Syntheses, spectroelectrochemical studies, and molecular and electronic structures of ferrocenyl ene-diynes

The readily available complex 1,1-dibromo-2-ferrocenylethylene provides a convenient entry point for the preparation of a wide range of cross-conjugated 1,1-bis(alkynyl)-2-ferrocenylethenes through simple Pd(0)/Cu(I)-mediated cross-coupling reactions with 1-alkynes. The ferrocene moiety in compounds of the general form FcCHC(CCR)2 is essentially electronically isolated from the cross-conjugated π system, as evidenced by IR and UV−vis spectroelectrochemical experiments and quantum chemical calculations. In contrast to the other examples which give stable ferrocenium derivatives upon electrochemical oxidation, the aniline derivatives [FcCHC(CCC6H4NH2-4)2]+ and [FcCHC(CCC6H4NMe2-4)2]+ proved to be unstable on the time scale of the spectroelectrochemical experiments, leading to passivation of the electrode surface over time. There is no significant thermodynamic stabilization of the radical anion [FcCHC(CCC6H4NO2-4)2]− relative to the neutral and dianionic analogues, although the dianion [FcCHC(CCC6H4NO2- 4)2]2− could be studied as a relatively chemically stable species and is well described in terms of two linked nitrophenyl radicals. The capacity to introduce a relatively isolated point charge at the periphery of the cross-conjugated π system appears to make these complexes useful templates for the construction of electrochemically gated quantum interference transistors.

Investigating flavonoids as molecular templates for the design of small-molecule inhibitors of cell signaling

Epidemiological and clinical trials reveal compelling evidence for the ability of dietary flavonoids to lower cardiovascular disease risk. The mechanisms of action of these polyphenolic compounds are diverse, and of particular interest is their ability to function as protein and lipid kinase inhibitors. We have previously described structure-activity studies that reinforce the possibility for using flavonoid structures as templates for drug design. In the present study, we aim to begin constructing rational screening strategies for exploiting these compounds as templates for the design of clinically relevant, antiplatelet agents. We used the platelet as a model system to dissect the structural influence of flavonoids, stilbenes, anthocyanidins, and phenolic acids on inhibition of cell signaling and function. Functional groups identified as relevant for potent inhibition of platelet function included at least 2 benzene rings, a hydroxylated B ring, a planar C ring, a C ring ketone group, and a C-2 positioned B ring. Hydroxylation of the B ring with either a catechol group or a single C-4' hydroxyl may be required for efficient inhibition of collagen-stimulated tyrosine phosphorylated proteins of 125 to 130 kDa, but may not be necessary for that of phosphotyrosine proteins at approximately 29 kDa. The removal of the C ring C-3 hydroxyl together with a hydroxylated B ring (apigenin) may confer selectivity for 37 to 38 kDa phosphotyrosine proteins. We conclude that this study may form the basis for construction of maps of flavonoid inhibitory activity on kinase targets that may allow a multitargeted therapeutic approach with analogue counterparts and parent compounds.

Characterization and antimicrobial efficacy against E. coli of a helium/air plasma at atmospheric pressure created in a plastic package

A plasma source, sustained by the application of a floating high voltage (±15 kV) to parallel-plate electrodes at 50 Hz, has been achieved in a helium/air mixture at atmospheric pressure (P = 105 Pa) contained in a zip-locked plastic package placed in the electrode gap. Some of the physical and antimicrobial properties of this apparatus were established with a view to ascertain its performance as a prototype for the disinfection of fresh produce. The current–voltage (I–V) and charge–voltage (Q–V) characteristics of the system were measured as a function of gap distance d, in the range (3 × 103 ≤ Pd ≤ 1.0 × 104 Pa m). The electrical measurements showed this plasma source to exhibit the characteristic behaviour of a dielectric barrier discharge in the filamentary mode and its properties could be accurately interpreted by the two-capacitance in series model. The power consumed by the discharge and the reduced field strength were found to decrease quadratically from 12.0 W to 4.5 W and linearly from 140 Td to 50 Td, respectively, in the range studied. Emission spectra of the discharge were recorded on a relative intensity scale and the dominant spectral features could be assigned to strong vibrational bands in the 2+ and 1− systems of N2 and ${\rm N}_2^+$ , respectively, with other weak signatures from the NO and OH radicals and the N+, He and O atomic species. Absolute spectral intensities were also recorded and interpreted by comparison with the non-equilibrium synthetic spectra generated by the computer code SPECAIR. At an inter-electrode gap of 0.04 m, this comparison yielded typical values for the electron, vibrational and translational (gas) temperatures of (4980 ± 100) K, (2700 ± 200) K and (300 ± 100) K, respectively and an electron density of 1.0 × 1017 m−3. A Boltzmann plot also provided a value of (3200 ± 200 K) for the vibrational temperature. The antimicrobial efficacy was assessed by studying the resistance of both Escherichia coli K12 its isogenic mutants in soxR, soxS, oxyR, rpoS and dnaK selected to identify possible cellular responses and targets related with 5 min exposure to the active gas in proximity of, but not directly in, the path of the discharge filaments. Both the parent strain and mutants populations were significantly reduced by more than 1.5 log cycles in these conditions, showing the potential of the system. Post-treatment storage studies showed that some transcription regulators and specific genes related to oxidative stress play an important role in the E. coli repair mechanism and that plasma exposure affects specific cell regulator systems.

The Functionality of the three-sited Ferroxidase center of E. coli Bacterial Ferritin (EcFtnA)

At least three ferritins are found in the bacterium Escherichia coli, the heme-containing bacterioferritin (EcBFR) and two non-heme bacterial ferritins (EcFtnA and EcFtnB). In addition to the conserved A- and B-sites of the diiron ferroxidase center, EcFtnA has a third iron-binding site (the C-site) of unknown function that is nearby the diiron site. In the present work, the complex chemistry of iron oxidation and deposition in EcFtnA has been further defined through a combination of oximetry, pH stat, stopped-flow and conventional kinetics, UV-visible, fluorescence and EPR spectroscopic measurements on the wildtype protein and site-directed variants of the A-, B- and C-sites. The data reveal that, while H2O2 is a product of dioxygen reduction in EcFtnA and oxidation occurs with a stoichiometry of Fe(II)/O2 ~ 3:1, most of the H2O2 produced is consumed in subsequent reactions with a 2:1 Fe(II)/H2O2 stoichiometry, thus suppressing hydroxyl radical formation. While the A- and B-sites are essential for rapid iron oxidation, the C-site slows oxidation and suppresses iron turnover at the ferroxidase center. A tyrosyl radical, assigned to Tyr24 near the ferroxidase center, is formed during iron oxidation and its possible significance to the function of the protein is discussed. Taken as a whole, the data indicate that there are multiple iron-oxidation pathways in EcFtnA with O2 and H2O2 as oxidants. Furthermore, the data are inconsistent with the C-site being a transit site, providing iron to the A- and B-sites, and does not support a universal mechanism for iron oxidation in all ferritins as recently proposed.

The logic of ideas in Christopher Hill's English revolution

This article examines the role played by ideas and their thinkers in Christopher Hill's histories of the English Revolution. Hill protested against a reductionist economic determinism with no place for the intrinsic power of ideas, but his account of ideas gave them a progressive logic parallel to, if not always easy to link with, that of economic development, and threatened to divorce them from their muddled and imperfect thinkers. This account of the logic of ideas had a striking impact on the way in which the more mainstream radicals of the English Revolution appeared in Hill's work, with both the Levellers and James Harrington being half assimilated to, and half pushed aside in favor of, the more thoroughgoing economic radicals who expressed, in however ragged a way, the intrinsic potential of their ideas. However, Hill's writings also betray a surprising attraction to religious over secular forms of radicalism.

GRID and docking analyses reveal a molecular basis for flavonoid inhibition of src-family kinase activity

Flavonoids reduce cardiovascular disease risk through anti-inflammatory, anti-coagulant and anti-platelet actions. One key flavonoid inhibitory mechanism is blocking kinase activity that drives these processes. Flavonoids attenuate activities of kinases including phosphoinositide-3-kinase (PI3K), Fyn, Lyn, Src, Syk, PKC, PIM1/2, ERK, JNK, and PKA. X-ray crystallographic analyses of kinase-flavonoid complexes show that flavonoid ring systems and their hydroxyl substitutions are important structural features for their binding to kinases. A clearer understanding of structural interactions of flavonoids with kinases is necessary to allow construction of more potent and selective counterparts. We examined flavonoid (quercetin, apigenin and catechin) interactions with Src-family kinases (Lyn, Fyn and Hck) applying the Sybyl docking algorithm and GRID. A homology model (Lyn) was used in our analyses to demonstrate that high quality predicted kinase structures are suitable for flavonoid computational studies. Our docking results revealed potential hydrogen bond contacts between flavonoid hydroxyls and kinase catalytic site residues. Identification of plausible contacts indicated that quercetin formed the most energetically stable interactions, apigenin lacked hydroxyl groups necessary for important contacts, and the non-planar structure of catechin could not support predicted hydrogen bonding patterns. GRID analysis using a hydroxyl functional group supported docking results. Based on these findings, we predicted that quercetin would inhibit activities of Src-family kinases with greater potency than apigenin and catechin. We validated this prediction using in vitro kinase assays. We conclude that our study can be used as a basis to construct virtual flavonoid interaction libraries to guide drug discovery using these compounds as molecular templates.

Living the Revolution: urban communes & soviet socialism, 1917-1932

This book follows a revolutionary trend popular among young activists and would-be radicals after 1917, the formation of collective units of cohabitation and association known as 'urban communes'. In these spaces, activists tried to live what they understood as the 'socialist lifestyle', self-consciously putting Marxist and Bolshevik theories into practice. By telling the story of the urban communes, this book reveals how grand revolutionary ideals, such as collectivism, equality, proletarian ethics, and modern practice, were experienced, understood, and appropriated on a human level. This enables us to better understand the messy realities of the early Soviet state, showing how ideological beliefs and revolutionary contingencies actually came into being during this time.

Chemoselective and stereoselective lithium carbenoid mediated cyclopropanation of acyclic allylic alcohols

The reaction of geraniol with different lithium carbenoids generated from n-BuLi and the corresponding dihaloalkane has been evaluated. The reaction occurs in a chemo and stereoselective manner, which is consistent with a directing effect from the oxygen of the allylic moiety. Furthermore, a set of polyenes containing allylic hydroxyl or ether groups were chemoselectively and stereoselectively converted into the corresponding gemdimethylcyclopropanes in one single step in moderate to good yields mediated by a lithium carbenoid generated in situ by reaction of n-BuLi and 2,2-dibromopropane.

Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

With many cancers showing resistance to current chemotherapies, the search for novel anti-cancer agents is attracting considerable attention. Natural flavonoids have been identified as useful leads in such programmes. However, since an in-depth understanding of the structural requirements for optimum activity is generally lacking, further research is required before the full potential of flavonoids as anti-proliferative agents can be realised. Herein a broad library of 76 methoxy and hydroxy flavones, and their 4-thio analogues, was constructed and their structure-activity relationships for anti-proliferative activity against the breast cancer cell lines MCF-7 (ER+ve), MCF-7/DX (ER+ve, anthracycline resistant) and MDA-MB-231 (ER-ve) were probed. Within this library, 42 compounds were novel, and all compounds were afforded in good yields and > 95% purity. The most promising lead compounds, specifically the novel hydroxy 4-thioflavones 15f and 16f, were further evaluated for their anti-proliferative activities against a broader range of cancer cell lines by the National Cancer Institute (NCI), USA and displayed significant growth inhibition profiles (e.g Compound-15f: MCF-7 (GI50 = 0.18 μM), T-47D (GI50 = 0.03 μM) and MDA-MB-468 (GI50 = 0.47 μM) and compound-16f: MCF-7 (GI50 = 1.46 μM), T-47D (GI50 = 1.27 μM) and MDA-MB-231 (GI50 = 1.81 μM). Overall, 15f and 16f exhibited 7-46 fold greater anti-proliferative potency than the natural flavone chrysin (2d). A systematic structure-activity relationship study against the breast cancer cell lines highlighted that free hydroxyl groups and the B-ring phenyl groups were essential for enhanced anti-proliferative activities. Substitution of the 4-C=O functionality with a 4-C=S functionality, and incorporation of electron withdrawing groups at C4’ of the B-ring phenyl, also enhanced activity. Molecular docking and mechanistic studies suggest that the anti-proliferative effects of flavones 15f and 16f are mediated via ER-independent cleavage of PARP and downregulation of GSK-3β for MCF-7 and MCF-7/DX cell lines. For the MDA-MB-231 cell line, restoration of the wild-type p53 DNA binding activity of mutant p53 tumour suppressor gene was indicated.

Evaluation of phenolic compounds in mate (Ilex paraguariensis) processed by gamma radiation

The radiation food processing has been demonstrating great effectiveness in the attack of pathogenic agents, while little compromising nutritional value and sensorial properties of foods. The mate (Ilex paraguariensis), widely consumed product in South America, generally in the form of infusions with hot or cold water, calls of chimarrao or terere, it is cited in literature as one of the best sources phenolic compounds. The antioxidants action of these constituent has been related to the protection of the organism against the free radicals, generated in alive, currently responsible for the sprouting of some degenerative illness as cancer, arteriosclerosis, rheumatic arthritis and cardiovascular clutters among others. The objective of that work was to evaluate the action of the processing for gamma radiation in phenolic compounds of terere beverage in the doses of 0, 3, 5, 7 and 10 kGy. The observed results do not demonstrate significant alterations in phenolic compounds of terere beverage processed by gamma radiation. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.

Microbicidal Action of Indole-3-Acetic Acid Combined with Horseradish Peroxidase on Prototheca zopfii from Bovine Mastitis

We investigated the toxic effect of indole-3-acetic acid (IAA) combined with horseradish peroxidase (HRP) on Prototheca zopfii from bovine mastitis. P. zopfii isolates were identified and characterized by morpho-physiological parameters; presences of P. zopfii genotype 2 were also investigated. Subsequently, P. zopfii was incubated in the absence (control) or presence of IAA/HRP and examined for: (i) cell viability; (ii) colonies number formation; (iii) antioxidant enzyme activity; and (iv) DNA integrity. Significance of differences was calculated using ANOVA and Tukey`s test (P a parts per thousand currency sign 0.05). As evidenced by Trypan blue exclusion and colony formation in Sabouraud dextrose agar, IAA/HRP addition to the culture reduced respective P. zopfii viability and P. zopfii colony formation in a concentration- and time-dependent manner. IAA/HRP specifically reduced cell viability in 10, 15, 20, 25, and 32% after 4, 6, 8, 10, and 12 h of incubation, respectively, compared with the control at the same time. The number of colony formation was inhibited (45, 82, and 88%) by IAA/HRP after 4, 6, and 9 h of incubation, respectively, compared with the control at the same time. In addition, P. zopfii antioxidant activity increased measurably in the presence of IAA/HRP (6 h); superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase increased by 90, 120, 150% and 3.4 times, compared with the controls. IAA/HRP did not appear to effect P. zopfii DNA integrity when examined by electrophoresis. In conclusion, IAA/HRP appears to function as a microbicidal mechanism on P. zopfii genotype 2 from bovine mastitis.

Garlic powder and wheat bran as fillers: Their effect on the physicochemical properties of edible biocomposites

Biocomposites with two different fillers, garlic and wheat bran, were studied. They were based on cassava starch and contained glycerol as a plasticizer and potassium sorbate as an antimicrobial agent and were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and infrared spectroscopy (IR). The mechanical performance at room and lower temperatures was also studied. SEM micrographies of fractured surfaces of the wheat bran composite films showed some ruptured particles of fiber while fibrils of garlic on the order of nanometers were observed when garlic composite films were studied. Mechanical tests, at room temperature, showed that the addition of wheat bran led to an increment in the storage modulus (E`) and hardening and a decrease in Tan delta, while the garlic composite showed a diminishing in the E` and hardening and did not produce significant changes in Tan delta values when compared with systems without fillers (matrix). In the range between -90 degrees C and 20 degrees C. all the materials studied presented two peaks in the Tan delta curve. In the case of the wheat bran composite, both relaxation peaks shifted slightly to higher temperatures, broadened and diminished their intensity when compared with those of the matrix; however garlic composite showed a similar behavior to the matrix. DSC thermograms of aqueous systems showed a slight shift of gelatinization temperature (T(gelatinization)) to higher values when the fillers were present. Thermograms of films showed that both, garlic and wheat bran composites, had a lower melting point than the matrix. IR data indicated that interaction between starch and fillers determined an increase in the availability of hydroxyl groups to be involved in a dynamic exchange with water. (C) 2010 Elsevier B.V. All rights reserved.

Development of films based on blends of gelatin and poly(vinyl alcohol) cross linked with glutaraldehyde

Both gelatin and poly(vinyl alcohol) (PVA) can be cross linked with glutaraldehyde (GLU). In the case of gelatin, the GLU reacts with each e-NH2 functional group of adjacent lysine residues, while for PVA, the GLU reacts with two adjacent hydroxyl groups, forming acetal bridges. Thus it can be considered possible to cross link adjacent macromolecules of gelatin and PVA using GLU. In this context, the aims of this work were the development of biodegradable films based on blends of gelatin and poly(vinyl alcohol) cross linked with GLU, and the characterization of some of their main physical and functional properties. All the films were produced from film-forming solutions (FFS) containing 2 g macromolecules (PVA + gelatin)/100 g FFS, 25 g glycerol/100 g macromolecules, and 4 g GLU (25% solution)/100 g FFS. The FFS were prepared with two concentrations of PVA (20 or 50 g PVA/100 g macromolecules) and two reaction temperatures: 90 or 55 degrees C, applied for 30 min. The films were obtained after drying (30 degrees C/24 h) and conditioning at 25 degrees C and 58% of relative humidity for 7 days, and were then characterized. The results for the color parameters, mechanical properties, phase transitions and infrared spectra showed that some chemical modifications occurred, principally for the gelatin. However, in general, all the characteristics of the films were either typical of films based on blends of these macromolecules without cross linking, or slightly higher. A greater improvement in the properties of this material was probably not observed due to the crystallinity of the PVA, which has a melting point above 90 degrees C. The presence of microcrystals in the polymer chain probably reduced macromolecular mobility, hindering the reaction. Thus more research is necessary to produce biodegradable films with improved properties. (C) 2011 Elsevier Ltd. All rights reserved.

Baroreflex sensitivity and oxidative stress in the LDL receptor knockout mice

This study alms at observing the effect of low-density lipoprotein (LDL) receptor deficiency in cholesterol blood levels, baroreflex sensitivity (BRS), nitric oxide (NO) bioavailability, and oxidative stress. The lack of LDL receptors in mice significantly increased the cholesterol blood levels (179 +/- 35 vs. 109 +/- 13 mg/dL) in the knockout (KO) mice compared to control. There was no difference in basal mean arterial pressure and heart rate between the groups. However, in KO mice the BRS was significantly attenuated and the antioxidant enzyme activities, measured in erythrocytes and heart, were significantly decreased. On the other hand, the oxidative damage measured by chemiluminescence and carbonyls was increased, while total plasma nitrate levels were lower in KO mice, indicating a decrease in NO availability. In conclusion, these results indicate that the lack of LDL receptor increased cholesterol blood levels, induced oxidative stress and decreased BRS. (C) 2008 Elsevier GmbH. All rights reserved.

Reactive oxygen species generated by NADPH oxidase are involved in neurodegeneration in the pilocarpine model of temporal lobe epilepsy

Reactive oxygen species (ROS) appear to be involved in several neurodegenerative disorders. We tested the hypothesis that oxidative stress could have a role in the hippocampal neurodegeneration observed in temporal lobe epilepsy induced by pilocarpine. We first determined the spatio-temporal pattern of ROS generation, by means of detection with dihydroethidium oxidation, in the CA1 and CA3 areas and the dentate gyrus of the dorsal hippocampus during status epilepticus induced by pilocarpine. Fluoro-Jade B assays were also performed to detect degenerating neurons. ROS generation was increased in CA1, CA3 and the dentate gyrus after pilocarpine-induced seizures, which was accompanied by marked cell death. Treatment of rats with a NADPH oxidase inhibitor (apocynin) for 7 days prior to induction of status epilepticus was effective in decreasing both ROS production (by an average of 20%) and neurodegeneration (by an average of 61%). These results suggest an involvement of ROS generated by NADPH oxidase in neuronal death in the pilocarpine model of epilepsy. (C) 2010 Elsevier Ireland Ltd. All rights reserved.