X.,China Pharmaceutical University | Hang T.,China Pharmaceutical University | Jia L.,U.S. National Cancer Institute
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2010

Compound Danshen tablets are composed of Panax notoginseng, Salvia miltiorrhiza and Borneol. The tablets are prescribed for treatment of cardiovascular diseases in China. The present study aimed at developing a specific and sensitive LC-MS/MS method to simultaneously determine three bioactive P. notoginseng saponins, i.e., notoginsenoside R1, ginsenoside Rg1 and Rb1, in dogs after a single oral administration of the compound tablets in order to obtain the clinically relevant saponin-related pharmacodynamics of the tablets in patients. The R1, Rg1 and Rb1 were extracted from dog plasma with acetone-methanol (80:20, v/v), separated by reversed phase liquid chromatography and determined by tandem mass spectrometry (LC-MS/MS) with positive electrospray ionization (ESI). The developed method reached lower limit of quantitation (LLOQ) at 0.10ng/ml for the three saponins. The method was validated in terms of selectivity, matrix effects, linearity, precision and accuracy, and then was applied to a pharmacokinetic study of the three bioactive saponins simultaneously in dogs after a single oral administration of compound Danshen tablets at a clinical equivalent dose. The Cmax and AUC(0-∞) for R1, Rg1 and Rb1 were 1.91, 3.34 and 28.6ng/ml, and 7.5, 11.0, and 1712 (hng/ml), respectively. © 2010 Elsevier B.V.

Liu J.,Medical College of Wisconsin | Liu J.,China Pharmaceutical University | Yuan Y.,Medical College of Wisconsin | Yuan Y.,Shanghai University of Traditional Chinese Medicine | And 9 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a negative immune-checkpoint protein that suppresses T-cell responses. To determine whether VISTA synergizes with another immune-checkpoint, programmed death 1 (PD-1), this study characterizes the immune responses in VISTA-deficient, PD-1-deficient (KO) mice and VISTA/PD-1 double KO mice. Chronic inflammation and spontaneous activation of T cells were observed in both single KO mice, demonstrating their nonredundancy. However, the VISTA/PD-1 double KO mice exhibited significantly higher levels of these phenotypes than the single KO mice. When bred onto the 2D2 T-cell receptor transgenic mice, which are predisposed to development of inflammatory autoimmune disease in the CNS, the level of disease penetrance was significantly enhanced in the double KO mice compared with in the single KO mice. Consistently, the magnitude of T-cell response toward foreign antigens was synergistically higher in the VISTA/PD-1 double KO mice. A combinatorial blockade using monoclonal antibodies specific for VISTA and PD-L1 achieved optimal tumor-clearing therapeutic efficacy. In conclusion, our study demonstrates the nonredundant role of VISTA that is distinct from the PD-1/PD-L1 pathway in controlling T-cell activation. These findings provide the rationale to concurrently target VISTA and PD-1 pathways for treating T-cell-regulated diseases such as cancer. © 2015, National Academy of Sciences. All rights reserved.

Ji G.,Nanjing Medical University | Ji G.,Nanjing Institute of Environmental Sciences | Long Y.,China Pharmaceutical University | Zhou Y.,CAS Shanghai Institutes for Biological Sciences | And 3 more authors.
BMC Medicine | Year: 2012

Background: The mismatch repair (MMR) pathway plays an important role in the maintenance of the genome integrity, meiotic recombination and gametogenesis. This study investigated whether genetic variations in MMR genes are associated with an increased risk of sperm DNA damage and male infertility.Methods: We selected and genotyped 21 tagging single nucleotide polymorphisms (SNPs) in five MMR genes (MLH1, MLH3, PMS2, MSH4 and MSH5) using the SNPstream 12-plex platform in a case-control study of 1,292 idiopathic infertility patients and 480 fertile controls in a Chinese population. Sperm DNA damage levels were detected with the Tdt-mediated dUTP nick end labelling (TUNEL) assay in 450 cases. Fluorescence resonance energy transfer (FRET) and co-immunoprecipitation techniques were employed to determine the effects of functional variants.Results: One intronic SNP in MLH1 (rs4647269) and two non-synonymous SNPs in PMS2 (rs1059060, Ser775Asn) and MSH5 (rs2075789, Pro29Ser) seem to be risk factors for the development of azoospermia or oligozoospermia. Meanwhile, we also identified a possible contribution of PMS2 rs1059060 to the risk of male infertility with normal sperm count. Among patients with normal sperm count, MLH1 rs4647269 and PMS2 rs1059060 were associated with increased sperm DNA damage. Functional analysis revealed that the PMS2 rs1059060 can affect the interactions between MLH1 and PMS2.Conclusions: Our results provide evidence supporting the involvement of genetic polymorphisms in MMR genes in the aetiology of male infertility. © 2012 Ji et al; licensee BioMed Central Ltd.

Chen J.,CAS Institute of Botany | Chen J.,Ghent University | Chen J.,China Pharmaceutical University | Mangelinckx S.,Ghent University | And 4 more authors.
Fitoterapia | Year: 2014

The phytochemical investigation of natural products of Gynura divaricata led to the isolation of eleven caffeoylquinic acid derivatives. They were characterized by spectrometric methods as 5-O-caffeoylquinic acid (1), 5-O-p-coumaroylquinic acid (2), 5-O-feruloylquinic acid (3), methyl 5-O-caffeoylquinate (4), 3,4-dicaffeoylquinic acid (5), 3,5-dicaffeoylquinic acid (6), 4,5-dicaffeoylquinic acid (7), methyl 3,4-dicaffeoylquinate (8), methyl 3,5-dicaffeoylquinate (9), methyl 4,5-dicaffeoylquinate (10) and ethyl 4,5-dicaffeoylquinate (11). The individual compounds were screened for the inhibition of yeast α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) using in vitro assays. Among the isolated compounds, 3,4-dicaffeoylquinic acid (5), 4,5-dicaffeoylquinic acid (7), methyl 3,4-dicaffeoylquinate (8) and methyl 4,5-dicaffeoylquinate (10) exhibited significant inhibitory activities against α-glucosidase. In addition, 5-O-p-coumaroylquinic acid (2), 3,5-dicaffeoylquinic acid (6) and 4,5-dicaffeoylquinic acid (7) had considerable inhibitory effect against PTP1B. Based on these findings, the caffeoylquinic acid derivatives were deduced to be potentially responsible for the anti-diabetic activity of G. divaricata. The preliminary structure-activity relationship study suggests that the number and positioning of caffeoyl groups in the quinic acid derivatives are important for both α-glucosidase and PTP1B inhibitory potency. Moreover, the corresponding methyl esters of some dicaffeoylquinic acids have enhanced inhibitory activity against yeast α-glucosidase. © 2014 Elsevier B.V.

Ma L.,Stanford University | Wang X.,Stanford University | Wang X.,Sun Yat Sen University | Jia T.,China Pharmaceutical University | And 3 more authors.
Oncotarget | Year: 2015

Deregulated WNT/ß-catenin signaling contributes to the development of a subgroup of hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide. Within this pathway, the tankyrase enzymes (TNKS1 and TNKS2) degrade AXIN and thereby enhance ß-catenin activity. We evaluate TNKS enzymes as potential therapeutic targets in HCC, and the anti-tumor efficacy of tankyrase inhibitors (XAV939, and its novel nitro-substituted derivative WXL-8) in HCC cells. Using semi-quantitative RT-PCR, we found significantly elevated levels of TNKS1/2 mRNA in tumor liver tissues compared to adjacent non-tumor livers, at protein levels only TNKS1 is increased. In HepG2, Huh7cells, siRNA-mediated knockdown suppression of endogenous TNKS1 and TNKS2 reduced cell proliferation, together with decreased nuclear ß-catenin levels. XAV939 and WXL-8 inhibited cell proliferation and colony formation in HepG2, Huh7, and Hep40 cells (p < 0.05), with stabilization of AXIN1 and AXIN2, and decreased ß-catenin protein levels. XAV939 and WXL-8 also attenuated rhWNT3A-induced TOPflash luciferase reporter activity in HCC cells, indicating reduced ß-catenin transcriptional activity, consistent with decreased nuclear ß-catenin levels. In vivo, intra-tumor injections of XAV939 or WXL-8 significantly inhibited the growth of subcutaneous HepG2 xenografts (P < 0.05). We suggest that tankyrase inhibition is a potential therapeutic approach for treating a subgroup HCC with aberrant WNT/ß-catenin signaling pathway. © 2015.

Ling Y.,China Pharmaceutical University | Ling Y.,Nantong University | Ye X.,Ningbo University | Zhang Z.,China Pharmaceutical University | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2011

Figure Presented. Novel furoxan-based nitric oxide (NO) releasing derivatives (8a-p) of farnesylthiosalicylic acid (FTS) were synthesized. Compound 8l displayed the strongest inhibition on the proliferation of human hepatocellular carcinoma (HCC) cells in vitro, superior to FTS, sorafenib, and furoxan moiety, selectively induced high frequency of HCC cell apoptosis, and produced high levels of NO in HCC cells but not in nontumor liver cells. Furthermore, 8l exhibited low acute toxicity to mice and significantly inhibited the growth of HCC tumors in vivo and the Ras-related signaling in the tumors. Therefore, our novel findings may provide a new framework for the design of new NO-releasing furoxan/FTS hybrids for the intervention of human HCC. © 2011 American Chemical Society.

Hang A.,China Pharmaceutical University | Wang Y.-J.,CAS Shanghai Institute of Materia Medica | He L.,China Pharmaceutical University | Liu J.-G.,CAS Shanghai Institute of Materia Medica
Acta Pharmacologica Sinica | Year: 2015

Anxiety disorders are the most common and prevalent forms of psychiatric disease, although the biological basis of anxiety is not well understood. The dynorphin/κ opioid receptor system is widely distributed in the central nervous system and has been shown to play a critical role in modulating mood and emotional behaviors. In the present review, we summarize current literature relating to the role played by the dynorphin/κ opioid receptor system in anxiety and κ opioid receptor antagonists as potential therapeutic agents for the treatment of anxiety disorders. © 2015 CPS and SIMM.

Fan Z.,CAS Shanghai Institute of Materia Medica | Wu K.,China Pharmaceutical University | Xing L.,University of Science and Technology of China | Yao Q.,China Pharmaceutical University | Zhang A.,CAS Shanghai Institute of Materia Medica
Chemical Communications | Year: 2014

A palladium-catalyzed dual C-H activation to construct C-C/C-N bonds for one-pot synthesis of benzo[c]pyrazolo[1,2-a]cinnolin-1-ones is successfully developed. This approach involves using a pyrazolone moiety as an internal directing group for C-H activation, and provides a flexible strategy to access this polycyclic skeleton. © 2014 The Royal Society of Chemistry.

Gan L.,CAS Shanghai Institute of Materia Medica | Han S.,CAS Shanghai Institute of Materia Medica | Shen J.,China Pharmaceutical University | Zhu J.,China Pharmaceutical University | And 3 more authors.
International Journal of Pharmaceutics | Year: 2010

The object of this study was to design novel self-assembled liquid crystalline nanoparticles (cubosomes) as an ophthalmic delivery system for dexamethasone (DEX) to improve its preocular retention and ocular bioavailability. DEX cubosome particles were produced by fragmenting a cubic crystalline phase of monoolein and water in the presence of stabilizer Poloxamer 407. Small angle X-ray diffraction (SAXR) profiles revealed its internal structure as Pn3m space group, indicating the diamond cubic phase. In vitro, the apparent permeability coefficient of DEX administered in cubosomes exhibited a 4.5-fold (F1) and 3.5-fold (F2) increase compared to that of Dex-Na phosphate eye drops. Preocular retention studies revealed that the retention of cubosomes was significantly longer than that of solution and carbopol gel, with AUC0→180min of Rh B cubosomes being 2-3-fold higher than that of the other two formulations. In vivo pharmacokinetics in aqueous humor was evaluated by microdialysis, which indicated a 1.8-fold (F1) increase in AUC0→240min of DEX administered in cubosomes relative to that of Dex-Na phosphate eye drops, with about an 8-fold increase compared to that of DEX suspension. Corneal cross-sections after incubation with DEX cubosomes demonstrated an unaffected corneal structure and tissue integrity, which indicated the good biocompatibility of DEX cubosomes. In conclusion, self-assembled liquid crystalline nanoparticles might represent a promising vehicle for effective ocular drug delivery. © 2010.

Ling C.,CAS Shanghai Institute of Materia Medica | Fu L.,CAS Shanghai Institute of Materia Medica | Gao S.,CAS Shanghai Institute of Materia Medica | Chu W.,CAS Shanghai Institute of Materia Medica | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2014

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4. © 2014 American Chemical Society.

Zhang X.,Harvard University | Zhang X.,China Pharmaceutical University | Tian Y.,Harvard University | Tian Y.,Sun Yat Sen University | And 6 more authors.
Journal of the American Chemical Society | Year: 2013

In this article, we first designed and synthesized curcumin-based near-infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species and then an inhibitor that could attenuate cross-linking of Aβ induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13-20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild-type mice as young as 4 months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the cross-linking of Aβ42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent cross-linking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy. © 2013 American Chemical Society.

Jiang X.,China Pharmaceutical University | Jiang X.,CAS Shanghai Institute of Materia Medica | Song Z.,CAS Shanghai Institute of Materia Medica | Xu C.,China Pharmaceutical University | And 2 more authors.
European Journal of Organic Chemistry | Year: 2014

A tandem one-pot Friedel-Crafts alkylation/double cyclization process to conveniently assemble diaryl-fused 2,8-dioxabicyclo[3.3.1]nonanes with aryl substituents at the C-1 position was developed. 2-Hydroxychalcones and naphthol derivatives reacted in refluxing toluene with (D,L)-10-camphorsulfonic acid (CSA) as the catalyst. The transformation conveniently provided the corresponding 2,8-dioxabicyclo[3.3.1]nonanes fused with one phenyl and one naphthyl group in moderate to good yields, and various substitutions on both reaction partners were tolerated. More importantly, aryl- and aza-aryl-fused 2,8-dioxabicyclo[3.3.1]nonanes were prepared for the first time using this procedure. An efficient approach to diaryl-fused 2,8-dioxabicyclo[3.3.1]nonanes with aryl substituents at the C-1 position was achieved. By using (D,L)-10-camphorsulfonic acid (CSA) as the catalyst, aryl- and aza-aryl-fused 2,8-dioxabicyclo[3.3.1]nonanes were prepared. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Li G.,China Pharmaceutical University | Wang Y.,Shandong University | Yang L.,Hunan Normal University | Ma W.,China Pharmaceutical University | Wang M.,Shandong University
European Journal of Inorganic Chemistry | Year: 2014

ZnMn2O4-ZnO-C nanohybrids have been synthesized by means of a simple carbonthermal reduction reaction between ZnMnO3 and acetylene black. ZnMn2O4-C nanohybrids are obtained by further washing with NaOH solution. The reversible discharge capacity of the ZnMn2O4-ZnO-C nanohybrids can reach 620 mA h g -1 at a current density of 100 mA g-1 and 520 mA h g -1 at 800 mA g-1 after 100 cycles. More importantly, ZnMn2O4-C shows better conductivity along with better rate performance after the removal of ZnO. The as-prepared ZnMn2O 4-C nanohybrids show a high specific capacity of approximately 750 mA h g-1 at a current density of 100 mA g-1 after 100 cycles and excellent rate performance. The reaction involved in the discharge/charge processes are discussed on the basis of ex situ high-resolution transmission of the electrode materials. The conclusions will be of benefit in the design and exploration of future binary transition-metal oxide anode materials for lithium-ion batteries. ZnMn2O4-ZnO-C hybrid anodes were synthesized by means of an in situ carbonthermal reduction reaction between ZnMnO3 and acetylene black. ZnMn2O4-C hybrids with better battery performance were obtained by further treating with NaOH solution. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Zhou Z.-F.,CAS Shanghai Institute of Materia Medica | Kurtan T.,Debrecen University | Yang X.-H.,China Pharmaceutical University | Mandi A.,Debrecen University | And 4 more authors.
Organic Letters | Year: 2014

A novel pyrrolizidine alkaloid, penibruguieramine A (1), characterized by an unprecedented 1-alkenyl-2-methyl-8-hydroxymethylpyrrolizidin-3-one skeleton, was isolated from the endophytic fungus Penicillium sp. GD6, associated with the Chinese mangrove Bruguiera gymnorrhiza. The absolute configuration of penibruguieramine A (1) was established by TDDFT ECD calculations of the vacuum and solution conformers, exploiting the transitions of the lactam chromophore. A plausible pathway for its biosynthesis has been proposed. © 2014 American Chemical Society.

Liu X.-H.,Anhui Medical University | Liu X.-H.,Guizhou University | Li J.,Anhui Medical University | Shi J.B.,Anhui Medical University | And 2 more authors.
European Journal of Medicinal Chemistry | Year: 2012

A series of novel 5-phenyl-N-piperidine ethanone-4,5-dihydropyrazole derivatives as potential telomerase inhibitors were synthesized. The bioassays demonstrated that compounds 4d, 4f, 7a and 7b occupied high antiproliferative activities against SGC-7901, MGC-803 and Bcap-37 cell lines. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound 7b showed the most potent inhibitory activity with IC 50 value at 2.00 ± 0.40 μM. The active compound 4d was also docked into the telomerase TERT active site to determine the probable binding model. The results indicated that conserved residues Lys189, Asp254 and Gln308 were important for ligand binding via hydrogen bond interactions. © 2012 Elsevier Masson SAS. All rights reserved.

Zhao M.-X.,Sun Yat Sen University | Xia Q.,China Pharmaceutical University | Feng X.-D.,China Pharmaceutical University | Zhu X.-H.,South China University of Technology | And 4 more authors.
Biomaterials | Year: 2010

A series of quantum dots (QDs), CdSe, CdSe/CdS and CdSe/ZnSe, coated with l-arginine-modified β-cyclodextrin (β-CD-l-Arg) were prepared in a solution of H2O and hexane by ultrasonic method and characterized using PL, UV-vis, TEM, EDX and FTIR techniques. We observed that β-CD-l-Arg-coated QDs are water-soluble and stable with high colloidal properties in water. Their photophysical properties are similar to those of trioctylphosphine oxide (TOPO)-coated nanocrystals. The quantum yield (QY) of β-CD-l-Arg/CdSe/ZnSe QDs in water is 68%, which is much higher than those of β-CD-l-Arg/CdSe/CdS (26%) and β-CD-l-Arg/CdSe (13%). The in vitro cytotoxicity of these QDs was evaluated in ECV-304, SH-SY5Y and Hela cells and low cytotoxicity was observed. In particular, the β-CD-l-Arg/CdSe/ZnSe QDs presented lower cytotoxicity to these cells (CC50 value is 173μg/mL in ECV-304 cells for 48h). This may be due to the presence of the ZnSe and β-CD-l-Arg outlayer, which may improve the biocompatibility of QDs. The QDs were further investigated for biological labeling in ECV-304 cells using confocal laser scanning fluorescence microscopy. We found that these QDs were capable of localing to the cytoplasm of cells. These results demonstrate that the β-CD-l-Arg-coated QDs could be used as a potential photoluminescent nanocrystal probing agent with good biocompatibility. © 2010 Elsevier Ltd.

Han C.,China Pharmaceutical University | Huang Z.,China Pharmaceutical University | Zheng C.,Chinese Academy of Sciences | Wan L.,China Pharmaceutical University | And 6 more authors.
Journal of Medicinal Chemistry | Year: 2013

A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 μM) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746-A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 μM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-κB activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC. © 2013 American Chemical Society.

Wang P.,CAS Shanghai Institute of Materia Medica | Wang P.,China Pharmaceutical University | Liao W.,CAS Shanghai Institute of Materia Medica | Fang J.,CAS Shanghai Institute of Materia Medica | And 4 more authors.
Carbohydrate Polymers | Year: 2014

Inhibition of Aβ aggregation and attenuation of its cytotoxicity are considered to valuable therapeutics for Alzheimer's disease (AD). Here, a glucan named as LJW0F2 was purified from flowers of Lonicera japonica Thunb. Using monosaccharides composition analysis, methylation analysis, IR and NMR spectroscopy, this polysaccharide was elucidated to be an α-d-(1→4)- glucan with an α-(1→4) linked branch attached to the C-6 position. Its inhibitory effect on Aβ42 aggregation was measured by fluorescence spectroscopic analysis with thioflavine T (ThT) and atomic force microscopy (AFM). We showed that polysaccharide LJW0F2 could inhibit Aβ42 aggregation in a dose-dependent-manner. Besides, LJW0F2 could attenuate the cytotoxicity induced by Aβ42 aggregation in SH-SY5Y neuroblastoma cells. To the best of our knowledge, this was the first report that the exogenous plant-derived polysaccharide might block Aβ42 aggregation directly and reduce its toxicity in SH-SY5Y cells. © 2014 Elsevier Ltd.

Guo B.,CAS Shanghai Institute of Materia Medica | Fan H.,CAS Shanghai Institute of Materia Medica | Xin Q.,CAS Shanghai Institute of Materia Medica | Chu W.,CAS Shanghai Institute of Materia Medica | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2013

The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED 50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid. © 2013 American Chemical Society.

Li Y.,China Pharmaceutical University | Li J.-J.,China Pharmaceutical University | Wen X.-D.,China Pharmaceutical University | Pan R.,AustarPharma LLC | And 2 more authors.
Molecular BioSystems | Year: 2014

Type 2 diabetes mellitus (T2DM) is increased worldwide in parallel with the obesity epidemic. Potentilla discolor is one of the most important crude materials in Traditional Chinese medicine (TCM) for therapy of hyperglycemia and hyperlipidemia. In this work, a plasma metabonomic approach based on the combination of UPLC-Q-TOF with multivariate data analysis was applied to investigate the therapeutic effects of the extract of P. discolor (EPD) and corosolic acid (CA), the main bioactive compounds of P. discolor. Male C57BL/6 mice were fed with high-fat diet (HFD-fed group) for 8 weeks and then treated with EPD (EPD-treated group) or CA (CA-treated group) for another 8 weeks. After the experimental period, samples of plasma were collected and analyzed by ultra-performance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC-Q-TOF). The principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models were built to find biomarkers of T2DM and investigate the therapeutic effects of EPD and CA. 26 metabolites, which are distributed in several metabolic pathways, were identified as potential biomarkers of T2DM. It was found that EPD and CA could reverse the pathological process of T2DM through regulating the disturbed pathway of metabolism. The metabonomic results are beneficial not only for the evaluation of the therapeutic effect of TCM but also for the elucidation of the underlying molecular mechanism. This journal is © the Partner Organisations 2014.

Han J.,China Pharmaceutical University | Huang X.,CAS Shanghai Institute of Materia Medica | Sun L.,China Pharmaceutical University | Li Z.,China Pharmaceutical University | And 2 more authors.
Biochemical Pharmacology | Year: 2013

A series of fatty chain conjugates of glucagon-like peptide-1(GLP-1) were designed and synthesized. First, eleven cysteine modified peptides (1-11) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. Peptides 1, 6, 9, and 11 which showed comparable GLP-1 receptor activate potency and glucose-lowering effect in vivo with Gly8-GLP-1(7-36)-NH2 were selected for second step modifications to yield conjugates 12-23. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable compound 14 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of compound 14 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. Our results suggest that compound 14 is a promising type 2 antidiabetic agent deserving further investigation. © 2013 Elsevier Inc. All rights reserved.

Wang C.-Z.,Tang Center for Herbal Medicine Research | Qi L.-W.,Tang Center for Herbal Medicine Research | Qi L.-W.,China Pharmaceutical University | Yuan C.-S.,Tang Center for Herbal Medicine Research | Yuan C.-S.,University of Chicago
American Journal of Chinese Medicine | Year: 2015

Ginger is a commonly used spice and herbal medicine worldwide. Besides its extensive use as a condiment, ginger has been used in traditional Chinese medicine for the management of various medical conditions. In recent years, ginger has received wide attention due to its observed antiemetic and anticancer activities. This paper reviews the potential role of ginger and its active constituents in cancer chemoprevention. The phytochemistry, bioactivity, and molecular targets of ginger constituents, especially 6-shogaol, are discussed. The content of 6-shogaol is very low in fresh ginger, but significantly higher after steaming. With reported anti-cancer activities, 6-shogaol can be served as a lead compound for new drug discovery. The lead compound derivative synthesis, bioactivity evaluation, and computational docking provide a promising opportunity to identify novel anticancer compounds originating from ginger. © 2015 World Scientific Publishing Company.

Zhang X.,CAS Shanghai Institute of Materia Medica | Jiang X.,China Pharmaceutical University | Ding C.,CAS Shanghai Institute of Materia Medica | Yao Q.,China Pharmaceutical University | Zhang A.,CAS Shanghai Institute of Materia Medica
Organic and Biomolecular Chemistry | Year: 2013

An unexpected N-glycosidation reaction of anthracen-1-amine with glycals was identified, and its use in the synthesis of C1′ N-linked analogues of natural product marmycin A was explored. The structures of all these products were determined by 1D and 2D NMR, CD spectra, and X-ray crystal analysis. These products were then subjected to Friedel-Crafts acylation, Dess-Martin oxidation and nucleophilic addition leading to novel natural product analogues bearing a quaternary carbon center. © 2013 The Royal Society of Chemistry.

Xu S.,China Pharmaceutical University | Xu S.,CAS Shanghai Institute of Materia Medica | Zhou Y.,CAS Shanghai Institute of Materia Medica | Xu J.,China Pharmaceutical University | And 3 more authors.
Green Chemistry | Year: 2013

The report describes a gold(i) complex and trifluoroacetic acid (TFA) cocatalyzed one-pot, Michael addition/intramolecular cyclization cascade reaction for the synthesis of unusual tetracyclic indoles containing a seven-membered ring in water with microwave irradiation (MW). This protocol presents an operationally simple, rapid and environmentally friendly strategy for preparing potential biologically interesting fused-indole molecular architectures from some simple starting materials. This journal is © 2013 The Royal Society of Chemistry.

Xiao D.,China Pharmaceutical University | Dramou P.,China Pharmaceutical University | He H.,China Pharmaceutical University | Pham-Huy L.A.,Stanford University | And 3 more authors.
Journal of Nanoparticle Research | Year: 2012

In this study, a new synthesis technique of magnetic multiwall carbon nanotubes (MMWCNTs) was achieved and its application for drug-loading ability was assessed. MMWCNTs were prepared by a simple solvothermal process, which can easily alter the size (100-350 nm), location, and denseness of Fe 3O 4 beads fixed on MWCNTs as well as the MWCNTs structure via controlling the reaction parameters. The characteristics of MMWCNTs obtained were assessed by scanning electron microscopy, X-ray diffraction, and FTIR. The MMWCNTs were used as a drug carrier to load an anticancer molecule, epirubicin hydrochloride. In addition, its adsorption ability was also evaluated. The Freundlich adsorption model was successfully used to describe the adsorption process. The kinetic data was well fitted with a pseudo-second-order model. Due to its magnetic properties, high adsorption surfaces, and excellent adsorption capacities, the MMWCNTs synthesized in this study are suitable to be applied to a magnetic targeted drug delivery system. © 2012 Springer Science+Business Media B.V.

Zhang Y.,China Pharmaceutical University | Jiang Z.,China Pharmaceutical University | Xue M.,Xiamen University | Zhang S.,China Pharmaceutical University | And 2 more authors.
Journal of Ethnopharmacology | Year: 2012

Ethnopharmacological relevance: Tripterygium wilfordii multiglycoside (GTW), which is an extract derived from Tripterygium wilfordii Hook.f., has been used for the treatment of rheumatoid arthritis and other immune diseases in China. However, its potential hepatotoxicity has not been completely investigated. The aim of the study: The aim of the study was to determine the hepatotoxicity of GTW in Wistar rats and to investigate the underlying cellular mechanism further by microarray analysis. Materials and methods: Doses of GTW at 60, 100 and 120 mg/kg/day were administered by oral gavage for subchronic toxicity in Wistar rats. Changes in the hepatic gene expression were identified with oligonucleotide microarrays at the 100-mg/kg/day dose level to study the hepatotoxic mechanism of GTW. Results and conclusions: A number of changes in the body weight and food consumption, absolute and relative liver weight, biochemical analysis and histopathology were observed after the subacute exposure to GTW, and a dose-dependent hepatotoxicity was observed. A total of 1312 genes were found to be significantly altered (2-fold, P < 0.05), including 582 up-regulated genes and 730 down-regulated genes. According to our biological pathway analysis, the GTW resulted in aberrant gene expression in metabolic pathways and the peroxisome proliferator-activated receptor (PPAR) signaling pathway and cellular stress. Real-time PCR analyses of several genes verified these results. Consequently, our gene expression microarray study will be useful for future GTW hepatotoxicity studies. © 2012 Elsevier Ireland Ltd. All rights reserved.

Shi D.,CAS Qingdao Institute of Oceanology | Li J.,CAS Qingdao Institute of Oceanology | Jiang B.,CAS Qingdao Institute of Oceanology | Guo S.,CAS Qingdao Institute of Oceanology | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

A series of bromophenol derivatives were synthesized and evaluated as protein tyrosine phosphatase 1B (PTP1B) inhibitors in vitro and in vivo based on bromophenol 4e (IC 50 = 2.42 μmol/L), which was isolated from red algae Rhodomela confervoides. The results showed that all of the synthesized compounds displayed weak to good PTP1B inhibition at tested concentration. Among them, highly brominated compound 4g exhibited promising inhibitory activity against PTP1B with IC 50 0.68 μmol/L, which was approximately fourfold more potent than lead compound 4e. Further, compound 4g demonstrated high selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). More importantly, in vivo antidiabetic activities investigations of compound 4g also demonstrated inspiring results. © 2012 Elsevier Ltd. All rights reserved.

Xiao D.,China Pharmaceutical University | Yuan D.,China Pharmaceutical University | He H.,China Pharmaceutical University | Pham-Huy C.,Paris Observatory | And 3 more authors.
Carbon | Year: 2014

A novel mixed hemimicelles solid phase extraction (SPE) based on magnetic carbon nanotubes (MCNTs) and ionic liquid (IL) is developed for the simultaneous extraction and determination of trace flavonoids in spiked human urine. In this novel SPE, the formation of C16mimBr with mixed hemimicelles on the surface of MCNTs@SiO2 nanoparticles (NPs) causes retention of analytes by strong hydrophobic, π-π and electrostatic interactions. This SPE technique combines the advantages of mixed hemimicelles and MCNTs. In order to establish the guidelines for the preparation of mixed hemimicelles on composite materials, different main factors affecting the preconcentration of analytes, such as material type, amount of surfactant, pH of solution, ionic strength, extraction time, desorption condition and regeneration property, were investigated and optimized. Under the selected conditions, the accuracy of the method was evaluated by recovery measurements on spiked samples, and good recoveries with low relative standard deviations from 3.5% to 4.9% were achieved. No interferences were caused by endogenous compounds in human urine. For our knowledge, this is the first development of a mixed hemimicelles SPE based on MCNTs and IL for the extraction of trace analytes in complex biological samples. © 2014 Elsevier Ltd. All rights reserved.

Wang J.-T.,Sun Yat Sen University | Li Y.,Sun Yat Sen University | Tan J.-H.,Sun Yat Sen University | Ji L.-N.,Sun Yat Sen University | And 2 more authors.
Dalton Transactions | Year: 2011

Herein we reported three new platinum(ii)-triarylpyridines complexes with peralkylated ammonium pendants that strongly stabilize G-quadruplex DNA. © 2011 The Royal Society of Chemistry.

Liu Y.,Sun Yat Sen University | Wu H.,China Pharmaceutical University | Nie Y.-C.,Sun Yat Sen University | Chen J.-L.,Sun Yat Sen University | And 2 more authors.
International Immunopharmacology | Year: 2011

Naringin has been reported as an effective anti-inflammatory compound. We previously showed that naringin had antitussive effect on experimentally induced cough in guinea pigs. However, the effects and mechanism of naringin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice are not fully understood. In this study, our aim was to evaluate the anti-inflammatory activities of naringin on LPS-induced ALI in mice and clarify its underlying mechanisms of action. We found that in vivo pretreatment with naringin markedly decreased the lung wet weight to dry weight ratio, and led to significant attenuation of LPS-induced evident lung histopathological changes. Meanwhile, naringin significantly reduced bronchoalveolar lavage fluid (BALF) total cell and neutrophil (PMN) counts after LPS challenge. Furthermore, naringin inhibited myeloperoxidase (MPO: a marker enzyme of neutrophil granule) and inducible nitric oxide synthase (iNOS) activities in lung tissue and alleviated LPS-induced tumor neurosis factor-α (TNF-α) secretion in BALF in a dose-dependent manner. Additionally, Western blotting showed that naringin efficiently blunt NF-κB activation by inhibiting the degradation of IKB-α and the translocation of p65. Taken together, these results suggest that naringin shows anti-inflammatory effects through inhibiting lung edema, MPO and iNOS activities, TNF-α secretion and pulmonary neutrophil infiltration by blockade of NF-κB in LPS-induced ALI. © 2011 Elsevier B.V. All rights reserved.

Miao X.N.,University of California at Los Angeles | Miao X.N.,China Pharmaceutical University | Siu K.L.,University of California at Los Angeles | Cai H.,University of California at Los Angeles
Journal of Molecular and Cellular Cardiology | Year: 2015

Rupture of abdominal aortic aneurysm (AAA) is a lethal event. No oral medicine has been available to prevent or treat AAA. We have recently identified a novel mechanism of eNOS uncoupling by which AAA develops, in angiotensin II (Ang II) infused hyper. phenylalaninemia 1 (hph-1) mice. Using this unique model we investigated effects on AAA formation of the L-type calcium channel blocker nifedipine, in view of the unclear relationship between hypertension and AAA, and unclear mechanisms of aneurysm protective effects of some blood pressure lowering drugs. Six-month old hph-1 mice were infused with Ang II (0.7 mg/kg/day) for 2 weeks, and fed nifedipine chow at two different doses (5 and 20 mg/kg/day). While the high dose of nifedipine reduced blood pressure, the lower dose had no effect. Interestingly, the incidence rate of AAA dropped from 71% to 7 and 12.5% for low and high dose nifedipine, respectively. Expansion of abdominal aorta, determined by ultrasound imaging, was abolished by both doses of nifedipine, which recoupled eNOS completely to improve NO bioavailability. Both also abrogated aortic superoxide production. Of note, Ang II activation of NADPH oxidase in vascular smooth muscle cells and endothelial cells, known to uncouple eNOS, was also attenuated by nifedipine. Although low dose was a sub-pressor while the high dose reduced blood pressure via inhibition of calcium channels, both doses were highly effective in preventing AAA by preserving eNOS coupling activity to eliminate sustained oxidative stress from uncoupled eNOS. These data demonstrate that oral treatment of nifedipine is highly effective in preserving eNOS function to attenuate AAA formation. Nifedipine may be used for AAA prevention either at low dose in AAA risk group, or at high dose in patients with co-existing hypertension. © 2015 Elsevier Ltd.

Zhang X.,CAS Shanghai Institute of Materia Medica | Li F.,CAS Shanghai Institute of Materia Medica | Guo S.,CAS Shanghai Institute of Materia Medica | Chen X.,China Pharmaceutical University | And 3 more authors.
Biomaterials | Year: 2014

Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. A polymer-lipid supported mesoporous silica nanoparticle (PLS-MSNs) is described here to facilitate intracellular delivery of anticancer drug and enhance the antitumor efficacy against MDR breast cancer cells. By coating MSNs with a synthetic dual-functional polymer-lipid material P123-DOPE, the supported membrane acted as an intact barrier against the escape of encapsulated drugs before reaching the target cells, leading to depolymerization and triggered storm release of loaded irinotecan (CPT-11) in acidic endosomal pH of tumor cells. In addition, P123-DOPE can inhibit breast cancer resistance protein (BCPR) mediated CPT-11 efflux in drug resistant MCF-7/BCRP breast cancer cells, thus acting as a "door blocker". Compared to free CPT-11, PLS-MSNs resulted in a maximum increase in the intracellular CPT-11 concentration (12.9-fold), had 7.1-fold higher cytotoxicity and processed a stronger cell cycle arrest in MCF-7/BCRP cells. Moreover, CPT-11 loaded PLS-MSNs showed high therapeutic performance and low toxicity in BALB/c nude mice bearing drug resistant breast tumors, with an inhibition rate of 81.2% compared to free CPT-11 treatment group. The reported PLS-MSNs provide promising applicability in future preclinical and clinical MDR cancer treatment. © 2014 Elsevier Ltd.

Fu J.,China Pharmaceutical University | Liu L.,China Pharmaceutical University | Liu L.,Henan University of Science and Technology | Huang Z.,China Pharmaceutical University | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2013

A series of hybrids from O2-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound, 21, released high levels of NO selectively in HCC cells but not in the normal cells and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, 21 exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of 21 occurred in the presence of GSTπ and was much more effective than in glutathione S-transferase α. Additionally, 21 induced apoptosis in HepG2 cells by arresting the cell cycle at the G2/M phase, activating both the mitochondrion-mediated pathway and the MAPK pathway and enhancing the intracellular production of ROS. © 2013 American Chemical Society.

Zhao M.-X.,Sun Yat Sen University | Huang H.-F.,China Pharmaceutical University | Xia Q.,China Pharmaceutical University | Ji L.-N.,Sun Yat Sen University | And 2 more authors.
Journal of Materials Chemistry | Year: 2011

Quantum dots (QDs) encapsulated with high affinity ligands, specifically binding organic ligands, such as antibodies, peptides or small molecules, have been used in intracellular imaging and targeting. In this work, a series of folate-receptor targeted QDs, in which tumor-targeting folic acid (FA) was conjugated to the surface of QDs through cell-penetrated γ-cyclodextrin (γ-CD), was synthesized. The QDs showed good optical properties and biocompatibility, such as strong optical emission, long luminescent lifetime, appropriate size (4-5 nm in diameter), and lower toxicity. In particular, the γ-CD-FA-coated CdSe-ZnSe QDs presented lower cytotoxicity to these cells at higher IC50 concentrations of above 200 μg mL-1 for 48 h. Folate-receptor overexpressed FR(+) and folate-receptor deficient FR(-) cells were incubated with folate-receptor targeted γ-CD-FA-coated QDs and non-targeted l-Cys-β-CD-coated QDs in vitro. It was found that folate-receptor targeted QDs could more effectively recognize cancer cells with folate receptor (FR) over-expression compared to non-targeted QDs by flow cytometry and confocal laser scanning microscopy (CLSM). Confirming the specificity of folate-receptor targeted QDs, binding and internalization were inhibited by free folate, and hardly any uptake was found in FR(+) cells. Inside the cells, the γ-CD-FA-functionalized QDs are mostly distributed within lysosomes. These properties not only offer insights into the mechanism of the functionalized QDs delivery but also will guide the design and development of nanoparticle probes for intracellular imaging and targeting applications. © 2011 The Royal Society of Chemistry.

Jiang M.,CAS Shanghai Institute of Materia Medica | Jiang M.,China Pharmaceutical University | Gan L.,CAS Shanghai Institute of Materia Medica | Zhu C.,CAS Shanghai Institute of Materia Medica | And 3 more authors.
Biomaterials | Year: 2012

To achieve enhanced gene transfection efficiency with ocular eye-drop therapy, a cationic core-shell liponanoparticle (DLCS-NP) was designed by enveloping the plasmid-laden chitosan nanoparticle (CS-NP) into a cationic lipid shell. The cellular uptake of DLCS-NP was up to 1.25-fold and 5-fold higher than that of CS-NP and lipid-coated chitosan nanoparticles (LCS-NP), respectively. Further endocytosis inhibition investigation discovered that facilitated by the cationic outer lipid layer, several other distinct pathways (besides clathrin-mediated endocytosis) were involved in the endocytosis of DLCS-NP. Endolysosome trafficking experiment verified that cationic lipid coating could facilitate the endolysosome escape of DLCS-NP. Consequently, using enhanced green fluorescence protein (EGFP) as a reporter gene, DLCS-NP-treated human conjunctival epithelial cells exhibited 3.1- and 3.5-fold more intense EGFP expression than that of LCS-NP and CS-NP, respectively. Finally, in vivo transfection experiments on rabbits revealed that EGFP expression exhibited 2.52-fold increase in DLCS-NP group than that of CS-NP group. In summary, this type of cationic core-shell liponanoparticle, possessing multiple functions including better DNA protecting effect, superior cellular uptake efficiency, utilization of multiple endocytic pathways, and endolysosome escaping ability, may represent a promising strategy for ocular gene delivery. © 2012 Elsevier Ltd.

Huang P.,China Pharmaceutical University | Lian F.,CAS Shanghai Institute of Materia Medica | Wen Y.,CAS Shanghai Institute of Materia Medica | Guo C.,Xiamen University | Lin D.,Xiamen University
Acta Biochimica et Biophysica Sinica | Year: 2013

The prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. According to the 'protein only' hypothesis, the key molecular event in the pathogenesis of prion disease is the conformational conversion of the host-derived cellular prion protein (PrPC) into a misfolded form (scrapie PrP, PrPsc). Increasing evidence has shown that the most infectious factor is the smaller subfibrillar oligomers formed by prion proteins. Both the prion oligomer and PrPsc are rich in β-sheet structure and resistant to the proteolysis of proteinase K. The prion oligomer is soluble in physiologic environments whereas PrPsc is insoluble. Various prion oligomers are formed in different conditions. Prion oligomers exhibited more neurotoxicity both in vitro and in vivo than the fibrillar forms of PrPsc, implying that prion oligomers could be potential drug targets for attacking prion diseases. In this article, we describe recent experimental evidence regarding prion oligomers, with a special focus on prion oligomer formation and its neurotoxicity. © The Author 2013.

Yu Q.,China Pharmaceutical University | Qi J.,China Pharmaceutical University | Wang L.,China Pharmaceutical University | Liu S.-J.,Anhui University of Traditional Chinese Medicine | Yu B.-Y.,China Pharmaceutical University
Phytotherapy Research | Year: 2015

Phytochemical investigation of methanol extract from the spikes of Prunella vulgaris L. led to the isolation of two new pentacyclic triterpenoid glycosides Vulgasides I (1) and II (2) along with 13 known compounds (3-15). Their structures were established on the basis of nuclear magnetic resonance (1D and 2D) and mass spectroscopic data analysis. All the isolated compounds were screened for glycogen phosphorylase inhibitory activity and also evaluated for their effect on insulin sensitivity in 3T3-L1 adipocytes. Two new compounds (1, 2) did not demonstrate the glycogen phosphorylase inhibitory activity, but other compounds (3-11) exhibited varying degrees of glycogen phosphorylase inhibitory activity with IC50 values in the range from 30.69 to 68.85 μM. Compounds 3, 6, 7, 11, and 13 demonstrated markedly increased insulin-mediated glucose consumption in 3T3-L1 adipocytes. Copyright © 2014 John Wiley & Sons, Ltd.

Li J.,CAS Shanghai Institutes for Biological Sciences | Li J.,China Pharmaceutical University | Li J.,Max Planck Institute for Evolutionary Anthropology | Zhang L.,China Pharmaceutical University | And 3 more authors.
Human Molecular Genetics | Year: 2011

Genetic polymorphisms in many genes related to drug absorption, distribution, metabolism and excretion (ADME genes) contribute to the high heterogeneity of drug responses in humans. However, the extent to which genetic variation in ADME genes may contribute to differences among human populations in drug responses has not been studied. In this work, we investigate the global distribution of genetic diversity for 31 core and 252 extended ADME genes. We find that many important ADME genes are highly differentiated across continental regions. Additionally, we analyze the genetic differentiation associated with clinically relevant, functional polymorphism alleles, which is important for evaluating potential among-population heterogeneity in drug treatment effects. We find that ADME genes show significantly greater variation in levels of population differentiation, and we find numerous signals of recent positive selection on ADME genes. These results suggest that genetic differentiation at ADME genes could contribute to population heterogeneity in drug responses. © The Author 2010. Published by Oxford University Press.

Wu K.,China Pharmaceutical University | Wu K.,CAS Shanghai Institute of Materia Medica | Fan Z.,CAS Shanghai Institute of Materia Medica | Xue Y.,China Pharmaceutical University | And 2 more authors.
Organic Letters | Year: 2014

An intermolecular C-H amination of 1-aryl-1H-pyrazol-5(4H)-ones was achieved under mild reaction conditions, using a low catalyst loading and with a broad scope of aminating reagents. This protocol not only provides the first example of rhodium(III)-catalyzed intermolecular aromatic C-H amination directed by an intrinsic functionality of the substrate/product but also features aminating an existing drug with either primary or secondary N-benzoate alkylamines as the coupling partners. © 2013 American Chemical Society.

Jiang Q.,China Pharmaceutical University | Yi M.,University of Sichuan | Guo Q.,China Pharmaceutical University | Wang C.,China Pharmaceutical University | And 6 more authors.
International Immunopharmacology | Year: 2015

The purpose of this study was to investigate the protective effect of PD against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore its potential mechanism. In vivo, PD and dexamethasone were intraperitoneally administered 1 h before LPS stimulation. Then, mice were sacrificed at 6 h post-LPS stimulation. Neutrophil number, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF) were determined, as well as lung wet to dry ratio (W/D) and polymorphonuclear (MPO) activity. The protein expressions of Toll like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), IL-1R-associated kinases 1 (IRAK1), IRAK4, inhibitor of nuclear factor kappa-B kinase (IKK)α, p-IKKα, IKKβ, p-IKKβ, inhibitor of NF-κB (IκBα), p-IκBα and NF-κB in lung tissues were assessed. Besides, we detected the IL-6, IL-1β, IL-8, TNF-α levels and TLR4, MyD88, NF-κB protein expressions in LPS-induced BEAS-2B cells. Consequently, PD significantly inhibited the levels of W/D, MPO, neutrophils number, TNF-α, IL-6, IL-1β and reversed TLR4-MyD88-NF-κB signaling pathway in lung tissues. In vitro assays, PD effectively negatively mediated the inflammatory cytokines and ameliorated the high expressions of TLR4, MyD88, NF-κB caused by LPS simulation in Human bronchial epithelial BEAS-2B cells. This study indicated that PD played a protective role in LPS-induced ALI and BEAS-2B cells. The results supported further study of PD as potential candidate for acute lung injury. © 2015 Elsevier B.V.

Zhao Z.,Jilin University | Gong S.,China Pharmaceutical University | Wang S.,Jilin University | Wang S.,Changchun University of Chinese Medicine | And 2 more authors.
International Immunopharmacology | Year: 2015

Evodiamine (EVD), a major alkaloid compound extracted from the dry unripened fruit Evodia fructus (Evodia rutaecarpa Benth., Rutaceae), has various pharmacological effects. The purpose of the present study was to investigate the possible anti-ulcerogenic potential of EVD and explore the underlying mechanism against ethanol-induced gastric ulcer in mice. Administration of EVD at the doses of 20, 40 mg/kg body weight prior to the ethanol ingestion could effectively protect the stomach from ulceration. The gastric lesion was significantly ameliorated in the EVD group compared with that in the model group. Pre-treatment with EVD prevented the oxidative damage and decreased the levels of prostaglandin E2 (PGE2) content, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In addition, EVD pretreatment markedly increased the serum levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT), decreased malonaldehyde (MDA) content in serum and activity of myeloperoxidase (MPO) in stomach tissues compared with those in the model group. In the mechanistic study, significant elevation of Rho, Rho-kinase 1 (ROCK1), ROCK2, cytosolic and nucleic NF-κBp65 expressions were observed in the gastric mucosa group, whereas EVD effectively suppressed the protein expressions of Rho, Rho-kinase 1 (ROCK1), ROCK2, cytosolic and nucleic NF-κBp65 in mice. Moreover, EVD showed protective activity on ethanol-induced GES-1 cells, while the therapeutic effects were not due to its cytotoxity. Taken together, these results strongly indicated that EVD exerted a gastro-protective effect against gastric ulceration. The underlying mechanism might be associated with the improvement of antioxidant and anti-inflammatory status through Rho/NF-κB pathway. © 2015 Elsevier B.V. All rights reserved.

Fu L.,University of Sichuan | Zhang S.,University of Sichuan | Zhang L.,University of Sichuan | Zhang L.,Shenyang Pharmaceutical University | And 8 more authors.
Oncotarget | Year: 2015

The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.

Han J.,China Pharmaceutical University | Sun L.,China Pharmaceutical University | Huang X.,CAS Shanghai Institute of Materia Medica | Li Z.,China Pharmaceutical University | And 3 more authors.
British Journal of Pharmacology | Year: 2014

Background and Purpose The short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. Experimental Approach Four cysteine-modified GLP-1 analogues (1-4) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6-13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro. In vivo, effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Key Results Most conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t1/2 than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Conclusions and Implications Cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation. © 2014 The British Pharmacological Society.

Ouahab A.,China Pharmaceutical University | Shao C.,China Pharmaceutical University | Shao C.,Changzhou Qianhong Biopharm Co. | Shen Y.,China Pharmaceutical University | Tu J.,China Pharmaceutical University
Drug Development and Industrial Pharmacy | Year: 2014

Objective: Double loaded micelles (DLM) in which paclitaxel (PTX) and docetaxel (DTX) were co-solubilized with monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PLA) copolymer were prepared and evaluated in an aim to investigate the effect of a combination of PTX and DTX on the stability of mPEG-PLA micelles compared to single drug-loaded micelles (SDM), especially that recent clinical anticancer formulations are limited by the existence of toxic excipients and stability issues. Materials and methods: The SDM and DLM of PTX and DTX were prepared by a solvent evaporation method. Micellar size, size distribution, drug loading content and drug release were investigated. Transmission electron microscopy was used to investigate the stabilization mechanism. Results: The drug loading efficiency of both PTX and DTX in DLM and SDM were 25% and 10%, respectively. 1H NMR showed a successful encapsulation of both drugs in the polymeric micelle. DLM showed better physical stability at drug concentrations higher than 1mg/mL compared to SDM. Moreover, DLM, SDM-PTX and SDM-DTX were stable for 24, 9 and 1h, respectively. The stabilization mechanism of DLM was investigated, a network structure of DLM was observed in TEM graphs. Furthermore, DLM showed complete and faster drug release compared to SDM. mPEG-PLA double loaded micelles can deliver two poorly water soluble anticancer drugs at clinically relevant doses. The obtained results offer a promising alternative for double drug therapy without any formulation associated undesirable effects and encourage further in vivo development and optimization of the DLM as a drug delivery system for anticancer drugs. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.

Inclusion complex of deoxypodophyllotoxin of cyclodextrin, the preparation method and the use for the treatment of cancer thereof are disclosed. The inclusion complex consists of deoxypodophyllotoxin and beta-cyclodextrin derivative, wherein the molar ration of deoxypodophyllotoxin to beta-cyclodextrin derivative is 1:1-1:10. The beta-cyclodextrin derivative is sulfobutyl ether-beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin.

Li B.,Jiangnan University | Li B.,China Pharmaceutical University | Zhang J.,Jiangnan University | Dai F.,China Pharmaceutical University | Xia W.,Jiangnan University
Carbohydrate Polymers | Year: 2012

The residual proteins in commercially available chitosan products potentially induce immunological responses, thus compromising their clinical usage. Conventional deproteinization processes use diluted base and heat. However this heterogeneous hydrolysis is inefficient. In the present study, pepsin was selected and immobilized with tetramethoxysilane (TMOS) and 3-aminopropyltriethoxysilane (APTES). The immobilized pepsin was utilized in an alternative approach for the purification of chitosan. Optimum deproteinization was carried out at pH 4.5 and 45 °C. Amino acid analysis proved a removal of 53.8-80.4% protein in chitosan after 160 min incubation, which was more efficient than conventional sodium hydroxide deproteinization. When chitosan was deproteinizated by immobilized pepsin, its molecular weight decreased, but in a much milder manner than the free pepsin. The study revealed that immobilized pepsin was an efficient method for deproteinizing chitosan. © 2011 Elsevier Ltd All rights reserved.

Wu X.,China Pharmaceutical University | Jiang J.,China Pharmaceutical University | Chen Y.,China Pharmaceutical University | Chen Y.,Rutgers University
ACS Catalysis | Year: 2011

Dynamic change of intracellular nicotinamide cofactor concentrations, the limiting factor for the bioreductions catalyzed by oxidoreductases, was monitored in Escherichia coli cells coexpressing diketoreductase and glucose dehydrogenase. On the basis of an unexpected observation, a relationship between catalytic efficiency and cofactor concentrations was established to optimize the process for the preparation of a chiral diol for statin drugs. Consequently, compared to previous reactions by E. coli cells expressing diketoreductase alone, exogenous addition of cofactors was completely eliminated to yield an increase of substrate concentration by 15-fold. The present strategy could be employed in the biocatalytic processes catalyzed by nicotinamide-dependent oxidoreductases. © 2011 American Chemical Society.

Cao M.,Central China Normal University | Chen H.,China Pharmaceutical University | Chen D.,China Pharmaceutical University | Xu Z.,Central China Normal University | And 3 more authors.
Chemical Communications | Year: 2016

A novel naphthalimide-based fluorescent probe employing a sulfonamide unit as a thiol-responsive group is reported. It is capable of efficiently distinguishing GSH from cysteine and homocysteine. Bioimaging shows that it has high selectivity in living cells and can visualize the level of GSH in lysosomes. It is worth mentioning that different groups on the imide unit can affect the selectivity and reaction dynamics of the probe towards thiols. © 2016 The Royal Society of Chemistry.

Qi Y.,U.S. National Institutes of Health | Qi Y.,China Pharmaceutical University | Jiang C.,U.S. National Institutes of Health | Cheng J.,U.S. National Institutes of Health | And 6 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2015

Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. © 2014 Elsevier B.V. All rights reserved.

Xin Q.,Chinese Academy of Sciences | Fan H.,Chinese Academy of Sciences | Guo B.,Chinese Academy of Sciences | He H.,Chinese Academy of Sciences | And 4 more authors.
Journal of Medicinal Chemistry | Year: 2011

A series of novel benzoxazinyl-oxazolidinones bearing nonaromatic heterocycle or aryl groups were designed and synthesized. Their in vitro and in vivo antibacterial activities were investigated. Most of the (3S, 3aS) biaryl benzoxazinyl-oxazolidinones exhibited potent activity against Gram-positive pathogens. SAR trends were observed; a pyridyl C ring was preferable to other 5- or 6-member aryl C rings, while fluorine substitution on the B ring generated derivatives with reduced activity. Various substituent group positions on the pyridyl ring were also evaluated. The resulting compounds displayed excellent activity against linezolid-resistant strains. Compound 45 exhibited excellent in vitro activity, with a MIC value of 0.25-0.5 μg/mL against MRSA and an activity against linezolid-resistant strains of 8-16-fold higher potency than linezolid. In a MRSA systemic infection model, compound 45 displayed an ED 50 < 5.0 mg/kg, a potency that is nearly 3-fold better than that of linezolid. This compound also showed excellent pharmacokinetic profiles, with a half-life of more than 5 h as well as an oral bioavailability of 81% in rats. © 2011 American Chemical Society.

Dong W.,Chinese Institute of Basic Medical Sciences | Li Y.,Chinese Institute of Basic Medical Sciences | Li Y.,China Pharmaceutical University | Gao M.,Chinese Institute of Basic Medical Sciences | And 7 more authors.
Nucleic Acids Research | Year: 2012

Exposure to ultraviolet B (UVB) irradiation from sunlight induces the upregulation of VEGF, a potent angiogenic factor that is critical for mediating angiogenesis-associated photodamage. However, the molecular mechanisms related to UVB-induced VEGF expression have not been fully defined. Here, we demonstrate that one of the catalytic subunits of the IκB kinase complex (IKK), IKKα, plays a critical role in mediating UVB-induced VEGF expression in mouse embryonic fibroblasts (MEFs), which requires IKKα kinase activity but is independent of IKKβ, IKKγ and the transactivation of NF-κB. We further show that the transcriptional factor AP-1 functions as the downstream target of IKKα that is responsible for VEGF induction under UVB exposure. Both the accumulation of AP-1 component, c-Fos and the transactivation of AP-1 by UVB require the activated IKKα located within the nucleus. Moreover, nuclear IKKα can associate with c-Fos and recruit to the vegf promoter regions containing AP-1-responsive element and then trigger phosphorylation of the promoter-bound histone H3. Thus, our results have revealed a novel independent role for IKKα in controlling VEGF expression during the cellular UVB response by regulating the induction of the AP-1 component and phosphorylating histone H3 to facilitate AP-1 transactivation. Targeting IKKα shows promise for the prevention of UVB-induced angiogenesis and the associated photodamage. © 2011 The Author(s).

Yang X.,China Pharmaceutical University | Zhang F.,Nanjing Pukou Hospital | Wang Y.,China Pharmaceutical University | Cai M.,China Pharmaceutical University | And 4 more authors.
Inflammatory Bowel Diseases | Year: 2013

Background: Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, are at a significantly increased risk of developing colorectal cancer, and aberrant interleukin (IL)-6/STAT3 signaling pathway exists in both inflammatory bowel disease and inflammationrelated gastrointestinal cancers. We have previously found that oroxylin A inhibited the NF-κB signaling in human colon tumor HCT-116 cells. However, whether oroxylin A could inhibit the colitis-associated carcinogenesis remains to be determined. Methods: HCT-116 cells were treated with various concentrations of oroxylin A. Expression of relative proteins of IL-6/STAT3 signaling pathway was assayed by Western blot and immunofluorescence analysis. Mouse model for colitis-associated colorectal cancer was induced by a combined treatment with 10 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulfate in C57BL/6 mice. IL-6 and IL-1β gene expression were analyzed by quantitative real-time PCR. Expression of relative proteins was examined by immunohistochemistry and Western blot. Results: Oroxylin A effectively inhibited IL-6/STAT3 pathway in human HCT-116 cells, and the effect of oroxylin A was reversible. Dietary administration of oroxylin A throughout the experimental period significantly reduced the tumor burden, inhibited cell proliferation, and induced apoptosis in colon carcinomas. The expression of inflammatory cytokines IL-6 and IL-1β decreased in tumors in oroxylin A-treated mice. The IL-6/STAT3 signaling pathway was attenuated in oroxylin A-treated mice. Conclusions: Our results demonstrated that oroxylin A inhibits colitis-associated carcinogenesis through modulating IL-6/STAT3 pathway in AOM/dextran sodium sulfate mouse model and in HCT-116 cells. Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.

Chu W.,China Pharmaceutical University | Zere T.R.,Texas State University | Zere T.R.,University of Florida | Weber M.M.,Texas A&M University | And 6 more authors.
Applied and Environmental Microbiology | Year: 2012

Indole production by Escherichia coli, discovered in the early 20th century, has been used as a diagnostic marker for distinguishing E. coli from other enteric bacteria. By using transcriptional profiling and competition studies with defined mutants, we show that cyclic AMP (cAMP)-regulated indole formation is a major factor that enables E. coli growth in mixed biofilm and planktonic populations with Pseudomonas aeruginosa. Mutants deficient in cAMP production (cyaA) or the cAMP receptor gene (crp), as well as indole production (tnaA), were not competitive in coculture with P. aeruginosa but could be restored to wild-type competitiveness by supplementation with a physiologically relevant indole concentration. E. coli sdiA mutants, which lacked the receptor for both indole and N-acyl-homoserine lactones (AHLs), showed no change in competitive fitness, suggesting that indole acted directly on P. aeruginosa. An E. coli tnaA mutant strain regained wild-type competiveness if grown with P. aeruginosa AHL synthase (rhlI and rhlI lasI) mutants. In contrast to the wild type, P. aeruginosa AHL synthase mutants were unable to degrade indole. Indole produced during mixed-culture growth inhibited pyocyanin production and other AHL-regulated virulence factors in P. aeruginosa. Mixed-culture growth with P. aeruginosa stimulated indole formation in E. coli cpdA, which is unable to regulate cAMP levels, suggesting the potential for mixed-culture gene activation via cAMP. These findings illustrate how indole, an early described feature of E. coli central metabolism, can play a significant role in mixed-culture survival by inhibiting quorum-regulated competition factors in P. aeruginosa. © 2012, American Society for Microbiology.

Sun S.,Macau University of Science and Technology | Liu H.,China Pharmaceutical University | Xu S.,Macau University of Science and Technology | Yan Y.,Macau University of Science and Technology | Xie P.,Macau University of Science and Technology
Journal of Pharmaceutical Analysis | Year: 2014

Due to the scarcity of resources of Ziziphi spinosae semen (ZSS), many inferior goods and even adulterants are generally found in medicine markets. To strengthen the quality control, HPLC fingerprint common pattern established in this paper showed three main bioactive compounds in one chromatogram simultaneously. Principal component analysis based on DAD signals could discriminate adulterants and inferiorities. Principal component analysis indicated that all samples could be mainly regrouped into two main clusters according to the first principal component (PC1, redefined as Vicenin II) and the second principal component (PC2, redefined as zizyphusine). PC1 and PC2 could explain 91.42% of the variance. Content of zizyphusine fluctuated more greatly than that of spinosin, and this result was also confirmed by the HPTLC result. Samples with low content of jujubosides and two common adulterants could not be used equivalently with authenticated ones in clinic, while one reference standard extract could substitute the crude drug in pharmaceutical production. Giving special consideration to the well-known bioactive saponins but with low response by end absorption, a fast and cheap HPTLC method for quality control of ZSS was developed and the result obtained was commensurate well with that of HPLC analysis. Samples having similar fingerprints to HPTLC common pattern targeting at saponins could be regarded as authenticated ones. This work provided a faster and cheaper way for quality control of ZSS and laid foundation for establishing a more effective quality control method for ZSS. © 2014 Xi'an Jiaotong University. Production and hosting by Elsevier B.V. All rights reserved.

Wu X.,China Pharmaceutical University | Chen C.,China Pharmaceutical University | Liu N.,China Pharmaceutical University | Chen Y.,China Pharmaceutical University | Chen Y.,Rutgers University
Bioresource Technology | Year: 2011

Diketoreductase from Acinetobacter baylyi ATCC 33305 is a unique carbonyl reductase, which can stereoselectively reduce ethyl-6-(benzyloxy)-3,5-dioxohexanoate to ethyl 3. R,5. S-6-(benzyloxy)-3,5-dihydroxy-hexanoate, an advanced intermediate for statin drugs. In the present study, we explored an aqueous-organic biphasic reaction system to make this biocatalyst more practical and valuable. Different from most oxidoreductases, diketoreductase displayed an excellent tolerance to certain organic solvents without any changes on the catalytic properties. After optimizing reaction conditions, an aqueous-hexane (1:1) biphasic system was established for the preparation of 3. R,5. S-dihydroxy product by diketoreductase. This system was further scaled up to 0.5. l at a substrate concentration of 105 g/l (378 mM), and the 3. R,5. S-hydroxy product was obtained with a yield of 83.5% and excellent stereoselectivity (de>. 99.5%, ee>. 99.5%). © 2010 Elsevier Ltd.

Zhang W.,Macau University of Science and Technology | Guo J.,Macau University of Science and Technology | Xiang B.,China Pharmaceutical University | Fan H.,China Pharmaceutical University | Xu F.,China Pharmaceutical University
Analyst | Year: 2014

Improving the detection sensitivity of analytical instruments has been a challenging task for chemometricians since undetectability has been almost unavoidable in trace analysis, even under optimized experimental conditions and with the use of modern instruments. Various chemometrics methods have been developed which attempt to address this detection problem but with limited success (e.g., fast Fourier transform and wavelet transform). However, the application of stochastic resonance (SR) creates an entirely new and effective methodology. Stochastic resonance is a phenomenon which is manifested in non-linear systems where a weak signal can be amplified and optimized with the assistance of noise. In this review, we summarize the use of basic SR, optimization of parameters and its modifications, including periodic modulation stochastic resonance (PSRA), linear modulation stochastic resonance (LSRA), single-well potential stochastic resonance (SSR) and the Duffing oscillator algorithm (DOA) for amplifying sub-threshold small signals. We also review the advantages and the disadvantages of various SR procedures. This journal is © the Partner Organisations 2014.

Saw C.L.L.,Rutgers University | Yang A.Y.,Rutgers University | Yang A.Y.,China Pharmaceutical University | Guo Y.,Rutgers University | And 2 more authors.
Food and Chemical Toxicology | Year: 2013

Oxidative stress is a major driver of many diseases, including cancer. The induction of Nrf2-ARE-mediated antioxidant enzymes provides a cellular defense against oxidative stress. Astaxanthin (AST), a red dietary carotenoid, possesses potent antioxidant activity, and inhibits oxidative damages. Polyunsaturated fatty acids (PUFAs), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are important nutritional essentials and potent antioxidants found in fish oil. In the present study, we investigated whether AST in combination with low concentrations of DHA or EPA has a synergistic antioxidant effect in a HepG2-C8-ARE-luciferase cell line system. Using free radical scavenging DPPH assay, AST was more potent DPPH radical scavenger than DHA and EPA. MTS assay revealed that AST was non-toxic up to 100. μM compared with more toxic DHA and EPA. The three compounds alone and in combination elevated cellular GSH levels, increased the total antioxidant activity, induced mRNA expression of Nrf2 and Nrf2 downstream target genes NQO1, HO-1, and GSTM2. Lower concentrations of AST show synergistic effects when combined with DHA or EPA. In summary, our study shows synergistic antioxidant effects of AST and PUFAs at low concentrations. The Nrf2/ARE pathway plays an important role in the antioxidative effects induced by AST, DHA, and EPA. © 2013 Elsevier Ltd.

Liu Z.,General Hospital of PLA | Luo Y.,Shenyang Yaoda Pharmaceutical Co | Zhou T.-T.,China Pharmaceutical University | Zhang W.-Z.,General Hospital of PLA
Cell Proliferation | Year: 2013

Plant lectins, a group of highly diverse carbohydrate-binding proteins of non-immune origin, are ubiquitously distributed through a variety of plant species, and have recently drawn rising attention due to their remarkable ability to kill tumour cells using mechanisms implicated in autophagy. In this review, we provide a brief outline of structures of some representative plant lectins such as concanavalin A, Polygonatum cyrtonema lectin and mistletoe lectins. These can target autophagy by modulating BNIP-3, ROS-p38-p53, Ras-Raf and PI3KCI-Akt pathways, as well as Beclin-1, in many types of cancer cells. In addition, we further discuss how plant lectins are able to kill cancer cells by modulating autophagic death, for therapeutic purposes. Together, these findings provide a comprehensive perspective concerning plant lectins as promising new anti-tumour drugs, with respect to autophagic cell death in future cancer therapeutics. © 2013 John Wiley & Sons Ltd.

Hu R.,China Pharmaceutical University | Saw C.L.-L.,Rutgers University | Yu R.,University of Texas Health Science Center at Houston | Kong A.-N.T.,Rutgers University
Antioxidants and Redox Signaling | Year: 2010

Cancer chemoprevention is a process of using either natural or synthetic compounds to reduce the risk of developing cancer. Observations that NF-E2-related factor 2 (Nrf2)-deficient mice lack response to some chemopreventive agents point to the important role of Nrf2 in chemoprevention. Nrf2 is a member of basic-leucine zipper transcription factor family and has been shown to regulate gene expression by binding to a response element, antioxidant responsive element. It is generally believed that activation of Nrf2 signaling is an adaptive response to the environmental and endogenous stresses. Under homeostatic conditions, Nrf2 is suppressed by association with Kelch-like ECH-associated protein 1 (Keap1), but is stimulated upon exposure to oxidative or electrophilic stress. Once activated, Nrf2 translocates into nuclei and upregulates a group of genes that act in concert to combat oxidative stress. Nrf2 is also shown to have protective function against inflammation, a pathological process that could contribute to carcinogenesis. In this review, we will discuss the current progress in the study of Nrf2 signaling, in particular, the mechanisms of Nrf2 activation by chemopreventive agents. We will also discuss some of the potential caveats of Nrf2 in cancer treatment and future opportunity and challenges on regulation of Nrf2-mediated antioxidant and antiinflammatory signaling in the context of cancer prevention. © 2010 Mary Ann Liebert, Inc.

Wei M.,China Pharmaceutical University | Deng J.,China Pharmaceutical University | Feng K.,China Pharmaceutical University | Yu B.,China Pharmaceutical University | And 2 more authors.
Analytical Chemistry | Year: 2010

Polymerase chain reaction (PCR) is a basic technique with wide applications in molecular biology. Despite the development of different methods with various modifications, the amplification of GC-rich DNA fragments is frequently troublesome due to the formation of complex secondary structure and poor denaturation. Given the fact that GC-rich genes are closely related to transcriptional regulation, transcriptional silencing, and disease progression, we developed a PCR method combining a stepwise procedure and a mixture of additives in the present work. Our study demonstrated that the PCR method could successfully amplify targeted DNA fragments up to 1.2 Kb with GC content as high as 83.5% from different species. Compared to all currently available methods, our work showed satisfactory, adaptable, fast and efficient (SAFE) results on the amplification of GC-rich targets, which provides a versatile and valuable tool for the diagnosis of genetic disorders and for the study of functions and regulations of various genes. © 2010 American Chemical Society.

Dramou P.,China Pharmaceutical University | Xiao D.,China Pharmaceutical University | He H.,China Pharmaceutical University | Liu T.,Zhejiang University of Science and Technology | Zou W.,China Pharmaceutical University
Journal of Separation Science | Year: 2013

The loading behavior of gatifloxacin (GTFX) in human urine and lake water on a novel magnetic molecularly imprinted polymer used as extraction sorbent with UV-Visible spectrometric analysis has been studied. The magnetic polymers had been prepared using GTFX as template molecule and Fe3O 4 as magnetic component. The polymer had been characterized by SEM, Fourier-transform infrared spectrometry, and appropriate magnet separator. Parameters affecting the extraction efficiency were evaluated in order to achieve optimal loading and reduce nonspecific interactions. Good linearity of the method had been obtained in the range between 0.25 and 15 μg mL -1 by UV-Vis spectrophotometry at 286 nm with spectral analysis from 240 to 400 nm. The method detection and quantification limits of GTFX in water were 0.075 and 0.25 μg mL-1, respectively. This study showed good selectivity and loading efficiency (α > 2) of the polymers. The loading behavior of GTFX in the samples spiked on polymers had been obtained and each other with recovery higher than 91% with RSD% between 2.5 and 3.3. No pretreatment of samples were needed and no interference of compounds in urine and lake water were observed during adsorption. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Kong L.-Y.,China Pharmaceutical University | Wang P.,China Pharmaceutical University | Wang P.,Yancheng Teachers University
Chinese Journal of Natural Medicines | Year: 2013

Structural elucidation of natural products is always one of the most important tasks for natural product researchers in related fields. Particularly, the absolute configuration (AC), being a great challenge for natural product chemists, has attracted much attention. During the past few decades, many techniques and approaches have been developed to determine the AC of natural products, including direct (or absolute) methods, e.g. X-ray diffraction (XRD), electronic and vibrational circular dichroism (ECD and VCD), and Raman optical activity (ROA), as well as indirect (or relative) methods using a reference or a derivatizing agent with known AC, e.g. CD with empirical rules and nuclear magnetic resonance (NMR) utilizing anisotropic effects of chiral derivatizing agents. However, none of the currently applied techniques is capable of dominating AC determination, since they each have their respective limitations corresponding to the different structural features. This mini review summarizes most of the techniques and methods which are commonly used in AC assignment of natural products, or have potential application prospects, and briefly describes their principles, advantages and limitations. © 2013 China Pharmaceutical University.

Zhang P.,China Pharmaceutical University | Zhang P.,Wuhu Institute for Food and Drug Control | Zhang L.,Anhui Normal University | Zhao G.,Anhui Normal University | Feng F.,China Pharmaceutical University
Microchimica Acta | Year: 2012

We report on the sensitive determination of glucose using a glassy carbon electrode modified with CuO nanowires and a Nafion film. The structure and morphology of CuO nanowires were established by scanning electron microscopy and X-ray diffraction. The electrochemical performance of the modified electrode was investigated by cyclic voltammetry and chronoamperometry. Compared to a bare glassy carbon electrode, a substantial increase in efficiency of the electrocatalytic oxidation of glucose can be observed. The new glucose sensor displays two useful linear ranges of response towards glucose, is not affected by commonly interfering species, and displays a detection limit as small as 45 nM. The response time is <2 s towards 0.5 mM of glucose. Additional features include high electrocatalytic activity, high sensitivity, excellent selectivity, and good stability. © 2011 Springer-Verlag.

Liu W.,China Pharmaceutical University | Wang J.,China Pharmaceutical University | Zhang Z.,China Pharmaceutical University | Xu J.,China Pharmaceutical University | And 3 more authors.
International Journal of Biological Macromolecules | Year: 2014

To explore new antioxidant resource from food, a water-soluble polysaccharide (ALP1) was extracted and purified from the roots of Arctium lappa L. (A. lappa L.) through hot water extraction followed by ethanol precipitation, ion-exchange chromatography and gel filtration. The antioxidant activity of ALP1 was then evaluated in vitro and in vivo. ALP1 was characterized as a fructan composed of fructose and glucose in the ratio of 13.0:1.0, with an average molecular weight of 4600Da. The linkages in ALP1 were →1)-Fruf-(2→, Fruf-(2→ and Glcp-(1→. In vitro antioxidant assays demonstrated that ALP1 possessed moderate ABTS+ scavenging activity, strong hydroxyl radical scavenging activity and strong ferrous ion chelating activity. In in vivo antioxidant assays, ALP1 administration significantly enhanced antioxidant enzyme activities and total antioxidant capacity, as well as decreased the levels of malondialdehyde (MDA) in both the serum and liver of aging mice. These results suggest that ALP1 has potential as a novel natural antioxidant in food industry and pharmaceuticals. © 2014.

Chu W.,China Pharmaceutical University | McLean R.J.C.,Texas State University
Journal of Aquatic Animal Health | Year: 2016

Quorum sensing (QS) is a process of bacterial communication used to control group behaviors, including bioluminescence, virulence factor production, biofilm formation, and biofilm antimicrobial tolerance. Many aquatic bacterial pathogens such as Aeromonas, Vibrio, and Edwardsiella spp. use QS to regulate virulence factor production. The disruption of QS has been shown to be an effective strategy in the competition between higher organisms and bacteria and more recently between bacterial species. For this reason, QS disruption has been proposed as a strategy to prevent bacterial pathogenicity. In this review, we summarize the current literature and illustrate the value of QS inhibitors in controlling virulence production in aquatic bacterial pathogens. This represents a new, nonantibiotic strategy to combat fish diseases. © American Fisheries Society 2016.

Sun J.-B.,China Pharmaceutical University | Qu W.,China Pharmaceutical University | Xiong Y.,Nanjing Lifenergy R and D Co. | Liang J.-Y.,China Pharmaceutical University
Biochemical Systematics and Ecology | Year: 2013

A new quinoline alkaloid named sonminine (1) along with nine known quinoline alkaloids dictamnine (2), isodictamnine (3), skimmianine (4), robustine (5), γ-fagarine (6), isopteleine (7), 5-methoxydictamnine (8), haplopine (9), 5-hydroxy-4,8-dimethoxy-furoquinoline (10) and two sesquiterpenes dictamnol (11), radicol (12) were obtained. Among them, compound 8 and 10 were isolated from the genus Dictamnus L. for the first time. Compounds 9, 11 and 12 were obtained from this species for the first time. © 2013 Elsevier Ltd.

Jiang Y.,China Pharmaceutical University | Ou Y.,China Pharmaceutical University | Cheng X.,University of Texas Medical Branch
Frontiers in Bioscience | Year: 2013

The tumor susceptibility gene 101 (TSG101) encodes a multidomain protein that contains a UEV (ubiquitin e2 variant) domain at is N-terminus and a putative DNA-binding motif at its C-terminus. In addition to being a bona fide component of the ESCRT (endosomal sorting complexes required for transport) complex 1 and playing a critical role in endosomal sorting and trafficking, TSG101 has also been implicated in an array of cellular functions including, cytokinesis, protein ubiquitination, transcriptional regulation, cell cycle and proliferation, as well as viral budding. The major focus of this article is on the role of TSG101 in tumorigenesis.

Xiong Y.,University of Cincinnati | Xiong Y.,China Pharmaceutical University | Shen L.,University of Cincinnati | Liu K.J.,Yale University | And 5 more authors.
Diabetes | Year: 2010

OBJECTIVE - Obesity and type 2 diabetes are national and worldwide epidemics. Because currently available antiobesity and antidiabetic drugs have limited efficacy and/or safety concerns, identifying new medicinal agents, such as ginsenoside Rb1 (Rb1) as reported here, offers exciting possibilities for future development of successful antiobesity and antidiabetic therapies. RESEARCH DESIGN AND METHODS - Changes in feeding behavior after acute intraperitoneal administration of Rb1 and the effects of intraperitoneal Rb1 for 4 weeks on body weight, energy expenditure, and glucose tolerance in high-fat diet (HFD)-induced obese rats were assessed. We also examined the effects of Rb1 on signaling pathways and neuropeptides in the hypothalamus. RESULTS - Acute intraperitoneal Rb1 dose-dependently suppressed food intake without eliciting signs of toxicity. This inhibitory effect on feeding may be mediated by central mechanisms because Rb1 stimulated c-Fos expression in brain areas involved in energy homeostasis. Consistent with this, Rb1 activated the phosphatidylinositol 3-kinase/Akt signaling pathway and inhibited NPY gene expression in the hypothalamus. Four-week administration of Rb1 significantly reduced food intake, body weight gain, and body fat content and increased energy expenditure in HFD-induced obese rats. Rb1 also significantly decreased fasting blood glucose and improved glucose tolerance, and these effects were greater than those observed in pair-fed rats, suggesting that although Rb1's antihyperglycemic effect is partially attributable to reduced food intake and body weight; there may be additional effects of Rb1 on glucose homeostasis. CONCLUSIONS - These results identify Rb1 as an antiobesity and antihyperglycemic agent. © 2010 by the American Diabetes Association.

Lu T.,Laboratory of Molecular Design and Drug Discovery | Lu T.,China Pharmaceutical University
Mini-Reviews in Organic Chemistry | Year: 2012

This review describes recent development in the aerobic oxidation of amines. A variety of ruthenium catalysts have shown excellent activity for the aerobic oxidation of amines. Several gold and copper catalysts are also effective for this reaction. Other metalcontaining complexes are revealed to be active catalysts and an enzyme is also investigated for this oxidation. Meanwhile, various supports have been explored for this reaction and the availability of various supports with differing physical properties allows chemists to design and create many catalytic systems. © 2012 Bentham Science Publishers.

Cong X.-D.,Zhejiang Chinese Medical University | Ding M.-J.,Zhejiang Chinese Medical University | Dai D.-Z.,China Pharmaceutical University | Wu Y.,Zhejiang Chinese Medical University | And 2 more authors.
Inflammation | Year: 2012

We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen. © 2011 Springer Science+Business Media, LLC.

Tian Y.,China Pharmaceutical University | Tian Y.,Jiangsu Union Vocational Technical Institute | Daoud A.,China Pharmaceutical University | Shang J.,China Pharmaceutical University
Molecular Medicine Reports | Year: 2012

Reactive oxygen species (ROS) are involved in myocardial injury. ROS are known to inactivate lipid phosphatase and tension homolog on chromosome 10 (PTEN), an enzyme that increases apoptosis in neonatal cardiomyocytes. BpV(pic) and bpV(phen), two bisperoxovanadium molecules and PTEN inhibitors, may be involved in limiting myocardial infarction. To compare the protective effects of bpV(pic) and bpV(phen) on ROS-induced cardiomyocyte injury and their possible mechanisms, we selected two popular models of hypoxia/reoxygenation (H/R) and H 2O 2-induced injury in H9c2 cardiomyoblasts to investigate their effects against injury. We found that pre-treatment with bpV(pic) and bpV(phen) increased the viability and protected the morphology of H9c2 cells under the conditions of H/R and H2O2 by inhibiting LDH release, apoptosis and caspases 3/8/9 activities. However, their respective inhibitory abilities in the two models were different, suggesting that the quantity of ROS from the two models might be different. However, the conflict between ROS and PTEN may affect the action of bpV(pic) and bpV(phen). Taken together, the results demonstrate that bpV(pic) and bpV(phen) have inhibitory effects on oxidative stress-induced cardiomyocyte injury that may be partially modulated by the action of ROS on PTEN.

Cao J.,Hangzhou Normal University | Li P.,China Pharmaceutical University | Yi L.,Hong Kong Baptist University
Journal of Chromatography A | Year: 2011

A new CE system using ionic liquids coated multi-walled carbon nanotubes (ILs-MWNTs) as pseudostationary phase was developed for the simultaneous determination of four flavonoids, four phenolic acids and two saponins. Several parameters affecting the separation were studied, including the choice of ILs, ILs-MWNTs concentration, the respective use of ILs and MWNTs, buffer pH, SDS concentration and borate content. Results revealed that the addition of ILs-MWNTs in running electrolytes enhanced the separation of target compounds compared to conventional micelle because the surface of carbon nanotubes interacted favorably with the analytes. Under the optimum conditions, a baseline separation was achieved for these analytes within 11min in a 41.5cm of effective length fused-silica capillary. At a voltage of 28.0kV, the separation was carried out in a 10mM borate buffer (pH 9.0) containing 100mM SDS, 6% propanol and 4μgmL -1 ILs-MWNTs. All calibration curves showed good linearity (r 2>0.9990) within the test ranges. The intra- and inter-day precisions as determined from standard solutions were below 3.30% and 6.23%, respectively. The recoveries for ten compounds were found to range from 85.5 to 101.8%. The method was successfully applied for the determination of three types of compounds in Qishenyiqi dropping pills. Our experimental results indicated that the proposed method offered new opportunities for the analysis of complex samples. © 2011 Elsevier B.V.

Ding X.-P.,China Pharmaceutical University | Wang X.-T.,China Pharmaceutical University | Chen L.-L.,China Pharmaceutical University | Guo Q.,Jiangsu Institute of Food and Drug Control | And 3 more authors.
Journal of Chromatography A | Year: 2011

An on-line analysis method for the simultaneous detection and identification of radical scavenging compounds in plant extracts was developed by combining HPLC with hydrogen dioxide radical scavenging and HPLC-DAD-MS-CL system. The structural identification and activity characteristics of various constituents could be rapidly achieved by the on-line assay of UV, MS and CL in one run. In 4 species of Epimedium studied 32 compounds, including phenolic acids, 8-isopentenyl-flavonoid glycosides and flavonoid glycosides containing a ortho-hydroxyl group, were identified by comparison with authentic standards and published mass data. Among these compounds, phenolic acids and flavonoid glycosides containing an ortho-hydroxyl group could obviously inhibit CL, which suggested their strong radical scavenging activity. These four species each exhibited different active properties, which might correlate to their respective quality. The results indicated that the on-line HPLC-DAD-MS-CL system would be a potential method to rapidly and sensitively screen radical scavengers in herbal medicines, and could display an integrated fingerprint based on different detectors. © 2011 Elsevier B.V.

Dong X.,China Pharmaceutical University | Ke X.,China Pharmaceutical University | Liao Z.,Nanchang University
Drug Development and Industrial Pharmacy | Year: 2011

Objective: The aim of this study was to characterize the microstructure of microemulsion consisting of oleic acid, Cremophor RH40, ethanol, and water (Km=2), and investigate the influence of microstructure on the solubilization potential of the microemulsion to meloxicam (MLX). Methods: Pseudo-ternary phase diagrams of microemulsion were constructed using the H2O titration method. The microstructures of microemulsion on dilution line N91 were identified by means of conductivity, viscosity, surface tension, and density. The freeze-fracture electron microscopy proved the specific microstructure. Differential scanning calorimetry (DSC) was used to evaluate the position of MLX in microemulsion, and the solubility of MLX in chosen microemulsions on dilution line N91 was measured. Results: The three microstructures along dilution line N91, including water-in-oil (W/O), bicontinuous (BC), and oil-in-water (O/W) microemulsion, were characterized. The solubilization capacity of W/O microemulsion is the best, compared with the other two, whereas the O/W is the weakest. A possible structure model has been applied for the explanation of difference. Conclusions: The solubilization capacity of microemulsion is closely related with its microstructure. © 2011 Informa Healthcare USA, Inc.

Zhang X.,China Pharmaceutical University | Yang C.,University of Maryland University College | Zhou J.,China Pharmaceutical University | Huo M.,China Pharmaceutical University
Small | Year: 2016

Nano-sized in vivo active targeting drug delivery systems have been developed to a high anti-tumor efficacy strategy against certain cancer-cells-specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO-PEG-OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor-mediated tumor-specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti-cancer drug doxorubicin (DOX), our DOX loaded NGO-PEG-OCT complex offers a remarkably improved cancer-cell-specific cellular uptake, chemo-cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO-PEG. More importantly, due to its strong near-infrared absorption, the NGO-PEG-OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Yang Y.,China Pharmaceutical University | Gu C.,University of Iowa | Luo C.,China Pharmaceutical University | Li F.,Nanchang University | Wang M.,China Pharmaceutical University
Medical Oncology | Year: 2015

Multiple myeloma (MM) is the second most common hematopoietic malignancy characterized by plasma cell proliferative disorder. In this study, we disclosed that expression of BUB1B significantly increased in high-risk myeloma patients especially in the most aggressive myeloma genetic subgroups of proliferation. Increased BUB1B expression promotes MM cell proliferation. Mechanism study showed that BUB1B expression was highly correlated to CDC20 and CCNB1/2 expression in MM cells, leading to increased MM cell proliferation. Therefore, BUB1B may be a potential target for MM treatment especially for high-risk MM patients. © 2015, Springer Science+Business Media New York.

Song J.,Hebei University | Li J.,China Pharmaceutical University | Li J.,Nanjing University | Hou F.,Hebei University | And 3 more authors.
Metabolism: Clinical and Experimental | Year: 2015

Background Endothelial dysfunction is tightly associated with cardiovascular complications in diabetic patients. This study aims to investigate the effects of mangiferin on the regulation of endothelial homeostasis under endoplasmic reticulum stress (ER stress) conditions. Results High glucose (25 mmol/L) exposure induced ER stress and promoted ROS production in endothelial cells. Mangiferin effectively inhibited ER stress-associated oxidative stress by attenuating IRE1α phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1β secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1β and IL-6 production, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation. NLRP3 inflammasome activation is responsible for mitochondrial cell death. Mangiferin restored the loss of the mitochondrial membrane potential (Δψm) and inhibited caspase-3 activity, and thereby protected cells from high glucose-induced apoptosis. Moreover, mangiferin inhibited ET-1 secretion and restored the loss of NO production when cells were exposed to high glucose. Mangiferin enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects, indicating the potential role of AMPK in its action. Conclusion Our work showed the beneficial effects of mangiferin on the improvement of endothelial homeostasis and elucidated the molecular pathway through which mangiferin ameliorated endothelial dysfunction by inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells. Significance These findings demonstrated the beneficial effects of mangiferin on the regulation of endothelial homeostasis and indicated its potential application in the management of diabetic cardiovascular complications. © 2015 Elsevier Inc.

Mo G.-L.,China Pharmaceutical University | Li Y.,China Pharmaceutical University | Du R.-H.,Nanjing University | Dai D.-Z.,China Pharmaceutical University | And 2 more authors.
Neurochemical Research | Year: 2014

Inflammatory changes in the cerebral network are present in early mechanisms involved in neurodegenerative disease, Alzheimer disease (AD), and aging brain. We intended to verify that these are likely due to an activation of NADPH oxidase (NOX) and endoplasmic reticulum (ER) stress. Apocynin (APO) an inhibitor of NOX is potential to ameliorate these changes. Rehmannia complex (Reh) a famous prescription in China and the triterpene acids (TTA) isolated from Reh may relieve the isoproterenol (ISO) induced chronic inflammation in the brain, compared with APO. Rats were administered with ISO for 10 days and astrocytes were incubated with ISO for 24 h. Changes in neural MMP (matrix metalloproteinase), Cx43, AQP4 (aquaporin 4), NFκB, IκBβ, and p-PERK (PKB like kinase) were conducted and intervened with APO, Reh and TTA, in vivo and in vitro, respectively. An increased MDA and upregulated NOX subunit p47phox, ETA, PERK in association with abnormal MMP-2/9 and Cx40/43 were found in cerebral tissue of ISO-injected rats. Astrocytes incubated with ISO exhibited upregulated APQ4, IκBβ, NFκB and p-PERK/PERK and downregulated Cx43. These were significantly abrogated by APO and Reh, in vivo, and APO and TTA in vitro. In conclusion, neural damages induced by ISO were characterized by inflammatory changes in cerebral tissue and astrocytes, which were blunted significantly by APO, Reh and TTA, respectively. Reh and TTA are potential in alleviating the early pathogenesis in neurodegenerative changes in AD in the clinical settings through suppressing NOX and ER stress in the brain. © 2014 Springer Science+Business Media New York.

Wu Y.-M.,Academia Sinica, Taiwan | Chang J.-W.,Academia Sinica, Taiwan | Wang C.-H.,Academia Sinica, Taiwan | Lin Y.-C.,Academia Sinica, Taiwan | And 7 more authors.
EMBO Journal | Year: 2012

In mammals, a distinct RNA polymerase II form, RNAPII(G) contains a novel subunit Gdown1 (encoded by POLR2M), which represses gene activation, only to be reversed by the multisubunit Mediator co-activator. Here, we employed single-particle cryo-electron microscopy (cryo-EM) to disclose the architectures of RNAPII(G), RNAPII and RNAPII in complex with the transcription initiation factor TFIIF, all to.. Difference analysis mapped Gdown1 mostly to the RNAPII Rpb5 shelf-Rpb1 jaw, supported by antibody labelling experiments. These structural features correlate with the moderate increase in the efficiency of RNA chain elongation by RNAP II(G). In addition, our updated RNAPII-TFIIF map showed that TFIIF tethers multiple regions surrounding the DNA-binding cleft, in agreement with cross-linking and biochemical mapping. Gdown1's binding sites overlap extensively with those of TFIIF, with Gdown1 sterically excluding TFIIF from RNAPII, herein demonstrated by competition assays using size exclusion chromatography. In summary, our work establishes a structural basis for Gdown1 impeding initiation at promoters, by obstruction of TFIIF, accounting for an additional dependent role of Mediator in activated transcription. © 2012 European Molecular Biology Organization | All Rights Reserved.

Li L.,China Pharmaceutical University | Zhu D.,China Pharmaceutical University | Huang L.,China Pharmaceutical University | Zhang J.,China Pharmaceutical University | And 6 more authors.
PLoS ONE | Year: 2012

Cell-secreted miRNAs are highly stable and can serve as biomarkers for various diseases and signaling molecules in intercellular communication. The mechanism underlying the stability of circulating miRNAs, however, remains incompletely understood. Here we show that Argonaute 2 (Ago2) complexes and microvesicles (MVs) provide specific and non-specific protection for miRNA in cell-secreted MVs, respectively. First, the resistance of MV-encapsulated miRNAs to RNaseA was both depended on intact vesicular structure of MVs and protease-sensitive. Second, an immunoprecipitation assay using a probe complementary to human miR-16, a miRNA primarily located in the MVs and showed a strong, protease-sensitive resistance to RNaseA, identified Ago2 as a major miR-16-associated protein. Compared with protein-free miR-16, Ago2-associated miR-16 was resistant to RNaseA in a dose- and time-dependent fashion. Third, when the miR-16/Ago2 complex was disrupted by trypaflavine, the resistance of miR-16 to RNaseA was decreased. In contrast, when the association of miR-16 with the Ago2 complexes was increased during cell apoptosis, although the total amount of miR-16 and Ago2 remained unchanged, the resistance of miR-16 to RNaseA in the MVs was enhanced. A similar correlation between the increase of miR-223/Ago2 association and the resistance of miR-223 against RNaseA was observed during all trans retinoic acid (ATRA)-induced cell differentiation of promyelocytic HL60 cells. In conclusion, the association of miRNAs with Ago2 complexes, an event that is linked to cell functional status, plays a critical role in stabilizing the circulating miRNAs in cell-secreted MVs. © 2012 Li et al.

Xiong Y.,Zhejiang Chinese Medical University | Chen J.,China Pharmaceutical University | Guo D.,Shanghai Institute for Food and Drug Control
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2014

Nobiliside A (Nob) is a new triterpenoid saponin separated from Holothuria noblilis. In this article, a liquid chromatography-electrospray ionization-tandem mass spectrometry method was established to quantify Nob, a hemolytic saponin, in rat blood and tissue homogenates. Standard curves were linear (r= 0.9988-0.9995) over the range 50-5000. ng/mL in blood and 100-10000. ng/g in tissues. The lower limit of quantification (LLOQ) was 50. ng/mL for Nob. The novel method was rapid, accurate, highly sensitive and highly selective. Using this method, the pharmacokinetics and biodistribution of Nob liposome and Nob solution in Sprague-Dawley rats after a single intravenous dose of 1. mg/kg were then investigated. Nob was cleared slowly from circulation. There was no significant difference of the pharmacokinetic parameters in blood between Nob solution and Nob liposome. The highest AUC of Nob was observed in liver for the two groups, followed by spleen, lungs, kidney and heart. Compared with Nob solution, Nob liposome showed much higher AUC in liver and spleen and much lower AUC in kidney, heart and lung, which might be one important reason for the decreased toxicity of Nob. © 2014 Elsevier B.V.

Rao Y.,China Pharmaceutical University | Rao Y.,National Research Council Canada | Xiang B.,China Pharmaceutical University | Bramanti E.,CNR Institute for Chemical and Physical Processes | And 2 more authors.
Journal of Agricultural and Food Chemistry | Year: 2010

A liquid chromatography method with mass spectrometric detection has been developed for the simultaneous determination of six thiols in the sulfur metabolic pathway, including cysteine (Cys), homocysteine (HCys), glutathione (GSH), cysteinyl-glycine (Cys-Gly), y-glutamyl-cysteine (Glu-Cys), and S-adenosyl-homocysteine (AdoHcy). Tris(2-carboxyethyl)phosphine (TCEP) was used as the reducing reagent and p-(hydroxymercuri)benzoate (PHMB) as the derivatization reagent. Thiols were extracted from 3 mg of yeast using water in an ultrasonic bath. The absolute detection limits for the compounds studied were in the subpicomole range. It was found that AdoHcy, Cys, GSH, Cys-Gly, Glu-Cys, and very little HCys were present in the selenium-enriched yeast sample studied, and GSH, Glu-Cys, very little AdoHcy, Cys, and Cys-Gly were present in three bakery yeasts. © 2010 American Chemical Society.

Yu W.,Wuhan University | Chen L.,Wuhan University | Yang Y.-Q.,China Pharmaceutical University | Falck J.R.,University of Texas Southwestern Medical Center | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2011

Purpose: Cytochrome P450 (CYP) ω-hydroxylase, mainly consisting of CYP4A and CYP4F, converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) that induces angiogenic responses in vivo and in vitro. The present study examined the role of CYP ω-hydroxylase in angiogenesis and metastasis of human non-small cell lung cancer (NSCLC). Methods: The effect of WIT003, a stable 20-HETE analog, on invasion was evaluated using a modified Boyden chamber in three NSCLC cell lines. A549 cells were transfected with CYP4A11 expression vector or exposed to CYP ω-hydroxylase inhibitor (HET0016) or 20-HETE antagonist (WIT002), and then ω-hydroxylation activity toward arachidonic acid and the levels of matrix metalloproteinases (MMPs) and VEGF were detected. The in vivo effects of CYP ω-hydroxylase were tested in established tumor xenografts and an experimental metastasis model in athymic mice. Results: Addition of WIT003 or overexpression of CYP4A11 with an associated increase in 20-HETE production significantly induced invasion and expression of VEGF and MMP-9. Treatment of A549 cells with HET0016 or WIT002 inhibited invasion with reduction in VEGF and MMP-9. The PI3 K or ERK inhibitors also attenuated expression of VEGF and MMP-9. Compared with control, CYP4A11 transfection significantly increased tumor weight, microvessel density (MVD), and lung metastasis by 2.5-fold, 2-fold, and 3-fold, respectively. In contrast, WIT002 or HET0016 decreased tumor volume, MVD, and spontaneous pulmonary metastasis occurrences. Conclusion: CYP ω-hydroxylase promotes tumor angiogenesis and metastasis by upregulation of VEGF and MMP-9 via PI3 K and ERK1/2 signaling in human NSCLC cells. © 2010 Springer-Verlag.

Wu Y.,China Pharmaceutical University | Qu W.,China Pharmaceutical University | Geng D.,Huaqiao University | Liang J.-Y.,China Pharmaceutical University | Luo Y.-L.,China Pharmaceutical University
Chinese Journal of Natural Medicines | Year: 2012

Aim: To investigate the chemical constituents of the aerial part of Euphorbia hirta Linn. Methods: The chemical constituents were isolated and purified by various chromatographic techniques, and their structures were elucidated on the basis of spectroscopic analysis. Results: Nine compounds were isolated and identified as scopoletin (1), scoparone (2), isoscopoletin (3), quercetin (4), isorhamnetin (5), pinocembrin (6), kaempferol (7), luteolin (8), gallic acid (9). Conclusion: Among them compounds 1-3, 5-8 were found from this plant for the first time. © 2012 China Pharmaceutical University.

Ma S.,Qiqihar University | Liu X.,China Pharmaceutical University | Xu Q.,Heilongjiang Academy of Traditional Chinese Medicine | Zhang X.,Guangdong Research Institute of Traditional Chinese Medicine
Life Sciences | Year: 2014

In this report, the transport of ginkgolides with different lipophilicities was investigated using an hCMEC/D3 cell monolayer as a blood-brain barrier (BBB) cell model in vitro in an attempt to explain ginkgolide transport path mediated by lipophilicity.Main methods: The log P values of ginkgolides were determined by measuring the distribution of the molecule between oil and water. Additionally, the cytotoxicity of ginkgolides on hCMEC/D3 cells was assayed with the MTT method. Ginkgolide contents were determined with an ultra performance liquid chromatograph equipped with an evaporative light scattering detector (ULPC-ELSD) method. Apparent permeability coefficients (Papp) and efflux ratios (PappBL → AP/PappAP → BL) were then calculated to describe the transport characteristics of ginkgolide.Key findings: The transport of ginkgolide A, ginkgolide B, ginkgolide C, and ginkgolide J across the hCMEC/D3 cell monolayer was non-directional. Additionally, ginkgolide C transport on the cell monolayer was time- and concentration-dependent in the paracellular pathway controlled by cytochalasin D (a tight junction modulator). The transport of ginkgolide N, ginkgolide L, and ginkgolide K across the cell monolayer displayed clear directionality at low ginkgolide concentrations. This behavior indicated that the transport of ginkgolide N, ginkgolide L, and ginkgolide K was influenced by the transcellular pathway containing an efflux protein accompanied by the paracellular pathway for passive diffusion. Additionally, the transport of ginkgolide K was increased significantly by co-culturing with a P-gp inhibitor.Significance: These findings provide important information for elucidating ginkgolide transport pathways and may be beneficial for the design of ginkgolide molecules with high neuroprotective effects. © 2014 Elsevier Ltd. All rights reserved.

Huang Y.,China Pharmaceutical University | Zhang B.,China Pharmaceutical University | Gao Y.,China Pharmaceutical University | Zhang J.,China Pharmaceutical University | Shi L.,University of Minnesota
Journal of Pharmaceutical Sciences | Year: 2014

The purpose of this study was to investigate the effect of preparation methods on cocrystallization between baicalein (BE) and nicotinamide (NCT), their intermolecular interaction, and to demonstrate that BE-NCT cocrystal can achieve the simultaneous enhancement in solubility, dissolution, and oral bioavailability of BE. The cocrystals from three preparation methods have the similar differential scanning calorimetry thermograms and X-ray powder diffraction patterns. Compared with crystalline BE, BE-NCT cocrystal has significantly improved the solubility and dissolution of BE. In addition, the cocrystal exhibits a 2.49-fold higher peak plasma concentration (C max) and 2.80-fold higher area under the curve (AUC) in rats. This prominent improvement in oral bioavailability is even greater than the previously reported BE nanocrystal. This investigation enriched the present understanding of cocrystals on their behavior in vitro and in vivo, and built the groundwork for future development of BE as a promising compound into efficacious drug products. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2330-2337, 2014 © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Ding Y.,University of Massachusetts Amherst | Ding Y.,China Pharmaceutical University | Jiang Z.,University of Massachusetts Amherst | Saha K.,University of Massachusetts Amherst | And 4 more authors.
Molecular Therapy | Year: 2014

Gold nanoparticles provide an attractive and applicable scaffold for delivery of nucleic acids. In this review, we focus on the use of covalent and noncovalent gold nanoparticle conjugates for applications in gene delivery and RNA-interference technologies. We also discuss challenges in nucleic acid delivery, including endosomal entrapment/escape and active delivery/presentation of nucleic acids in the cell.© The American Society of Gene & Cell Therapy.

Kim Y.-K.,China Pharmaceutical University | Cho C.-S.,Seoul National University | Cho M.-H.,Seoul National University | Cho M.-H.,Seoul National University of Science and Technology | And 2 more authors.
Journal of Biomedical Materials Research - Part A | Year: 2014

The clinical success of gene therapy critically depends upon the safety and efficiency of delivery system used. Although polyethylenimine (PEI) has been commonly used as an efficient cationic polymeric gene carrier due to its high transfection efficiency, its cytotoxicity and nondegradability limit the polymer's therapeutic applications in clinical trials. In this study, biocompatible polyspermine based on spermine (SPE) and poly(ethylene glycol) (PEG) diacrylate (SPE-alt-PEG) was synthesized using a Michael-type addition reaction, and its ability as an alternative gene carrier for lung cancer therapy was evaluated. SPE-alt-PEG polyspermine was complexed with plasmid DNA, and the resulting complexes were characterized by particle size and surface charge by dynamic light scattering, complex formation and DNA protection ability by gel retardation, and complex shape by energy-filtering transmission electron microscopy. The SPE-alt-PEG copolymer showed low cytotoxicity, and SPE-alt-PEG/DNA complexes showed efficacious transfection efficiency compared with 25 kDa PEI (PEI 25K). Also SPE-alt-PEG/GFP complexes were efficiently transferred into the lungs after aerosol administration without toxicity, and delivery of Pdcd4 gene as a therapeutic gene with SPE-alt-PEG polyspermine greatly reduced tumor size as well as tumor numbers in K-rasLA1 lung cancer model mice compared relative to the effect observed for PEI 25K. These results suggest that SPE-alt-PEG has potential as a gene carrier for lung cancer gene therapy. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2230-2237, 2014. © 2013 Wiley Periodicals, Inc.

Chen Z.,Nanjing University | Chen Z.,Johns Hopkins University | Chen Z.,China Pharmaceutical University | Zhang P.,Johns Hopkins University | And 5 more authors.
Journal of Controlled Release | Year: 2014

Covalent modification of a drug with a peptide moiety has been extensively used as an effective strategy to improve the drug's therapeutic outcome. One important consideration in the design of such a prodrug is the release of the free drug from the covalently bound form in a desired fashion. In most cases, the free drug release rate is controlled by the use of various chemical linkers that bridge the drug to the auxiliary segment. We report here that the degree of drug conjugation per peptide could also regulate the drug release in addition to its apparent effect on drug loading of the resulting conjugates. In this work, we synthesized three peptide-drug conjugates (NTD, d-NTD and q-NTD) in which the cell penetrating peptide Tat is covalently connected to one, two, or four doxorubicin, respectively, through a cathepsin B degradable tetrapeptide linker (-Gly-Phe-Leu-Gly-).We found that the number of doxorubicin within the conjugate impacts the release of doxorubicin in a significant way, with q-NTD showing the slowest release rate while NTD showing the fastest release rate. Our cellular uptake experiments reveal that q-NTD accumulated most effectively within cancer cells while NTD shows the lowest intracellular accumulation concentration. Interestingly, our cell viability assessment using a SRB assay reveals that d-NTD is the most potent conjugate against HepG2 human liver cancer cells. These results suggest that intracellular accumulation efficiency and the free drug release rate are two important factors that determine the in vitro efficacy of drug conjugates. To further validate this conclusion, we conjugated a short hydrocarbon onto the NTD to improve its cellular uptake, and found that the resulting conjugate, C16NTD, exhibited comparable intracellular accumulation as the q-NTD conjugate but superior anticancer activity due to its more effective release of free doxorubicin. © 2014 Elsevier B.V. All rights reserved.

Jiang T.,Seoul National University | Singh B.,Seoul National University | Li H.-S.,Seoul National University | Kim Y.-K.,China Pharmaceutical University | And 4 more authors.
Biomaterials | Year: 2014

M cells, the key players of the mucosal immunity induction, are one of the intestinal barriers for the efficient delivery of vaccines to mucosal immune tissues. To overcome the barrier, we have developed an efficient oral vaccine carrier that constitutes poly (lactic-co-glycolic acid) (PLGA) microparticle coated with M cell targeting peptide. In this study, a membrane protein B of Brachyspira hyodysenteriae (BmpB) as a model vaccine against swine dysentery was loaded into porous PLGA microparticles (MPs). The PLGA MPs were further coated with the water-soluble chitosan (WSC) conjugated with M cell homing peptide (CKS9) to prepare BmpB-CKS9-WSC-PLGA MPs. Oral immunization of BmpB vaccine with CKS9-WSC-PLGA MPs in mice showed elevated secretory IgA responses in the mucosal tissues and systemic IgG antibody responses, providing a complete immune response. Specifically, the immunization with these MPs demonstrated to induce both Th1- and Th2-type responses based on elevated IgG1 and IgG2a titers. The elevated immune responses were attributed to the enhanced M cell targeting and transcytosis ability of CKS9-WSC-PLGA MPs to Peyer's patch regions. The high binding affinity of CKS9-WSC-PLGA MPs with the M cells to enter into the Peyer's patch regions of mouse small intestine was investigated by closed ileal loop assay and it was further confirmed by confocal laser scanning microscopy. These results suggest that the M cell targeting approach used in this study is a promising tool for targeted oral vaccine delivery. © 2013 Elsevier Ltd.

Wei Y.-B.,Guangxi Medical University | Wei Y.-B.,China Pharmaceutical University | Yang X.-D.,China Pharmaceutical University
BioMetals | Year: 2012

Vanadium complexes are potent hypoglycemic agents and of great potential for therapeutical treatment of diabetes. In the present work, a novel vanadium compound, bis ((5-hydroxy-4-oxo-4Hpyran- 2-yl)methyl benzoatato) oxovanadium (IV) (BBOV) has been synthesized. Treatment of STZinduced diabetic rats with BBOV restored the blood glucose to normal level and ameliorated glucose tolerance. The hypoglycemic effect of BBOV is similar to that of bis (maltolato) oxovanadium but is less toxic in median lethal dose. Overall, the present work will provide useful information for further development of new anti-diabetic vanadium compounds. Copyright © Springer Science+Business Media, LLC. 2012.

Kim Y.-K.,China Pharmaceutical University | Minai-Tehrani A.,Seoul National University | Lee J.-H.,Seoul National University | Cho C.-S.,Seoul National University | And 4 more authors.
International Journal of Nanomedicine | Year: 2013

Background: Chitosan and chitosan derivatives have been proposed as alternative and biocompatible cationic polymers for nonviral gene delivery. However, the low transfection efficiency and low specificity of chitosan is an aspect of this approach that must be addressed prior to any clinical application. In the present study, folated poly(ethylene glycol)-chitosan-graft-polyethylenimine (FPCP) was investigated as a potential folate receptor-overexpressed cancer cell targeting gene carrier. Methods: The FPCP copolymer was synthesized in two steps. In the first step, folate-PEG was synthesized by an amide formation reaction between the activated carboxyl groups of folic acid and the amine groups of bifunctional poly(ethylene glycol) (PEG). In the second step, FPCP was synthesized by an amide formation reaction between the activated carboxyl groups of folate-PEG and amine groups of CHI-g-polyethyleneimine (PEI). The composition of FPCP was characterized by 1H nuclear magnetic resonance. Results: FPCP showed low cytotoxicity in various cell lines, and FPCP-DNA complexes showed good cancer cell specificity as well as good transfection efficiency in the presence of serum. Further, FPCP-Pdcd4 complexes reduced tumor numbers and progression more effectively than PEI 25 kDa in H-ras12V liver cancer mice after intravenous administration. Conclusion: Our data suggest that FPCP, which has improved transfection efficiency and cancer cell specificity, may be useful in gene therapy for liver cancer. © 2013 Kim et al, publisher and licensee Dove Medical Press Ltd.

Ma C.,China Pharmaceutical University | Zhu L.,China Pharmaceutical University | Wang J.,China Pharmaceutical University | He H.,China Pharmaceutical University | And 4 more authors.
Journal of Ethnopharmacology | Year: 2015

Ethnopharmacological relevance Taraxacum mongolicum Hand.-Mazz is a famous medicinal plant in China, has been listed in the Pharmacopoeia of the People's Republic of China and used to treat infection, fever, upper respiratory tract infection, pneumonia, and other infectious diseases. This study aims to evaluate the possible mechanisms responsible for the anti-inflammation effects of water extract of T. mongolicum Hand.-Mazz (WETMHM) on lipopolysaccharide (LPS)-induced inflammatory in acute lung injury. Materials and methods Female BALB/c mice were randomly divided into five groups with 10 mice in each group: (1) control group (saline), (2) LPS group, (3) LPS+dexamethasone (LPS+Dex, 2 mg/kg, administered by gavage), (4) LPS+WETMHM (5 g/kg, administered by gavage), (5) LPS+WETMHM (10 g/kg, administered by gavage). The cell counting in the bronchoalveolar lavage fluid (BALF) was measured. The animal lung edema degree was evaluated by wet/dry weight (W/D) ratio. The superoxidase dismutase (SOD) activity and myeloperoxidase (MPO) activity were assayed by SOD and MPO kits, respectively. The levels of inflammation mediators including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were assayed by an enzyme-linked immunosorbent assay method. Pathological changes of lung tissues were observed by hematoxylin and eosin (HE) staining. The levels of P-PI3K, PI3K, P-Akt, Akt, P-mTOR and mTOR were measured by Western blotting. Results The data showed that treatment with the WETMHM inhibited LPS-induced inflammation: (1) WETMHM attenuated inflammation cell numbers in the BALF, (2) decreased protein levels of lung PI3K/Akt/mTOR, and (3) improved SOD activity and (4) inhibited MPO activity; (5) histological studies demonstrated that WETMHM substantially inhibited LPS-induced neutrophils in lung tissue. Conclusion The results indicated that the WETMHM had a protective effect on LPS-induced ALI in mice. © 2015 Elsevier Ireland Ltd. All rights reserved.

Hsieh M.-T.,China Medical University at Taichung | Shia K.-S.,National Health Research Institute | Liu H.-J.,National Tsing Hua University | Kuo S.-C.,China Pharmaceutical University
Organic and Biomolecular Chemistry | Year: 2012

A highly efficient annulative approach towards the construction of the structurally attractive methylenecyclohexane ring was developed through a convenient 1,4-addition of 4-pentenylmagnesium bromide to 2-cyano-2- cycloalkenones followed by a Pd(ii)-mediated oxidative cyclization of the resulting ω-unsaturated α-cyano ketones. Based on this newly developed protocol, polycyclic adducts bearing various ring sizes and substitutions can be prepared in moderate to high yields. © 2012 The Royal Society of Chemistry.

Zhao F.-J.,China Pharmaceutical University | Tang H.,China Pharmaceutical University | Zhang Q.-H.,General Hospital of Guangzhou Military Command | Yang J.,China Pharmaceutical University | And 2 more authors.
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2012

A convenient, robust, economical and selective sample preparation method for the quantitative determination of entecavir in human plasma by LC-MS was developed and validated. Entecavir and the internal standard of acyclovir were extracted from 500μL of human plasma by a salting-out homogeneous liquid-liquid extraction approach (SHLLE) with acetonitrile as the organic extractant and magnesium sulfate as the salting-out reagent. They were analyzed on a Hanbon ® Lichrospher RP C18 HPLC column (150mm×2.0mm; 5μm) with gradient elution. The mobile phase comprised 0.1% acetic acid-0.2mmol ammonium acetate in water (mobile phase A) and acetonitrile (mobile phase B). The flow rate is 0.2mL/min. The analytes were detected by a LC-MS 2010 single quadrupole mass spectrometer instrument equipped with an electrospray ionization interface using selective ion monitoring positive mode. A "post cut" column switch technique was incorporated into the method to remove interferences of earlier and later eluting matrix components than entecavir and internal standard, including salting-out reagent used in sample pre-processing. The method was validated over the concentration range of 0.05-20ng/mL. The intra-day and inter-day precision of the assay, as measured by the coefficient of variation (%CV), was within 3.59%, and the intra-day assay accuracy was found to be within 4.88%. The average recovery of entecavir was about 50% and the ion suppression was approximately 44% over the standard curve. Comparison of matrix effect between SHLLE and SPE by continuous post column infusion showed that these two methods got similar, slight ion suppression. The SHLLE method has been successfully utilized for the analysis of entecavir in post-dose samples from a clinical study. © 2011.

Yang D.J.,China Pharmaceutical University | Li C.,China Pharmaceutical University | Ding L.,China Pharmaceutical University | Guo Q.,China Pharmaceutical University | And 2 more authors.
Journal of Natural Products | Year: 2012

Gambogic acid (1) is a cytotoxic caged xanthone derived from the resin of Garcinia hanburyi. Compound 1 selectively induces apoptosis in cancer cells, at least partially, by targeting the stress response to reactive oxygen species (ROS). However, the molecular mechanism of ROS toxicity stimulated by 1 remains poorly understood. In this study, mass spectrometric and biochemical pharmacological approaches were used that resulted in the identification of both cytosolic thioredoxin (TRX-1) and mitochondrial thioredoxin (TRX-2) as the molecular targets of 1. The results obtained showed that 1 deactivates TRX-1/2 proteins by covalent binding to the active cysteine residues in the functional domain via Michael addition reactions. Since both TRX-1 and TRX-2 play key roles in regulating the redox signaling of cancer cells, the present findings may shed light on the relationship between protein binding and cellular ROS accumulation induced by 1. This provides support for the current clinical trials of gambogic acid (1) being conducted alone or in combination with other agents that appear to increase ROS generation in order to selectively kill cancer cells. © 2012 American Chemical Society and American Society of Pharmacognosy.

Liang J.,China Pharmaceutical University | Aihua Z.,Xuzhou Normal University | Yu W.,China Pharmaceutical University | Yong L.,China Pharmaceutical University | Jingjing L.,China Pharmaceutical University
Vaccine | Year: 2010

Mucosal administration of autoantigen HSP65 can induce anti-inflammatory immune response and decrease organ-specific inflammation and disease in several models of autoimmunity, such as arthritis and atherosclerosis. We have been interested in whether the HSP65 serves as an immunogenic carrier for a diabetogenic peptide P277 can also induce anti-inflammatory immune response in NOD mice by mucosal administration. Thus, the dual functions of anti-type 1 diabetes of HSP65 and P277 will be obtained. To test this hypothesis, we examined the effect of intranasal vaccination with P277 tandem repeat sequences carried by HSP65 in the absence of adjuvants on autoimmune diabetes in NOD mice. We found a significant decrease in the incidence of diabetes, inhibition of insulitis, reduction in IgG2a isotype antibodies to P277 and proinflammatory cytokines IFN-γ and IL-2 secretion, increased IgG1, IgG2b subclass antibodies to P277 and anti-inflammatory cytokines IL-10 and IL-4 secretion, and reduced proliferation in nasal administration of the fusion protein HSP65-6 × P277. Our results demonstrate that HSP65 may serve as a particularly advantageous carrier for P277-based vaccines and mucosal administration may be a therapeutic approach for treatment of type 1 diabetes. © 2010 Elsevier Ltd. All rights reserved.

Chen H.,China Pharmaceutical University | Yang J.,China Pharmaceutical University | Zhang Q.,Nanjing Maternity and Child Health Care Hospital | Chen L.-H.,Nanjing University | Wang Q.,China Pharmaceutical University
Circulation Journal | Year: 2012

Background: Corosolic acid (CRA) is a pentacyclic triterpene acid that has been shown to exhibit an anti-atherosclerotic effect when added to diets of low-density lipoprotein-deficient mice, but the mechanisms are unclear. The purpose of the present study was to investigate the molecular mechanisms by which CRA ameliorates atherosclerosis. Methods and Results: The anti-atherosclerosis effect of CRA in apolipoprotein E-deficient mice fed a Western-type diet was evaluated using atherosclerosis lesion area, serum profiles, gene expression and histological lesions. In vitro, the mechanisms responsible for the anti-inflammatory effect of CRA were investigated on a lipopolysaccharide-induced inflammation model. This model was also used to investigate in detail the effects of CRA on gene expression and nuclear factor (NF)-κB activation. Compared with the control group, the CRA-treated group exhibited a significant decrease in atherosclerotic lesion area, as well as expression of monocyte chemoattractant protein-1 (MCP-1) and CCR2. In vitro studies showed that CRA treatment downregulated the mRNA levels of MCP-1, and inhibited monocyte adhesion and migration, together with suppression of NF-κB signaling pathway. Conclusions: CRA is capable of ameliorating atherosclerosis in apolipoprotein E-deficient mice by, partly at least, inhibition of NF-κB activity along with decreased MCP-1 expression.

Zhang F.,China Pharmaceutical University | Wang J.-S.,China Pharmaceutical University | Gu Y.-C.,Hill International | Kong L.-Y.,China Pharmaceutical University
Journal of Natural Products | Year: 2010

Six new triterpenoids (1-6), along with 10 known compounds, were isolated from the stems of Aglaia abbreviata. The structures of 1-6 were elucidated on the basis of their spectroscopic data. Compounds 1-6 were evaluated for their cytotoxic activities against a small panel of human tumor cell lines. © 2010 The American Chemical Society and American Society of Pharmacognosy.

Ge H.-X.,Huzhou Teachers College | Zhang J.,China Pharmaceutical University | Kai C.,China Pharmaceutical University | Liu J.-H.,China Pharmaceutical University | Yu B.-Y.,China Pharmaceutical University
Applied Microbiology and Biotechnology | Year: 2012

The microbial transformation of a series of tetrahydroprotoberberines (THPBs, 1-5) by Gliocladium deliquescens NRRL1086 was investigated. In this research, the novel glycosylation of tetrahydroberberrubine (1) was observed with fast rate and high regio- and enantio-selectivity. One pair of unique enantiomorphic alkaloidal glycosides T-1 and T-2 was isolated and their structures were elucidated unambiguously by HR-MS, CD, 1D and 2D NMR spectrum. It is interesting that different amounts of glucose in the potato broth medium could influence the ratio of T-1 and T-2; in the 1.5% glucose medium, the ratio was about 15:1 and the yield of the S-form product T-1 may reach the theoretical maximum yield of about 50% which could provide one practical method to prepare the enantiomerically pure product and one alternative resolution method of tetrahydroberberrubine. The preliminary enzymatic research by using sodium dodecyl sulfate (SDS) and imidazole as glycosyltransferase and glycosidase inhibitors revealed that glycosyltransferase may contribute to glycosylation process. This is the first successful approach to glycosylation of tetrahydroprotoberberines. © Springer-Verlag 2011.

Feng R.,China Pharmaceutical University | Feng R.,Kagoshima University | Xu J.,Kagoshima University | Minobe E.,Kagoshima University | And 5 more authors.
American Journal of Physiology - Cell Physiology | Year: 2014

The present study is to investigate the mechanism by which ATP regulates Cav1.2 channel activity. Ventricular tissue was obtained from adult guinea pig hearts using collagenase. Ca2+ channel activity was monitored using the patch-clamp technique. Proteins were purified using wheat germ agglutinin-Sepharose, and the concentration was determined using the Coomassie brilliant blue technique. ATP binding to the Cav1.2 channel was examined using the photoaffinity method. EDA-ATP-biotin maintains Ca2+ channel activity in inside-out membrane patches. ATP directly bound to the Cav1.2 channel in a dose-dependent manner, and at least two molecules of ATP bound to one molecule of the Cav1.2 channel. Low levels of calmodulin (CaM increased ATP binding to the Cav1.2 channel, but higher levels of CaM decreased ATP binding to the Cav1.2 channel. In addition, Ca2+ was another regulator for ATP binding to the Cav1.2 channel. Furthermore, ATP bound to GST-fusion peptides of NH2-terminal region (amino acids 6-140 and proximal COOH-terminal region (amino acids 1,509-1,789 of the main subunit (α1C of the Cav1.2 channel. Our data suggest that ATP might regulate Cav1.2 channel activity by directly binding to the Cav1.2 channel in a dose-dependent manner. In addition, the ATP-binding effect to the Cav1.2 channel was both CaM- and Ca2+ dependent. © 2014 the American Physiological Society.

Hu W.,China Pharmaceutical University | Hu W.,Key Laboratory of Drug Quality Control and Pharmacovigilance | Hong T.,China Pharmaceutical University | Hong T.,Key Laboratory of Drug Quality Control and Pharmacovigilance | And 4 more authors.
TrAC - Trends in Analytical Chemistry | Year: 2014

Nanoparticles, novel materials with considerable potential in various applications, have made a significant contribution to the development of stationary phases in chromatography. In capillary electrochromatography (CEC), the process for creating stationary phases has a substantial effect on separation performance. Due to their extraordinary properties, nanoparticles (NPs) can generally improve the separation selectivity, the column efficiency and the chemical stability of CEC.This review focuses on the latest applications and achievements of immobilizing NPs in stationary phases for CEC. For each type of NP, we describe different immobilization strategies, including physical adsorption on surfaces, covalent bonding and other methods. Also, we present more practical applications based on functional post-modifications of the stationary phase containing NPs. Further, we discuss potential directions and issues worth exploring for novel stationary phases containing NPs. © 2014 Elsevier B.V.

Liu E.-H.,China Pharmaceutical University | Zhao P.,China Pharmaceutical University | Duan L.,China Pharmaceutical University | Zheng G.-D.,Guangzhou University | And 3 more authors.
Food Chemistry | Year: 2013

A rapid resolution liquid chromatography/electrospray ionisation tandem mass spectrometry (RRLC-ESIMSn) method has been firstly developed and validated for simultaneous determination of six bioactive flavonoids in Citri Reticulatae Pericarpium (CRP). The antiproliferative activities of the six flavonoids in CRP, namely naringin, hesperidin, nobiletin, 3,5,6,7,8,3′, 4′-heptamethoxyflavone, tangeretin and 5-hydroxy-6,7,8,3′,4′- pentamethoxyflavone, were evaluated and compared by Cell Counting Kit-8 Assay. Quantification was carried out on an Agilent triple quadrupole LC-MS system using multiple reaction monitoring mode. The established method was successfully applied for determination of the six flavonoids in samples collected from different regions in China. Compared with the reported analytical methods, the RRLC-ESI-MSn method is powerful in quantitative analysis of multi-component in terms of time savings and sensitivity. Hierarchical cluster analysis (HCA) was also performed to differentiate and classify the samples based on the contents of the six characteristic flavonoids. The HCA results indicated that Citrus reticulata 'Chachi' samples could be easily distinguished from other CRP samples. The developed RRLC-ESI-MSn method combined with HCA might be utilised as a quality control method for CRP. © 2013 Elsevier Ltd. All rights reserved.

Zhang Y.,China Pharmaceutical University | Wang J.-S.,China Pharmaceutical University | Wang X.-B.,China Pharmaceutical University | Gu Y.-C.,Hill International | And 4 more authors.
Journal of Agricultural and Food Chemistry | Year: 2013

Seven new prieurianin-type limonoids, aphapolynins C-I (1-7), and a new aphanamolide-type limonoid, aphanamolide B (8), along with seventeen known compounds, were isolated from the fruits of Aphanamixis polystachya. The structures of these compounds were established on the basis of spectroscopic studies. The absolute configurations were determined by combination of electronic circular dichroism (ECD) calculation, CD exciton chirality method, and single crystal X-ray diffraction. All these isolates were evaluated for their cytotoxicities against three human cancer cell lines, for their inhibitory effects on lipopolysaccharide (LPS) induced RAW264.7 murine macrophages, and for their fungicidal, herbicidal, and insecticidal activities. Compounds 1, 14, 16, and 17 exhibited significant fungicidal activities; 1 and 25 in particular showed good insecticidal activities. The α,β-unsaturated lactone and 14,15-epoxy ring moieties were essential for the insecticidal activity. © 2013 American Chemical Society.

Qin Y.,Korea University | Guo X.W.,China Pharmaceutical University | Li L.,Chongqing Medical University | Wang H.W.,Shandong Agricultural University | Kim W.,Korea University
Journal of Medicinal Food | Year: 2013

The present study examined, for the first time, the in vitro wound healing potential of chitosan green tea polyphenols (CGP) complex based on the activation of transglutaminase (TGM) genes in epidermal morphogenesis. Response surface methodology was applied to determine the optimal processing condition that gave maximum extraction of green tea polyphenols. The antioxidant activity, scavenging ability, and chelating ability were studied and expressed as average EC50 values of CGP and other treatments. In silico analysis and gene coexpression network was subjected to the TGM sequences analysis. The temporal expressions of TGMs were profiled by semi-quantitative reverse transcription (RT)-PCR technology within 10 days after wounding and 2 days postwounding. CGP showed the effectiveness of antioxidant properties, and the observations of histopathological photography showed advanced tissue granulation and epithelialization formation by CGP treatment. In silico and coexpression analysis confirmed the regulation via TGM gene family in dermatological tissues. RT-PCR demonstrated increased levels of TGM1-3 expression induced by CGP treatment. The efficacy of CGP in wound healing based on these results may be ascribed to its antioxidant properties and activation of the expression of TGMs, and is, thus, essential for the facilitated repair of skin injury. © Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition.

Wang J.,National Health Research Institute | Pang T.,National Health Research Institute | Pang T.,China Pharmaceutical University | Hafko R.,National Health Research Institute | And 4 more authors.
Neuropharmacology | Year: 2014

Sartans (Angiotensin II AT1 Receptor Blockers, ARBs) are powerful neuroprotective agents in vivo and protect against IL-1β neurotoxicity in vitro. The purpose of this research was to determine the extent of sartan neuroprotection against glutamate excitotoxicity, a common cause of neuronal injury and apoptosis. The results show that sartans are neuroprotective, significantly reducing glutamate-induced neuronal injury and apoptosis in cultured rat primary cerebellar granule cells (CGCs). Telmisartan was the most potent sartan studied, with an order of potency telmisartan > candesartan > losartan > valsartan. Mechanisms involved reduction of pro-apoptotic caspase-3 activation, protection of the survival PI3K/Akt/GSK-3β pathway and prevention of glutamate-induced ERK1/2 activation. NMDA receptor stimulation was essential for glutamate-induced cell injury and apoptosis. Participation of AT1A receptor was supported by glutamate-induced upregulation of AT1A gene expression and AT 1 receptor binding. Conversely, AT1B or AT2 receptors played no role. Glutamate-induced neuronal injury and the neuroprotective effect of telmisartan were decreased, but not abolished, in CGCs obtained from AT1A knock-out mice. This indicates that although AT1 receptors are necessary for glutamate to exert its full neurotoxic potential, part of the neuroprotective effect of telmisartan is independent of AT1 receptor blockade. PPARγ activation was also involved in the neuroprotective effects of telmisartan, as telmisartan enhanced PPARγ nuclear translocation and the PPARγ antagonist GW9662 partially reversed the neuroprotective effects of telmisartan. The present results substantiate the therapeutic use of sartans, in particular telmisartan, in neurodegenerative diseases and traumatic brain disorders where glutamate neurotoxicity plays a significant role.

Zhang F.,China Pharmaceutical University | Wang J.-S.,China Pharmaceutical University | Gu Y.-C.,Hill International | Kong L.-Y.,China Pharmaceutical University
Journal of Natural Products | Year: 2012

Toonaciliatavarins A-H (1-8), including three new protolimonoids (1-3), two new tirucallane-type triterpenoids (4 and 5), and three new tetranortriterpenoids (6-8), and 10 known compounds were isolated from the stem barks of Toona ciliata Roem. var. henryi. Their structures were identified on the basis of spectroscopic analysis. The absolute configurations of 2 and 8 were determined by ECD calculation. The new isolates were evaluated for their cytotoxicities using six human cancer cell lines and also for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. Compounds 4 and 5 showed moderate cytotoxicities, and the protolimonoids (1-3) exhibited marked inhibitory effects on LPS-stimulated NO production. © 2012 The American Chemical Society and American Society of Pharmacognosy.

Yang K.-N.,China Pharmaceutical University | Yang K.-N.,CAS National Center for Nanoscience and Technology | Zhang C.-Q.,CAS National Center for Nanoscience and Technology | Wang W.,China Pharmaceutical University | And 3 more authors.
Cancer Biology and Medicine | Year: 2014

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles (MSNs) with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanoparticles, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail. Copyright © 2014 by Cancer Biology & Medicine.

Zhang Y.,China Pharmaceutical University | Wang J.-S.,China Pharmaceutical University | Gu Y.-C.,Hill International | Kong L.-Y.,China Pharmaceutical University
Phytochemistry Letters | Year: 2013

Two new limonoids aphanamolides C (1) and D (2), together with two known limonoids aphanamolide A (3) and aphapolynin A (4), were isolated from the fruits of Aphanamixis grandifolia. Their structures were assigned on the basis of spectroscopic data, with the absolute configurations of 1 and 2 being established by electronic circular dichroism (ECD) spectroscopic analyses. Those limonoids varied in the ring A: aphanamolide C featured two oxygenated bridges, and aphanamolide D was the second example containing β-hydroxy-α, β:γ,δ-dienoate moiety. The cytotoxic activities were also evaluated in vitro against four human cancer cell lines (MCF-7, A549, SMMC-7721, and HL-60). © 2013 Phytochemical Society of Europe.

Zheng G.-D.,Guangzhou University | Zhou P.,China Pharmaceutical University | Yang H.,China Pharmaceutical University | Li Y.-S.,Guangzhou University | And 2 more authors.
Food Chemistry | Year: 2013

Citri Reticulatae Pericarpium (CRP) is one of the most commonly used traditional Chinese medicines with great medicinal and dietary values. In this work, we developed an approach utilising rapid resolution liquid chromatography/electrospray ionisation tandem mass spectrometry (RRLC-ESI-MS/MS) for the identification and profiling of chemical composition in CRP. On the basis of RRLC retention times, cochromatography with available authentic standards, mass spectral fragmentation patterns and literature information, a total of 41 chemical compounds, including 4 flavone-C-glycosides, 7 flavonoid-O-glycosides and 19 polymethoxyflavones were unambiguously identified or tentatively characterised in CRP. The occurrence of 1 flavone-C-glycoside and 3 cyclic peptides in particular has not yet been described. The results indicated that the developed method could serve as a rapid, effective tool for structural characterisation of chemical constituents in CRP. © 2012 Elsevier Ltd. All rights reserved.

Ge H.-X.,China Pharmaceutical University | Ge H.-X.,Huzhou Teachers College | Zhang J.,China Pharmaceutical University | Dong Y.,China Pharmaceutical University | And 2 more authors.
Chemical Communications | Year: 2012

In this communication, we document a facile kinetic glycosylation resolution of racemic tetrahydroberberrubine. We also demonstrate that the enantiomeric excess of the resolved products is increased via a second resolution of the minor product of the first glycosylation resolution. This provides a rare example of tandem kinetic resolution of racemates. © 2012 The Royal Society of Chemistry.

Wang J.,Changchun University of Chinese Medicine | Wang J.,China Pharmaceutical University | Zhang T.,Changchun University of Chinese Medicine | Ma C.,Changchun University of Chinese Medicine | And 2 more authors.
Immunology Letters | Year: 2015

Puerarin is an isoflavonoid isolated from the root of the plant Pueraria lobata and has been used as a prescribed drug in China for the treatment of many diseases in the clinical practice. The present study aimed to determine the protective effects and the underlying mechanisms of puerarin on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 50 mice were randomly assigned to five experimental groups: control, model, dexamethasone (2. mg/kg), and puerarin (10. mg/kg, 20. mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Th1/Th2 cytokines were measured by enzyme-linked immunosorbent assay, eotaxin-3 was evaluated by western blotting. Our study demonstrated that, compared with model group, puerarin inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-γ level in bronchoalveolar lavage fluid; histological studies demonstrated that puerarin substantially inhibited OVA-induced eosinophilia in lung tissue compared with model group. Western blotting studies demonstrated that puerarin substantially inhibited eotaxin-3 compared with model group. Our findings support puerarin can prevent some signs of allergic asthma in the mouse model. © 2015.

Yuan X.,China Pharmaceutical University | Ghosh A.,China Pharmaceutical University | Jie Q.,China Pharmaceutical University | He G.,Hefei Industrial Pharmaceutical Institute Co. | Wu Y.,China Pharmaceutical University
International Forum of Allergy and Rhinology | Year: 2015

Background: Allergic rhinitis (AR) is a very common worldwide problem; patients display a number of symptoms, such as sneezing, nasal itching, and rhinorrhea, and their lifestyle is affected. Desloratadine is a novel, long-acting inhibitor of histamine. However, very little is known about the effect of desloratadine citrate disodium injection (DLC injection) on AR, and the underlying mechanisms are yet unexplored. Herein, we sought to explore the effects and mechanisms of actions of DLC injection in ovalbumin (OVA)-induced immune responses in a rat model of AR. Methods: Sixty rats were subjected to immunization with OVA (intraperitoneal [IP]), followed by a nasal challenge with OVA. Drugs or saline were given daily for treatment. Nasal symptoms and histology of the nasal mucosa were examined. Cytokines such as interleukin (IL)-4, IL-12, interferon (IFN)-γ, adhesion molecules such as soluble vascular cell adhesion molecule 1 (sVCAM-1), and inducible nitric oxide synthase (iNOS) expression were assessed by enzyme-linked immunosorbent assay (ELISA) kit. Nitric oxide (NO) concentration was also measured by NO assay kit. Results: DLC treatment (intravenous [IV]) significantly decreased the frequency of sneezing and nasal scratching and alleviated nasal inflammation by increasing the serum levels of IFN-γ and IL-12, while lowering the expression of IL-4. Thus, DLC (IV) treatment led to a marked elevation in T-helper 1/T-helper 2 (Th1/Th2) ratio when administered in the AR rats. The expression of sVCAM-1, iNOS, and NO were also reversed. Conclusion: DLC (IV), given after an allergen challenge, improved Th1 cytokines level and restrained Th2 responses alleviating the symptoms of AR. Our results indicate that DLC injection may exhibit such effects through the modulation of T-cell responses. © 2015 ARS-AAOA, LLC.