Anion directed template synthesis of Cu(II) complexes of a N,N,O donor mono-condensed Schiff base ligand: A molecular scaffold forming highly ordered H-bonded rectangular grids

Anion directed, template syntheses of two dinuclear copper(II) complexes of mono-condensed Schiff base ligand Hdipn (4-[(3-aminopentylimino)-methyl]-benzene-1,3-diol) involving 2,4- dihydroxybenzaldehyde and 1,3-diaminopentane were realized in the presence of bridging azide and acetate anions. Both complexes, [Cu-2(dipn)(2)(N-3)(2)] (1) and [Cu-2(dip(n))(2)(OAc)(2)] (2) have been characterized by X-ray crystallography. The two mononuclear units are joined together by basal-apical, double end-on azido bridges in complex 1 and by basal-apical, double mono-atomic acetate oxygen-bridges in 2. Both complexes form rectangular grid-like supramolecular structures via H-bonds connecting the azide or acetate anion and the p-hydroxy group of 2,4- dihydroxybenzaldehyde. Variable-temperature (300-2 K) magnetic susceptibility measurements reveal that complex 1 has antiferromagnetic coupling (J = -2.10 cm (1)) through the azide bridge while 2 has intra-dimer ferromagnetic coupling through the acetate bridge and inter-dimer antiferromagnetic coupling through H-bonds (J = 2.85 cm (1), J' = -1.08 cm (1)). (C) 2009 Elsevier B. V. All rights reserved.

Preparation and ring-opening reactions of N,O-bis(diphenylphosphinyl) hydroxymethylaziridine ('Di-Dpp')

N,O-bis(diphenylphosphinyl)-2-(hydroxymethyl)aziridine ('DiDpp', 1) is efficiently prepared from 2-aminoethane-1,3-diol: this activated aziridine undergoes two sequential reactions with copper(I)-modified Grignard reagents, yielding alpha-branched N-Dpp amines in good yield. (C) 2003 Elsevier Science Ltd. All rights reserved.

Partial aerial oxidation of nonpolar alcohols over Teflon-modified noble metal catalysts in supercritical carbon dioxide

We have reported earlier that modification of commercial graphite Pt-supported catalysts with Teflon fluorinated polymeric coating of a very strong hydrophobic nature can significantly improve catalytic activity for aerial oxidation of water-insoluble alcohols such as anthracene methanol in supercritical carbon dioxide (scCO(2)). Thus, this paper presents some further characterization of these new catalyst materials and the working fluid phase during the catalysis. Using the same Teflon-modified metal catalysts, this paper addresses the oxidation of another water-insoluble alcohol molecule, m-hydrobenzoin in scCO(2). It is found that conversion and product distribution of this diol oxidation critically depend on the temperature and pressure of the scCO(2) used, which suggest the remarkable solvent properties of the scCO(2) under these unconventional oxidation conditions. (C) 2004 Elsevier Inc. All rights reserved.

Flavonoids: antioxidants or signalling molecules?

Many studies are accumulating that report the neuroprotective, cardioprotective, and chemopreventive actions of dietary flavonoids. While there has been a major focus on the antioxidant properties, there is an emerging view that flavonoids, and their in vivo metabolites, do not act as conventional hydrogen-donating antioxidants but may exert modulatory actions in cells through actions at protein kinase and lipid kinase signalling pathways. Flavonoids, and more recently their metabolites, have been reported to act at phosphoinositide 3-kinase (PI 3-kinase), Akt/protein kinase B (Akt/PKB), tyrosine kinases, protein kinase C (PKC), and mitogen activated protein kinase (MAP kinase) signalling cascades. Inhibitory or stimulatory actions at these pathways are likely to affect cellular function profoundly by altering the phosphorylation state of target molecules and by modulating gene expression. A clear understanding of the mechanisms of action of flavonoids, either as antioxidants or modulators of cell signalling, and the influence of their metabolism on these properties are key to the evaluation of these potent biomolecules as anticancer agents, cardioprotectants, and inhibitors of neurodegeneration (C) 2004 Elsevier Inc. All rights reserved.

Prebiotics and bowel cancer

Bowel cancer is a growing malignancy, with more than a million annual cases reported worldwide. It has been suggested that there is microbial involvement in onset of the disease and that an altered composition has previously been observed in those suffering from the malignancy, compared to healthy counterparts. The use of prebiotic functional foods to modify the colonic microflora may provide a method of reducing genotoxic potential within the colon, whilst offering-Protective strategies in the form of metabolites such as butyrate. The following review highlights some of the studies that demonstrate the potentia role for prebiotics as protective factors against bowel cancer.

Prebiotic interventions for the improvement of gut health

The increasing awareness of the role that the colonic microflora plays in maintaining host health within the gastrointestinal tract and systemically through the absorption of metabolites, has attracted a lot of interest, within the nutritional sciences, in developing dietary tools for controlling the colonic microflora. Among those dietary tools, prebiotics aim to improve health by stimulating numbers and/or activities of the beneficial bacteria in the gut, mainly bifidobacteria and lactobacilli. The ability of incorporating prebiotics in various food processes together with recent developments in understanding how prebiotics are metabolised by health promoting bacteria, allow us to specifically aim such dietary interventions towards selected population groups, such as infants and elderly, and disease states, such as colon cancer and irritable bowel disease.

Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons

There is growing interest in the potential beneficial effects of flavonoids in the aging and diseased brain. We have investigated the potential of the flavanone hesperetin and two of its metabolites, hesperetin-7-O-beta-D-glucuronide and 5-nitro-hesperetin, to inhibit oxidative stress-induced neuronal apoptosis. Exposure of cortical neurons to hydrogen peroxide led to the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser963, the phosphorylation of c-jun N-terminal kinase and c-Jun (Ser73) and the activation of caspase 3 and caspase 9. Whilst hesperetin glucuronide failed to exert protection, both hesperetin and 5-nitro-hesperetin were effective at preventing neuronal apoptosis via a mechanism involving the activation/phosphorylation of both Akt/protein kinase B and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Protection against oxidative injury and the activation of Akt and ERK1/2 followed a bell-shaped response and was most apparent at 100 nmol/L concentrations. The activation of ERK1/2 and Akt by flavanones led to the inhibition of the pro-apoptotic proteins, apoptosis signal-regulating kinase 1, by phosphorylation at Ser83 and Bad, by phosphorylation at both Ser136 and Ser112 and to the inhibition of peroxide-induced caspase 9 and caspase 3 activation. Thus, flavanones may protect neurons against oxidative insults via the modulation of neuronal apoptotic machinery.

Inhibition of cellular proliferation by the genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone is mediated by DNA damage and activation of the ATR signalling pathway

The cellular actions of genistein, and its in vivo metabolites, are believed to mediate the decreased risk of breast cancer associated with high soy consumption. The genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone (THIF), induced G2-M cell cycle arrest in T47D tumorigenic breast epithelial cells via a mechanism involving the activation of ataxia telangiectasia and Rad3-related kinase (ATR) via its phosphorylation at Ser(428). This activation of ATR appeared to result from THIF-induced increases in intracellular oxidative stress, a depletion of cellular GSH and an increase in DNA strand breakage. THIF treatment also led to an inhibition of cdc2, which was accompanied by the phosphorylation of both p53 (Ser(15)) and Chk1 (Ser(296)) and the de-activation of cdc25C phosphatase. We suggest the anti-proliferative actions of THIF may be mediated by initial oxidative DNA damage, activation of ATR and downstream regulation of the p53 and Chk1 pathways leading to cell cycle arrest in G2-M. This may represent one mechanism by which genistein exerts its cellular activity in vivo. (c) 2007 Elsevier Inc. All rights reserved.

Moderate Champagne consumption promotes an acute improvement in acute endothelial-independent vascular function in healthy human volunteers

Epidemiological studies have suggested an inverse correlation between red wine consumption and the incidence of CVD. However, Champagne wine has not been fully investigated for its cardioprotective potential. In order to assess whether acute and moderate Champagne wine consumption is capable of modulating vascular function, we performed a randomised, placebo-controlled, cross-over intervention trial. We show that consumption of Champagne wine, but not a control matched for alcohol, carbohydrate and fruit-derived acid content, induced an acute change in endothelium-independent vasodilatation at 4 and 8 h post-consumption. Although both Champagne wine and the control also induced an increase in endothelium-dependent vascular reactivity at 4 h, there was no significant difference between the vascular effects induced by Champagne or the control at any time point. These effects were accompanied by an acute decrease in the concentration of matrix metalloproteinase (MMP-9), a significant decrease in plasma levels of oxidising species and an increase in urinary excretion of a number of phenolic metabolites. In particular, the mean total excretion of hippuric acid, protocatechuic acid and isoferulic acid were all significantly greater following the Champagne wine intervention compared with the control intervention. Our data suggest that a daily moderate consumption of Champagne wine may improve vascular performance via the delivery of phenolic constituents capable of improving NO bioavailability and reducing matrix metalloproteinase activity.

Flavanol monomer-induced changes to the human faecal microflora

We have investigated the bacterial-dependent metabolism of (-)-epicatechin and (+)-catechin using a pH-controlled, stirred, batch-culture fermentation system reflective of the distal region of the human large intestine. Incubation of (-)-epicatechin or (+)-catechin (150mg/l or 1000mg/l) with faecal bacteria, led to the generation of 5-(3,4'-dihydroxyphenyl)-gamma-valerolactone, 5-phenyl-gamma-valerolactone and phenylpropionic acid. However, the formation of these metabolites from (+)-catechin required its initial conversion to (+)-epicatechin. The metabolism of both flavanols occurred in the presence of favourable carbon sources, notably sucrose and the prebiotic fructo-oligosaccharides, indicating that bacterial utilisation of flavanols also occurs when preferential energy sources are available. (+)-Catechin incubation affected the growth of select microflora, resulting in a statistically significant increase in the growth of the Clostridium coccoides-Eubacterium rectale group, Bifidobacterium spp. and Escherichia coli, as well as a significant inhibitory effect on the growth of the C. histolyticum group. In contrast, the effect of (-)-epicatechin was less profound, only significantly increasing the growth of the C. coccoides-Eubacterium rectale group. These potential prebiotic effects for both (+)-catechin and (-)-epicatechin were most notable at the lower concentration of 150 mg/l. As both (-)-epicatechin and (+)-catechin were converted to the same metabolites, the more dramatic change in the growth of distinct microfloral populations produced by (+)-catechin incubation may be linked to the bacterial conversion of (+)-catechin to (+)-epicatechin. Together these data suggest that the consumption of flavanol-rich foods may support gut health through their ability to exert prebiotic actions.

Effect of circulating forms of soy isoflavones on the oxidation of low density lipoprotein

Soy isoflavones are thought to have a cardioprotective effect that is partly mediated by an inhibitory influence on the oxidation of low density lipoprotein (LDL). However, the aglycone forms investigated in many previous studies do not circulate in appreciable quantities because they are metabolised in the gut and liver. We investigated effects of various isoflavone metabolites, including for the first time the sulphated conjugates formed in the liver and the mucosa of the small intestine, on copper-induced LDL oxidation. The parent aglycones inhibited oxidation, although only 5% as well as quercetin. Metabolism increased or decreased their effectiveness. Equol inhibited 2.65-fold better than its parent compound daidzein and 8-hydroxydaidzein, not previously assessed, was 12.5-fold better than daidzein. However, monosulphated conjugates of genistein, daidzein and equol were much less effective and disulphates completely ineffective. Since almost all isoflavones circulate as conjugates, these data suggest that despite the increased potency produced by some metabolic changes, isoflavones may not be effective antioxidants in vivo unless they are deconjugated again.

Modulation of the human gut microflora towards improved health using prebiotics: assessment of efficacy

There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An 'optimal' gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and/or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.

Studying the Human Gut Microbiota in the Trans-Omics Era - Focus on Metagenomics and Metabonomics

The human gut microbiota comprises a diverse microbial consortium closely co-evolved with the human genome and diet. The importance of the gut microbiota in regulating human health and disease has however been largely overlooked due to the inaccessibility of the intestinal habitat, the complexity of the gut microbiota itself and the fact that many of its members resist cultivation and are in fact new to science. However, with the emergence of 16S rRNA molecular tools and "post-genomics" high resolution technologies for examining microorganisms as they occur in nature without the need for prior laboratory culture, this limited view of the gut microbiota is rapidly changing. This review will discuss the application of molecular microbiological tools to study the human gut microbiota in a culture independent manner. Genomics or metagenomics approaches have a tremendous capability to generate compositional data and to measure the metabolic potential encoded by the combined genomes of the gut microbiota. Another post-genomics approach, metabonomics, has the capacity to measure the metabolic kinetic or flux of metabolites through an ecosystem at a particular point in time or over a time course. Metabonomics thus derives data on the function of the gut microbiota in situ and how it responds to different environmental stimuli e.g. substrates like prebiotics, antibiotics and other drugs and in response to disease. Recently these two culture independent, high resolution approaches have been combined into a single "transgenomic" approach which allows correlation of changes in metabolite profiles within human biofluids with microbiota compositional metagenomic data. Such approaches are providing novel insight into the composition, function and evolution of our gut microbiota.

An engineering model of the human colon

The development and performance of a three-stage tubular model of the large human intestine is outlined. Each stage comprises a membrane fermenter where flow of an aqueous polyethylene glycol solution on the outside of the tubular membrane is used to control the removal of water and metabolites (principally short chain fatty acids) from, and thus the pH of, the flowing contents on the fermenter side. The three stage system gave a fair representation of conditions in the human gut. Numbers of the main bacterial groups were consistently higher than in an existing three-chemostat gut model system, suggesting the advantages of the new design in providing an environment for bacterial growth to represent the actual colonic microflora. Concentrations of short chain fatty acids and Ph levels throughout the system were similar to those associated with corresponding sections of the human colon. The model was able to achieve considerable water transfer across the membrane, although the values were not as high as those in the colon. The model thus goes some way towards a realistic simulation of the colon, although it makes no pretence to simulate the pulsating nature of the real flow. The flow conditions in each section are characterized by low Reynolds numbers: mixing due to Taylor dispersion is significant, and the implications of Taylor mixing and biofilm development for the stability, that is the ability to operate without washout, of the system are briefly analysed and discussed. It is concluded that both phenomena are important for stabilizing the model and the human colon.

Metabolism of dietary phytochemicals: a review of the metabolic forms identified in humans

Dietary derived phytochemicals have been proposed to act as beneficial agents in a multitude of disease states, including cancer, cardiovascular disease and neurodegenerative disorders. However, the biological effect of such compounds will ultimately depend on the cellular effects of their circulating metabolites. The focus of this review is to examine the current knowledge regarding the biotransformation of different classes of phytochemicals in humans. Notably, the data compiled here represents only that obtained from human studies following consumption of phytochemicals in meals or in a dose comparable with normal dietary intake. In addition, we have considered only those studies where more powerful analytical techniques have been used in the characterisation of metabolic forms. We provide clear information regarding the types of metabolites that are likely to be present in humans following oral ingestion. Ultimately this will help identify metabolic forms that should represent the focus of future cellular mechanistic investigations.