Comparative effect of dairy fatty acids on cell adhesion molecules, nitric oxide and relative gene expression in healthy and diabetic human aortic endothelial cells

Dairy intake, despite its high saturated fatty acid (SFA) content, is associated with a lower risk of cardiovascular disease and diabetes. This in vitro study determined the effect of individual fatty acids (FA) found in dairy, and FA mixtures representative of a high SFA and a low SFA dairy lipid on markers of endothelial function in healthy and type II diabetic aortic endothelial cells.

Dimer formation by symbiotic donor–acceptor interaction between two molecules of a specially designed dioxomolybdenum(VI) complex containing both donor and acceptor centers – A structural, spectroscopic and DFT study

This work presents a model study for the formation of a dimeric dioxomolybdenum(VI) complex [MoO2L]2, generated by simultaneous satisfaction of acceptor and donor character existing in the corresponding monomeric Mo(VI) complex MoO2L. This mononuclear complex is specially designed to contain a coordinatively unsaturated Mo(VI) acceptor centre and a free donor group, (e.g. –NH2 group) strategically placed in the ligand skeleton [H2L = 2-hydroxyacetophenonehydrazone of 2-aminobenzoylhydrazine]. Apart from the dimer [MoO2L]2, complexes of the type MoO2L·B (where B = CH3OH, γ-picoline and imidazole) are also reported. All the complexes are characterized by elemental analysis, spectroscopic (UV–Vis, IR, 1H NMR) techniques and cyclic voltammetry. Single crystal X-ray structures of [MoO2L]2 (1), MoO2L·CH3OH (2), and MoO2L.(γ-pic) (3) have been determined and discussed. DFT calculation on these complexes corroborates experimental data and provides clue for the facile formation of this type of dimer not reported previously. The process of dimer formation may also be viewed as an interaction between two molecules of a specially designed complex acting as a monodentate ligand. This work is expected to open up a new field of design and synthesis of dimeric complexes through the process of symbiotic donor–acceptor (acid–base) interaction between two molecules of a specially designed monomer.

Tripodal molecules for the promotion of phosphoester hydrolysis

A series of low molecular weight tripodal amide/histidine-containing compounds (1–2) have been synthesised and shown to increase the rate of bis-(p-nitrophenyl) phosphate (BNPP) and soman (GD) breakdown in buffered aqueous solution.

Adsorption of organic molecules at the TiO2(110) surface: the effect of van der Waals interactions

Understanding the interaction of organic molecules with TiO2 surfaces is important for a wide range of technological applications. While density functional theory (DFT) calculations can provide valuable insight about these interactions, traditional DFT approaches with local exchange-correlation functionals suffer from a poor description of non-bonding van der Waals (vdW) interactions. We examine here the contribution of vdW forces to the interaction of small organic molecules (methane, methanol, formic acid and glycine) with the TiO2 (110) surface, based on DFT calculations with the optB88-vdW functional. The adsorption geometries and energies at different configurations were also obtained in the standard generalized gradient approximation (GGA-PBE) for comparison. We find that the optB88-vdW consistently gives shorter surface adsorbate-to-surface distances and slightly stronger interactions than PBE for the weak (physisorbed) modes of adsorption. In the case of strongly adsorbed (chemisorbed) molecules both functionals give similar results for the adsorption geometries, and also similar values of the relative energies between different chemisorption modes for each molecule. In particular both functionals predict that dissociative adsorption is more favourable than molecular adsorption for methanol, formic acid and glycine, in general agreement with experiment. The dissociation energies obtained from both functionals are also very similar, indicating that vdW interactions do not affect the thermodynamics of surface deprotonation. However, the optB88-vdW always predicts stronger adsorption than PBE. The comparison of the methanol adsorption energies with values obtained from a Redhead analysis of temperature programmed desorption data suggests that optB88-vdW significantly overestimates the adsorption strength, although we warn about the uncertainties involved in such comparisons.

Self-assembly of a dual functional bioactive peptide amphiphile incorporating both matrix metalloprotease substrate and cell adhesion motifs

We describe a bioactive lipopeptide that combines the capacity to promote the adhesion and subsequent self-detachment of live cells, using template-cell-environment feedback interactions. This self-assembling peptide amphiphile comprises a diene-containing hexadecyl lipid chain (C16e) linked to a matrix metalloprotease-cleavable sequence, Thr-Pro-Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln, and contiguous with a cell-attachment and signalling motif, Arg-Gly-Asp-Ser. Biophysical characterisation revealed that the PA self-assembles into 3 nm diameter spherical micelles above a critical aggregation concentration (cac). In addition, when used in solution at 5–150 nM (well below the cac), the PA is capable of forming film coatings that provide a stable surface for human corneal fibroblasts to attach and grow. Furthermore, these coatings were demonstrated to be sensitive to metalloproteases expressed endogenously by the attached cells, and consequently to elicit the controlled detachment of cells without compromising their viability. As such, this material constitutes a novel class of multi-functional coating for both fundamental and clinical applications in tissue engineering.

Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl

Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO−), polysulfides, and dinitrososulfite N-nitrosohydroxylamine-N-sulfonate (SULFI/NO), each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO− is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO− synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.

Emulation of chiral hydrogenation catalysts by adsorbtion of small molecules onto Ni surfaces

Adsorption of small molecules on the Ni{111} and NiO{111} surfaces is investigated under UHV and elevated pressures (~10-1 mbar) of hydrogen and water. The molecules considered are chosen for their relevance to understanding the mechanism of enantioselective hydrogenation on Raney Nickel modified by chiral molecules. Adsorption of water onto, and its subsequent reaction with, oxygen-covered Ni{111} is dependent on the initial atomic oxygen coverage. An OH species (O1s binding energy 531.5eV), oriented perpendicular to the surface, forms at atomic oxygen coverages <0.25ML. The reaction does not consume all the adsorbed oxygen for coverages ≥0.12ML. The p(2×2) atomic oxygen uperstructure is unreactive, while an OH species is formed on the p(√3×√3) superstructure at binding energy 530.9eV. L-alanine is adsorbed on Ni{111} as a model chiral modifier molecule. At low coverages, alanine forms a presumed tridentate alaninate species for coverages ≥0.11ML at 250K. A minority, bidentate zwitterionic species forms at coverages >0.11ML, but was not observed at 300K. Saturation occurs at 0.25ML. At high alanine coverages (≥0.19ML) and H2 pressure (≥1×10-2 mbar), the tridentate L-alaninate converts to bidentate zwitterionic L-alanine at 300K. Thermal evolution of L-alanine on Ni{111} under varying hydrogen pressures is examined. Adsorption of L-alanine onto hydroxylated NiO{111} at 300K in UHV, mimicking a catalyst surface under aqueous conditions, yields the tridentate alaninate which is immune to the effects of elevated hydrogen pressure. Exposing the L-alanine/Ni{111} adsorption system to water (≤10-1 mbar) oxidises the surface and recreates the L-alanine/hydroxylated NiO{111} system. Pyruvic acid on Ni{111} is examined as a model for hydrogenation substrate adsorption. Behaviour is coverage dependent and several conformations are possible at low coverages (≤0.1ML). Annealing at coverages <0.2ML causes a condensation reaction, releasing water onto the surface. High coverages do not condense and a saturation coverage of ~0.35ML is found.

Nitrosopersulfide (SSNO-) targets soluble guanylyl cyclase and induces vasodilation in vivo

Background Recent experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide signaling pathways are intimately intertwined particularly in the vasculature, with mutual attenuation or potentiation of biological responses under control of the soluble guanylyl cyclase (sGC) / phopshodiesterase (PDE) pathway. There is now compelling evidence that part of the NO/sulfide cross talk has a chemical foundation via the formation of S/N-hybrid molecules including thionitrous acid (HSNO) and nitrosopersulfde (SSNO-). The aim of this study was to characterize the bioactive products of the interaction between sulfide and NO metabolites targeting sGC that may potentially regulate vasodilation. Results We found that the chemical interaction of sulfide with NO or nitrosothiols leads to formation of S/N-hybrid metabolites including SSNO- via intermediate formation of HSNO. Contrary to a recent report in the literature but consistent with the transient nature of HSNO, its formation was not detectable by high-resolution mass spectrometry under physiologically relevant conditions. SSNO- is also formed in non-aqueous media by the reaction of nitrite with oxidized sulfur species including colloidal sulfur and polysulfides. SSNO- is stable in the presence of high concentrations of thiols, release NO, and activates sGC in RFL-6 cells in an NO-dependent fashion. Moreover, SSNO- is a potent vasodilator in aortic rings in vitro and lowers blood pressure in rats in vivo. The presence of high concentrations of SOD or thiols does not affect SSNO- mediated sGC activation, while it potentiates and inhibits the effects of the nitroxyl (HNO) donor Angeli's salt, suggesting that HNO release from SSNO- is not involved in sGC activation. Conclusion The reaction between NO and sulfide leads to fomation of S/N-hybrid molecules including SSNO-, releasing NO, activating sGC and inducing vasodilation. SSNO- is considerably more stable than HSNO at pH 7.4 and thus a more likely biological mediator that can account for the chemical cross-talk between NO and sulfide.

GPVI potentiation of platelet activation by thrombin and adhesion molecules independent of Src kinases and Syk.

We show that Syk is critical for lamellipodia formation on a range of immobilized proteins but that this can be overcome by addition of thrombin. Further, we reveal a novel role for GPVI in supporting thrombin-induced activation, independent of Syk and Src kinases.

Elucidating the structure of chiral molecules by using amplified vibrational circular dichroism: from theory to experimental realization

Recent experimental observations of enhanced vibrational circular dichroism (VCD) in molecular systems with low-lying electronically excited states suggest interesting new applications of VCD spectroscopy. The theory describing VCD enhancement through vibronic coupling schemes was derived by Nafie in 1983, but only recently experimental evidence of VCD amplification has demonstrated the extent to which this effect can be exploited as a structure elucidation tool to probe local structure. In this Concept paper, we give an overview of the physics behind vibrational circular dichroism, in particular the equations governing the VCD amplification effect, and review the latest experimental developments with a prospective view on the application of amplified VCD to locally probe biomolecular structure.

From molecules to neural morphology: understanding neuroinflammation in autism spectrum condition

Growing evidence points toward a critical role for early (prenatal) atypical neurodevelopmental processes in the aetiology of autism spectrum condition (ASC). One such process that could impact early neural development is inflammation. We review the evidence for atypical expression of molecular markers in the amniotic fluid, serum, cerebrospinal fluid (CSF), and the brain parenchyma that suggest a role for inflammation in the emergence of ASC. This is complemented with a number of neuroimaging and neuropathological studies describing microglial activation. Implications for treatment are discussed.

Production of bioactive diterpenoids in the Euphorbiaceae depends on evolutionarily conserved gene clusters

The Euphorbiaceae produce a diverse range of diterpenoids, many of which have pharmacological activities. These diterpenoids include ingenol mebutate, which is licensed for the treatment of a precancerous skin condition (actinic keratosis), and phorbol derivatives such as resiniferatoxin and prostratin, which are undergoing investigation for the treatment of severe pain and HIV, respectively. Despite the interest in these diterpenoids, their biosynthesis is poorly understood at present, with the only characterized step being the conversion of geranylgeranyl pyrophosphate into casbene. Here, we report a physical cluster of diterpenoid biosynthetic genes from castor (Ricinus communis), including casbene synthases and cytochrome P450s from the CYP726A subfamily. CYP726A14, CYP726A17, and CYP726A18 were able to catalyze 5-oxidation of casbene, a conserved oxidation step in the biosynthesis of this family of medicinally important diterpenoids. CYP726A16 catalyzed 7,8-epoxidation of 5-keto-casbene and CYP726A15 catalyzed 5-oxidation of neocembrene. Evidence of similar gene clustering was also found in two other Euphorbiaceae, including Euphorbia peplus, the source organism of ingenol mebutate. These results demonstrate conservation of gene clusters at the higher taxonomic level of the plant family and that this phenomenon could prove useful in further elucidating diterpenoid biosynthetic pathways.

Five vicarious genera from Gondwana: the Velloziaceae as shown by molecules and morphology

Background and Aims The amount of data collected previously for Velloziaceae neither clarified relationships within the family nor helped determine an appropriate classification, which has led to huge discordance among treatment by different authors. To achieve an acceptable phylogenetic result and understand the evolution and roles of characters in supporting groups, a total evidence analysis was developed which included approx. 20 % of the species and all recognized genera and sections of Velloziaceae, plus outgroups representatives of related families within Pandanales. Methods Analyses were undertaken with 48 species of Velloziaceae, representing all ten genera, with DNA sequences from the atpB-rbcL spacer, trnL-trnF spacer, trnL intron, trnH-psbA spacer, ITS ribosomal DNA spacers and morphology. Key Results Four groups consistently emerge from the analyses. Persistent leaves, two phloem strands, stem cortex divided in three regions and violet tepals support Acanthochlamys as sister to Velloziaceae s. s., which are supported mainly by leaves with marginal bundles, transfusion tracheids and inflorescence without axis. Within Velloziaceae s. s., an African Xerophyta + Talbotia clade is uniquely supported by basal loculicidal capsules; an American clade, Barbacenia s. l. + Barbaceniopsis + Nanuza + Vellozia, is supported by only homoplastic characters. Barbacenia s. l. (Aylthonia + Barbacenia + Burlemarxia + Pleurostima) is supported by a double sheath in leaf vascular bundles and a corona; Barbaceniopsis + Nanuza + Vellozia is not supported by an unambiguous character, but Barbaceniopsis is supported by five characters, including diclinous flowers, Nanuza + Vellozia is supported mainly by horizontal stigma lobes and stem inner cortex cells with secondary walls, and Vellozia alone is supported mainly by pollen in tetrads. Conclusions The results imply recognition of five genera (Acanthochlamys (Xerophyta (Barbacenia (Barbaceniopsis, Vellozia)))), solving the long-standing controversies among recent classifications of the family. They also suggest a Gondwanan origin for Velloziaceae, with a vicariant pattern of distribution.