3-(3,4,5-Trimethoxyphenyl)-1-oxo-2-propene: a novel pharmacophore displaying potent multidrug resistance reversal and selective cytotoxicity

This study revealed that various alicyclic and acyclic compounds containing the 3-(3,4,5-trimethoxyphenyl)-2-propenoyl group displayed potent MDR reversal properties. In particular, a concentration of 4 microg/ml of 2,5-bis(3,4,5-trimethoxyphenylmethylene)cyclopentanone was 31 times more potent than verapamil as a MDR revertant. In general, they were selectively toxic to malignant rather than normal cells. Two representative compounds induced apoptosis in human HL-60 cells and markedly activated caspase-3.     

Engaging neuroscience to advance translational research in brain barrier biology

The delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by brain barriers, of which the most well known are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Recent studies have shown numerous additional roles of these barriers, including an involvement in neurodevelopment, in the control of cerebral blood flow, and--when barrier integrity is impaired--in the pathology of many common CNS disorders such as Alzheimer's disease, Parkinson's disease and stroke.     

Dynamics of isolated <Emphasis Type="Italic">Saponaria bellidifolia</Emphasis> Sm. populations at northern range periphery

Four populations of Saponaria bellidifolia situated at the species’ northern range periphery (Apuseni Mountains, southeastern Carpathians) were monitored over a period of 5 years. They were chosen to represent different habitat types (rocky, fixed screes, open screes and grassy), disturbance regime (fire), and population sizes (categorized as large and small). The reproductive effort was quantified, and matrix models were used to describe the population dynamics and to assess population viability. Saponaria bellidifolia had very stable population dynamics in the harsh and stable abiotic conditions of the outcrops where populations occur. Habitat conditions exerted a notable influence on the species’ population reproductive performance, growth rate, and vital rates, whereas population size and climate did not have a clear-cut effect on the dynamics of the species. Saponaria bellidifolia maintains viable populations in the southeastern Carpathians, at its northern range periphery.     

Lateral entorhinal cortex lesions rearrange afferents, glutamate receptors, increase seizure latency and suppress seizure-induced c-fos expression in the hippocampus of adult rat

The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurones in chronic epilepsy. Here we analysed the effects of one-sided lateral EC (LEC) and temporoammonic (alvear) path lesion on the development and properties of 4-aminopyridine-induced seizures. Electroencephalography (EEG) analysis of freely moving rats identified that the lesion increased the latency of the hippocampal seizure significantly and decreased the number of brief convulsions. Seizure-induced neuronal c-fos expression was reduced in every hippocampal area following LEC lesion. Immunocytochemical analysis 40 days after the ablation of the LEC identified sprouting of cholinergic and calretinin-containing axons into the dentate molecular layer. Region and subunit specific changes in the expression of ionotropic glutamate receptors (iGluRs) were identified. Although the total amount of AMPA receptor subunits remained unchanged, GluR1(flop) displayed a significant decrease in the CA1 region. An increase in NR1 and NR2B N-methyl-d-aspartate (NMDA) receptor subunits and KA-2 kainate receptor subunit was identified in the deafferented layers of the hippocampus. These results further emphasize the importance of the lateral entorhinal area in the spread and regulation of hippocampal seizures and highlight the potential role of the rewiring of afferents and rearrangement of iGluRs in the dentate gyrus in hippocampal convulsive activity.     

Serotonin-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue culture

The effects of serotonin (5-hydroxytryptamine; 5-HT) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay after a 1 or 2 h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following 5-HT administration, depending on the 5-HT dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the 5-HT antagonist ketanserin or metergoline. WAY-100635 did not influence the increased VP secretion induced by 5-HT, but the elevated OT production was prevented by WAY-100635 before 5-HT administration. The application of WAY-100635, ketanserin or metergoline, after 5-HT administration proved ineffective. The results indicate that NH hormone release is influenced directly by the serotonergic system. The serotonergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.     

Isolation and structure elucidation of anhydroluteins from cooked sorrel (Rumex rugosus Campd.)

Anhydrolutein I (= (all-E,3R,6'R)-3',4'-didehydro-beta,gamma-caroten-3-ol; 2) and anhydrolutein II (= (all-E, 3R,6'S)-2',3'-didehydro-beta,epsilon-caroten-3-ol; 3) have been isolated and characterized from the extract of steam-cooked sorrel. The presence of these compounds in cooked vegetable is postulated to be due to acid-catalyzed dehydration of lutein (1; Scheme). The structures of the isolated anhydroluteins were established by UV/VIS, CD, and 1H-NMR spectroscopy, and mass spectrometry.     

Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators

Lipid homeostasis is controlled by various nuclear receptors (NRs), including the peroxisome proliferator-activated receptors (PPARalpha, delta, and gamma), which sense lipid levels and regulate their metabolism. Here we demonstrate that human PPARs have a high basal activity and show ligand-independent coactivator (CoA) association comparable with the NR constitutive androstane receptor. Using PPARgamma as an example, we found that four different amino acid groups contribute to the ligand-independent stabilization of helix 12 of the PPAR ligand-binding domain. These are: (i) Lys329 and Glu499, mediating a charge clamp-type stabilization of helix 12 via a CoA bridge; (ii) Glu352, Arg425, and Tyr505, directly stabilizing the helix via salt bridges and hydrogen bonds; (iii) Lys347 and Asp503, interacting with each other as well as contacting the CoA; and (iv) His351, Tyr(355), His477, and Tyr501, forming a hydrogen bond network. These amino acids are highly conserved within the PPAR subfamily, suggesting that the same mechanism may apply for all three PPARs. Phylogenetic trees of helix 12 amino acid and nucleotide sequences of all crystallized NRs and all human NRs, respectively, indicated a close relationship of PPARs with constitutive androstane receptor and other constitutive active members of the NR superfamily. Taking together, the ligand-independent tight control of the position of the PPAR helix 12 provides an effective alternative for establishing an interaction with CoA proteins. This leads to high basal activity of PPARs and provides an additional view on PPAR signaling.     

Novel approaches to the syntheses of N-substituted S-glycosyl-sulfenamides

Bis(tetra-O-acetyl-beta-D-glucopyranosyl)disulfide reacts, under silver ion activation, with primary and secondary aliphatic as well as aromatic amines to furnish the title compounds in moderate to good yields. The same derivatives could also be obtained from (tetra-O-acetyl)-beta-D-glucopyranosyl methanethiolsulfonate 1 by nucleophilic substitution with amines. It was shown that the polarization of the S-S-bond in 1 is enhanced by Ag+ so as to allow reaction with sterically hindered amines as well.