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41.
Luc Demange Fatma Nait Abdellah Olivier Lozach Yoan Ferandin Nohad Gresh Laurent Meijer Hervé Galons 《Bioorganic & medicinal chemistry letters》2013,23(1):125-131
Cyclin dependent kinase 5 (CDK5) is a serine/threonine kinase belonging to the cyclin dependent kinase (CDK) family. CDK5 is involved in numerous neuronal diseases (including Alzheimer’s or Parkinson’s diseases, stroke, traumatic brain injury), pain signaling and cell migration. In the present Letter, we describe syntheses and biological evaluations of new 2,6,9-trisubstituted purines, structurally related to roscovitine, a promising CDK inhibitor currently in clinical trials (CDK1/Cyclin B, IC50 = 350 nM; CDK5/p25, IC50 = 200 nM). These new molecules were synthesized using an original Buchwald–Hartwig catalytic procedure; several compounds (3j, 3k, 3l, 3e, 4k, 6b, 6c) displayed potent kinase inhibitory potencies against CDK5 (IC50 values ranging from 17 to 50 nM) and showed significant cell death inducing activities (IC50 values ranging from 2 to 9 μM on SH-SY5Y). The docking of the inhibitors into the ATP binding domain of the CDK5 catalytic site highlighted the discriminatory effect of a hydrogen bond involving the CDK5 Lys-89. In addition, the calculated final energy balances for complexation measured for several inhibitors is consistent with the ranking of the IC50 values. Lastly, we observed that several compounds exhibit submicromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (3g, 3h, 4m; IC50 values ranging from 300 to 400 nM). 相似文献
42.
The effects of intraventricular carbachol injections on the free-running activity rhythm of the hamster 总被引:2,自引:0,他引:2
The effects of light on the circadian pacemaker in the suprachiasmatic nucleus (SCN) are mediated by the retinohypothalamic tract (RHT) and by the retinogeniculosuprachiasmatic tract (RGST). The neurotransmitter of the RGST is neuropeptide Y. The RHT may contain glutamate and aspartate. Recent evidence indicates that acetylcholine could also be involved in phase shifting by light. We determined that intraventricular injections with an acetylcholine agonist, carbachol, induces phase advances during the subjective day and phase delays during the early subjective night. No differences were observed between phase shifts induced in constant darkness and those induced in continuous light. A dose-response curve for carbachol was described at circadian time 6 (CT6). Injections at CT14 with various dosages of carbachol indicated the same dose dependency for this circadian time. Finally, carbachol injections in split animals resulted in similar responses of the two components of the split activity rhythm. 相似文献
43.
44.
The suprachiasmatic nuclei (SCN) of the mammalian hypothalamus are in important circadian pacemaker. The electrical activity of these nuclei exhibits an intrinsic circadian rhythm. The rhythmicity of the SCN is also reflected in cyclic glucose consumption and serotonin metabolism. These rhythms are entrained to the light-dark cycle via the retinohypothalamic projection. This pathway, possibly together with a visual projection via the ventral lateral geniculate nuclei, innervates light-responsive SCN cells, which exhibit the functional properties of luminance detectors. The SCN contain various peptides, acetylcholine, and serotonin either intrinsically or in terminals of afferent projections. For acetylcholine it has been demonstrated that the SCN mediate the process of photic entrainment and light suppression of pineal synthetic activity. In the case of serotonin and vasopressin it seems certain that the SCN do not depend on their presence for generating circadian rhythms or for entrainment. Both substances may modulate the intrinsic pacemaker frequency through mechanisms that remain to be established. 相似文献
45.
Methods used to date for the isolation of DNA from polyacrylamide gels are elution based, time-consuming and with low yield in DNA. This paper describes an improved system employing polyacrylamide gels made of a meltable matrix. The new system was successfully applied to in situ DNA footprinting following gel retardation assays. 相似文献
46.
G.W. Meijer J.E.M. Groener A.C. Beynen A. Van Tol 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》1996,114(4):403-407
We investigated the relationship between the development of hypercholesterolemia in rabbits and cholesteryl ester transfer protein (CETP) activity secretion by their perfused livers. Two inbred strains of rabbits were compared which differ markedly in their hypercholesterolemic response to dietary cholesterol. Feeding a high-cholesterol (0.3%) diet, increased plasma and liver cholesterol levels in the two strains, the increments being 15 mM and 30 μmol/g greater in the hyperresponders, respectively. The high-cholesterol diet caused an about 2-fold increased hepatic secretion of CETP activity, but there was no difference between the two rabbit strains. Feeding a lower amount of dietary cholesterol (0.08%) also caused higher cholesterolemic (2 mM) and hepatocholesterolic (28 μmol/g) responses in hyper- than in hyporesponsive rabbits. The activity of hepatic CETP secretion was not increased by the low-cholesterol diet, and there was no difference between hypo- and hyperresponsive rabbits. Cholesterol feeding increased plasma CETP activity by 90% in both rabbit strains, but there was no difference between the strains. Our combined data suggest that with increasing plasma cholesterol levels, hepatic CETP secretion may be increased in a parabolic manner, reaching its maximum rate far before plasma cholesterol concentrations are maximal. There were no differences in hepatic CETP activity secretion or plasma CETP activity levels between the genetically different strains of hypo- and hyperresponsive rabbits. 相似文献
47.
It is evident that parental depressive symptoms negatively influence adolescent behavior and various psychosocial outcomes. Certain family types like families with a chronically ill parent and single parent families are more vulnerable to parental depressive symptoms. However, the relationship between these symptoms, family type, and adolescent functioning remains largely unclear. This study examined relations between self-report of parental depressive symptoms and adolescent functioning in 86 two-parent families including a parent with a chronic medical condition, 94 families with healthy single parents, and 69 families with 2 healthy parents (comparison group). Parents completed the Beck Depression Inventory. Adolescents filled in the Youth Self-Report measuring problem behavior, and other instruments measuring psychosocial outcomes (stress, grade point average, school problems, and self-esteem). Multilevel analyses were used to examine the effects of family type, parental depressive symptoms, adolescents'' gender and age, and interaction effects on adolescent functioning. The results indicated that adolescents with chronically ill and single parents had a lower grade point average (p<.01) than the comparison group. Adolescents of single parents reported more internalizing problems (p<.01) and externalizing problems (p<.05) than children from the other family types. Parental depressive symptoms were strongly related to child report of stress (p<.001). Adolescents of depressed chronically ill parents were particularly vulnerable to internalizing problems (interaction effect, p<.05). Older children and girls, and especially older girls, displayed more internalizing problems and stress. It can be concluded that growing up with a chronically ill parent in a family with 2 parents may have less impact on adolescent problem behavior than growing up in a single parent family. Health practitioners are encouraged to be attentive to the unique and combined influence of family type and parental depressive symptoms on adolescent functioning. Older and female adolescents deserve particular attention. 相似文献
48.
Krens SF He S Lamers GE Meijer AH Bakkers J Schmidt T Spaink HP Snaar-Jagalska BE 《Developmental biology》2008,319(2):370-383
The MAPKs are key regulatory signaling molecules in many cellular processes. Here we define differential functions for ERK1 and ERK2 MAPKs in zebrafish embryogenesis. Morpholino knockdown of ERK1 and ERK2 resulted in cell migration defects during gastrulation, which could be rescued by co-injection of the corresponding mRNA. Strikingly, Erk2 mRNA cross-rescued ERK1 knockdown, but erk1 mRNA was unable to compensate for ERK2 knockdown. Cell-tracing experiments revealed a convergence defect for ERK1 morphants without a severe posterior-extension defect, whereas ERK2 morphants showed a more severe reduction in anterior-posterior extension. These defects were primary changes in gastrulation cell movements and not caused by altered cell fate specification. Saturating knockdown conditions showed that the absence of FGF-mediated dual-phosphorylated ERK2 from the blastula margin blocked initiation of epiboly, actin and tubulin cytoskeleton reorganization processes and further arrested embryogenesis, whereas ERK1 knockdown had only a mild effect on epiboly progression. Together, our data define distinct roles for ERK1 and ERK2 in developmental cell migration processes during zebrafish embryogenesis. 相似文献
49.
L Meijer A R Brash R W Bryant K Ng J Maclouf H Sprecher 《The Journal of biological chemistry》1986,261(36):17040-17047
Oocyte maturation (meiosis reinitiation) in starfish is induced by the natural hormone 1-methyladenine. This induction of meiotic divisions can be triggered also by four fatty acids: 5,8,11-20:3; 5,8,11,14-20:4 (arachidonic acid); 6,9,12,15-20:4; 5,8,11,14,17-20:5, all other fatty acids being completely inactive. This maturation triggered by eicosanoids occurs in the micromolar range and is facilitated by the presence of calcium. A variety of arachidonic acid derivatives (esters, epoxides, etc.) and metabolites (cyclooxygenase and lipoxygenase products) has been tested; the biological activity is restricted to 8-hydroxyeicosatetraenoic acid (8-HETE), other mono- and poly-HETEs being completely inactive. Maturation triggered by 8-HETE occurs around 10 nM and is insensitive to the presence of calcium. 8-HETE methyl ester and 8-hydroperoxyeicosatetraenoic acid are able to induce maturation at higher concentrations. Both (8S) and (8R) stereoisomers have been tested; the biological activity is strictly restricted to the (8R) isomer. 8-HETE triggers a complete maturation, i.e. maturation-promoting factor appearance, germinal vesicle breakdown, emission of the polar bodies, and formation of a female pronucleus. (8R)-HETE, but not (8S)-HETE, triggers the typical decrease in cyclic AMP concentration induced by 1-methyladenine and the burst of protein phosphorylation associated with maturation. Starfish oocytes oxidize exogenous arachidonic acid into 8-HETE and other HETEs. 8-HETE was identified, after high pressure liquid chromatography purification, by gas chromatography mass spectrometry. Furthermore, it was found that the starfish oocytes only produce the (8R)-HETE isomer. This highly stereospecific induction of oocyte maturation by (8R)-HETE suggests that this fatty acid, or a very closely related fatty acid, may play a role in the transduction of the 1-methyladenine message at the plasma membrane level. 相似文献
50.
Ellen A. Meijer Sacco C. de Vries Peter Sterk Dorus W. J. Gadella Jr. Karel W. A. Wirtz Theo Hendriks 《Molecular and cellular biochemistry》1993,123(1-2):159-166
The extracellular protein EP2 was previously identified as non-specific lipid transfer protein based on its cDNA-derived amino acid sequence. Here, the purification of the EP2 protein from the medium of somatic embryo cultures is described. After two cycles of ion-exchange and gel permeation chromatography, a single silver-stained protein band with an apparent molecular mass of 10 kDa was observed on SDS-PAGE. This protein band was recognized by the antiserum raised against a EP2--galactosidase fusion-protein. Employing a fluorescent phospholipid analog, it was shown that the purified EP2 protein is capable of binding phospholipids and is able to enhance their transfer between artificial membranes. Employing a gel permeation assay, it could be demonstrated that the EP2 protein is also capable of binding palmitic and oleic acid as well as oleyl-CoA. Because in plants these fatty acids are used as precursor molecules for cutin, these results are in support of the proposed role of the EP2 protein to transport cutin monomers from their site of synthesis through the cell wall of epidermal cells to sites of cutin polymerization. 相似文献