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71.
David?J?MellorEmail author Robert?A?Cummins Evelyn?Karlinski Shane?P?Storer 《Health and quality of life outcomes》2003,1(1):39
Background
This study tested the homeostatic model of subjective quality of life in a group of 47 short stay patients as they progressed through the stages of hospitalization for surgery. 相似文献72.
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Cummins LL Chen S Blyn LB Sannes-Lowery KA Drader JJ Griffey RH Hofstadler SA 《Journal of natural products》2003,66(9):1186-1190
In this work we describe a high-throughput screening approach based on electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR) that rapidly interrogates the noncovalent interaction between RNA-based drug targets and components derived from a bacterial natural product library. The screening process detects molecules present in the natural product library that bind to a synthetic RNA target that mimics the prokaryotic 16S rRNA A-site, while simultaneously measuring specificity for the synthetic A-site target using a control RNA target that lacks the critical structural element of the A-site construct. This screening approach known as multitarget affinity/specificity screening (MASS) demonstrated the expected binding of paromomycin from a fractionated natural product library derived from Streptomyces rimosus sp. paromomycinus. A new molecule was observed to bind with specificity to the 16S A-site RNA construct. MS/MS characterization of this species yielded partial structural information suggesting it is an aminoglycoside consisting of a paromomycin core with one or more modified rings. This work demonstrates the tremendous utility of MASS for screening natural product fractions against macromolecular targets. 相似文献
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The built environment embraces a wide range of concepts, from the design and integrity of housing, to land-use urban planning. A high-quality environment is essential for children to achieve optimal health and development. Building and land-use policies, including the quality and design of a child's physical environment, can cause or prevent illness, disability, and injury, and can degrade or preserve natural resources. Though many common pediatric conditions such as obesity, asthma, and lead poisoning, as well as injuries, are associated with risk factors within a child's built environment, this issue has received little attention from researchers or policymakers. This new field is ripe for etiologic and prevention research, and we need pediatric advocates to speak out for children's needs within this arena. 相似文献
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The considerable overlap in the substrate selectivity and tissue localization of CYP3A and P-glycoprotein has led to the hypothesis that this transporter and enzyme pair act as a coordinated absorption barrier against xenobiotics. A historical perspective on the investigation of this interactive alliance is given, starting from the understanding of the role of intestinal metabolism in explaining cyclosporine clinical data. Several animal studies using mdr1a-/- knockout mice have demonstrated P-glycoprotein's importance in limiting drug absorption and decreasing bioavailability. Human clinical studies investigating the importance of intestinal CYP3A and P-glycoprotein through inhibition or induction of these proteins have provided further evidence of this interaction. Recent in vitro studies using CYP3A4-expressing Caco-2 cells are reported. These studies reveal that the role of P-glycoprotein in the intestine extends beyond simply limiting parent drug absorption but also includes increasing the access of drug to metabolism by CYP3A through repeated cycles of absorption and efflux. 相似文献
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Purpose. To examine the changes in expression levels of CYP3A4 and efflux transporters in CYP3A4-transfected Caco-2 (colon carcinoma) cells in the presence of the inducers sodium butyrate (NaB) and 12-O-tetradecanoylphorbol-13-acetate (TPA). To characterize the transport of [3H]-digoxin and the metabolism of midazolam in the cells under different inducing conditions.
Methods. CYP3A4-Caco-2 cells were seeded onto cell culture inserts and were grown for 13-14 days. Transport and metabolism studies were performed on cells induced with NaB and/or TPA for 24 h. The expression and localization of P-gp, MRP1, MRP2, and CYP3A4 were examined by Western blot and confocal microscopy.
Results. In the presence of both inducers, CYP3A4 protein levels were increased 40-fold over uninduced cells, MRP2 expression was decreased by 90%, and P-gp and MRP1 expression were unchanged. Midazolam 1-OH formation exhibited a rank order correlation with increased CYP3A4 protein, whereas [3H]-digoxin transport (a measure of P-gp activity) was unchanged with induction. P-gp and MRP2 were found on the apical membrane, whereas MRP1 was found peri-nuclear within the cell. CYP3A4 displayed a punctate pattern of expression consistent with endoplasmic reticulum localization and exhibited preferential polarization towards the apical side of the cell.
Conclusions. The present study characterized CYP3A4-Caco-2 cell monolayers when induced for 24 h in the presence of both NaB and TPA. These conditions provide intact cells with significant CYP3A4 and P-gp expression suitable for the concurrent study of transport and metabolism. 相似文献
79.
Waxman SG Cummins TR Dib-Hajj SD Black JA 《Journal of rehabilitation research and development》2000,37(5):517-528
Pain pathways begin with spinal sensory (dorsal root ganglion, DRG) neurons that produce nociceptive signals and convey them centrally. Following injury to the nervous system, DRG neurons can become hyperexcitable, generating spontaneous action potentials or abnormal high-frequency activity that contributes to chronic pain. Because the generation of action potentials in DRG neurons depends on voltage-gated sodium channels, an understanding of the expression and function of these channels in DRG neurons is important for an understanding of pain. Molecular studies have indicated that at least eight distinct voltage-gated sodium channels, sharing a common overall motif but encoded by different genes that endow them with different amino acid sequences, are present within the nervous system. The DRG neurons express six different sodium channels, including several sensory-neuron-specific sodium channels that are not present at significant levels within other parts of the nervous system. Following injury to their axons within peripheral nerve, DRG neurons down-regulate some sodium channel genes, and up-regulate others. As a result, a different repertoire of sodium channels is inserted into the DRG neuron cell membrane following injury, which is a molecular change that is accompanied by changes in physiological properties that contribute to hyperexcitability in these cells. Sodium channel expression is also altered in experimental models of inflammatory pain. The multiplicity of sodium channels, and the dynamic nature of their expression, makes them important targets for pharmacologic manipulation in the search for new therapies for pain. 相似文献
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