Prodrug and covalent linker strategies for the solubilization of dual-action antioxidants/iron chelators

Water soluble prodrugs of hybrid free radical scavenger/iron chelating molecules, based on 3,5-disubstituted-4-hydroxyphenyl derivatives and 3-hydroxy-2-methyl-4(1H)-pyridinone (deferiprone), have been prepared. Related hybrid molecules containing a covalent poly(ethylene)glycol or an amine linker were also synthesized.     

On the potential of fatty acids as trophic markers in Arctic grazers: feeding experiments with sea urchins and amphipods fed nine diets of macroalgae

To elucidate dietary preferences of benthic grazers at the Arctic Kongsfjorden by means of fatty acid trophic markers, ten different parallel treatments (starvation, 3 species of red macroalgae, 4 species of brown macroalgae and 2 species of green macroalgae) were offered as mono-algal diet to specimens of the dominant sea urchin Strongylocentrotus droebachiensis (Echinodermata, Echinoidea) and the gammarid amphipod Gammarellus homari (Crustacea, Amphipoda). At the end of the 3-week feeding experiments, amphipods and sea urchins (soft tissue) were deep-frozen and analysed for total lipid contents as well as fatty acid (FA) compositions. In addition, FA profiles of the algal species were determined and screened for specific FA patterns or single FAs qualifying as potential trophic markers in the grazers. Despite their diets of nine algal species with different FA compositions, FA patterns of the sea urchins and amphipods revealed a pronounced similarity between treatments. This strong similarity was also observed in the faecal pellets of the sea urchins. Hence, deviating FA compositions of the macroalgae were neither reflected in the FA patterns of the grazers’ tissue nor in their faecal pellets. Suitable algal FA trophic markers could thus not be identified in the two grazers from Kongsfjorden. The rather low lipid levels, especially in the amphipods, as well as a pronounced degradation and modification of FAs may explain that the FA trophic marker approach did not provide evidence of dietary preferences. Future experiments may obtain a higher resolution of potential FA trophic markers by analysing separate lipid classes or single tissues of lipid-poor grazers. Alternatively, different methods are needed to reveal high-resolution trophic relationships between macroalgae and herbivores in Kongsfjorden.     

Nutritional status, dietary intake and oral quality of life in elderly complete denture wearers

doi: 10.1111/j.1741‐2358.2011.00545.x Nutritional status, dietary intake and oral quality of life in elderly complete denture wearers Background and objective: The prevalence of malnutrition increases with age because of many factors. Edentulousness leads to the avoidance of many types of foods. The aim of this study was to determine whether elderly complete denture wearers have a higher risk of malnutrition than dentate controls. Material and methods: A Mini‐Nutritional Assessment (MNA) and a 3‐day dietary record were compiled for a group of fully dentates (21 women and 29 men; mean age 70.1 ± 6.1) and for a group of complete denture wearers (31 women and 16 men; mean age 70.1 ± 8.1). Socio‐demographic data and scores on the General Oral Health Assessment Index (GOHAI) questionnaire were collected. Results: Inter‐group comparison of MNA scores showed that more subjects in the edentulous group (21.3%) risked malnutrition than in the dentate group (0%). The variability of the MNA could be explained for 22% by dental status, 7% by loneliness and 4% by the GOHAI score (regression analysis). Both groups had insufficient energy intakes and deficits in vitamins and micronutrients; moreover, edentulous subjects had lower intakes than dentate subjects. Conclusion: The use of conventional dentures increases the risk of malnutrition in the elderly.     

Highly dynamic exon shuffling in candidate pathogen receptors ... what if brown algae were capable of adaptive immunity?

Pathogen recognition is the first step of immune reactions. In animals and plants, direct or indirect pathogen recognition is often mediated by a wealth of fast-evolving receptors, many of which contain ligand-binding and signal transduction domains, such as leucine-rich or tetratricopeptide repeat (LRR/TPR) and NB-ARC domains, respectively. In order to identify candidates potentially involved in algal defense, we mined the genome of the brown alga Ectocarpus siliculosus for homologues of these genes and assessed the evolutionary pressures acting upon them. We thus annotated all Ectocarpus LRR-containing genes, in particular an original group of LRR-containing GTPases of the ROCO family, and 24 NB-ARC-TPR proteins. They exhibit high birth and death rates, while a diversifying selection is acting on their LRR (respectively TPR) domain, probably affecting the ligand-binding specificities. Remarkably, each repeat is encoded by an exon, and the intense exon shuffling underpins the variability of LRR and TPR domains. We conclude that the Ectocarpus ROCO and NB-ARC-TPR families are excellent candidates for being involved in recognition/transduction events linked to immunity. We further hypothesize that brown algae may generate their immune repertoire via controlled somatic recombination, so far only known from the vertebrate adaptive immune systems.     

The adhering junctions of valvular interstitial cells: molecular composition in fetal and adult hearts and the comings and goings of plakophilin-2 in situ, in cell culture and upon re-association with scaffolds

The interstitial cells of cardiac valves represent one of the most frequent cell types in the mammalian heart. In order to provide a cell and molecular biological basis for the growth of isolated valvular interstitial cells (VICs) in cell culture and for the use in re-implantation surgery we have examined VICs in situ and in culture, in fetal, postnatal and adult hearts, in re-associations with scaffolds of extracellular matrix (ECM) material and decellularized heart valves. In all four mammalian species examined (human, bovine, porcine and ovine), the typical mesenchymal-type cell-cell adherens junctions (AJs) connecting VICs appear as normal N-cadherin based puncta adhaerentia. Their molecular ensemble, however, changes under various growth conditions insofar as plakophilin-2 (Pkp2), known as a major cytoplasmic plaque component of epithelial desmosomes, is recruited to and integrated in the plaques of VIC-AJs as a major component under growth conditions characterized by enhanced proliferation, i.e., in fetal heart valves and in cell cultures. Upon re-seeding onto decellularized heart valves or in stages of growth in association with artificial scaffolds, Pkp2 is - for the most part - lost from the AJs. As Pkp2 has recently also been detected in AJs of cardiac myxomata and diverse other mesenchymal tumors, the demonstrated return to the normal Pkp2-negative state upon re-association with ECM scaffolds and decellularized heart valves may now provide a safe basis for the use of cultured VICs in valve replacement surgery. Even more surprising, this type of transient acquisition of Pkp2 has also been observed in distinct groups of endothelial cells of the endocardium, where it seems to correspond to the cell type ready for endothelial-mesenchymal transition (EMT).     

PTEN loss defines a TGF-β-induced tubule phenotype of failed differentiation and JNK signaling during renal fibrosis

We investigated the signaling basis for tubule pathology during fibrosis after renal injury. Numerous signaling pathways are activated physiologically to direct tubule regeneration after acute kidney injury (AKI) but several persist pathologically after repair. Among these, transforming growth factor (TGF)-β is particularly important because it controls epithelial differentiation and profibrotic cytokine production. We found that increased TGF-β signaling after AKI is accompanied by PTEN loss from proximal tubules (PT). With time, subpopulations of regenerating PT with persistent loss of PTEN (phosphate and tension homolog) failed to differentiate, became growth arrested, expressed vimentin, displayed profibrotic JNK activation, and produced PDGF-B. These tubules were surrounded by fibrosis. In contrast, PTEN recovery was associated with epithelial differentiation, normal tubule repair, and less fibrosis. This beneficial outcome was promoted by TGF-β antagonism. Tubule-specific induction of TGF-β led to PTEN loss, JNK activation, and fibrosis even without prior AKI. In PT culture, high TGF-β depleted PTEN, inhibited differentiation, and activated JNK. Conversely, TGF-β antagonism increased PTEN, promoted differentiation, and decreased JNK activity. Cre-Lox PTEN deletion suppressed differentiation, induced growth arrest, and activated JNK. The low-PTEN state with JNK signaling and fibrosis was ameliorated by contralateral nephrectomy done 2 wk after unilateral ischemia, suggesting reversibility of the low-PTEN dysfunctional tubule phenotype. Vimentin-expressing tubules with low-PTEN and JNK activation were associated with fibrosis also after tubule-selective AKI, and with human chronic kidney diseases of diverse etiology. By preventing tubule differentiation, the low-PTEN state may provide a platform for signals initiated physiologically to persist pathologically and cause fibrosis after injury.     

Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA

Psychostimulants induce neuroadaptations in excitatory and fast inhibitory transmission in the ventral tegmental area (VTA). Mechanisms underlying drug-evoked synaptic plasticity of slow inhibitory transmission mediated by GABA(B) receptors and G protein-gated inwardly rectifying potassium (GIRK/Kir(3)) channels, however, are poorly understood. Here, we show that 1 day after methamphetamine (METH) or cocaine exposure both synaptically evoked and baclofen-activated GABA(B)R-GIRK currents were significantly depressed in VTA GABA neurons and remained depressed for 7 days. Presynaptic inhibition mediated by GABA(B)Rs on GABA terminals was also weakened. Quantitative immunoelectron microscopy revealed internalization of GABA(B1) and GIRK2, which occurred coincident with dephosphorylation of serine 783 (S783) in GABA(B2), a site implicated in regulating GABA(B)R surface expression. Inhibition of protein phosphatases recovered GABA(B)R-GIRK currents in VTA GABA neurons of METH-injected mice. This psychostimulant-evoked impairment in GABA(B)R signaling removes an intrinsic brake on GABA neuron spiking, which may augment GABA transmission in the mesocorticolimbic system.     

Dichotomous organization of the external globus pallidus

Different striatal projection neurons are the origin of?a?dual organization essential for basal ganglia function. We have defined an analogous division of labor in the external globus pallidus (GPe) of Parkinsonian rats, showing that the distinct temporal activities of two populations of GPe neuron in?vivo are?underpinned by distinct molecular profiles and axonal connectivities. A first population of prototypic GABAergic GPe neurons fire antiphase to subthalamic nucleus (STN) neurons, often express parvalbumin, and target downstream basal ganglia nuclei, including STN. In contrast, a second population (arkypallidal neurons) fire in-phase with STN neurons, express preproenkephalin, and only innervate the striatum. This novel cell type provides the largest extrinsic GABAergic innervation of striatum, targeting both projection neurons and interneurons. We conclude that GPe exhibits several core components of?a dichotomous organization as fundamental as?that in striatum. Thus, two populations of GPe neuron?together orchestrate activities across all basal ganglia nuclei in a cell-type-specific manner.