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91.
Estrogen has a profound impact on human physiology and affects numerous genes. The classical estrogen reaction is mediated by its receptors (ERs), which bind to the estrogen response elements (EREs) in target gene's promoter region. Due to tedious and expensive experiments, a limited number of human genes are functionally well characterized. It is still unclear how many and which human genes respond to estrogen treatment. We propose a simple, economic, yet effective computational method to predict a subclass of estrogen responsive genes. Our method relies on the similarity of ERE frames across different promoters in the human genome. Matching ERE frames of a test set of 60 known estrogen responsive genes to the collection of over 18,000 human promoters, we obtained 604 candidate genes. Evaluating our result by comparison with the published microarray data and literature, we found that more than half (53.6%, 324/604) of predicted candidate genes are responsive to estrogen. We believe this method can significantly reduce the number of testing potential estrogen target genes and provide functional clues for annotating part of genes that lack functional information. 相似文献
92.
The simulations in this paper show that exposure measurement error affects the parameter estimates of the biologically motivated two-stage clonal expansion (TSCE) model. For both Berkson and classical error models, we show that likelihood-based techniques of correction work reliably. For classical errors, the distribution of true exposures needs to be known or estimated in addition to the distribution of recorded exposures conditional on true exposures. Usually the exposure uncertainty biases the model parameters toward the null and underestimates the precision. But when several parameters are allowed to be dependent on exposure, e.g. initiation and promotion, then their relative importance is also influenced, and more complicated effects of exposure uncertainty can occur. The application part of this paper shows for two different types of Berkson errors that a recent analysis of the data for the Colorado plateau miners with the TSCE model is not changed substantially when correcting for such errors. Specifically, the conjectured promoting action of radon remains as the dominant radiation effect for explaining these data. The estimated promoting action of radon increases by a factor of up to 1.2 for the largest assumed exposure uncertainties. 相似文献
93.
Suresh Babu K Tiwari AK Srinivas PV Ali AZ China Raju B Rao JM 《Bioorganic & medicinal chemistry letters》2004,14(14):3841-3845
The methanolic extract of rhizome of Himalayan rhubarb Rheum emodi displayed mild yeast as well as mammalian intestinal alpha-glucosidase inhibitory activity. However, further fractionation of active extract led to the isolation of several potent molecules in excellent yields, displaying varying degrees of inhibition on two test models of alpha-glucosidase. Rhapontigenin, desoxyrhapontigenin, chrysophanol-8-O-beta-d-glucopyranoside, torachrysone-8-O-beta-d-glucopyranoside displayed potent yeast alpha-glucosidase inhibition. However chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin and torachrysone-8-O-beta-d-glucopyranoside displayed potent to moderate mammalian alpha-glucosidase inhibitory activity. Other compounds displayed mild activity on both the tests. Except desoxyrhapontigenin and rhapontigenin that increased Vmax, other compounds including crude extract decreased the Vmax significantly (p<0.02) in yeast alpha-glucosidase test. Further kinetic analysis on mammalian alpha-glucosidase inhibition showed that chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin and torachrysone-8-O-beta-d-glucopyranoside may be classified as mixed-noncompetitive inhibitors. However, desoxyrhapontigenin and rhapontigenin may be classified as modulators of enzyme activity. Presence and position of glycoside moiety in compounds appear important for better inhibition of mammalian alpha-glucosidase. This is the first report assigning particularly, mammalian intestinal alpha-glucosidase inhibitory activity to these compounds. Chrysophanol-8-O-beta-d-glucopyranoside, desoxyrhaponticin, desoxyrhapontigenin and rhapontigenin have been isolated in substantial yields from R. emodi for the first time. Therefore, these compounds may have value in the treatment and prevention of hyperglycemia associated diabetes mellitus. 相似文献
94.
Koltun DO Marquart TA Shenk KD Elzein E Li Y Nguyen M Kerwar S Zeng D Chu N Soohoo D Hao J Maydanik VY Lustig DA Ng KJ Fraser H Zablocki JA 《Bioorganic & medicinal chemistry letters》2004,14(2):549-552
New inhibitors of palmitoylCoA oxidation were synthesized based on a structurally novel lead, CVT-3501 (1). Investigation of structure-activity relationships was conducted with respect to potency of inhibition of cardiac mitochondrial palmitoylCoA oxidation and metabolic stability. Potent and metabolically stable analogues 33, 42, and 43 were evaluated in vitro for cytochrome P450 inhibition and potentially adverse electrophysiological effects. Compound 33 was also found to have favorable pharmacokinetic properties in rat. 相似文献
95.
Elzein E Ibrahim P Koltun DO Rehder K Shenk KD Marquart TA Jiang B Li X Natero R Li Y Nguyen M Kerwar S Chu N Soohoo D Hao J Maydanik VY Lustig DA Zeng D Leung K Zablocki JA 《Bioorganic & medicinal chemistry letters》2004,14(24):6017-6021
New inhibitors of palmitoyl-CoA oxidation are based on the introduction of nitrogen heterocycles in the ‘Western Portion’ of the molecule. SAR studies led to the discovery of CVT-4325 (shown), a potent FOXi (IC50 = 380 nM rat mitochondria) with favorable PK properties (F = 93%, t1/2 = 13.6 h, dog). 相似文献
96.
Suresh Babu CV Lee J Lho DS Yoo YS 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,807(2):307-313
Interest in the analysis of low abundance neuropeptides particularly using matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF-MS) is increasing because these neuropeptides are essential to the mechanism of transportation and the metabolism. This article describes an immunoprecipitation procedure that is suitable for MALDI-MS analysis of substance P (SP), a neuropeptide, in rat brain tissues. Substance P was precipitated from brain tissue extracts by immunoprecipitation with antibodies directed against SP, and are analyzed by MALDI-TOF-MS. Mass spectrometric analysis showed a singly charged [M+H]+ ion peak that corresponded to the SP molecular mass and was observed with a detection error of 1.6%. The average mass errors between the observed and theoretical molecular mass were within the 0.11 Da range. Capillary zone electrophoresis analysis was subsequently performed, and the effects of the different separation parameters were examined. Beginning with milligram quantities of brain tissue, picomole quantities of SP could be detected using this method. 相似文献
97.
Depressive illness is generally associated with cognitive impairment. Serotonergic selective antidepressant drugs, fluoxetine (FLX), sertraline (SER) and tianeptine (TIA), are claimed to have less or no effect on cholinergic system, the key system involved in memory. In the present study, these drugs were evaluated for their influence on cognitive behavior in both depressive and non-depressive animals. Depression was induced by two models, (i) 60 days social isolation of litter; and ii) by applying chronic unpredictable mild stress for 21 days. Depression in the rats was confirmed by behavioral despair test. Transfer latency on elevated plus maze and inflexion ratio in passive avoidance step through behavior were employed to assess learning and memory. The results indicated that administration of fluoxetine; sertraline and tianeptine attenuated the cognitive deficits observed in depressive rats. In non-depressive rats these drugs produced retention deficit, which was found to be parameter and model dependent. Data suggested that, FLX and SER (SSRI's) effectively attenuated the isolation-induced depression and cognitive deficit, whereas TIA (SSRE) produced better effect in stress-induced depressive conditions. It was concluded that behavioral profiles of fluoxetine, sertraline and tianeptine on cognition were model and parameter dependent. 相似文献
98.
NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4 总被引:34,自引:0,他引:34
Helbig G Christopherson KW Bhat-Nakshatri P Kumar S Kishimoto H Miller KD Broxmeyer HE Nakshatri H 《The Journal of biological chemistry》2003,278(24):21631-21638
99.
Bispecific and bifunctional monoclonal antibodies as second generation monoclonals, produced by conventional chemical or somatic methods, have proved useful in the immunodiagnosis and immunotherapy of cancer and other diseases. Recombinant antibodies produced by genetic engineering techniques have also become available for use in preclinical and clinical studies. Furthermore, through genetic engineering, it is possible to remove or add on key protein domains in order to create designer antibody molecules with two or more desired functions. This review summarizes the strategies for development of single chain variable fragment (scFv) bifunctional and bispecific antibodies. The advantages and disadvantages as well as the problems of generating the various bispecific and bifunctional antibody constructs are reported and discussed. Since conventionally prepared bispecific and bifunctional monoclonal antibodies have already shown promise in clinical trials and results from preclinical studies of recombinant bispecific antibodies are encouraging, clinical trials in humans of recombinant bispecific and bifunctional antibodies, as a new generation of biologicals, are likely to be the thrust in the next decade and beyond. 相似文献
100.
Giri R Selvaraj S Miller CA Hofman F Yan SD Stern D Zlokovic BV Kalra VK 《American journal of physiology. Cell physiology》2002,283(3):C895-C904
During normal aging and amyloid beta-peptide (Abeta) disorders such as Alzheimer's disease (AD), one finds increased deposition of Abeta and activated monocytes/microglial cells in the brain. Our previous studies show that Abeta interaction with a monolayer of normal human brain microvascular endothelial cells results in increased adherence and transmigration of monocytes. Relatively little is known of the role of Abeta accumulated in the AD brain in mediating trafficking of peripheral blood monocytes (PBM) across the blood-brain barrier (BBB) and concomitant accumulation of monocytes/microglia in the AD brain. In this study, we showed that interaction of Abeta(1--40) with apical surface of monolayer of brain endothelial cells (BEC), derived either from normal or AD individuals, resulted in increased transendothelial migration of monocytic cells (HL-60 and THP-1) and PBM. However, transmigration of monocytes across the BEC monolayer cultivated in a Transwell chamber was increased 2.5-fold when Abeta was added to the basolateral side of AD compared with normal individual BEC. The Abeta-induced transmigration of monocytes was inhibited in both normal and AD-BEC by antibodies to the putative Abeta receptor, receptor for advanced glycation end products (RAGE), and to the endothelial cell junction molecule, platelet-endothelial cell adhesion molecule-1 (PECAM-1). We conclude that interaction of Abeta with the basolateral surface of AD-BEC induces cellular signaling, promoting transmigration of monocytes from the apical to basolateral direction. We suggest that Abeta in the AD brain parenchyma or cerebrovasculature initiates cellular signaling that induces PBM to transmigrate across the BBB and accumulate in the brain. 相似文献