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In the current study, a series of novel quinolinedione-linked sulfonylpiperazine derivatives have been reported as NQO1-directed antitumor agents. A majority of compounds in this study were found to be more effective in resisting the proliferation of cancer cells than that of the positive control 5-Fu and TSA. Among the tested compounds, the derivative 22r exhibited considerable effect (IC50, 3.29-5.19 µM) against the proliferation of three NQO1-rich cancer cells (HepG2, MCF-7, and A549), and was recognized to be an excellent NQO1 substrate as revealed by in vitro enzyme reduction assay and molecular docking study with NQO1. In studies on the mechanisms involved, 22r induced reactive oxygen species (ROS) production, caused DNA damage, and induced apoptosis in HepG2 cells. Remarkably, compound 22r exhibited excellent anticancer activity against HepG2 xenograft models in vivo. The study demonstrated that compound 22r provided a promising strategy for the management of malignant tumors.

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Curcumin (CUR) is a food additive approved by World Health Organization. But the shortcomings, such as poor water solubility, easy oxidation and degradation, limit its application. In this study, the CUR-loaded poloxamer188-based nanoparticles (CUR/PTT NPs) were fabricated to improve the stability and water solubility of CUR. Studies found the spherical CUR/PTT NPs had an average size of 98.71 ± 0.64 nm. Stability experiments displayed CUR/PTT NPs were extremely stable in different conditions. XRD analysis indicated the changes of crystal structures of CUR might be the main cause of the improved water solubility. Reducing power and anti-degradation tests suggested CUR/PTT NPs could improve the anti-oxidation and anti-degradation of CUR. Additionally, the results of body weight gains, hematological examination, organ coefficients, hematoxylin and eosin staining demonstrated CUR/PTT NPs bearing the excellent in vivo bio-security. Therefore, this study may provide a new idea for the combination of food industry and nanoparticles.

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A facile and efficient [3 + 2 + 1] annulation of aryl methyl ketoxime acetates and triethylamine for the synthesis of 2-methylpyridines was disclosed. This reaction demonstrated that I2 was effective in triggering N-O bond cleavage of oxime acetates generating imine radicals. It was noteworthy that this transformation employed triethylamine as the carbon source for the direct formation of pyridines and introduction of methyl groups.

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An amphipathic copolymer of poly(polyethylene glycol-b-polycaprolactone-co-hydroxypropyl methyl cyclodextrin) [poly(mPEG-b-PCL-co-HPCD)] was synthesized via the free radical polymerization. The copolymer was used to prepare novel nanoparticles (NPs) by a solvent evaporation method. Curcumin (CUR) was selected as a model drug and loaded in the both sites of inner NPs and the cavities of HPCD. 1H nuclear magnetic resonance (1H NMR) study was carried out to confirm the synthesis of poly(mPEG-b-PCL-co-HPCD). The morphology and particle size distribution of the cargo-free NPs were monitored with transmission electron microscopy (TEM) and Malvern particle sizer. The distribution state of CUR in the CUR-loaded NPs was studied with differential scanning calorimetry (DSC) and X-ray diffraction (XRD) methods. The 1H NMR spectrum demonstrated the successful preparation of poly(mPEG-b-PCL-co-HPCD) copolymer. TEM photograph illustrated that the cargo-free NPs had a spherical morphology with an average diameter of 229±32.8nm. The cargo-free NPs had a low critical micelle concentration of 2.9×10-2mg/mL. The HepG2 cells incubated with 1.0mg/mL NPs suspension showed high cell viability. The drug release profile showed that the medicated NPs could continuously release CUR for 24h. Therefore, the poly(mPEG-b-PCL-co-HPCD) NPs had a potential application on the drug delivery.

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The amphiphilic PEG-b-PCL block copolymers were synthesized by ring-opening polymerization. The specific and selective antagonists of platelet activating factor, Ginkgolide B (GB), was successfully encapsulated in the synthesized PEG-PCL nanoparticles (NPs) with high Encapsulation Efficiency and Drug Loading. The synthesis of different PEG-PCL copolymers were confirmed with FTIR and 1H NMR spectra. The morphology and particles size distribution of cargo-free PEG-PCL NPs were studied by transmission electron microscope (TEM) analysis and Malvern laser particle analyzer. The bio-distribution and pharmacodynamics studies of GB were studied with Wistar mice as the animal models via tail injecting of GB-PEG-PCL NPs. Results from Malvern laser particle analyzer and TEM analysis illustrated that the cargo-free NPs showed narrow distribution and well separated particles size of about 60 nm in diameter. The in vitro experiment of GB-PEG-PCL NPs exhibited an extended release behavior. The bio-distribution data suggested that Tween-80 covered GB-PEG-PCL NPs showed a brain-targeting behavior. The pharmacodynamics results confirmed that the GB-PEG-PCL NPs had an obvious cerebral protection effect.

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The pharmacokinetics (PK) of ordinary tablets and sustained release capsules of diltiazem hydrochloride in human clinical trials had been studied. The PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules, a new dosage form, has not been reported, although it is very important to clinical use. In this paper, we investigated the PK of diltiazem hydrochloride delay-onset sustained-release pellet capsules and the food influence in Chinese healthy volunteers. The PK parameters indicated that the diltiazem hydrochloride delay-onset sustained-release pellet capsules appeared marked characteristics of delayed and controlled release. An opened-label, randomized and parallel clinical trial was conducted in 36 Chinese healthy volunteers with single oral dose (90 mg, 180 mg or 270 mg) and a multiple oral dose (90 mg d-1×6 d) administration. The effect of food on the PK of one single oral dose (360 mg) was investigated in 24 healthy Chinese volunteers. Plasma diltiazem concentration was determined by reversed-phase high-performance liquid chromatography (RP-HPLC) and the main pharmacokinetic parameters were analyzed by PKSolver (Ver 2.0). All clinical studies were conducted in the Clinical Pharmacological Center (No. JDX1999064) of Xiangya Hospital Affiliated Central South University, China. The PK parameters suggested that the new formulation had marked characteristics of delayed and controlled release of diltiazem, and food intake did not alter significantly diltiazem pharmacokinetic parameters.

Embora a farmacocinética (PK) do cloridrato de diltiazem nas formas de comprimidos de liberação imediata e cápsulas de liberação modificada em ensaios clínicos já tenha sido relatada, a pesquisa da PK do cloridrato de diltiazem na forma de cápsulas com peletes de liberação retardada e sustentada ainda é muito importante. Neste trabalho, propusemos avaliar a farmacocinética do cloridrato de diltiazem administrado através desta nova forma farmacêutica em voluntários chineses sadios, assim como a influência da ingestão de alimentos neste perfil farmacocinético. Foi realizado um ensaio clínico aberto, randomizado e paralelo em 36 voluntários, que receberam dose oral única de 90 mg, 180 mg ou 270 mg e dose múltiplas (90 mg/d × 6 d) pela mesma via de administração. Para avaliar o efeito da ingestão de alimentos sobre a PK do diltiazem foi realizada a administração de dose única (360 mg) em 24 voluntários chineses sadios. A concentração plasmática do diltiazem foi determinada por Cromatografia Liquida de Alta Eficiência em fase reversa (CLAE-FR) e os principais parâmetros farmacocinéticos foram analisados através do emprego do software PKSolver (Ver 2.0). O ensaio de farmacocinética clínica foi conduzido na clínica Pharmacological Center (No.JDX1999064) do Hospital de Xiangya, Central South University, China. Os parâmetros PK obtidos indicaram que a nova formulação de cápsulas de liberação retardada e sustentada de cloridrato de diltiazem possue marcantes características de liberação retardada e controlada do fármaco.

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AIM: Tea polyphenols are known to play roles in critical steps of human lung carcinoma cell metastasis. For understanding the mechanisms whereby they inhibit tumor metastasis, the present study was conducted to investigate their effects on the adhesion of highly metastatic lung carcinoma cell lines (PG cells) to endothelial cells (EC cells) and adhesion molecule expression in vitro. METHODS: The expression of CD44 or CD54 in the PG cells was detected by flow cytometry and adhesion of PG cells to EC cells was assessed by confocal microscopy double fluorescence staining. RESULTS: The results showed that tea polyphenols: (1) inhibited the expression of CD44 and CD54, two important adhesion molecules in the PG cells in a dose-dependent manner; (2) significantly blocked the adhesion of PG cells to EC cells not only in a state of rest but also when active; and (3) influenced CD44 and CD54 expression during the adhesion process of PG cells to EC cells. CONCLUSION: The data indicated that the blocking role of tea polyphenols in the adhesion of PG cells to EC cells is related to CD44 and CD54. The mechanism of tea polyphenol prevention of human lung carcinoma metastasis might be through inhibiting adhesion molecule expression to block cancer cell adhesion.

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Our previous studies have demonstrated that oxytocin (OXT) in the central nervous system plays a role in pain modulation. Many studies have found that caudate nucleus (CdN) enriches OXT and OXT receptors by the methods of historadioautograph and gene expression. The communication was designed to investigate OXT effect in the rat CdN on pain modulation. The results showed that (1) intra-CdN microinjection of OXT receptor antagonist, desGly-NH(2), d(CH(2))(5)[D-Tyr(2), Thr-sup-4]OVT decreased the pain threshold, whereas the local administration of OXT increased the pain threshold in a dose-dependent manner; (2) OXT receptor antagonist can attenuate the analgesic role induced intra-CdN administration of OXT; and (3) pain stimulation could increase OXT concentration in the CdN perfusion liquid. The data suggested that OXT in the CdN was involved in this pain process via OXT receptors.

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Our previous study has proven that hypothalamic paraventricular nucleus (PVN) plays a role in antinociception. The effects of studied classical neurotransmitter on PVN antinociceptive modulation were investigated in the rat. The results showed: (1) Pain stimulation increased norepinephrine (NE), but not epinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DA metabolic product), homovanilic acid (DA metabolic product), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HT metabolic product), acetycholine (Ach), choline (Ach metabolic product), gamma-aminobutyric acid (GABA), and L-glutamate acid concentrations in the PVN perfusion liquid; (2) PVN stimulation with L-glutamate sodium, which excited local neurons only, did not influence the concentrations of the studied classical neurotransmitter and metabolic product in the PVN perfusion liquid; (3) Microinjection of NE, epinephrine, or L-glutamate sodium into the PVN elevated pain threshold, and local administration of GABA decreased pain threshold in a dose-dependent manner, but PVN administration of Ach, DA, or 5-HT did not change pain threshold; (4) Microinjection of phentolamine (alpha-receptor antagonist) or MK801 [NMDA-receptor antagonist] into the PVN reduced pain threshold, and local administration of bicuculline (GABA-receptor antagonist) raised pain threshold, but PVN administration of propranolol (beta-receptor antagonist), atropine (Muscarinic cholinergic receptor antagonist), 6-OH gallamine (Nicotinic cholinergic receptor antagonist), fluperidol (DA-receptor antagonist), or cyproheptadine (5-HT-receptor antagonist) did not alter pain threshold. The data suggested that endogenous NE, not epinephrine, 5-HT, Ach, GABA, and L-glutamate acid played an important role in the PVN antinociceptive modulation.

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OBJECTIVE: To research the chemical constituents from Eleutherine americana. METHODS: Column chromatography with silica gel was employed to isolate and purify the constituents. Their structures were elucidated by means of MS and NMR. RESULTS: Eight constituents were obtained and identified as Isoeleutherol (1), eleutherin (2), isoeleutherin (3), beta-sitosterol(4), 8-hydroxy-3, 4-Dimethoxy-1-methyl-anthra-9, l0-quinone-2-carboxylic acid methyl ester (5), Hongconin (6), 4,8-Dihydroxy-3-Methoxy-1-methyl-anthra-9,10-quinone-2-carboxylic acid methyl ester (7), Eleutherinone (8), Kadsuric acid (9). CONCLUSION: Compound 9 is isolated from the plant for the first time.

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OBJECTIVE: To optimize the preparation process of gemcitabine polybutylcyanoacrylate nanoparticles (GCTB- PBCA-NP). METHODS: According to the particle size, the entrapment efficiency and the loading quantity of GCTB-PBCA-NP, single factor analysis was carried out to optimize the component composition and preparation process based on an orthogonal design. RESULTS: The mean particle size of the NP was (112-/+9) nm with an entrapment efficiency of (54.12-/+2.43)% and drug loading of (11.08-/+0.89)%. CONCLUSION: An optimized nanoparticular drug delivery system is obtained by emulsion polymerization.

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OBJECTIVE: To prepare 10-hydroxycamptothecin-semisolid lipid nanoparticles (HCPT-SSLN) and investigate its stability. METHODS: HCPT-SSLN was prepared by the method of "emulsion evaporation at a high temperature and solidification at a low temperature"; The morphology was examined by transmission electron microscope; The particle size and xi potential were determined by laser granularity equipment; The physical stability of both suspl and freeze drying powder of HCPT-SSLN were investigated. RESULTS: The mean particle size of the prepared HCPT-SSLN was 130.5 nm, drug loading was 2.51%, entrapment efficiency was 79.19%, xi potential was -33.1 mV; Placed at room temperature and 4 degrees C for 6 months, the appearance, particle size and entrapment efficiency of HCPT-SSLN were all stable. Moreover, the freeze drying powder was more stable than the suspl. CONCLUSION: The HCPT-SSLN has high entrapment efficiency and drug loading, uniform particle size, good stability, which initially indicates that HCPT is fit for being incorporated into SSLN.

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Magnetic fluid containing Fe(3)O(4) as mother nucleus was prepared by chemical coprecipitation and treated with dextran-70 for surface modification. The dextran-70-modified magnetic fluid was reacted with 6-bromohexanoic acid and their chemical stability was studied, with the structure characterized by using laser granulometer, X-ray diffraction, Fourier-transform infrared analysis and transmission electron microscopy. The results showed that the magnetic fluid with surface modification by dextran-70 exhibited high stability in the presence strong alkali or acid. No chemical changes occurred in the magnetic Fe(3)O(4) nucleus surrounded by alkali-treated dextran-70 and the organic chain linked to the surface dextran rendered the reaction to the anti-cancer drug such as mitomycin C possible, suggesting the potential of the preparation as a drug carrier.

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OBJECTIVE: To establish a method by high-performance liquid chromatography (HPLC) for determining the concentration of magnetic mitomycin C-polybutylcyanoacrylate nanoparticles in mouse plasma. METHODS: Chromatography was performed on a LiChroCART C18 (250 mm x 4 mm, 5 microm) column with the mobile phase consisting of acetonitrile-NaAC (15:85), the flow rate of 1.0 ml/min, and the detection wavelength of 365 nm. Sample extraction was carried out with ethylacetate. RESULTS: The linear range of mouse plasma mitomycin C concentration was 0.04-1.00 microg/ml, and the linear equation of Y=16 388X-17.17 (r=0.999 8) was derived. CONCLUSION: This method is very easy to operate and suits the need of perclinical pharmacokinetic studies of mitomycin-magnetic nanoparticles and yields accurate and precise results.

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