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Cloning and prokaryotic expression analysis of HDS from Salvia miltiorrhiza bge.f.alba.

Dan JIANG ; Qi-Xian RONG ; Qing-Jun YUAN ; Wen-Jing ZHANG ; Yong-Qing ZHANG ; Lu-Qi HUANG

Acta Pharmaceutica Sinica.2014;49(11):1614-1620.

According to the designed specific primers of gene fragment based on the Salvia miltiorrhiza transcriptome data, with the method of reverse transcription polymerase chain reaction (RT-PCR), this study cloned full-length cDNA sequence of 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase gene from Salvia miltiorrhiza bge.f.alba, this sequence is named as SmHDS and its GenBank registration number is KJ746807. SmHDS, 2 529 bp long, contains an ORF of 2 229 bp, encodes 742 amino acids, including 5' UTR 170 bp and 3' UTR 130 bp. Using bioinformatics software, having made a homology analysis of the obtained sequence, we can have a conclusion that SmHDS have a close genetic relationship with HDS of Salvia miltiorrhiza. Analysis result of prokaryotic expression revealed that in Escherichia coli, SmHDS expressed target proteins which in size are comparable with the protein predicted. Meanwhile, the 4 factors which can influence the protein expression were optimized, the 4 factors are inducing temperature, inducing time, IPTG concentrations and density of inducing host bacterium (A600). The optimal expression conditions of SmHDS were 30 degrees C until the A600 is 0.6, and add IPTG to a final concentration of 0.2 mmol x L(-1), and the induction time of 20 h. It provides theoretical basis for the further study of the function of 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase in the biosynthesis of tanshinone compounds.
Cloning, Molecular ; DNA, Complementary ; genetics ; Diterpenes, Abietane ; biosynthesis ; Enzymes ; biosynthesis ; genetics ; Escherichia coli ; metabolism ; Plant Proteins ; biosynthesis ; genetics ; Salvia miltiorrhiza ; enzymology ; genetics

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Preparation and characterization of tetrandrine-loaded PLGA nanocomposite particles by premix membrane emulsification coupled with spray-drying method.

Tao HU ; Hua-Xu ZHU ; Li-Wei GUO ; Lin-Mei PAN ; Bo LI ; Fei-Yan SHI ; Jin LU

Acta Pharmaceutica Sinica.2014;49(11):1607-1613.

For effective inhalable dry-powder drug delivery, tetrandrine-PLGA (polylactic-co-glycolic acid) nanocomposite particles have been developed to overcome the disadvantages of nanoparticles and microparticles. The primary nanoparticles were prepared by using premix membrane emulsification method. To prepare second particles, they were spray dried. The final particles were characterized by scanning electron microscopy (SEM), dry laser particle size analysis, high performance liquid chromatography (HPLC), X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared analysis (IR) and confocal laser scanning microscope (CLSM). The average size of the primary particles was (337.5 ± 6.2) nm, while that second particles was (3.675 ± 0.16) μm which can be decomposed into primary nanoparticles in water. And the second particles were solid sphere-like with the drug dispersed as armorphous form in them. It is a reference for components delivery to lung in a new form.
Administration, Inhalation ; Benzylisoquinolines ; chemistry ; Calorimetry, Differential Scanning ; Drug Delivery Systems ; Dry Powder Inhalers ; Lactic Acid ; chemistry ; Microscopy, Electron, Scanning ; Nanocomposites ; chemistry ; Nanoparticles ; chemistry ; Particle Size ; Pharmaceutical Preparations ; Polyglycolic Acid ; chemistry ; X-Ray Diffraction

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Preparation, formation mechanism and preliminary evaluation of oral absorption of a Bicyclol-phospholipid complex.

Lin LI ; Wu-Jun DONG ; Li SHENG ; Xue-Jun XIA ; Yan LI ; Yu-Ling LIU

Acta Pharmaceutica Sinica.2014;49(11):1600-1606.

Bicyclol with benzyl alcohol structure, is a poorly water-soluble drug, used for the treatment of chronic hepatitis B. To increase the drug solubility and oral bioavailability, a Bicyclol-phospholipid complex was studied on its preparation, formation mechanism, and the influence on drug physicochemical properties and oral absorption. The complex was prepared by a solvent evaporation method. The optimal formulation was selected by orthogonal experimental design, and a reasonable evaluating method of the complexation rate was established. Various methods, such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and 31P nuclear magnetic resonance (31P-NMR), were used to explore the phase state and formation mechanism of the complex. The solubility of drug in complex was investigated in water/n-octanol. Preliminary study of its absorption and liver tissue distribution in rats was also carried out. The results showed that Bicyclol and phosphatidylcholine can be complexed entirely in the molar ratio 1 : 2. Bicyclol was dispersed in phospholipids as amorphous state. They were combined by intermolecular hydrogen bond due to charge transfer effect which occurred between the two polarities of the double bond between phosphorus and oxygen (P=O) of phosphatidylcholine and benzalcohol group of Bicyclol. The solubility of the complex compared to the active pharmaceutical ingredient (API) was effectively enhanced 5.75 times in water and 7.72 times in n-octanol, separately. In addition, drug concentrations were also enhanced 43 times in plasma and 13 times in liver with one hour after administering the complex to rats via oral gavage. All of these indicated that Bicyclol with benzalcohol group can interact with phospholipids to form complex, improving drug's physicochemical properties, thus further increasing its absorption and target tissue distribution. This study also provided theoretical reference for the research of other benzalcohol derivatives complexed with phospholipids.
1-Octanol ; Animals ; Biological Availability ; Biphenyl Compounds ; pharmacokinetics ; Calorimetry, Differential Scanning ; Chemistry, Pharmaceutical ; Phospholipids ; pharmacokinetics ; Rats ; Solubility ; Spectroscopy, Fourier Transform Infrared ; Tissue Distribution ; X-Ray Diffraction

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Determination of γ-aminobutyric acid in human plasma by LC-MS/MS and its preliminary application to a human pharmacokinetic study.

Yao CHEN ; Xiao-Jian DAI ; Jiang-Bo DU ; Kan ZHONG ; Xiao-Yan CHEN ; Da-Fang ZHONG

Acta Pharmaceutica Sinica.2014;49(11):1593-1599.

A rapid, sensitive and convenient LC-MS/MS method was developed for the determination of γ-aminobutyric acid (GABA) in human plasma. d2-γ-Aminobutyric acid (d2-GABA) was synthesized as internal standard (IS). After extraction from human plasma by protein precipitation with acetonitrile, all analytes were separated on a Luna HILIC column (100 mm x 3.0 mm, 3 μm) using an isocratic mobile phase of water: acetonitrile: formic acid (20 : 80 : 0.12) with a flow rate of 0.5 mL x min(-1). Acquisition of mass spectrometric data was performed in multiple reaction monitoring mode (MRM) in positive electrospray ionization using the transitions of m/z 104 --> 69 for GABA and m/z 106 --> 71 for d2-GABA. The method was linear in the concentration range of 5.00 to 1 000 ng x mL(-1). The intra- and inter-day precisions were within 9.9%, and accuracy ranged from 99.1% to 104%, within the acceptable limit across all concentrations. The method was successfully applied to a pharmacokinetic study of GABA tablets in healthy Chinese volunteers.
Chromatography, Liquid ; Humans ; Tandem Mass Spectrometry ; gamma-Aminobutyric Acid ; blood

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Effect of the chelator Zn-DTPA on the excretion of lead in lead intoxication mice detected with ICP-MS.

Chen LI ; Kai-zhi LU ; Qi ZHOU ; Qiong WANG ; Yu-liang ZENG ; Hong-jun YIN ; Xuan-hui HE ; Ying TIAN ; Jun-Xing DONG

Acta Pharmaceutica Sinica.2014;49(11):1588-1592.

To study the lead excretion effect of the chelator Zn-DTPA on the lead intoxication mice, inductively coupled plasma mass spectrometry (ICP-MS) was applied to detect the lead content of biological samples. The acute lead intoxication mice model was established by injecting lead acetate intraperitoneally with the dose of 1 mg. Zn-DTPA was administered intraperitoneally to mice once daily for five consecutive days 4 h after intoxication. Control group, model group, combination of Zn-DTPA and Ca-DTPA group were evaluated at the same time. The urine was collected every day. The mice were sacrificed in batches in the 2rd, 4th, 6th day. Biological samples including urine, whole blood, femur and brain were prepared and nitrated. Lead concentration was detected by ICP-MS. The result showed that Zn-DTPA could increase lead content in urine markedly and reduce lead content in blood, femur and brain.
Animals ; Chelating Agents ; pharmacology ; Lead ; pharmacokinetics ; urine ; Lead Poisoning ; drug therapy ; Mass Spectrometry ; Mice ; Pentetic Acid ; pharmacology

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Comparative study of pharmacokinetics and tissue distribution of 8-cetylberberine and berberine in rats.

Yu-Li HU ; Chao CHEN ; Zong-Yao ZOU ; Xue-Gang LI ; Xiao-Li YE

Acta Pharmaceutica Sinica.2014;49(11):1582-1587.

The concentrations of berberine (BBR) and 8-cetylberberine (8-BBR-C16) in rat plasma and tissue were determined by RP-HPLC. Both the plasma pharmacokinetics characteristic and tissue distribution differences of BBR and 8-BBR-C16 were compared to provide experimental data for the mechanism research and further drug development. After the oral administrations of BBR and 8-BBR-C16 at the dose of 80 mg x kg(-1) for rats, the pharmacokinetics result showed that compared with BBR, the C(max) and AUC(0-t), of 8-BBR-C16 increased by 2.8 times and 12.9 times respectively, t1/2 extended from 3.61 h to 11.90 h. The tissue distribution result showed that compared with BBR, the concentration of 8-BBR-C16 in various organizations increased and the retention time extended remarkably. The maximum concentration was achieved in lung and the highest concentration in it was 3 731.82 ng x g(-1). After being derived, the C(max) in plasma and bioavailability of 8-BBR-C16 increased remarkably and the circulation time in vivo extended. The drug concentration in tissue increased remarkably, and the distribution ratio changed too, with strong targeting selection in lung.
Administration, Oral ; Animals ; Berberine ; analogs & derivatives ; pharmacokinetics ; Biological Availability ; Chromatography, High Pressure Liquid ; Rats ; Tissue Distribution

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Two new sesquiterpenoids from basidiomycete Tyromyces chioneus.

Hua GUO ; Tao FENG ; Zheng-Hui LI ; Ji-Kai LIU

Acta Pharmaceutica Sinica.2014;49(11):1578-1581.

Two new sesquiterpenoids, named as tyromols A and B (1 and 2), were isolated from cultures of basidiomycete Tyromyces chioneus, along with two previously reported 15-hydroxy-6 α, 12-epoxy-7β, 10αH, 11βH-spiroax-4-ene (3) and agripilol C (4). Compounds 1-4 were separated and purified by silica gel, RP-18, Sephadex LH-20 column chromatography. Their structures were elucidated on the basis of extensive spectroscopic analysis including IR, MS, 1D and 2D NMR experiments.
Basidiomycota ; chemistry ; Magnetic Resonance Spectroscopy ; Sesquiterpenes ; chemistry ; isolation & purification ; Sesterterpenes

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Chemical constituents of bufadienolides in cinobufacino injection.

Ling-Yu HAN ; Nan SI ; Jun-Qiu LIU ; Hai-Yu ZHAO ; Jian YANG ; Bao-Lin BIAN ; Hong-Jie WANG

Acta Pharmaceutica Sinica.2014;49(11):1574-1577.

Cinobufacino injection is purified from water extraction of the skin of Bufo bufo gargarizans, which has been widely used for various cancers in clinic with significant anti-tumor effects. Bufadienolides were regarded as the main active constituents of cinobufacino injection in previous reports. In present study, 6 bufadienolides were isolated and purified from Cinobufacino injection. Their structures were identified as 3-epi-ψ-bufarenogin (1), ψ-bufarenogin (2), 3-epi-arenobufagin (3), arenobufagin (4), 3-epi-gamabufotalin (5), and 3-oxo-arenobufagin (6), separately. Among them, 1 and 3 were new compounds, 5 and 6 were new natural products. Compounds 1, 2 and compounds 3, 4 were two pairs configuration isomers at C-3, separately.
Animals ; Bufanolides ; chemistry ; isolation & purification ; Bufo bufo ; Injections ; Skin ; chemistry

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The compounds from n-butanol fraction of Alpinia oxyphylla.

Bin-Bin XIE ; Lei HOU ; Bao-Lin GUO ; Wen-Hua HUANG ; Jing-Guang YU

Acta Pharmaceutica Sinica.2014;49(11):1569-1573.

Nine compounds were isolated from the n-butanol fraction of 95% ethanol extract of the fruit of Alpinia oxyphylla Miq. with a combination of various chromatographic approaches, including MDS resin, silica gel, reverse phase C18 and preparative HPLC. On the basis of spectroscopic data analysis, they were elucidated as (1R, 4R, 10R)-1β, 4α-dihydroxy-11, 12, 13-trinor-5, 6-eudesmen-7-one (1), 1β, 4β-dihydroxy-11, 12, 13-trinor-8, 9-eudesmen-7-one (2), oxyphyllenone A (3), oxyphyllenone B (4), rhamnocitrin (5), staphylionoside D (6), benzyl-1-O-β-D-glucopyranoside (7), 2-O-β-D-glucopyranosyl-(1S)-phenylethylene glycol (8), and (S)-1-phenylethyl-β-D-glucopyranoside (9). Among them, compound 1 is a new sesquiterpene, named as oxyphyllenone C; compounds 8 and 9 are new natural products; compounds 2 and 6 were isolated from the genus Alpinia for the first time, and compound 7 was isolated from A. oxyphylla for the first time.
1-Butanol ; Alpinia ; chemistry ; Chromatography, High Pressure Liquid ; Fruit ; chemistry ; Phytochemicals ; chemistry ; isolation & purification ; Sesquiterpenes ; chemistry ; isolation & purification

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Derivatization of berberine based on its synergistic antifungal activity with fluconazole against fluconazole-resistant Candida albicans.

Shu-Juan TIAN ; Yue GAO ; Cheng-Xu ZANG ; Zhan CAI ; Ting-jun-hong NI ; Shan-Lun TAN ; Yong-Bing CAO ; Yuan-Ying JIANG ; Da-Zhi ZHANG

Acta Pharmaceutica Sinica.2014;49(11):1563-1568.

Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.
Antifungal Agents ; pharmacology ; Berberine ; pharmacology ; Candida albicans ; drug effects ; Drug Resistance, Fungal ; Drug Synergism ; Fluconazole ; pharmacology ; Isoquinolines ; pharmacology ; Microbial Sensitivity Tests

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