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941.
942.
943.
The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations
in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS
process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction
ranged from 45 to 100°C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II
involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity
of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder
diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization
from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion
to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies
revealed the formation of eutectic mixtures and solid solutions of CPD+urea. Formation of the solid solutions resulted in
the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these
results were the reductions in melting point (up to 9°C) and in the ΔHfvalues of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude
upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic
conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability
to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous
to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional
solvent-based cocrystallizations. 相似文献
944.
Drosophila imaginal discs are sac-like appendage primordia comprising apposed peripodial and columnar cell layers. Cell survival in disc columnar epithelia requires the secreted signal Decapentaplegic (DPP), which also acts as a gradient morphogen during pattern formation. The distribution mechanism by which secreted DPP mediates global cell survival and graded patterning is poorly understood. Here we report detection of DPP in the lumenal cavity between apposed peripodial and columnar cell layers of both wing and eye discs. We show that peripodial cell survival hinges upon DPP signal reception and implicate DPP-dependent viability of the peripodial epithelium in growth of the entire disc. These results are consistent with lumenal transmission of the DPP survival signal during imaginal disc development. 相似文献
945.
Wang JF Yang Y Sullivan MF Min J Cai J Zeldin DC Xiao YF Morgan JP 《Experimental biology and medicine (Maywood, N.J.)》2002,227(3):182-188
Cytochrome P450 (P450) is a ubiquitous family of enzymes responsible for the metabolism of a wide variety of drugs and their metabolites, including cocaine. To investigate the effects of cocaine on myocardial injuries and cardiac P450 expression, BALB/c mice were injected daily intraperitoneally with cocaine (30 mg/kg) or cocaine plus pretreatment of P450 inhibitors for 14 days. Tumor necrosis factor-alpha (TNF-alpha) content and creatine phosphokinase (CPK) activity in mice hearts and serums were significantly increased after long-term treatment with cocaine. Pretreatment with the P450 inhibitor, cimetidine (Cime, 50 mg/kg) or metyrapone (Mety, 40 mg/kg) abolished or significantly attenuated the effects of cocaine on TNF-alpha and CPK activity. Western blot analysis shows that mouse cardiac tissues express the P450 isoforms CYP1A1, CYP1A2, and CYP2J2. The protein levels normalized with cyclophilin A were 1.20 plus minus 0.07, 0.67 plus minus 0.03, and 1.48 plus minus 0.01 for CYP1A1, CYP1A2, and CYP 2J2, respectively. After cocaine administration, CYP2J2 increased by 43.6% and CYP1A1 increased by 108.5%, but CYP1A2 was not significantly altered. However, the cytochrome P450 inhibitors Cime and Mety suppressed the cocaine-induced increase in CYP1A1 and CYP2J2 expression. Moreover, application of Cime or Mety alone did not alter the level of cardiac TNF-alpha or the expression of P450. Our results demonstrate that long-term exposure to cocaine causes an increase in cardiac CYP1A1 and CYP2J2 concentration. We speculate that induction of P450 isoforms may cause cardiac injury due to cocaine metabolites locally catalyzed by P450 or the increase in P450 expression itself. 相似文献
946.
Schizosaccharomyces pombe Git7p,a member of the Saccharomyces cerevisiae Sgtlp family,is required for glucose and cyclic AMP signaling,cell wall integrity,and septation 下载免费PDF全文
947.
Direct cocktail analysis of drug discovery compounds in pooled plasma samples using liquid chromatography-tandem mass spectrometry 总被引:2,自引:0,他引:2
Hsieh Y Bryant MS Brisson JM Ng K Korfmacher WA 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2002,767(2):353-362
Direct plasma injection technology coupled with a LC-MS/MS assay provides fast and straightforward method development and greatly reduces the time for the tedious sample preparation procedures. In this work, a simple and sensitive bioanalytical method based on direct plasma injection using a single column high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) was developed for direct cocktail analysis of double-pooled mouse plasma samples for the quantitative determination of small molecules. The overall goal was to improve the throughput of the rapid pharmacokinetic (PK) screening process for early drug discovery candidates. Each pooled plasma sample was diluted with working solution containing internal standard and then directly injected into a polymer-coated mixed-function column for sample clean-up, enrichment and chromatographic separation. The apparent on-column recovery of six drug candidates in mouse plasma samples was greater than 90%. The single HPLC column was linked to either an atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI) source as a part of MS/MS system. The total run cycle time using single column direct injection methods can be achieved within 4 min per sample. The analytical results obtained by the described direct injection methods were comparable with those obtained by semi-automated protein precipitation methods within +/- 15%. The advantages and challenges of using direct single column LC-MS/MS methods with two ionization sources in combination of sample pooling technique are discussed. 相似文献
948.
Southan C Cutler P Birrell H Connell J Fantom KG Sims M Shaikh N Schneider K 《Proteomics》2002,2(2):187-196
A proteomic study of rat urine was undertaken using two-dimensional gel electrophoresis, microbore high performance liquid chromatography, mass spectrometry and N-terminal sequencing. Five known urinary proteins were identified but two novel peptide fragments matched a large number of rat expressed sequence tags (ESTs) from a liver library. By combining protein chemical and nucleotide data, two 101-residue open reading frames with 90% amino acid identity were determined, rat urinary protein 1 (RUP-1) and RUP-2. The data established signal peptide removal and provided evidence for N-glycosylation. A third related sequence, rat spleen protein (RSP-1) was confirmed from EST searches. These three proteins have been submitted to SWISS-PROT as P81827, P81828 and Q9QXN2, respectively. A fourth novel homologue was found in porcine and bovine ESTs from embryo libraries. Alignment with known homologues showed conserved cysteine positions characteristic of a secreted subfamily of Ly-6 proteins. In two cases, antineoplastic urinary protein and caltrin, these homologues have unverified functional annotations. The RUP sequences showed high scoring matches to three unrelated rat mRNAs subsequently established to be chimeric. Two of these share extended sectional identity to RUP-1 but the third may represent another novel Ly-6 homologue. These chimeras have caused serious annotation errors in secondary databases. 相似文献
949.
Borole AP Kaufman EN Grossman MJ Minak-Bernero V Bare R Lee MK 《Biotechnology progress》2002,18(1):88-93
Biodesulfurization of fuel oils is a two-phase (oil/water) process which may offer an interesting alternative to conventional hydrodesulfurization due to the mild operating conditions and reaction specificity afforded by the biocatalyst. For biodesulfurization to realize commercial success, a variety of process considerations must be addressed including reaction rate, emulsion formation and breakage, biocatalyst recovery, and both gas and liquid mass transport. This study evaluates emulsion formation and breakage using two biocatalysts with differing hydrophobic characteristics. A Gram-positive (Rhodococcus erythropolis) biocatalyst, expressing the complete 4S desulfurization pathway, and a Gram-negative biocatalyst (Escherichia coli), expressing only the gene for conversion of dibenzothiophene (DBT) to DBT sulfone, are compared relative to their ability to convert DBT and the ease of phase separation as well as biocatalyst recovery following desulfurization. 相似文献
950.
SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts 总被引:16,自引:0,他引:16
Takeshita S Namba N Zhao JJ Jiang Y Genant HK Silva MJ Brodt MD Helgason CD Kalesnikoff J Rauh MJ Humphries RK Krystal G Teitelbaum SL Ross FP 《Nature medicine》2002,8(9):943-949
The hematopoietic-restricted protein Src homology 2-containing inositol-5-phosphatase (SHIP) blunts phosphatidylinositol-3-kinase-initiated signaling by dephosphorylating its major substrate, phosphatidylinositol-3,4,5-trisphosphate. As SHIP(-/-) mice contain increased numbers of osteoclast precursors, that is, macrophages, we examined bones from these animals and found that osteoclast number is increased two-fold. This increased number is due to the prolonged life span of these cells and to hypersensitivity of precursors to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Similar to pagetic osteoclasts, SHIP(-/-) osteoclasts are enlarged, containing upwards of 100 nuclei, and exhibit enhanced resorptive activity. Moreover, as in Paget disease, serum levels of interleukin-6 are markedly increased in SHIP(-/-) mice. Consistent with accelerated resorptive activity, 3D trabecular volume fraction, trabecular thickness, number and connectivity density of SHIP(-/-) long bones are reduced, resulting in a 22% loss of bone-mineral density and a 49% decrease in fracture energy. Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis. 相似文献