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101.
Thalia Liargkova Dimitra J. Hadjipavlou-Litina Caterina Koukoulitsa Efstathia Voulgari Constantinos Avgoustakis 《Journal of enzyme inhibition and medicinal chemistry》2016,31(2):302-313
The synthesis, the antioxidative properties and the lipoxygenase (LOX) and acetylcholinesterase (AChE) inhibition of a number of 4-hydroxy-chalcones diversely substituted as well as of a series of bis-chalcones ether derivatives are reported. The chalcones derivatives were readily produced using a Claisen–Schmidt condensation in a ultra sound bath in good yields. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Their lipophilicity is experimentally determined by reversed-phase thin-layer chromatography method. Most of them are potent in vitro inhibitors of lipid peroxidation and of LOX. Compounds b2 and b3 were found to be the most potent LOX and AChE inhibitors among the tested derivatives with a significant anti-lipid peroxidation profile. The results led us to propose these enone derivatives as new multifunctional compounds against Alzheimer's disease. The results are discussed in terms of structural and physicochemical characteristics of the compounds. Moreover, the pharmacokinetic profile of these compounds was investigated using computational methods. 相似文献
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Kristin L. Boswell Robert Paris Eli Boritz David Ambrozak Takuya Yamamoto Sam Darko Kaska Wloka Adam Wheatley Sandeep Narpala Adrian McDermott Mario Roederer Richard Haubrich Mark Connors Julie Ake Daniel C. Douek Jerome Kim Constantinos Petrovas Richard A. Koup 《PLoS pathogens》2014,10(1)
The interaction between follicular T helper cells (TFH) and B cells in the lymph nodes and spleen has a major impact on the development of antigen-specific B cell responses during infection or vaccination. Recent studies described a functional equivalent of these cells among circulating CD4 T cells, referred to as peripheral TFH cells. Here, we characterize the phenotype and in vitro B cell helper activity of peripheral TFH populations, as well as the effect of HIV infection on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we identified a CCR7highCXCR5highCCR6highPD-1high CD4 T cell population that secretes IL-21 and enhances isotype-switched immunoglobulin production. This population is significantly decreased in treatment-naïve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in co-cultures from HIV-infected individuals and found no correlation between the frequency of peripheral TFH cells and memory B cells, or with neutralization activity in untreated HIV infection in our cohort. Furthermore, we found that within the peripheral TFH population, the expression level of TFH-associated genes more closely resembles a memory, non-TFH population, as opposed to a TFH population. Overall, our data identify a heterogeneous population of circulating CD4 T cells that provides in vitro help to B cells, and challenges the origin of these cells as memory TFH cells. 相似文献
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Sasa Vukelic Olivera Stojadinovic Irena Pastar Constantinos Vouthounis Agata Krzyzanowska Sharmistha Das Herbert H. Samuels Marjana Tomic-Canic 《The Journal of biological chemistry》2010,285(3):1980-1988
Farnesyl pyrophosphate (FPP), a key intermediate in the mevalonate pathway and protein farnesylation, can act as an agonist for several nuclear hormone receptors. Here we show a novel mechanism by which FPP inhibits wound healing acting as an agonist for glucocorticoid receptor (GR). Elevation of endogenous FPP by the squalene synthetase inhibitor zaragozic acid A (ZGA) or addition of FPP to the cell culture medium results in activation and nuclear translocation of the GR, a known wound healing inhibitor. We used functional studies to evaluate the effects of FPP on wound healing. Both FPP and ZGA inhibited keratinocyte migration and epithelialization in vitro and ex vivo. These effects were independent of farnesylation and indicate that modulation of FPP levels in skin may be beneficial for wound healing. FPP inhibition of keratinocyte migration and wound healing proceeds, in part, by repression of the keratin 6 gene. Furthermore, we show that the 3-hydroxy-3-methylglutaryl-CoA-reductase inhibitor mevastatin, which blocks FPP formation, not only promotes epithelialization in acute wounds but also reverses the effect of ZGA on activation of the GR and inhibition of epithelialization. We conclude that FPP inhibits wound healing by acting as a GR agonist. Of special interest is that FPP is naturally present in cells prior to glucocorticoid synthesis and that FPP levels can be further altered by the statins. Therefore, our findings may provide a better understanding of the pleiotropic effects of statins as well as molecular mechanisms by which they may accelerate wound healing. 相似文献
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Paspalas Constantinos Gerics Balázs Halasy Katalin Papadopoulos Georgios Hajós Ferenc 《Brain Cell Biology》2000,29(8):541-549
Light microscopic analysis of the rat midbrain periaqueductal grey (PAG) showed vasoactive intestinal polypeptide immunoreactive (VIP-ir) neurons localized at the lateral and ventral walls of the aqueduct. Some varicose VIP-ir elements were detected closely associated with the ependyma. While several VIP-ir elements were encountered immediately under the ependyma, in a few cases, VIP-ir cell bodies were seen on the luminal surface of the ependymal cells lining the aqueduct. Electron microscopy revealed that most of these cells possessed the characteristics of a local circuit neuron. All VIP-ir cells had indented nuclei. Two types were distinguished: one with rounded cell body receiving numerous axo-somatic synapses established by VIP-negative axons. The other cell type was fusiform and its surface was almost fully isolated from axonal contacts by a glial sheath. The VIP-ir processes were interconnected with other periaqueductal cells by a variety of synaptic contacts. VIP-ir axon terminals formed asymmetric synapses with immunonegative dendritic shafts often in glomerulus-like assemblies. The postsynaptic immunonegative dendrites were of the aspinous, beaded type. We suggest that VIP-ir cells and processes in the midbrain PAG establish connections between the longitudinal functional columns of this region. On the basis of their morphology, VIP-ir cells in the PAG appear to be excitatory, terminating on inhibitory interneurons. Thus, a VIP-stimulated inhibition may be instrumental in the coordination of responses evoked by the stimulation of PAG columns. 相似文献