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Particulate matter (PM) exposure is linked to the worsening of respiratory conditions, including allergic rhinitis (AR), as it can trigger nasal and systemic inflammation. To unveil the underlying molecular mechanisms, we investigated the effects of PM exposure on the release of plasmatic extracellular vesicles (EV) and on the complex cross-talk between the host and the nasal microbiome. To this aim, we evaluated the effects of PM10 and PM2.5 exposures on both the bacteria-derived-EV portion (bEV) and the host-derived EVs (hEV), as well as on bacterial nasal microbiome (bNM) features in 26 AR patients and 24 matched healthy subjects (HS). In addition, we assessed the role exerted by the bNM as a modifier of PM effects on the complex EV signaling network in the paradigmatic context of AR. We observed that PM exposure differently affected EV release and bNM composition in HS compared to AR, thus potentially contributing to the molecular mechanisms underlying AR. The obtained results represent the first step towards the understanding of the complex signaling network linking external stimuli, bNM composition, and the immune risponse.

Objective To demonstrate the in vitro activities of panthenol, palmitoylethanolamide (PEA), and niacinamide (NAM) and determine the biophysical properties, clinical safety, tolerability together with efficacy of two developmental anti‐redness (AR) formulations containing these ingredients, in alleviating facial redness associated with winter xerosis in healthy volunteers with sensitive skin. Methods The anti‐inflammatory and skin protective properties of panthenol, PEA and NAM were evaluated in vitro. The physical properties of the AR formulations were analysed using measurement of water vapour transport rate (WVTR) and infrared spectroscopy. Clinical studies were performed between the months of December and April (2014–2015) with efficacy assessed during the winter. Facial redness, irritation, sensitization potential, photo‐irritation, and photo‐sensitization were evaluated. Self‐assessed adverse reactions were reported in diaries of use. Results Panthenol and PEA reduced prostaglandin E2, interleukin‐6, and thymic stromal lymphopoietin levels in vitro, while NAM induced nicotinamide adenine dinucleotide (NAD) levels and the keratinocyte differentiation markers: filaggrin (2‐fold increase, P, This article demonstrates the in vitro activities of panthenol, palmitoylethanolamide (PEA), and niacinamide (NAM) and determines the biophysical properties, clinical safety, tolerability together with efficacy of two developmental anti‐redness formulations containing these ingredients, in alleviating facial redness associated with winter xerosis in healthy volunteers with sensitive skin.

Background: Increasing evidence suggests a possible link between the bacterial nasal microbiota (bNM) to allergic diseases such as allergic Rhinitis (AR), as it might modulate the allergic response by acting on the onset and progression of allergic inflammation. In this case-control study, we aimed to compare the bNM between 25 AR patients and 25 matched healthy subjects (HS) as well as to evaluate possible modifications within the host-microbiota cross-talk, investigating the release pattern of both bacterial- and host-Extracellular Vesicles (EVs).Results: bNM analysis showed that Actinobacteria (AR: 2.5%-83.5%; HS: 18.6%-92.7%), Firmicutes (AR: 6.1%-63.5%; HS: 6.4%-72.2%) and Proteobacteria (AR: 0.6%-89.6%; HS 0.7%-38%) were the most abundant phyla in the study population. Diversity reduction in AR patient bNM was pointed out compared to the HS group bNM (Observed OTUs: p =0.018; PD whole tree: p =0.014). Moreover, the distribution of the weighted normalized intra-group UniFrac distances analysis showed a less uniform bacterial community within AR patients rather than HS group (nonparametric test p =0.01). Since EVs may have a central role in the cross-talk between bNM and the host, we evaluated their size and concentration in the plasma of the study subjects. AR patients were characterized by a higher concentration of EVs ranging between 130-231 nm, 257-287 nm and 323-348 nm (p Conclusion: Our results suggest that AR patients are characterized by a less diverse and wide intra-group variable bNM compared to that of HS, as well as an altered host-microbiota EV communication network. Further studies are needed to disentangle the relationship between the host and the nasal bacterial community during pathological conditions and health.

Objectives The present work analyzed the antioxidative activity of phenol-based antioxidants by using an Electron Spin Resonance method to predict the activity and stability of these antioxidants in cosmetic products. Methods The Antioxidative Power (AP) method was chosen to measure both the capacity and kinetics of an antioxidative reaction by detecting the DPPH (diphenylpicrylhydrazyl) radical. The antioxidative capacity (wc) relates to the amount of free radicals that can be reduced, whereas the antioxidative reactivity (tr) relates to the reaction speed and offers a fingerprinting of the redox state of the antioxidant molecules. Fifteen phenolic molecules, have been analyzed. They differed in the position of the hydroxyl groups and substituents on the aromatic ring. The AP of two distinct formulations containing hydroxytyrosol are presented as well as three phenol based antioxidants within the same formulation vehicle. Results The rate at which phenol (ArOH) reacts with DPPH radicals, defined by the term reactivity (tr) in this paper, was dependent upon the bond dissociation enthalpy (BDE) of the OH bond. Molecules having weak OH bonds and consequently low BDE values showed high antioxidant reactivity. On the other hand, the capacity factor (wc), which is the concentration of phenol required to reduce a fixed concentration of DPPH radical, depends on the number and position of hydroxyl groups. The results showed that ortho and para positions of the two hydroxyl groups are important for higher capacity. If one of the two hydroxyl-groups is blocked by methylation, both the antioxidative capacity and reactivity are reduced, mainly for ortho disubstituted compounds. The presence of a vinylic side chain improved reactivity and capacity tremendously. AP values may be useful in formulation design when identifying antioxidants that are likely to be physically and chemically stable. The importance of optimization of the formulation vehicle itself for a given antioxidant is also illustrated. Conclusion Based on the presented findings, it is possible to predict the antioxidative performance of a phenol-based molecule and its stability and oxidation-resistance within a cosmetic formulation. This is essential for antioxidant containing dermal formulations designed to combat skin ageing. This article is protected by copyright. All rights reserved.

Finding sustainable and commercially viable sources of occlusive materials, as an alternative to petroleum, is of great interest. Inspired by the fundamental role of long chain fatty acids in maintaining skin barrier, ultralong fatty acyl derivatives with diverse structures (varied acyl chain length and different polar head; i.e. glycerol, ethylene glycol, and diethylene glycol) were synthesized. These molecules can be feasibly obtained via enzymatic esterification of fatty acids or fractionated from commercial glycerides mixture via short path distillation. The molecular packing behaviors of compounds were characterized via differential scanning calorimetry, Fourier transform infrared, and Langmuir isotherm measurements. The structure–property relationship study reveals that a glycerol molecule monoacylated with an ultralong fatty acyl is the derivative which entails the most occlusive properties of the series of ultralong chain fatty acid derivatives. Fast Fourier transform filtering (FFTF) analysis of ...

The permeability of multicomponent phospholipid bilayers in the gel phase is investigated via molecular dynamics simulation. The physical role of the different molecules is probed by comparing multiple mixed-component bilayers containing distearylphosphatidylcholine (DSPC) with varying amounts of either the emollient isostearyl isostearate or long-chain alcohol (dodecanol, octadecanol, or tetracosanol) molecules. Permeability is found to depend on both the tail packing density and hydrogen bonding between lipid headgroups and water. Whereas the addition of emollient or alcohol molecules to a gel-phase DSPC bilayer can increase the tail packing density, it also disturbed the hydrogen-bonding network, which in turn can increase interfacial water dynamics. These phenomena have opposing effects on bilayer permeability, which is found to depend on the balance between enhanced tail packing and decreased hydrogen bonding.

Intrinsic and extrinsic factors that induce cellular oxidative stress damage tissue integrity and promote ageing, resulting in accumulative strand breaks to the mitochondrial DNA (mtDNA) genome. Limited repair mechanisms and close proximity to superoxide generation make mtDNA a prominent biomarker of oxidative damage. Using human DNA we describe an optimised long-range qPCR methodology that sensitively detects mtDNA strand breaks relative to a suite of short mitochondrial and nuclear DNA housekeeping amplicons, which control for any variation in mtDNA copy number. An application is demonstrated by detecting 16-36-fold mtDNA damage in human skin cells induced by hydrogen peroxide and solar simulated radiation.

A series of O-acylated-ω-hydroxy fatty acids (Acyl acids) of up to 34 carbons were synthesized and characterized through DSC, FTIR and Langmuir isotherm measurements to identify potential replacements to petrolatum, a highly used occlusive technology that if unrefined, it can potentially be classified as carcinogenic. Fourier transform infrared spectroscopy studies demonstrated that long acyl acids engender orthorhombic packing; packing behavior that is predominant in the lipid matrix of healthy stratum corneum, the outmost layer of the skin. In addition, Differential Scanning Calorimetry (DSC) and Langmuir isotherm studies suggested that the length of the hydrocarbon chain and the position of the ester bond influence the molecular organization of the acyl acids. For instance, 16-(tetradecanoyloxy)hexadecanoic acid (30 carbons) displayed a higher melting point (mp=68°C) than 10-(stearoyloxy)decanoic acid (28 carbons; mp=63°C) and 10-(tetradecanoyloxy)decanoic acid (24 carbons; mp=55°C) according to DSC. Moreover, Langmuir isotherm studies showed that mixtures of acyl acid with distearoylphosphatidylcholine improved packing behavior. Finally, Water Vapor Transmission Rate (WVTR) measurements showed that the compounds in fact decrease WVTR compared to untreated control (P0.001) which demonstrates the potential of these ingredients as occlusive technologies to combat skin barrier diseases.

The structural properties of two-component gel-phase bilayers of distearylphosphatidylcholine (DSPC) and alcohol molecules with different compositions and chain lengths (12-24 carbons long) are studied via molecular dynamics simulations. Several bilayer properties, including area per lipid, tilt angle, chain interdigitation, and headgroup offset, are studied for each system and compared, revealing important structural implications depending upon headgroup size and chain length. While tail tilt is the primary mechanism for single-component bilayers to balance tail attraction and headgroup repulsion, our results demonstrate that the lipid mixtures studied adjust this balance via an offset between the depths of the different molecular species in the bilayer; this behavior is found to depend both on composition and on the length of alcohol molecules relative to the length of DSPC tails. It is shown that the structural properties of bilayers with asymmetric tail lengths depend strongly on the bilayer composition, while the composition has less influence on mixed-component bilayers with nearly symmetric tail lengths. These findings are explained on the basis of the interdigitation between bilayer leaflets and how interdigitation is related to other structural properties.

Single- and multicomponent lipid bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphatidylcholine (DSPC), isostearyl isostearate, and heptadecanoyl heptadecanoate in the gel phase are studied via molecular dynamics simulations. It is shown that the structural properties of multicomponent bilayers can deviate strongly from the structures of their single-component counterparts. Specifically, the lipid mixtures are shown to adopt a compact packing by offsetting the positioning depths at which different lipid species are located in the bilayer. This packing mechanism affects the area per lipid, the bilayer height, and the chain tilt angles and has important consequences for other bilayer properties, such as interfacial hydrogen bonding and bilayer permeability. In particular, the simulations suggest that bilayers containing isostearyl isostearate or heptadecanoyl heptadecanoate are less permeable than pure 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine or DSPC bilayers. Furthermore, hydrogen-bond analysis shows that the residence times of lipid-water hydrogen bonds depend strongly on the bilayer composition, with longer residence times for bilayers that have a higher DSPC content. The findings illustrate and explain the fundamental differences between the properties of single- and multicomponent bilayers.

Objective The focus of this communication is the study of phospholipid structured-emulsions whose phase behavior is modified with monoalkyl fatty amphiphiles. Ideally these systems would mimic key physical and structural attributes observed in human stratum corneum (SC)7 so that they better alleviate xerotic skin conditions. Methods Phosphatidylcholine structured emulsions were prepared and their phase behavior modified with monoalkyl fatty amphiphiles. The effect of molecular volume, acyl chain length and head-group interactions was studied using a combination of physical methods. Water Vapor Transmission Rate (WVTR) was used as a primary test to assess occlusive character. Changes in the vibrational modes observed in Fourier transform infra-red (FTIR) spectroscopy and bilayer spacing measured by X-Ray Diffraction (XRD) were then applied to elucidate the lateral and lamellar micro-structural characteristics in the systems.28,29 Results WVTR demonstrated that as the phosphatidylcholine acyl chain length increased from C14, to C18, to C22 there was a corresponding increase in occlusive character. The addition of monoalkyl fatty amphiphiles such as behenic acid, behenyl alcohol or cetostearyl alcohol to a base formulation incorporating distearylphosphatidylcholine (C18) were seen to further increase barrier characteristics of the emulsions. FTIR methods used to probe lipid chain conformational ordering demonstrated that as phosphatidylcholine acyl chain lengths increased there was a corresponding improvement in acyl chain ordering, with an increase in thermal transition temperatures. The addition of a monoalkyl fatty amphiphile resulted in conformational order and thermal transition temperatures improvements trending towards those observed in stratum corneum. FTIR also demonstrated that systems containing behenic acid or behenyl alcohol exhibited features associated with orthorhombic character. X-Ray Diffraction data showed that addition of monoalkyl fatty amphiphile also resulted in thicker lamellar structures than when those agents are not present. Conclusion The generalized approach described herein is shown to mechanistically describe the occlusive character of phospholipid-structured formulations in the presence of long chain fatty acids or alcohols and that they exhibit characteristics mimicking those found in human SC lipids. This article is protected by copyright. All rights reserved.

Lung pathology in cystic fibrosis is linked to dehydration of the airways epithelial surface which in part results from inappropriately raised sodium reabsorption through the epithelial sodium channel (ENaC). To identify a small-interfering RNA (siRNA) which selectively inhibits ENaC expression, chemically modified 21-mer siRNAs targeting human ENaCα were designed and screened. GSK2225745, was identified as a potent inhibitor of ENaCα mRNA (EC(50) (half maximal effective concentration) = 0.4 nmol/l, maximum knockdown = 85%) and protein levels in A549 cells. Engagement of the RNA interference (RNAi) pathway was confirmed using 5' RACE. Further profiling was carried out in therapeutically relevant human primary cells. In bronchial epithelial cells, GSK2225745 elicited potent suppression of ENaCα mRNA (EC(50) = 1.6 nmol/l, maximum knockdown = 82%). In human nasal epithelial cells, GSK2225745 also produced potent and long-lasting (≥72 hours) suppression of ENaCα mRNA levels which was associated with significant inhibition of ENaC function (69% inhibition of amiloride-sensitive current in cells treated with GSK2225745 at 10 nmol/l). GSK2225745 showed no evidence for potential to stimulate toll-like receptor (TLR)3, 7 or 8. In vivo, topical delivery of GSK2225745 in a lipid nanoparticle formulation to the airways of mice resulted in significant inhibition of the expression of ENaCα in the lungs. In conclusion, GSK2225745 is a potent inhibitor of ENaCα expression and warrants further evaluation as a potential novel inhaled therapeutic for cystic fibrosis.Molecular Therapy - Nucleic Acids (2013) 2, e65; doi:10.1038/mtna.2012.57; published online 15 January 2013.