BIOCHEMICAL PROPERTIES OF GABA (B) RECEPTORS (BACLOFEN, ADENYLATE CYCLASE, CYCLIC-AMP, PHOSPHOLIPASE, PROTEIN KINASE C)

(gamma)-Aminobutyric acid (GABA), a neurotransmitter in the mammalian central nervous system, influences neuronal activity by interacting with at least two pharmacologically and functionally distinct receptors. GABA(,A) receptors are sensitive to blockade by bicuculline, are associated with benzodiazepine and barbiturate binding sites, and mediate chloride flux. The biochemical and pharmacolocal properties of GABA(,B) receptors, which are stereoselectively activated by (beta)-p-chlorophenyl GABA (baclofen), are less well understood. The aim of this study was to define these features of GABA(,B) receptors, with particular emphasis on their possible relationship to the adenylate cyclase system in brain.^ By themselves, GABA agonists have no effect on cAMP accumulation in rat brain slices. However, some GABA agonists markedly enhance the cAMP accumulation that results from exposure to norepinephrine, adenosine, VIP, and cholera toxin. Evidence that this response is mediated by the GABA(,B) system is provided by the finding that it is bicuculline-insensitive, and by the fact that only those agents that interact with GABA(,B) binding sites are active in this regard. GABA(,B) agonists are able to enhance neurotransmitter-stimulated cAMP accumulation in only certain brain regions, and the response is not influenced by phosphodiesterase inhibitors, although is totally dependent on the availability of extracellular calcium. Furthermore, data suggest that inhibition of phospholipase A(,2), a calcium-dependent enzyme, decreases the augmenting response to baclofen, although inhibitors of arachidonic acid metabolism are without effect. These findings indicate that either arachidonic acid or lysophospholipid, products of PLA(,2)-mediated degradation of phospholipids, mediates the augmentation. Moreover, phorbol esters, compounds which directly activate protein kinase C, were also found to enhance neurotransmitter-stimulated cAMP accumulation in rat brain slices. Since this enzyme is known to be stimulated by unsaturated fatty acids such as arachidonate, it is proposed that GABA(,B) agonists enhance cAMP accumulation by fostering the production of arachidonic acid which stimulates protein kinase C, leading to the phosphorylation of some component of the adenylate cyclase system. Thus, GABA, through an interaction with GABA(,B) receptors, modulates neurotransmitter receptor responsiveness in brain. The pharmocological manipulation of this response could lead to the development of therapeutic agents having a more subtle influence than current drugs on central nervous system function. ^

Oxygen Isotopic and Soluble Ionic Composition of a Shallow Firn Core, Inilchek Glacier, Central Tien Shan

Oxygen isotopic and soluble ionic measurements made on snow-pit (2 in depth) and firn-core (12.4 m depth samples recovered from the accumulation zone 5100 m) of Inilchek glacier 43degrees N, 79degrees E) provide information on recent (1992-98) climatic and environmental conditions in the central Tien Shan region of central Asia. The combined 14.4 m snow-pit/firn-core profile lies within the firn zone, arid contains only one observed melt feature (10 m temperature = - 12 degreesC), Although some post-depositional attenuation of the sub-seasonal delta(18)O record is possible, annual cycles are apparent throughout the isotope profile. We therefore use the preserved delta(18)O record to establish a depth/age scale for the core. Mean delta(18)O values for the entire core and for summer periods are consistent with delta(18)O/temperature observations, and suggest the delta(18)O record provides a means to reconstruct past changes in summer surface temperature at the site. Major-ion (Na(+), K(+), Mg(2+), Ca(2+), NH(4)(+), Cl(-), NO(3)(-), SO(4)(2-)) data from the core demonstrate the dominant influence of dust deposition on the soluble chemistry at the site, arid indicate significant interannual variability in atmospheric-dust loading during the 1900s. Anthropogenic impacts oil NH(4)(+) concentrations are observed at the site, and suggest a summer increase in atmospheric NH(4)(+) that may be related to regional agricultural (nitrogen-rich fertilizer use activities.

Atmospheric Soluble Dust Records from a Tibetan Ice Core: Possible Climate Proxies and Teleconnection With the Pacific Decadal Oscillation

In autumn 2005, a joint expedition between the University of Maine and the Institute of Tibetan Plateau Research recovered three ice cores from Guoqu Glacier (33 degrees 34'37.80 '' N, 91 degrees 10'35.3 '' E, 5720 m above sea level) on the northern side of Mt. Geladaindong, central Tibetan Plateau. Isotopes ( delta(18)O), major soluble ions (Na(+), K(+), Mg(2+), Ca(2+), Cl(-), NO(3)(-), SO(4)(2-)), and radionuclide (beta-activity) measurements from one of the cores revealed a 70-year record (1935-2005). Statistical analysis of major ion time series suggests that atmospheric soluble dust species dominate the chemical signature and that background dust levels conceal marine ion species deposition. The soluble dust time series have interspecies relations and common structure (empirical orthogonal function (EOF) 1), suggesting a similar soluble dust source or transport route. Annual and seasonal correlations between the EOF 1 time series and National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis climate variables (1948-2004) suggest that the Mt. Geladaindong ice core record provides a proxy for local and regional surface pressure. An approximately threefold decrease of soluble dust concentrations in the middle to late 1970s, accompanied by regional increases in pressure and temperature and decreases in wind velocity, coincides with the major 1976-1977 shift of the Pacific Decadal Oscillation (PDO) from a negative to a positive state. This is the first ice core evidence of a potential teleconnection between central Asian atmospheric soluble dust loading and the PDO. Analysis of temporally longer ice cores from Mt. Geladaindong may enhance understanding of the relationship between the PDO and central Asian atmospheric circulation and subsequent atmospheric soluble dust loading.

In pneumococcal meningitis a novel water-soluble inhibitor of matrix metalloproteinases and TNF-alpha converting enzyme attenuates seizures and injury of the cerebral cortex

Matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) contribute to the pathophysiology of bacterial meningitis. To date, MMP-inhibitors studied in models of meningitis were compromised by their hydrophobic nature. We investigated the pharmacokinetics and the effect of TNF484, a water-soluble hydroxamate-based inhibitor of MMP and TACE, on disease parameters and brain damage in a neonatal rat model of pneumococcal meningitis. At 1 mg/kg q6h TNF484 reduced soluble TNF-alpha and the collagen degradation product hydroxyproline in the cerebrospinal fluid. Clinically, TNF484 attenuated the incidence of seizures and was neuroprotective in the cortex. Water-soluble MMP-inhibitors may hold promise in the therapy of bacterial meningitis.

Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function.

Vascular endothelial growth factor and its receptors, FLK1/KDR and FLT1, are key regulators of angiogenesis. Unlike FLK1/KDR, the role of FLT1 has remained elusive. FLT1 is produced as soluble (sFLT1) and full-length isoforms. Here, we show that pericytes from multiple tissues produce sFLT1. To define the biologic role of sFLT1, we chose the glomerular microvasculature as a model system. Deletion of Flt1 from specialized glomerular pericytes, known as podocytes, causes reorganization of their cytoskeleton with massive proteinuria and kidney failure, characteristic features of nephrotic syndrome in humans. The kinase-deficient allele of Flt1 rescues this phenotype, demonstrating dispensability of the full-length isoform. Using cell imaging, proteomics, and lipidomics, we show that sFLT1 binds to the glycosphingolipid GM3 in lipid rafts on the surface of podocytes, promoting adhesion and rapid actin reorganization. sFLT1 also regulates pericyte function in vessels outside of the kidney. Our findings demonstrate an autocrine function for sFLT1 to control pericyte behavior.

The Biological Side of Water-Soluble Arene Ruthenium Assemblies

This review article covers the synthetic strategies, structural aspects, and host-guest properties of ruthenium metalla-assemblies, with a special focus on their use as drug delivery vectors. The two-dimensional metalla-rectangles show interesting host-guest possibilities but seem less appropriate for being used as drug carriers. On the other hand, metalla-prisms allow encapsulation and possible targeted release of bioactive molecules and consequently show some potential as drug delivery vectors. The reactivity of these metalla-prisms can be fine-tuned to allow a fine control of the guest’s release. The larger metalla-cubes can be used to stabilize the formation of G-quadruplex DNA and can be used to encapsulate and release photoactive molecules such as porphins. These metalla-assemblies demonstrate great prospective in photodynamic therapy.

Systemic levels of the anti-inflammatory decoy receptor soluble RAGE (receptor for advanced glycation end products) are decreased in dogs with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a common condition in dogs, and a dysregulated innate immunity is believed to play a major role in its pathogenesis. S100A12 is an endogenous damage-associated molecular pattern molecule, which is involved in phagocyte activation and is increased in serum/fecal samples from dogs with IBD. S100A12 binds to the receptor of advanced glycation end products (RAGE), a pattern-recognition receptor, and results of studies in human patients with IBD and other conditions suggest a role of RAGE in chronic inflammation. Soluble RAGE (sRAGE), a decoy receptor for inflammatory proteins (e.g., S100A12) that appears to function as an anti-inflammatory molecule, was shown to be decreased in human IBD patients. This study aimed to evaluate serum sRAGE and serum/fecal S100A12 concentrations in dogs with IBD. Serum and fecal samples were collected from 20 dogs with IBD before and after initiation of medical treatment and from 15 healthy control dogs. Serum sRAGE and serum and fecal S100A12 concentrations were measured by ELISA, and were compared between dogs with IBD and healthy controls, and between dogs with a positive outcome (i.e., clinical remission, n=13) and those that were euthanized (n=6). The relationship of serum sRAGE concentrations with clinical disease activity (using the CIBDAI scoring system), serum and fecal S100A12 concentrations, and histologic disease severity (using a 4-point semi-quantitative grading system) was tested. Serum sRAGE concentrations were significantly lower in dogs with IBD than in healthy controls (p=0.0003), but were not correlated with the severity of histologic lesions (p=0.4241), the CIBDAI score before (p=0.0967) or after treatment (p=0.1067), the serum S100A12 concentration before (p=0.9214) and after treatment (p=0.4411), or with the individual outcome (p=0.4066). Clinical remission and the change in serum sRAGE concentration after treatment were not significantly associated (p=0.5727); however, serum sRAGE concentrations increased only in IBD dogs with complete clinical remission. Also, dogs that were euthanized had significantly higher fecal S100A12 concentrations than dogs that were alive at the end of the study (p=0.0124). This study showed that serum sRAGE concentrations are decreased in dogs diagnosed with IBD compared to healthy dogs, suggesting that sRAGE/RAGE may be involved in the pathogenesis of canine IBD. Lack of correlation between sRAGE and S100A12 concentrations is consistent with sRAGE functioning as a non-specific decoy receptor. Further studies need to evaluate the gastrointestinal mucosal expression of RAGE in healthy and diseased dogs, and also the formation of S100A12-RAGE complexes.

Oil-soluble vitamins: illegal use for lip augmentation.

Fillers for lip augmentation have become more and more popular in recent years and seem to be indispensable in the cosmetic market nowadays. A series of six young females is presented who developed massive swellings and pain after vitamins A and/or E lip augmentation. The vitamins were extracted from gelatinous capsules (Gericaps [Adipharm EAD, Sofia, Bulgaria], Geritamins [Actavis EAD, Balkanpharma-Dubnitsa AD, Bulgaria], or vitamin E yellow gel capsules) and injected by unprofessional physicians and beauticians in different cosmetic centers. Physical examination revealed firm indurations of the lips and perioral skin, tenderness, erythema, and hard dermal nodules. Histological analysis revealed numerous round-to-ovoid cavities of varying sizes, resulting in a Swiss cheese-like appearance, consistent with lipogranulomas. The patients were treated with systemic and intralesional triamcinolone injections and broad-spectrum antibiotics with good clinical response. In conclusion, these cases demonstrate the danger of the use of unregistered products as fillers injected by unprofessional physicians and beauticians.

Jasmonate-dependent depletion of soluble sugars compromises plant resistance to Manduca sexta

Jasmonates regulate plant secondary metabolism and herbivore resistance. How they influence primary metabolites and how this may affect herbivore growth and performance are not well understood. We profiled sugars and starch of jasmonate biosynthesis-deficient and jasmonate-insensitive Nicotiana attenuata plants and manipulated leaf carbohydrates through genetic engineering and in vitro complementation to assess how jasmonate-dependent sugar accumulation affects the growth of Manduca sexta caterpillars. We found that jasmonates reduce the constitutive and herbivore-induced concentration of glucose and fructose in the leaves across different developmental stages. Diurnal, jasmonate-dependent inhibition of invertase activity was identified as a likely mechanism for this phenomenon. Contrary to our expectation, both in planta and in vitro approaches showed that the lower sugar concentrations led to increased M. sexta growth. As a consequence, jasmonate-dependent depletion of sugars rendered N. attenuata plants more susceptible to M. sexta attack. In conclusion, jasmonates are important regulators of leaf carbohydrate accumulation and this determines herbivore growth. Jasmonate-dependent resistance is reduced rather than enhanced through the suppression of glucose and fructose concentrations, which may contribute to the evolution of divergent resistance strategies of plants in nature.

Seasonal variation of high-molecular-weight compounds in the water-soluble fraction of organic urban aerosols

Aerosol samples were collected in Zurich, Switzerland, at an urban background site and were analyzed with size exclusion chromatography (SEC) and laser/desorption ionization mass spectrometry (LDI-MS) for water-soluble organic compounds with high molecular weight. Daily samples were collected during two campaigns in winter and summer, for 1 month each. The concentration of high-molecular-weight compounds (humic-like substances (HULIS)) was between 0.4 and 4 μg/m3 in winter and summer. The most intense signals in the LDI-MS mass spectra were measured between m/z150 and 500, comparing well with the mode of the two main high mass peaks determined with SEC corresponding to masses between 200 and 600 Da. For the maximum molecular weight, however, different results were obtained by the two techniques: whereas a maximum molecular weight between 1300 and 3300 Da was found with SEC, hardly any peaks above m/z700 were measured with LDI-MS. During summer the maximum molecular weight of HULIS (determined with SEC) correlates positively with several parameters such as ozone and increased temperature indicative of enhanced atmospheric photo-oxidation. The HULIS concentration also correlates positively with the oxalic acid concentration in the particles. This suggests that HULIS are generated by secondary processes in summer. The lack of such correlations during winter suggests that other sources and processes might be important during colder seasons.