Specific protection of sensitive skin against environmental stress by maintenance and improvement of barrier function.

BACKGROUND: Sensitive skin is a common condition that can severely impact quality of life. Several mechanisms are thought to be involved, including those affecting the skin barrier function, hydration and skin innervation. OBJECTIVES: To investigate the benefit of cream and balm formulations dedicated to sensitive skin and containing Aquaphilus dolomiae extract-G3 (ADE-G3) on skin barrier functions (lipid composition, pH, TEWL), as well as protective responses to dry and pollution stresses. METHODS: In vitro sensitized (using histamine) reconstructed human epidermis (RHE) were subjected to dehydration and pollution stress in the absence and presence of the formulations. Endpoint measurements included transepithelial electric resistance (TEER), stratum corneum protein expression and lipid contents. Clinical measurements included transepithelial water loss (TEWL), skin pH and the lipid index. RESULTS: When applied in cream and balm formulations, ADE-G3, increased the TEER in sensitized RHEs. In non-sensitized dehydrated RHEs, both formulations increased recovery of skin barrier integrity after dehydration, evident as a return of the ratios of filaggrin/profilaggrin and caspase-14/procaspase-14 to values measured in control non-stressed RHEs, as well as reducing the 'natural moisturizing factor' to control levels. In clinical studies performed on dry human skin, the formulations helped to maintain and improve the skin barrier function. This was evident as an intense and sustained moisturization (total lipids and lipid esters were increased), an increase in pH and a decrease in the TEWL by both formulations. When exposed to pollution stress by treating the models with benzo[a]pyrene and airborne particulate matter (PM10), application of both formulations prior to exposure attenuated the induction of CYP1A1, CYP1B1 and UGT1A7 expression, indicating a protective effect. CONCLUSIONS: ADE-G3 cream and balm formulations increased the hydration of the skin but also protected and improved the skin barrier integrity of sensitive skin exposed to dry and cold and airborne pollutant-induced stress environments.

Cutaneous sensitivity modulation by Aquaphilus dolomiae extract-G3 on in vitro models of neuro-inflammation.

BACKGROUND: Inflammatory skin disorders, including atopic dermatitis (AD), associated pruritus and sensitive skin, have a complex multifactorial pathogenesis including neurogenic inflammation involving the release in blood and skin of neurotransmitters such as substance P (SP). AIMS AND METHODS: In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae extract-G3 (ADE-G3) on cutaneous neurogenic inflammation. RESULTS: ADE-G3 significantly inhibited SP-stimulated release of IL-1ß and TNF-α from normal human epidermal keratinocytes; significantly and dose-dependently inhibited SP-stimulated activation of human mast cells; significantly inhibited veratridine-stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine-sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL-8 and histamine release. CONCLUSIONS: Topically applied ADE-G3, once formulated, may improve neuro-inflammation in patients with inflammatory skin disorders.

Molecular characterization of inflammation and Staphylococcus aureus colonization of involved skin of atopic dermatitis patients. A non-invasive approach.

Atopic dermatitis (AD) is a multifactorial chronic inflammatory disease mainly stemming from a genetic predisposition that leads to hypersensitivity to environmental factors and a common involvement of Staphylococcus aureus (SA) colonization. The aim of this work was to propose a new non-invasive approach to enumerate the genes coding for the toxins of SA in atopic skin samples. In parallel, the study aimed to evaluate the change in AD through 3 markers of the inflammatory response: IL-8, IL-1RA/IL-1alpha and IL-18. These methods were tested on 31 patients with AD, and finally on a group of 19 subjects for whom clinical improvement had been reported after various treatments. The study revealed the presence of a large number of genes encoding toxins in atopic samples, indicating a high rate of SA colonization, and also an increase in the level of all cytokine markers in atopic skin compared to the skin of healthy subjects. Finally, we found a positive correlation between increases in the SCORAD (Scoring Atopic Dermatitis Index) value after treatment and the corresponding evolution of the SA density. These methods provide a means to clinically evaluate the course of AD, and may help in the development of potential treatments.

Enzymatic reduction studies of nitroheterocycles.

The nitroimidazole derivative Megazol is a highly active compound used against several strains of Trypanosoma cruzi, the causative agent of Chagas' disease (American trypanomiasis). With the aim of gaining an insight into the probable mode of action, the interaction of Megazol with different redox enzymes was studied in comparison to that of Nifurtimox and Metronidazole. The three nitroaromatic compounds are reduced by L-lactate cytochrome c-reductase, adrenodoxin reductase, and NADPH:cytochrome P-450 reductase (EC 1.6.2.4), the efficiencies of the enzymatic reductions being roughly related to the reduction potentials of these pseudo-substrates. As the enzyme responsible for the reduction of Megazol within the parasite has not yet been identified, the nitroimidazole was assayed with T. cruzi lipoamide dehydrogenase and trypanothione reductase. Megazol did not inhibit the physiological reactions but proved to be a weak substrate of both flavoenzymes. The single electron reduction of the compound by NADPH:cytochrome P-450 reductase, by rat liver as well as by trypanosome microsomes was confirmed by ESR experiments. As shown here, Megazol interferes with the oxygen metabolism of the parasite, but its extra activity when compared to Nifurtimox may be related to other features not yet identified.

Topical chemotherapy for experimental African trypanosomiasis with cerebral involvement: the use of melarsoprol combined with the 5-nitroimidazole, megazol.

Megazol, one of a number of related 5-nitroimidazoles, can be dissolved in dimethylsulphoxide and the solution can be converted into a gel by the addition of hydroxypropylcellulose which facilitates the ease and accuracy of administration. This megazol gel, when used in combination with melarsoprol (3.6%) in propylene glycol gel, will cure experimental CNS-trypanosomiasis in mice. A single application of 0.1 ml of melarsoprol (3.6%) gel plus 0.1 ml of either 8 or 16 mg/ml megazol gel successfully treated experimental CNS-trypanosomiasis while two consecutive days' treatment with 0.05 ml melarsoprol and 0.1 ml of 16 or 32 mg/ml megazol gels also produced satisfactory cures.

Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells.

Nonpancreatic secretory phospholipase A2 (sPLA2) displays proinflammatory properties; however, its physiological substrate is not identified. Although inactive toward intact cells, sPLA2 hydrolyzed phospholipids in membrane microvesicles shed from Ca(2+)-loaded erythrocytes as well as from platelets and from whole blood cells challenged with inflammatory stimuli. sPLA2 was stimulated upon degradation of sphingomyelin (SPH) and produced lysophosphatidic acid (LPA), which induced platelet aggregation. Finally, lysophospholipid-containing vesicles and sPLA2 were detected in inflammatory fluids in relative proportions identical to those used in vitro. We conclude that upon loss of phospholipid asymmetry, cell-derived microvesicles provide a preferential substrate for sPLA2. SPH hydrolysis, which is provoked by various cytokines, regulates sPLA2 activity, and the novel lipid mediator LPA can be generated by this pathway.