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Weak Effect (weak + effect)
Selected AbstractsA model predicting waterborne cadmium bioaccumulation in Gammarus pulex: The effects of dissolved organic ligands, calcium, and temperatureENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2009Bastien Pellet Abstract Metal bioavailability depends on the presence of organic ligands in the water and on the concentrations of competitive cations. The present study aims at testing whether the diffusive gradient in thin films technique (DGT) could be used to take into account Cd speciation and its consequences on bioavailability in a bioaccumulation model and whether the influences of the Ca concentration and temperature also should be considered. Four kinetic experiments were conducted on Gammarus pulex: a calibration of Cd turnover rates and of the DGT lability in mineral water, a study of the influence of ethylenediaminetetraacetic acid (EDTA) and humic acids (HA) on uptake rates, and two experiments testing the influence of the Ca concentrations and temperature on Cd uptake clearance rates (ku). In mineral water, where Cd was considered fully labile, the ku was 0.46 L g,1 d,1, and the depuration rate was 0.032 d,1. The initial Cd influxes were lowered significantly by additions of 10 ,g L,1 of EDTA or 10 mg L,1 of HA in the water but not at 5 mg L,1 HA, even if DGT measurements proved that Cd formed Cd,HA complexes in that treatment. Increasing Ca concentrations lowered ku values, and a competitive inhibition model between Ca and Cd fitted the data. A 30% enhancement of ku values was observed when the temperature was increased by 8°C, which appeared comparatively as a weak effect. Thus, taking into account the metal speciation and the influence of the Ca concentration should improve Cd bioaccumulation modeling in amphipods. In freshwater, where metal bioavailability is reduced by the presence of dissolved organic matter, forecasting Cd waterborne uptake using the labile concentrations should allow robust comparisons between laboratory and field studies. [source] Structural, Photophysical and Chiro-Optical Properties of Lanthanide Complexes with a Bis(benzimidazole)pyridine-Based Chiral LigandEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 22 2003Gilles Muller Abstract The neutral LnIII 1:1 nitrato complexes with the chiral ligand 2,6-bis(1- S -neopentylbenzimidazol-2-yl)pyridine (L11) have been synthesised and their stability constants measured in acetonitrile (log K1 = 4.0,6.4). The crystal and molecular structure of [Eu(NO3)3(L11)(MeCN)] shows the typical meridional planar coordination of L11 to the metal ion and low symmetry of the coordination polyhedron. The influence of the steric hindrance generated by the substituent at R2 on the crystal packing and bond lengths is discussed. Photophysical measurements show that ligand L11 induces a 3,,*-to-Ln energy-transfer process in the EuIII complex, while the TbIII compound is ten times less luminescent. Addition of a second molecule of L11 to give [Ln(ClO4)2(L11)2]+ leads to a large quenching of the EuIII luminescence (140-fold) due to several factors: a less efficient 1,,*,3,,* transfer (ca. fourfold), a smaller intrinsic quantum yield QEu (ca. threefold), and a substantially less efficient ligand-to-metal transfer (ca. 12-fold). In the case of the TbIII complex, the decrease in the energy of the triplet state reduces further the TbIII emission through increased back transfer. The specific rotary dispersion of the 1:1 and 1:2 complexes points to the chirality of the complexes arising mainly from the ligand, while the circularly polarized luminescence of these complexes with EuIII and TbIII displays a weak effect, pointing to a small diastereomeric excess in solution. Altogether, this study demonstrates that electronic, thermodynamic and photophysical properties of lanthanide complexes with aromatic terdentate ligands can be tuned by modifying the number and the arrangement of the ligands, as well as their substituents, particularly those in the R2 and R3 positions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Afferent-induced facilitation of primary motor cortex excitability in the region controlling hand muscles in humansEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2009H. Devanne Abstract Sensory inputs from cutaneous and limb receptors are known to influence motor cortex network excitability. Although most recent studies have focused on the inhibitory influences of afferent inputs on arm motor responses evoked by transcranial magnetic stimulation (TMS), facilitatory effects are rarely considered. In the present work, we sought to establish how proprioceptive sensory inputs modulate the excitability of the primary motor cortex region controlling certain hand and wrist muscles. Suprathreshold TMS pulses were preceded either by median nerve stimulation (MNS) or index finger stimulation with interstimulus intervals (ISIs) ranging from 20 to 200 ms (with particular focus on 40,80 ms). Motor-evoked potentials recorded in the abductor pollicis brevis (APB), first dorsalis interosseus and extensor carpi radialis muscles were strongly facilitated (by up to 150%) by MNS with ISIs of around 60 ms, whereas digit stimulation had only a weak effect. When MNS was delivered at the interval that evoked the optimal facilitatory effect, the H-reflex amplitude remained unchanged and APB motor responses evoked with transcranial electric stimulation were not increased as compared with TMS. Afferent-induced facilitation and short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) mechanisms are likely to interact in cortical circuits, as suggested by the strong facilitation observed when MNS was delivered concurrently with ICF and the reduction of SICI following MNS. We conclude that afferent-induced facilitation is a mechanism which probably involves muscle spindle afferents and should be considered when studying sensorimotor integration mechanisms in healthy and disease situations. [source] The preadult origins of postmaterialism: A longitudinal sibling studyEUROPEAN JOURNAL OF POLITICAL RESEARCH, Issue 5 2009MARTIN KROH Using a research design that traces siblings' preferences for postmaterialist values in Germany over two decades, this article provides new evidence on the origins of value preferences. Focusing on Inglehart's thesis of value change, the combined socialisation and scarcity hypothesis is tested against the social learning hypothesis , a prominent rival account of preadult value preference formation. Sibling estimates show that the shared preadult environment does indeed exert lasting effects on preferences for postmaterialist policies. In addition to the weak effect of the shared experience of socioeconomic scarcity, it is found that the intergenerational transmission of postmaterialism, disregarded by Inglehart's original thesis, plays a significant role in value preference acquisition. The implications of individual-level findings for forecasts of aggregate-level trends in value change are discussed. [source] Identification of a new promoter for the response regulator rcsB expression in Salmonella enterica serovar TyphimuriumFEMS MICROBIOLOGY LETTERS, Issue 2 2009María de las Mercedes Pescaretti Abstract The RcsCDB (Rcs) phosphorelay system regulates capsule synthesis, flagella production and other cellular activities in several enteric bacteria. This system consists of three proteins: the sensor RcsC, the cognate response regulator RcsB and the histidine-containing phosphotransfer protein RcsD (YojN), which is hypothesized to act as an intermediary in the phosphotransfer from RcsC to RcsB. The rcsC gene is convergently transcribed toward rcsB, which follows rcsD in what appears to be a two-gene operon. Here, it is reported that the overproduction of the rcsB gene represses rcsD transcription, but has a weak effect on its own expression. We demonstrated that the differential rcsD and rcsB expression is due to the activity of two promoters to transcribe the rcsB gene: (1) PrcsDB located upstream of rcsD and (2) PrcsB located within the rcsD coding region. In addition, here it was demonstrated that in Salmonella typhimurium, PrcsB is important to activate the rcsB expression during the stationary growth phase. [source] The Effects of a Variant of the Program for All-inclusive Care of the Elderly on Hospital Utilization and OutcomesJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 2 2006Robert L. Kane MD OBJECTIVES: To compare the effects of the Wisconsin Partnership Program (WPP) on hospital, emergency department (ED), and nursing home utilization with those of traditional care. DESIGN: Quasi-experimental longitudinal cohort design. SETTING: Selected counties in Wisconsin. PARTICIPANTS: WPP elderly enrollees and two matched control groups consisting of frail older people enrolled in fee-for-service insurance plans, Medicare, and Medicaid and receiving home- and community-based waiver services, one from the same geographic area as the WPP and another from a location in the state where the WPP was not offered. MEASUREMENTS: Data came from administrative records. Regression and survival analyses were adjusted for case-mix variables. RESULTS: No significant differences in hospital utilization, ED visits, preventable hospitalizations, risk of entry into nursing homes, or mortality were found. WPP enrollees had more contact with care providers than did controls. CONCLUSION: WPP did not dramatically alter the pattern of care. Part of the weak effect may be attributable to the small numbers of WPP cases per participating physician. [source] Protein phosphatase 2A,negative regulation of the protective signaling pathway of Ca2+/CaM-dependent ERK activation in cerebral ischemiaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2008Jie Zhao Abstract Extracellular-signal-regulated kinase (ERK) undergoes rapid inactivation following the intense activation evoked by cerebral ischemia and reperfusion. However, the precise mechanism of this inactivation has not been elucidated. To investigate how phosphatases regulate the ERK cascade following ischemia, the PP2A inhibitors cantharidin and okadaic acid were administrated to the CA1 subregion of the rat hippocampus. The resulting sustained ERK activity implies that PP2A is a major phosphatase contributing to the rapid inactivation, but not activation, of ERK following cerebral ischemia. The increase in PP2A activity induced by ceramide has a weak effect on the activation of Raf via dephosphorylation of Ser259 in response to ischemia. In contrast, ketamine (Keta) and cyclosporine A (CsA), two chemicals that block calcium signal in ischemia, decrease ERK activity by blocking Raf dephosphorylation of Ser259. We also observed that activation of an upstream protein, Ras-GRF, leads to calcium/calmodulin-dependent activation of the ERK signaling cascade in response to ischemic stimuli. In addition, the activity of cyclic AMP response element-binding protein (CREB) and estrogen receptor , (ER,), target proteins of ERK and protective elements against ischemic lesion, parallels the activity of ERK. These data indicate that PP2A plays a significant role in blocking the protective effect induced by the ERK kinase pathway and that fast inactivation of ERK is the result of cross talk between calcium/calmodulin-dependent, positively regulated signal cascades and a ceramide-dependent negative signaling pathway. © 2008 Wiley-Liss, Inc. [source] Species-specific interaction of HIV protease inhibitors with accumulation of cholyl-glycylamido-fluorescein (CGamF) in sandwich-cultured hepatocytesJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2010Zhi-wei Ye Abstract Using sandwich-cultured hepatocytes from rat, dog, pig, and human, we investigated the species-specificity of interaction of HIV protease inhibitors (PI) with in vitro hepatic accumulation of the bile salt analogue cholyl-glycylamido-fluorescein (CGamF). Extracellular sodium depletion or coincubation with the OATP/Oatp inhibitors rifampicin and digoxin revealed that about 35% of active CGamF accumulation was mediated by Ntcp/NTCP in rat and human hepatocytes, while the contribution of this sodium-dependent transporter reached 50,60% in dog and pig hepatocytes. One or more sodium-independent transporters, likely belonging to the Oatp/OATP family, constitute a major transport mechanism for CGamF accumulation. Various HIV PI (0.5, 5, 25,µM) exhibited pronounced species differences in their interaction with active CGamF accumulation (1,µM), although some similarity was observed between the dog and human interaction profiles when HIV PI were tested at 0.5,µM. Atazanavir, indinavir, and darunavir were the most potent inhibitors of CGamF accumulation in human hepatocytes. Potent inhibition of CGamF accumulation by ritonavir in rat hepatocytes contrasted with a weak effect in human hepatocytes. Thorough characterization of in vitro disposition of probe substrates in preclinical species compared to human hepatocytes will ultimately support a better insight in species-specific mechanisms underlying drug interactions and drug-mediated toxicity. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2886,2898, 2010 [source] Contrasting patterns of mitochondrial and microsatellite population structure in fragmented populations of greater prairie-chickensMOLECULAR ECOLOGY, Issue 12 2003Jeff A. Johnson Abstract Greater prairie-chickens (Tympanuchus cupido pinnatus) were once found throughout the tallgrass prairie of midwestern North America but over the last century these prairies have been lost or fragmented by human land use. As a consequence, many current populations of prairie-chickens have become isolated and small. This fragmentation of populations is expected to lead to reductions in genetic variation as a result of random genetic drift and a decrease in gene flow. As expected, we found that genetic variation at both microsatellite DNA and mitochondrial DNA (mtDNA) markers was reduced in smaller populations, particularly in Wisconsin. There was relatively little range-wide geographical structure (FST) when we examined mtDNA haplotypes but there was a significant positive relationship between genetic (FST) and geographical distance (isolation by distance). In contrast, microsatellite DNA loci revealed significant geographical structure (FST) and a weak effect of isolation by distance throughout the range. These patterns were much stronger when populations with reduced levels of genetic variability (Wisconsin) were removed from the analyses. This suggests that the effects of genetic drift were stronger than gene flow at microsatellite loci, whereas these forces were in range-wide equilibrium at mtDNA markers. These differences between the two molecular markers may be explained by a larger effective population size (Ne) for mtDNA, which is expected in species such as prairie-chickens that have female-biased dispersal and high levels of polygyny. Our results suggest that historic populations of prairie-chickens were once interconnected by gene flow but current populations are now isolated. Thus, maintaining gene flow may be important for the long-term persistence of prairie-chicken populations. [source] Phylogeographical structure, postglacial recolonization and barriers to gene flow in the distinctive Valais chromosome race of the common shrew (Sorex araneus)MOLECULAR ECOLOGY, Issue 4 2002N. Lugon-Moulin Abstract Using one male-inherited and eight biparentally inherited microsatellite markers, we investigate the population genetic structure of the Valais chromosome race of the common shrew (Sorex araneus) in the Central Alps of Europe. Unexpectedly, the Y-chromosome microsatellite suggests nearly complete absence of male gene flow among populations from the St-Bernard and Simplon regions (Switzerland). Autosomal markers also show significant genetic structuring among these two geographical areas. Isolation by distance is significant and possible barriers to gene flow exist in the study area. Two different approaches are used to better understand the geographical patterns and the causes of this structuring. Using a principal component analysis for which testing procedure exists, and partial Mantel tests, we show that the St-Bernard pass does not represent a significant barrier to gene flow although it culminates at 2469 m, close to the highest altitudinal record for this species. Similar results are found for the Simplon pass, indicating that both passes represented potential postglacial recolonization routes into Switzerland from Italian refugia after the last Pleistocene glaciations. In contrast with the weak effect of these mountain passes, the Rhône valley lowlands significantly reduce gene flow in this species. Natural obstacles (the large Rhône river) and unsuitable habitats (dry slopes) are both present in the valley. Moreover, anthropogenic changes to landscape structures are likely to have strongly reduced available habitats for this shrew in the lowlands, thereby promoting genetic differentiation of populations found on opposite sides of the Rhône valley. [source] Imaging OmpR localization in Escherichia coliMOLECULAR MICROBIOLOGY, Issue 6 2006Eric Batchelor Summary We have used a fusion of GFP to the response regulator OmpR to image the spatial distribution of OmpR in live cells of Escherichia coli. We observed foci of increased OmpR,GFP fluorescence that appear to be due to interactions with the histidine kinase EnvZ. We also observed colocalization of OmpR,GFP with clusters of plasmids carrying OmpR binding sites, which enabled us to develop a simple method for imaging the binding of OmpR to DNA in live cells. We used the peak fluorescence intensity within cells to quantify the extent of OmpR,GFP localization either due to interactions with EnvZ or due to binding DNA. With these assays we compared the effects of osmolarity and procaine, both of which are believed to modulate EnvZ activity. Our results suggest that, at least under our growth conditions, procaine activates EnvZ,OmpR signalling whereas osmolarity has, at best, a weak effect on the EnvZ,OmpR system. [source] Influence of the rubbery phase on the crystallinity and thermomechanical properties of poly(3-hydroxybutyrate)/elastomer blendsPOLYMER INTERNATIONAL, Issue 6 2010Patrícia S Calvão Abstract Poly(3-hydroxybutyrate) (PHB) is a very promising biopolymer. In order to improve its processability and decrease its brittleness, PHB/elastomer blends can be prepared. In the work reported, the effect of the addition of a rubbery phase, i.e. ethylene,propylene,diene terpolymer (EPDM) or poly(vinyl butyral) (PVB), on the properties of PHB was studied. The effects of rubber type and of changing the PHB/elastomer blend processing method on the crystallinity and physical properties of the blends were also investigated. For blends based on PHB, the main role of EPDM is its nucleating effect evidenced by a decrease of crystallization temperature and an increase of crystallinity with increasing EPDM content regardless of the processing route. While EPDM has a weak effect on PHB glass transition temperature, PVB induces a marked decrease of this temperature thank to its plasticizer that swells the PHB amorphous phase. A promising solution to improve the mechanical properties of PHB seems to be the melt-processing of PHB with both plasticizer and EPDM. In fact, the plasticizer is more efficient than the elastomer in decreasing the PHB glass transition temperature and, because of the nucleating effect of EPDM, the decrease of the PHB modulus due to the plasticizer can be counterbalanced. Copyright © 2010 Society of Chemical Industry [source] Longitudinal Examination of the Relationship Between Supplies,Values Fit and Work OutcomesAPPLIED PSYCHOLOGY, Issue 1 2001Ruben Taris This study focuses on the robustness of the relationship between supplies,values (S,V) fit and work outcomes. Specifically, the functional form that best describes the relationships of three different dimensions of S,V fit (i.e. intrinsic work aspects, extrinsic work aspects, and social relations at work) with job satisfaction, intention to leave the organisation and psychological well-being was investigated using the moderated regression technique proposed by Edwards (1991, 1994). This study extends previous research by examining the stability of these relationships across two occasions, separated by a period of four years. Results showed that the functional form of the relationship of S,V fit with work outcomes differed by the S,V fit dimension and the work outcome under investigation. However, the functional form of each of these relationships on the first occasion was almost identical to the form of the relationships on the second occasion. Additionally, results showed that all three S,V fit dimensions affected job satisfaction and intention to leave, but had only a weak effect on psychological well-being. The organisational supplies component, as well as its quadratic term in particular, had a large influence on job satisfaction and intention to leave. Implications for future research in the P,O fit area are discussed. Cette e´tude est centre´e sur la force de la relation entre la correspondance contributions-valeurs (supplies-values ou S,V) et les re´sultats du travail. Plus particulie`rement, la forme fonctionnelle qui de´crit le mieux les rapports des trois dimensions de la correspondance S,V (c'est-a`-dire les relations sociales au travail et les aspects intrinse`ques et extrinse`ques du travail) avec la satisfaction professionnelle, le projet de quitter l'organisation et le bien-être psychologique a e´te´ explore´e a` l'aide de la technique de la re´gression mode´re´e propose´e par Edwards (1991, 1994). Cette recherche e´largit les travaux ante´rieurs en s'inte´ressant a` la stabilite´ de ces relations a` deux pe´riodes se´pare´es par un laps de temps de quatre ans. Les analyses montrent que la forme fonctionnelle de la relation de la correspondance S,V avec les re´sultats du travail diffe´rent selon les dimensions de la correspondance S,V et selon les aspects des re´sultats du travail pris en conside´ration. Cependant, la forme fonctionnelle de chacune de ces relations sur la premie`re pe´riode e´tait presque identique a` la forme des relations sur la seconde. En outre, les analyses montrent que les trois dimensions de la correspondance S,V affectent la satisfaction professionnelle et le projet de de´mission, mais n'ont qu'un faible effet sur le bien-être psychologique. La composante "contribution organisationnelle", aussi bien que son terme quadratique en particulier, a une grande influence sur la satisfaction professionnelle et le projet de de´part. On discute aussi des retombe´es sur les futures recherches dans le domaine personne-organisation. [source] Determinants of floristic diversity and vegetation composition on the islands of Lake Burollos, EgyptAPPLIED VEGETATION SCIENCE, Issue 2 2000Abdel-Hamid Khedr Täckholm 1974; Boulos 1995 Abstract. A floristic and environmental survey was carried out on 22 uninhabited islands (0.1-8.4 ha) in Lake Burollos, Egypt. A total of 58 vascular plant species was recorded. The number of habitats on each island was counted. There was a positive correlation between island area and number of habitat types. Island area was significantly positively correlated with various measures of floristic diversity, including the total number of species present, and the numbers of annual, herbaceous, and shrublet species. Perennial and shrub species numbers did not differ significantly with island area. In addition to island area, elevation and soil salinity, as well as distance to the Mediterranean Sea, all contributed significantly to variation in species composition in the terrestrial habitats. Water salinity and transparency accounted for 69% of the variation in aquatic species numbers. There was a weak effect of isolation on similarity of species composition on islands. Eight vegetation types, represented by 13 indicator species identified after TWINSPAN analysis, were distinguished by soil characteristics. Species richness was inversely correlated with clay, organic carbon and total nitrogen in the soil, but positively correlated with calcium carbonate content. From a management perspective, long-term monitoring of threatened habitats in the lake is urgently required as a starting point to preserve biodiversity. Finally, we conclude that the present study supports the hypothesis indicating that larger areas feature higher species richness due to increased numbers of habitats. [source] Gas,liquid mass transfer in three-phase inverse fluidized bed reactor with Newtonian and non-Newtonian fluidsASIA-PACIFIC JOURNAL OF CHEMICAL ENGINEERING, Issue 2 2010V. Sivasubramanian Abstract Liquid-phase volumetric mass transfer coefficients, kLa were determined in three-phase inverse fluidized beds of low-density polyethylene (LDPE) and polypropylene (PP) spheres fluidized by a countercurrent flow of air and Newtonian (water and glycerol solutions) or non-Newtonian liquids [carboxy methyl cellulose (CMC) solutions]. The effects of liquid and gas velocities, particle size, solid loading and addition of organic additives (glycerol and CMC) on the volumetric mass transfer coefficient, kLa were determined. The superficial liquid velocity had a weak effect on the mass transfer whereas the gas flow rate affected the mass transfer positively. kLa increased with increase in particle diameter and decreased with increase in initial bed height (solid loading). kLa decreased as the concentration of glycerol (viscosity) and CMC increased. Empirical correlations are presented to predict the gas,liquid volumetric mass transfer coefficient in terms of operating variables. Copyright © 2009 Curtin University of Technology and John Wiley & Sons, Ltd. [source] Potential role of formaldehyde in the mechanism of action of ascorbigens on the basis of BioArena studiesBIOMEDICAL CHROMATOGRAPHY, Issue 4 2009György Kátay Abstract The effect of ascorbigen and 1,-methylascorbigen as a model compound pair was studied on the phytopathogenic bacterium Pseudomonas savastanoi pv. phaseolicola in the BioArena experimental system after overpressured layer chromatography. Results showed a characteristic, strong antibacterial effect of 1,-methylascorbigen and weak effect of ascorbigen present on the adsorbent layer as chromatographic spot. Addition of formaldehyde capture compounds (l -arginine, glutathione, dimedone) partially or totally reduced the antibacterial effect of 1,-methylascorbigen and ascorbigen. On adding Cu(II) ions,which mobilize and coordinate formaldehyde,to the culture medium, the antibacterial effect of both compounds became stronger. It is supposed that the weak antibacterial effect of ascorbigen may have originated from the 1,-methylascorbigen formed in situ on the adsorbent layer by partial enzymatic methylation of ascorbigen. Copyright © 2008 John Wiley & Sons, Ltd. [source] The effects of heparin and related molecules on vascular permeability and neutrophil accumulation in rabbit skinBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2002Helen Jones Unfractionated heparin (UH) has been shown to possess a wide range of properties which are potentially anti-inflammatory. Many of these studies, including effects of heparin on adhesion of inflammatory cells to endothelium, have been carried out in vitro. In the present study, we have used radioisotopic techniques to study the effect of UH, and related molecules, on in vivo inflammatory responses (plasma exudation (PE) and PMN accumulation) in rabbit skin induced by cationic proteins, mediators and antigen. Intradermal (i.d.) pretreatment with UH dose-dependently inhibited poly-L-lysine (PLL)-induced responses. The same treatment had no effect on antigen (extract of Alternaria tenuis, AT)-, formyl-methionyl-leucyl-phenylalanine (fMLP)- or leukotriene (LT) B4 -induced responses, although i.d. dextran sulphate (DS) significantly inhibited responses to all of these mediators. High dose (10,000 u kg,1) intravenous UH significantly decreased cutaneous responses to fMLP and LTB4. By comparison, the selectin inhibitor, fucoidin, and DS, were very effective inhibitors of these responses, and of responses to AT and PLL. In contrast to the weak effect in the in vivo studies, UH significantly inhibited in vitro homotypic aggregation of rabbit PMNs, showing that it can modify PMN function. Our data with i.d. UH confirm the important ability of this molecule to interact with and neutralize polycationic peptides in vivo, suggesting that this is a prime role of endogenous heparin. The lack of effect of exogenous heparin on acute inflammatory responses induced by allergen, suggests that cationic proteins are unlikely to be primary mediators of the allergen-induced PE or PMN accumulation. British Journal of Pharmacology (2002) 135, 469,479; doi:10.1038/sj.bjp.0704505 [source] Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7-Substituted CoumarinsCHEMISTRY & BIODIVERSITY, Issue 2 2006Angelo Carotti Abstract A series of coumarin derivatives (1,22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC50 values in the micromolar to low-nanomolar range. A structure,activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r2=0.72) between pIC50 and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1,h after intraperitoneal administration of high doses (100 and 300,,mol kg,1), revealing its ability to cross the blood,brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues. [source] | ||||||||||||||||