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981.
The identification of 2'-O-methyl substituted adenosine-3',5'-cyclic monophosphate (cAMP) analogs that activate the Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs, also known as Epac1 and Epac2), has ushered in a new era of cyclic nucleotide research in which previously unrecognized signalling properties of the second messenger cAMP have been revealed. These Epac-Selective Cyclic AMP Analogs (ESCAs) incorporate a 2'-O-methyl substitution on the ribose ring of cAMP, a modification that impairs their ability to activate protein kinase A (PKA), while leaving intact their ability to activate Epac (the Exchange Protein directly Activated by Cyclic AMP). One such ESCA in wide-spread use is 8-pCPT-2'-O-Me-cAMP. It is a cell-permeant derivative of 2'-O-Me-cAMP, and it is a super activator of Epac. A wealth of newly published studies demonstrate that 8-pCPT-2'-O-Me-cAMP is a unique tool with which to asses atypical actions of cAMP that are PKA-independent. Particularly intriguing are recent reports demonstrating that ESCAs reproduce the PKA-independent actions of ligands known to stimulate Class I (Family A) and Class II (Family B) GTP-binding protein-coupled receptors (GPCRs). This topical review summarizes the current state of knowledge regarding the molecular pharmacology and signal transduction properties of Epac-selective cAMP analogs. Special attention is focused on the rational drug design of ESCAs in order to improve their Epac selectivity, membrane permeability, and stability. Also emphasized is the usefulness of ESCAs as new tools with which to assess the role of Epac as a determinant of intracellular Ca2+ signalling, ion channel function, neurotransmitter release, and hormone secretion. 相似文献
982.
Cavani L Trubetskaya O Grigatti M Trubetskoj O Ciavatta C 《Bioresource technology》2008,99(10):4360-4367
Humic acids (HA)-like extracted from compost at the beginning (t(0)) and after 130 days of composting (t(130)) were fractionated by coupling size exclusion chromatography to polyacrylamide gel electrophoresis (SEC-PAGE). HA-like fractions with the same molecular size (MS) and electrophoretic mobility were pooled and further characterised by analytical polyacrylamide gel electrofocusing (EF) and compared with HA separated from a Typic Chernozem soil. During the composting process all fractions were subjected to quantitative and qualitative modifications: the high MS fraction was degraded, the mid MS fractions were qualitatively changed, the content of low MS fractions increased and changed qualitatively. The main changes in EF pattern of the non fractionated HA-like t(130) were associated to low MS fractions. Such data seem to be reliable for explanation what mechanisms and monitoring of the evolution of the compost organic matter for their agricultural uses. 相似文献
983.
Vovk AI Mischenko IM Tanchuk VY Kachkovskii GA Sheiko SY Kolodyazhnyi OI Kukhar VP 《Bioorganic & medicinal chemistry letters》2008,18(16):4620-4623
The inhibition effects of enantiomerically pure alpha-(N-benzylamino)benzylphosphonic acids and their derivatives on human prostatic acid phosphatase have been investigated. As expected, (R)-alpha-(N-benzylamino)benzylphosphonic acid demonstrated higher affinity for the enzyme than (S)-enantiomer. At the same time, (1R,2S)-phenyl[(1-phenylethyl)amino]methylphosphonic acid was found to be a significantly weaker inhibitor than its (1S,2R)-analogue. The enantioselectivity has been explained using a molecular modeling approach by computational docking of inhibitors into active center of prostatic acid phosphatase. 相似文献
984.
Mackman RL Lin KY Boojamra CG Hui H Douglas J Grant D Petrakovsky O Prasad V Ray AS Cihlar T 《Bioorganic & medicinal chemistry letters》2008,18(3):1116-1119
Modified purine analogs of GS-9148 [5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid (2'-Fd4AP) were synthesized and their anti-HIV potency evaluated. The antiviral activity of guanosine analog (2'-Fd4GP) was comparable that of to 2'-Fd4AP in MT-2 cells, but selectivity was reduced. 相似文献
985.
Erdmann J Kallabis B Oppel U Sypchenko O Wagenpfeil S Schusdziarra V 《American journal of physiology. Endocrinology and metabolism》2008,294(3):E568-E575
Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m(2) BMI within 4(1/2) mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher post-weight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively. 相似文献
986.
987.
High-resolution array comparative genomic hybridization of single micrometastatic tumor cells 总被引:1,自引:0,他引:1
Fuhrmann C Schmidt-Kittler O Stoecklein NH Petat-Dutter K Vay C Bockler K Reinhardt R Ragg T Klein CA 《Nucleic acids research》2008,36(7):e39
Only few selected cancer cells drive tumor progression and are responsible for therapy resistance. Their specific genomic characteristics, however, are largely unknown because high-resolution genome analysis is currently limited to DNA pooled from many cells. Here, we describe a protocol for array comparative genomic hybridization (array CGH), which enables the detection of DNA copy number changes in single cells. Combining a PCR-based whole genome amplification method with arrays of highly purified BAC clones we could accurately determine known chromosomal changes such as trisomy 21 in single leukocytes as well as complex genomic imbalances of single cell line cells. In single T47D cells aberrant regions as small as 1–2 Mb were identified in most cases when compared to non-amplified DNA from 106 cells. Most importantly, in single micrometastatic cancer cells isolated from bone marrow of breast cancer patients, we retrieved and confirmed amplifications as small as 4.4 and 5 Mb. Thus, high-resolution genome analysis of single metastatic precursor cells is now possible and may be used for the identification of novel therapy target genes. 相似文献
988.
Amphiphysin is a component of clathrin coats formed during synaptic vesicle recycling at the lamprey giant synapse 总被引:2,自引:0,他引:2
Evergren E Marcucci M Tomilin N Löw P Slepnev V Andersson F Gad H Brodin L De Camilli P Shupliakov O 《Traffic (Copenhagen, Denmark)》2004,5(7):514-528
Amphiphysin is a protein enriched at mammalian synapses thought to function as a clathrin accessory factor in synaptic vesicle endocytosis. Here we examine the involvement of amphiphysin in synaptic vesicle recycling at the giant synapse in the lamprey. We show that amphiphysin resides in the synaptic vesicle cluster at rest and relocates to sites of endocytosis during synaptic activity. It accumulates at coated pits where its SH3 domain, but not its central clathrin/AP-2-binding (CLAP) region, is accessible for antibody binding. Microinjection of antibodies specifically directed against the CLAP region inhibited recycling of synaptic vesicles and caused accumulation of clathrin-coated intermediates with distorted morphology, including flat patches of coated presynaptic membrane. Our data provide evidence for an activity-dependent redistribution of amphiphysin in intact nerve terminals and show that amphiphysin is a component of presynaptic clathrin-coated intermediates formed during synaptic vesicle recycling. 相似文献
989.
990.