Lysosphingolipids in ceramide-deficient skin lipid models.

Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction.

Lipid Monolayer on Cell Surface Protein Templates Functional Extracellular Lipid Assembly.

When the ancestors of men moved from aquatic habitats to the drylands, their evolutionary strategy to restrict water loss is to seal the skin surface with lipids. It is unknown how these rigid ceramide-dominated lipids with densely packed chains squeeze through narrow extracellular spaces and how they assemble into their complex multilamellar architecture. Here it is shown that the human corneocyte lipid envelope, a monolayer of ultralong covalently bound lipids on the cell surface protein, templates the functional barrier assembly by partly fluidizing and rearranging the free extracellular lipids in its vicinity during the sculpting of a functional skin lipid barrier.

Time-Dependent Differences in the Effects of Oleic Acid and Oleyl Alcohol on the Human Skin Barrier.

Oleic acid and oleyl alcohol are commonly used permeation and penetration enhancers to facilitate topical drug delivery. Here, we aimed to better understand the mechanism of their enhancing effects in terms of their interactions with the human skin barrier using diclofenac diethylamine (DIC-DEA), a nonsteroidal anti-inflammatory drug for topical pain management. Oleic acid promoted DIC-DEA permeation through ex vivo human skin more rapidly than oleyl alcohol (both applied at 0.

Synthesis and self-assembling of hyaluronan grafted with ceramide NP for topical drug delivery.

In this work, amphiphilic hyaluronan was synthesized by grafting succinylated N-oleoyl-phytosphingosine via esters bonds. Succinylated N-oleoyl-phytosphingosine (sCER) was first prepared by esterification of hydroxyl moieties of the ceramide with succinic anhydride. The esterification of hyaluronan was governed by crowding effect.

Skin Barrier Fine Tuning through Low-Temperature Lipid Chain Transition.

The lipids in the mammalian stratum corneum (SC) adopt an unusually rigid arrangement to form a vital barrier preventing water loss and harmful environmental impacts. Just above the physiological temperature, a subset of barrier lipids undergoes a phase transition from a very tight orthorhombic to a looser hexagonal arrangement and vice versa. The purpose of this lipid transition in skin physiology is unknown.

Polymorphism, Nanostructures, and Barrier Properties of Ceramide-Based Lipid Films.

Ceramides belong to sphingolipids, an important group of cellular and extracellular lipids. Their physiological functions range from cell signaling to participation in the formation of barriers against water evaporation. In the skin, they are essential for the permeability barrier, together with free fatty acids and cholesterol.

Recent Advances of Hyaluronan for Skin Delivery: From Structure to Fabrication Strategies and Applications.

Hyaluronan (HA) plays a fundamental role in maintaining the homeostasis on skin health. Furthermore, the effect of HA in skin inflammatory diseases is worth studying in the next future. HA and its conjugates change the solubility of active pharmaceutical ingredients, improve emulsion properties, prolong stability, reduce immunogenicity, and provide targeting.

Cholesterol sulfate fluidizes the sterol fraction of the stratum corneum lipid phase and increases its permeability.

Desulfation of cholesterol sulfate (CholS) to cholesterol (Chol) is an important event in epidermal homeostasis and necessary for stratum corneum (SC) barrier function. The CholS/Chol ratio decreases during SC maturation but remains high in pathological conditions, such as X-linked ichthyosis, characterized by dry and scaly skin. The aim of this study was to characterize the influence of the CholS/Chol molar ratio on the structure, dynamics, and permeability of SC lipid model mixtures.

Effects of ()- and ()-α-Hydroxylation of Acyl Chains in Sphingosine, Dihydrosphingosine, and Phytosphingosine Ceramides on Phase Behavior and Permeability of Skin Lipid Models.

Ceramides (Cers) with α-hydroxylated acyl chains comprise about a third of all extractable skin Cers and are required for permeability barrier homeostasis. We have probed here the effects of Cer hydroxylation on their behavior in lipid models comprising the major SC lipids, Cer/free fatty acids (C -C )/cholesterol, and a minor component, cholesteryl sulfate. Namely, Cers with ()-α-hydroxy lignoceroyl chains attached to sphingosine (Cer AS), dihydrosphingosine (Cer AdS), and phytosphingosine (Cer AP) were compared to their unnatural ()-diastereomers and to Cers with non-hydroxylated lignoceroyl chains attached to sphingosine (Cer NS), dihydrosphingosine (Cer NdS), and phytosphingosine (Cer NP).

PLGA based film forming systems for superficial fungal infections treatment.

As proven in clinical trials, superficial fungal infections can be effectively treated by single topical application of terbinafine hydrochloride (Ter-HCl) in a film forming system (FFS). Poly(lactic-co-glycolic acid) (PLGA) derivatives, originally synthesized with intention to get carriers with optimized properties for drug delivery, and multifunctional plasticizers - ethyl pyruvate, methyl salicylate, or triacetin - were used for formulation of Ter-HCl loaded FFSs. After spraying, a biodegradable, transparent, adhesive, and occlusive thin layer is formed on the skin, representing drug depot.

Transdermal Permeation and Skin Retention of Diclofenac and Etofenamate/Flufenamic Acid From Over-the-Counter Pain Relief Products.

Topical pain relief products differ in the type of drug, concentration, and formulation. All these factors influence the drug transit through the skin barrier, and its eventual retention in the skin as a reservoir for subsequent release. In addition, the drug potency can be different, which is important for the product efficacy.

The Sphingosine and Acyl Chains of Ceramide [NS] Show Very Different Structure and Dynamics That Challenge Our Understanding of the Skin Barrier.

The lipid phase of the uppermost human skin layer is thought to comprise highly rigid lipids in an orthorhombic phase state to protect the body against the environment. By synthesizing sphingosine-d deuterated N-lignoceroyl-d-erythro-sphingosine (ceramide [NS]), we compare the structure and dynamics of both chains of that lipid in biologically relevant mixtures using X-ray diffraction, H NMR analysis, and infrared spectroscopy. Our results reveal a substantial fraction of sphingosine chains in a fluid and dynamic phase state at physiological temperature.

Impact of intercellular crosstalk between epidermal keratinocytes and dermal fibroblasts on skin homeostasis.

Dermal fibroblasts seem critical for epidermal maturation and differentiation and recent work demonstrated that diseased fibroblasts may drive pathophysiological processes. Nevertheless, still very little is known about the actual crosstalk between epidermal keratinocytes and dermal fibroblasts and the impact of dermal fibroblasts on epidermal maturation and differentiation. Aiming for a more fundamental understanding of the impact of the cellular crosstalk between keratinocytes and fibroblasts on the skin homeostasis, we generated full-thickness skin equivalents with and without fibroblasts and subsequently analysed them for the expression of skin differentiation markers, their barrier function, skin lipid content and epidermal cell signalling.

Behavior of 1-Deoxy-, 3-Deoxy- and N-Methyl-Ceramides in Skin Barrier Lipid Models.

Ceramides (Cer) are essential components of the skin permeability barrier. To probe the role of Cer polar head groups involved in the interfacial hydrogen bonding, the N-lignoceroyl sphingosine polar head was modified by removing the hydroxyls in C-1 (1-deoxy-Cer) or C-3 positions (3-deoxy-Cer) and by N-methylation of amide group (N-Me-Cer). Multilamellar skin lipid models were prepared as equimolar mixtures of Cer, lignoceric acid and cholesterol, with 5 wt% cholesteryl sulfate.

Permeation enhancers in transdermal drug delivery: benefits and limitations.

: Transdermal drug delivery has several clinical benefits over conventional routes of drug administration. To open the transdermal route for a wider range of drugs, including macromolecules, numerous physical and chemical techniques to overcome the natural low skin permeability have been developed.: This review focuses on permeation enhancers (penetration enhancers, percutaneous absorption promoters or accelerants), which are chemicals that increase drug flux through the skin barrier.

Effects of omega--acylceramide structures and concentrations in healthy and diseased skin barrier lipid membrane models.

Ceramides (Cers) with ultralong (∼32-carbon) chains and ω-esterified linoleic acid, composing a subclass called omega--acylceramides (acylCers), are indispensable components of the skin barrier. Normal barriers typically contain acylCer concentrations of ∼10 mol%; diminished concentrations, along with altered or missing long periodicity lamellar phase (LPP), and increased permeability accompany an array of skin disorders, including atopic dermatitis, psoriasis, and ichthyoses. We developed model membranes to investigate the effects of the acylCer structure and concentration on skin lipid organization and permeability.

Investigation of TEMPO partitioning in different skin models as measured by EPR spectroscopy - Insight into the stratum corneum.

Electron paramagnetic resonance (EPR) spectroscopy represents an established tool to study properties of microenvironments, e.g. to investigate the structure and dynamics of biological and artificial membranes.

Long and very long lamellar phases in model stratum corneum lipid membranes.

Membrane models of the stratum corneum (SC) lipid barrier, either healthy or affected by recessive X-linked ichthyosis, constructed from ceramide [Cer; nonhydroxyacyl sphingosine -tetracosanoyl-d--sphingosine (CerNS24) alone or with omega-acylceramide -(32-linoleyloxy)dotriacontanoyl-d--sphingosine (CerEOS)], FFAs(C16-24), cholesterol (Chol), and sodium cholesteryl sulfate (CholS) were investigated. X-ray diffraction (XRD) revealed a previously unreported polymorphism of the membranes. In the absence of CerEOS, the membranes formed a short lamellar phase (SLP; the repeat distance = 5.

Fibroblast origin shapes tissue homeostasis, epidermal differentiation, and drug uptake.

Preclinical studies frequently lack predictive value for human conditions. Human cell-based disease models that reflect patient heterogeneity may reduce the high failure rates of preclinical research. Herein, we investigated the impact of primary cell age and body region on skin homeostasis, epidermal differentiation, and drug uptake.

Fluorescent Penetration Enhancers Reveal Complex Interactions among the Enhancer, Drug, Solvent, and Skin.

Skin penetration/permeation enhancers facilitate drug delivery through the skin barrier. However, the specific mechanisms that govern the enhancer interactions with the skin, drug, and donor solvent are not fully understood. We designed and synthesized fluorescent-labeled enhancers by attaching 7-nitrobenzo[c][1,2,5]oxadiazol-4-yl (NBD) groups to 6-aminohexanoic acid esters.

Ultrastructural and Molecular Analysis of Ribose-Induced Glycated Reconstructed Human Skin.

Aging depicts one of the major challenges in pharmacology owing to its complexity and heterogeneity. Thereby, advanced glycated end-products modify extracellular matrix proteins, but the consequences on the skin barrier function remain heavily understudied. Herein, we utilized transmission electron microscopy for the ultrastructural analysis of ribose-induced glycated reconstructed human skin (RHS).

Permeability and microstructure of cholesterol-depleted skin lipid membranes and human stratum corneum.

Cholesterol (Chol) is one of the major skin barrier lipids. The physiological level of Chol in the stratum corneum (SC) appears to exceed its miscibility with other barrier lipids, as some Chol is phase separated. Chol synthesis is essential for epidermal homeostasis, yet the role of these Chol domains in SC permeability is unknown.

Probing the role of ceramide hydroxylation in skin barrier lipid models by H solid-state NMR spectroscopy and X-ray powder diffraction.

In this work, we studied model stratum corneum lipid mixtures composed of the hydroxylated skin ceramides N-lignoceroyl 6-hydroxysphingosine (Cer[NH]) and α-hydroxylignoceroyl phytosphingosine (Cer[AP]). Two model skin lipid mixtures of the composition Cer[NH] or Cer[AP], N-lignoceroyl sphingosine (Cer[NS]), lignoceric acid (C24:0) and cholesterol in a 0.5:0.

Effects of Ceramide and Dihydroceramide Stereochemistry at C-3 on the Phase Behavior and Permeability of Skin Lipid Membranes.

Ceramides (Cer) are key components of the skin permeability barrier. Sphingosine-based CerNS and dihydrosphingosine-based CerNdS (dihydroCer) have two chiral centers; however, the importance of the correct stereochemistry in the skin barrier Cer is unknown. We investigated the role of the configuration at C-3 of CerNS and CerNdS in the organization and permeability of model skin lipid membranes.