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排序方式: 共有426条查询结果,搜索用时 31 毫秒
381.
Kung DW Coffey SB Jones RM Cabral S Jiao W Fichtner M Carpino PA Rose CR Hank RF Lopaze MG Swartz R Chen HT Hendsch Z Posner B Wielis CF Manning B Dubins J Stock IA Varma S Campbell M DeBartola D Kosa-Maines R Steyn SJ McClure KF 《Bioorganic & medicinal chemistry letters》2012,22(13):4281-4287
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds. 相似文献
382.
Somjen D Katzburg S Posner GH Livne E Kaye AM 《Journal of cellular biochemistry》2007,100(6):1406-1414
We demonstrated previously that daily injection for 3 days of the less calcemic vitamin D analogs: JK 1624 F(2)-2 (JKF) and QW 1624F(2)-2 (QW) followed by estradiol-17beta (E(2)) in female rats upregulated creatine kinase-specific activity (CK) in skeletal tissues. In this study, we evaluated both histomorphological and biochemical changes due to a regime of 4 days treatment with JKF or QW, followed by injection of E(2) on day 5, repeated for 2.5 months. Ovariectomized female rats (Ovx) were injected 2 weeks after surgery, with JKF or QW at 0.2 ng/g BW followed by injections of E(2) (1 microg/rat) on day 5 of each week for 2.5 months. Rats were sacrificed 24 h after the last injection and bones were analyzed. JKF alone decreased growth plate width, increased % total bone volume (%TBV), with no change in cortical thickness. In contrast, QW restored growth plate width and %TBV with no change in cortical thickness. Combined with E(2), JKF restored %TBV and growth plate width but with no change in cortical thickness, while QW restored significantly all parameters including cortical thickness. Moreover, there was also an increase in the responsiveness of CK to E(2) in epiphyseal cartilage and diaphyseal bone but not in uterus. Thus, vitamin D less calcemic analogs increased responsiveness to E(2) morphologically as well as biochemically. We, therefore, conclude that combined treatment of less calcemic analogs vitamin D and E(2) might be superior for treatment of bone damage caused by ovariectomy in female rats and might be applied for post-menopausal osteoporosis. 相似文献
383.
Zhang J Posner GH Danilenko M Studzinski GP 《The Journal of steroid biochemistry and molecular biology》2007,105(1-5):140-149
Low calcemic analogs of vitamin D are candidates for differentiation therapy of human myeloid leukemias. We report here that the seco-steroid synthesized to have resistance to intracellular degradation and low calcemia-inducing activity, 1alpha-hydroxymethyl-3beta-16-ene-24,24-difluoro-25-hydroxy-vitamin D3 (JKF), induces monocytic differentiation in four established human myeloid leukemia cell lines, HL60, U937, THP-1, NB-4, and murine myeloid leukemia cells WEHI-3B D−. JKF has differentiation-inducing potency which is slightly lower than the physiologically active form of vitamin D, 1,25(OH)2vitamin D3 (1,25D). However, simultaneous addition of carnosic acid (CA), an antioxidant, and SB20190 (SB), an inhibitor of p38MAP kinase, increases the differentiation efficiency of JKF to a level similar to the level observed when 1,25D is used in such combinations. We also show for the first time that SB inhibits the phosphorylation of MAPKAPK2, a downstream target of p38MAPK, but upregulates the phosphorylation of at least one of the isoforms of JNK (p46 JNK1) and of c-jun in all four human myeloid cell lines studied here. These studies indicate that the JNK1 pathway is positively associated with monocytic differentiation of several subtypes of myeloid leukemia cells arrested at different developmental stages. Further, since JKF is less calcemic than 1,25D, the data suggest that JKF combined with CA and SB is likely to have a therapeutic advantage over 1,25D-based experimental regimens for myeloid leukemias. 相似文献
384.
Patrick Knott Eden Pappo Michelle Cameron JC deMauroy Charles Rivard Tomasz Kotwicki Fabio Zaina James Wynne Luke Stikeleather Josette Bettany-Saltikov Theodoros B Grivas Jacek Durmala Toru Maruyama Stefano Negrini Joseph P O’Brien Manuel Rigo 《Scoliosis》2014,9(1):1-9
This 2012 Consensus paper reviews the literature on side effects of x-ray exposure in the pediatric population as it relates to scoliosis evaluation and treatment. Alternative methods of spinal assessment and imaging are reviewed, and strategies for reducing the number of radiographs are developed. Using the Delphi technique, SOSORT members developed consensus statements that describe how often radiographs should be taken in each of the pediatric and adolescent sub-populations. 相似文献
385.
Somjen D Katzburg S Kohen F Gayer B Sharon O Hendel D Posner GH Kaye AM 《The Journal of steroid biochemistry and molecular biology》2006,98(2-3):139-146
We have reported previously, that female-derived bone cells responded to 17beta-estradiol (E(2)) and raloxifene (Ral), and male-derived cells responded only to dihydrotestosterone (DHT) when the stimulation of creatine kinase specific activity (CK), which is a marker for hormone responsiveness, was measured. We also found that pre-treatment with the less-calcemic analog of Vitamin D, JK 1624 F(2)-2 (JKF), upregulated the response of CK to E(2) and Ral. In this study, we analyzed the response of human bone cells from pre- and post-menopausal females and males, to phytoestrogens. Bone cells derived from pre-menopausal women showed greater stimulation of CK than cells from post-menopausal women, after treatment with E(2) (30 nM), daidzein (D, 3000 nM), genistein (G, 3000 nM) and Ral (3000 nM); whereas the responses to biochainin A (BA 3000 nM), quecertin (Qu 3000 nM) or the carboxy derivative of G (cG 300 nM) were not age-dependent. Male-derived cells did not respond to phytoestrogens. When cells derived from female bones at both age groups were pre-treated with JKF, by daily addition of 1nM, for 3 days, there was an upregulation of the response to E(2), Ral, G and D but not to BA or Qu. Nuclear binding of (3)[H] E(2) was characteristic of the different phytoestrogens, with increase of the specific binding after pre-treatment with JKF. In contrast, the membranal binding of E(2)-Ov-Eu, which was specific for the estrogenic compounds except Ral, was inhibited by pre-treatment with JKF except for ICI 161480 (ICI). Male bone cells did not bind E(2)-Ov-Eu but bound T-BSA-Eu; this binding was abolished by pre-treatment with JKF. Pre-treatment with JKF increased mRNA for ERalpha and decreased mRNA for ERbeta in bone cells from both age groups of females and from males, all of which expressed both ERs, with a ratio of ERalpha to ERbeta of 121:1 in pre- and 78:1 in post-menopausal and 105:1 in male bone cells. This study raises the possibility of combined Vitamin D analog and phytoestrogen for hormonal replacement therapy to prevent post-menopausal osteoporosis, which is a subject of ongoing research in animal models. 相似文献
386.
Joshua Colvin Michael I Monine Ryan N Gutenkunst William S Hlavacek Daniel D Von Hoff Richard G Posner 《BMC bioinformatics》2010,11(1):404
Background
The system-level dynamics of many molecular interactions, particularly protein-protein interactions, can be conveniently represented using reaction rules, which can be specified using model-specification languages, such as the BioNetGen language (BNGL). A set of rules implicitly defines a (bio)chemical reaction network. The reaction network implied by a set of rules is often very large, and as a result, generation of the network implied by rules tends to be computationally expensive. Moreover, the cost of many commonly used methods for simulating network dynamics is a function of network size. Together these factors have limited application of the rule-based modeling approach. Recently, several methods for simulating rule-based models have been developed that avoid the expensive step of network generation. The cost of these "network-free" simulation methods is independent of the number of reactions implied by rules. Software implementing such methods is now needed for the simulation and analysis of rule-based models of biochemical systems. 相似文献387.
A nuclear gene for higher level phylogenetics: phosphoenolpyruvate carboxykinase tracks mesozoic-age divergences within Lepidoptera (Insecta) 总被引:3,自引:0,他引:3
The sequence of phosphoenolpyruvate carboxykinase (PEPCK) has been
previously identified as a promising candidate for reconstructing
Mesozoic-age divergences (Friedlander, Regier, and Mitter 1992, 1994). To
test this hypothesis more rigorously, 597 nucleotides of aligned PEPCK
coding sequence (approximately 30% of the coding region) were generated
from 18 species representing Mesozoic-age lineages of moths (Insecta:
Lepidoptera) and outgroup taxa. Relationships among basal Lepidoptera are
well established by morphological analysis, providing a strong test for the
utility of a gene which has not previously been used in systematics.
Parsimony and other phylogenetic analyses were conducted on nucleotides by
codon positions (nt1, nt2, nt3) separately and in combination, and on amino
acids, for comparison to the test phylogeny. The highest concordance was
achieved with nt1 + nt2, for which one of two most-parsimonious trees was
identical to the test phylogeny, and with all nucleotides when nt3 was
down-weighted sevenfold or higher, for which a single most-parsimonious
tree identical to the test phylogeny resulted. Substitutions in nt3
approached saturation in many, but not all, pairwise comparisons and their
exclusion or severe downweighting greatly increased the degree of
concordance with the test phylogeny. Neighbor-joining analysis confirms
this finding. The utility of PEPCK for phylogenetics is demonstrated over a
time span for which few other suitable genes are currently available.
相似文献
388.
I Posner J DeSanctis 《Comparative biochemistry and physiology. B, Comparative biochemistry》1987,87(1):137-141
The effects of bovine serum albumin on rat pancreatic lipase and bovine milk lipoprotein lipase were studied in a system of triacylglycerol emulsions stabilized by 1 1 mg/ml albumin. At concentrations greater than 1 mg/ml, albumin inhibited the activity of pancreatic lipase and interfered with enzyme binding to emulsified triacylglycerol particles. These effects could be countered by occupying five fatty acid binding sites on albumin with oleic acid. Following an initial lag period which increased with albumin concentrations, enzyme activity escaped from inhibition presumably due to saturation of fatty acid sites on albumin with oleic acid. Pancreatic lipase was active at 1 mg/ml albumin and 1 mM emulsion-bound oleic acid in the system. The effects of albumin on lipoprotein lipase were diametrically opposed to the above; enzyme activity was completely inhibited by 0.1 mM oleic acid, it increased with increasing fatty acid-free albumin concentrations and decreased as the fatty acid sites on albumin were filled. At 1 mM oleic acid and no added albumin the enzyme failed to bind at the oil water interface, whereas fatty acid-free or saturated albumin had no effect on binding. It is concluded that if the inhibition of pancreatic lipase by albumin is due to the inaccessibility of the enzyme to an oil-water interface blocked by denatured albumin, then albumin saturated with oleic acid would seem to be protected from unfolding at the interface and more readily displaced by the lipase. Pancreatic lipase and lipoprotein lipase, although sharing a number of common features, are distinct enzymes both functionally and mechanistically. 相似文献
389.
390.