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Proopiomelanocortin is a precursor peptide that gives rise to several neuropeptides including adrenocorticotrophic hormone (ACTH) and β-endorphin. POMC-derived peptides have been shown to be synthesized in human epidermis where they modulate numerous skin functions. Because we previously observed that melanocortin receptor-2 and μ-opioid receptor 1, the respective receptors for ACTH and β-endorphin decreased with ageing in human epidermis, we have selected an active ingredient (INCI name: Achillea millefolium extract) able to upregulate receptor expressions. The aim of the present work was first to evaluate the effect of A. millefolium extract on the expression pattern of various epidermal differentiation markers ex vivo in normal human skin biopsies using quantitative image analysis and second to evaluate its capacity to rejuvenate the appearance of skin surface in vivo. Results show an improved expression profile of cytokeratin 10, transglutaminase-1 and filaggrin in cultured skin biopsies as well as an increased epidermal thickness. In vivo, a 2-month treatment with A. millefolium extract at 2% significantly improved the appearance of wrinkles and pores compared with placebo. Results were also directionally better than those of glycolic acid that was chosen as reference resurfacing molecule.

Most of adult women exhibit cellulite on the hips, buttock and thighs. Although extracellular matrix and lymphatic system disorders can increase its appearance, cellulite basically results from an excessive fat storage in the adipose tissue which exerts considerable pressure on the surrounding skin tissue and creates a dimpled irregular appearance. Caffeine, the most widely used anti-cellulite ingredient, favours fat break-down by inhibiting the phosphodiesterase enzyme and encouraging a high intracellular level of cAMP. A series of studies has shown that spermine and spermidine, two ubiquitous polyamines, encouraged fat storage and slowed fat break-down in the adipose tissue. Besides, it was shown that heparan sulfate glycosaminoglycans had a strong affinity for polyamines. To design a new cosmetic ingredient with anti-cellulite properties, we used molecular modelling to screen several ingredients with a structure similar to that of heparan sulfate glycosaminoglycans. This way, we identified sulfo-carrabiose as a potent molecule for trapping spermine and spermidine. These virtual results were first confirmed in tubo where sulfo-carrabiose was shown to dose-dependently inactivate spermine and spermidine. In vitro, adipocytes cultured with sulfo-carrabiose exhibited a significant reduction of lipogenesis and a significant increase of lipolysis. When sulfo-carrabiose was incorporated in a cosmetic formula, significant improvements were observed in thigh circumference, with better results than those obtained with caffeine after 28 days of use. Furthermore, a combination of caffeine and sulfo-carrabiose led to results significantly better than those obtained with caffeine alone. As measured by fringe projection, thigh volume was also significantly reduced after sulfo-carrabiose treatment. Finally, the appearance of cellulite assessed by clinical evaluation was also significantly reduced within 28 days.

Lysyl oxidase-like (LOXL) is an extracellular enzyme that catalyses the cross-linking between microfibrils and tropoelastin (TE), thereby ensuring elastic fibre functionality. With ageing, LOXL expression decreases, thus participating in the loss of skin elasticity. In a previous study, we showed that a dill seed extract [INCI name: Peucedanum graveolens (Dill) extract] could increase LOXL expression in cultured dermal fibroblasts. Besides, we showed a good correlation between the measurements of skin elasticity obtained in vitro and in vivo using a fully automated bio-tribometer designed to measure the biomechanical properties of soft and complex materials like skin. The aim of this study was to evaluate the ability of the dill extract to improve skin elasticity in vitro and in vivo using different models. Using the bio-tribometer, we first showed that the lateral elasticity of dermis equivalents (DEs) treated with the dill extract at 1% was significantly increased by +29% (P < 0.01) when compared to untreated DEs. In vivo, skin firmness and elastic recovery measured using cutometry methods were also significantly improved compared to placebo in volunteers treated for 56 days with a formula containing 1% of dill extract. Moreover, the clinical evaluation evidenced significant improvements in 'skin elasticity' compared to placebo. A majority of subjects treated with the dill extract also noted significant improvements in skin elasticity, firmness and slackness of the jaw line. Finally, mean wrinkle area and length were also significantly reduced compared to placebo after 84 days as measured using silicone replicas taken from the crow's feet. In summary, this study showed that the dill extract could improve elasticity of DEs in vitro as well as skin biomechanical properties and appearance in vivo. It also highlights the relevance of using the bio-tribometer as an exploratory tool for the measurement of skin elasticity in vitro.

Overproduction of sebum is very common and results in an undesirable oily, shiny complexion with enlarged pores. Sebum secretion is basically under the control of 5-α reductase, and more particularly under that of type 1 isozyme. But it is also highly sensitive to environmental factors such as temperature, humidity and food. Moreover, in Asia, the edicts of a flawless facial skin turn oily skin into a major concern for Asian women. We identified Orthosiphon stamineus leaf extract as an interesting ingredient for reducing the oily appearance of skin thanks to its ability to reduce 5-α reductase type 1 expression in normal human epidermal keratinocytes in vitro. This was confirmed ex vivo, where Orthosiphon stamineus leaf extract was shown to reduce 5-α reductase activity as well as the production of squalene, one of the main components of sebum that was used as a tracer of sebum. To evaluate the efficacy of Orthosiphon stamineus leaf extract at reducing sebum-related skin imperfections in vivo, we performed two different clinical studies, one in France on a panel of Caucasian volunteers and the other one in Thailand on a panel of Asian volunteers. Using instrumental techniques as well as clinical evaluation and self-evaluation, we could highlight that an O/W cosmetic formula containing 2% of Orthosiphon stamineus leaf extract could visibly reduce the oily appearance of skin as well as the size of pores, thus leading to a significant improvement of complexion evenness and radiance. Overall, the results obtained were better than those observed with the same formula containing 1% of zinc gluconate, an ingredient frequently used in oily skin care products.

Synopsis Much effort has been placed in cosmetic research for better understanding of the effects of ageing on skin’s appearance, structure, mechanical properties and function. It is now of common knowledge that UV radiations induce pre-mature skin ageing notably in the epidermis where UV radiations induce keratinocyte differentiation. As UV radiations have also been shown to regulate the pro-opiomelanocortin (POMC) peptide family in the skin and because no study has been conducted so far to investigate the age-related changes in POMC and related receptors, we analysed POMC, MC-1R, MC-2R and MOR-1 at mRNA level and MC-1R, MC-2R and MOR-1 at protein level too in primary cultures of normal human keratinocytes obtained from female donors aged from 17 to 75 years old. Regarding the gene expressions, we observed that MC-1R, MC-2R and MOR-1 suffered a dramatic decrease after 50 years of age, whereas POMC increased five-fold. Western blot analysis confirmed these results except for MOR-1 whose expression appeared to decrease at older age, around 70 years old. Immunostainings specific to MC-1R, MC-2R and MOR-1 performed on full-thickness skin biopsies also revealed an intense staining in the basal and spinous layers of a 30-year-old donor, whereas no reactivity could be observed in a 60-year-old one. We conclude that POMC and POMC-related receptors suffer a dramatically disturbed balance with ageing and that this may be implicated in the general process of skin ageing.

We report on a high resolution X-ray diffraction analysis of three antimonide-based mid-infrared laser samples (designed for optical pumping) with an active type-II structure. The deformation of the layer unit cells is determined with high accuracy, taking into account relaxation, layer tilting, and asymmetrical strain. Layer compositions are determined and layer sequences are examined accurately also considering the results of reflective high-energy electron diffraction studies during growth. Layer thicknesses and strain values of the type-II structure quantum wells as well as stoichiometry of the mixed anion interfaces are extracted. By designing the antimonide-to-arsenide interfaces in sample II, we achieved exact lattice matching of the active region to the substrate. Based on the knowledge of the determined structural parameters, non-radiative recombination processes are investigated with time resolved photoluminescence as well as laser properties under optically pumped laser operation.

We report on the temperature and carrier density dependence of non-radiative recombination processes in an InAs/GaSb/InAs type-II W-laser emitting at 3.4 μm. The measurements were performed with a sub-picosecond photoluminescence upconversion set-up in a temperature range between 10 K and 300 K and with initial excited carrier densities in the range between 2.96 × 1018 cm−3 and 4.44 × 1019 cm−3. The excellent growth quality of the device is indicated by a Shockley–Read–Hall coefficient of 2.2 × 108 s−1 at 10 K and 1.1 × 108 s−1 at 300 K. The cubic Auger recombination (AR) coefficient decreases in a characteristic manner with increasing initial excited carrier density. From a convergence equation, we obtained a cubic AR coefficient C03 of 1.2 × 10−28 cm6 s−1 for low carrier densities at 200 K. For low temperatures, due to degenerate carrier population of valence and conduction bands, a sublinear increase of the reciprocal lifetime versus carrier density is measured. With rising temperature the sublinear increase becomes linear and at 300 K a quadratic AR coefficient C02 of 1.73 × 10−11 cm3 s−1 was determined.

Tyrosinase is the rate-limiting enzyme in the melanogenesis process. It remains the most efficient way to downregulate melanin production and improve unsightly pigmentary disorders. The aim of our investigations was to find a structurally characterized molecule with better efficacy than existing molecules without cell toxicity. We focused our investigations on compounds that could act as substrate-mimicking inhibitors of tyrosinase and identified N-feruloyldopamine as the best candidate. In vitro, N-feruloyldopamine inhibited human tyrosinase with higher efficacy than the reference inhibitor arbutin without cell toxicity at least up to 100 μM as measured in cultured normal human epidermal melanocytes (NHEMs). Moreover, the inhibition appeared to be specific to mammalian tyrosinases as shown by a very poor inhibition of mushroom tyrosinase, but a significant decrease of total melanin in B16-F10 cells. The antioxidant capacity assessed using DPPH (1,1-diphenyl-2-picrylhydrazyl) assay was comparable to that of vitamin C and finally, N-feruloyldopamine exerted a significant inhibition of Pmel17 gene expression when used at 100 μM on cultured NHEM. Taken together, these results suggest that N-feruloyldopamine is a serious candidate for in vivo application as complexion-brightening ingredient.

Proopiomelanocortin is a precursor peptide that gives rise to several neuropeptides including adrenocorticotrophic hormone (ACTH) and β-endorphin. POMC-derived peptides have been shown to be synthesized in human epidermis where they modulate numerous skin functions. Because we previously observed that melanocortin receptor-2 and μ-opioid receptor 1, the respective receptors for ACTH and β-endorphin decreased with ageing in human epidermis, we have selected an active ingredient (INCI name: Achillea millefolium extract) able to upregulate receptor expressions. The aim of the present work was first to evaluate the effect of A. millefolium extract on the expression pattern of various epidermal differentiation markers ex vivo in normal human skin biopsies using quantitative image analysis and second to evaluate its capacity to rejuvenate the appearance of skin surface in vivo. Results show an improved expression profile of cytokeratin 10, transglutaminase-1 and filaggrin in cultured skin biopsies as well as an increased epidermal thickness. In vivo, a 2-month treatment with A. millefolium extract at 2% significantly improved the appearance of wrinkles and pores compared with placebo. Results were also directionally better than those of glycolic acid that was chosen as reference resurfacing molecule.

Lysyl oxidase-like (LOXL) is an extracellular enzyme that catalyses the cross-linking between microfibrils and tropoelastin (TE), thereby ensuring elastic fibre functionality. With ageing, LOXL expression decreases, thus participating in the loss of skin elasticity. In a previous study, we showed that a dill seed extract [INCI name: Peucedanum graveolens (Dill) extract] could increase LOXL expression in cultured dermal fibroblasts. Besides, we showed a good correlation between the measurements of skin elasticity obtained in vitro and in vivo using a fully automated bio-tribometer designed to measure the biomechanical properties of soft and complex materials like skin. The aim of this study was to evaluate the ability of the dill extract to improve skin elasticity in vitro and in vivo using different models. Using the bio-tribometer, we first showed that the lateral elasticity of dermis equivalents (DEs) treated with the dill extract at 1% was significantly increased by +29% (P0.01) when compared to untreated DEs. In vivo, skin firmness and elastic recovery measured using cutometry methods were also significantly improved compared to placebo in volunteers treated for 56 days with a formula containing 1% of dill extract. Moreover, the clinical evaluation evidenced significant improvements in 'skin elasticity' compared to placebo. A majority of subjects treated with the dill extract also noted significant improvements in skin elasticity, firmness and slackness of the jaw line. Finally, mean wrinkle area and length were also significantly reduced compared to placebo after 84 days as measured using silicone replicas taken from the crow's feet. In summary, this study showed that the dill extract could improve elasticity of DEs in vitro as well as skin biomechanical properties and appearance in vivo. It also highlights the relevance of using the bio-tribometer as an exploratory tool for the measurement of skin elasticity in vitro.

Overproduction of sebum is very common and results in an undesirable oily, shiny complexion with enlarged pores. Sebum secretion is basically under the control of 5-α reductase, and more particularly under that of type 1 isozyme. But it is also highly sensitive to environmental factors such as temperature, humidity and food. Moreover, in Asia, the edicts of a flawless facial skin turn oily skin into a major concern for Asian women. We identified Orthosiphon stamineus leaf extract as an interesting ingredient for reducing the oily appearance of skin thanks to its ability to reduce 5-α reductase type 1 expression in normal human epidermal keratinocytes in vitro. This was confirmed ex vivo, where Orthosiphon stamineus leaf extract was shown to reduce 5-α reductase activity as well as the production of squalene, one of the main components of sebum that was used as a tracer of sebum. To evaluate the efficacy of Orthosiphon stamineus leaf extract at reducing sebum-related skin imperfections in vivo, we performed two different clinical studies, one in France on a panel of Caucasian volunteers and the other one in Thailand on a panel of Asian volunteers. Using instrumental techniques as well as clinical evaluation and self-evaluation, we could highlight that an O/W cosmetic formula containing 2% of Orthosiphon stamineus leaf extract could visibly reduce the oily appearance of skin as well as the size of pores, thus leading to a significant improvement of complexion evenness and radiance. Overall, the results obtained were better than those observed with the same formula containing 1% of zinc gluconate, an ingredient frequently used in oily skin care products.

Much effort has been placed in cosmetic research for better understanding of the effects of ageing on skin's appearance, structure, mechanical properties and function. It is now of common knowledge that UV radiations induce pre-mature skin ageing notably in the epidermis where UV radiations induce keratinocyte differentiation. As UV radiations have also been shown to regulate the pro-opiomelanocortin (POMC) peptide family in the skin and because no study has been conducted so far to investigate the age-related changes in POMC and related receptors, we analysed POMC, MC-1R, MC-2R and MOR-1 at mRNA level and MC-1R, MC-2R and MOR-1 at protein level too in primary cultures of normal human keratinocytes obtained from female donors aged from 17 to 75 years old. Regarding the gene expressions, we observed that MC-1R, MC-2R and MOR-1 suffered a dramatic decrease after 50 years of age, whereas POMC increased five-fold. Western blot analysis confirmed these results except for MOR-1 whose expression appeared to decrease at older age, around 70 years old. Immunostainings specific to MC-1R, MC-2R and MOR-1 performed on full-thickness skin biopsies also revealed an intense staining in the basal and spinous layers of a 30-year-old donor, whereas no reactivity could be observed in a 60-year-old one. We conclude that POMC and POMC-related receptors suffer a dramatically disturbed balance with ageing and that this may be implicated in the general process of skin ageing.

The authors report on high-resolution X-ray diffraction studies of two antimonide-based mid-infrared W-laser samples. Both samples are of the same layer structure but with different mixed anion interface compositions in order to achieve lattice matching of the active region to the substrate in the second sample. A structural analysis, taking effects into account such as layer relaxation, layer tilting and asymmetrical strain enables an accurate determination of the average lattice constant of the active regions. The authors verify that the aim of lattice matching of the active region in the second sample is clearly achieved, and they also determine the strain values of the W-structure quantum-well layers and estimate the mixed anion interface stoichiometry. With a knowledge of the determined structural parameters, non-radiative recombination processes are investigated with time-resolved photoluminescence as well as laser properties under optically pumped laser operation.

The pharmacokinetics of (+)-, (-)-, and (+/-)-verapamil were studied in five healthy volunteers following i.v. administration of the drugs. Pronounced differences of the various pharmacokinetic parameters were observed between the (-)- and (+)-isomers. The values for CL, V, Vz, and Vss of the (-)-isomer were substantially higher as compared to the (+)-isomer, whereas terminal t 1/ 2Z was nearly identical for both isomers. No dose dependency of the pharmacokinetics could be observed in two subjects who received 5, 7.5 and 10 mg of (-)- and 5, 25 and 50 mg of (+)-verapamil. Protein binding for the two isomers was also different. The fu of (-)- (0.11) was almost twice as much as that of (+)-verapamil (0.064). Pharmacokinetic parameters of (+/-)-verapamil, which was administered to three subjects who had received (+)- and (-)-verapamil, were very similar to the averaged values of the isomers given separately. Due to the higher CL of (-)-verapamil the extraction ratio of the (-)-isomer is substantially higher. Thus, it can be anticipated that following oral administration of racemic verapamil bioavailability of (-)-verapamil will be substantially less. Since the (-)-isomer is more potent than the (+)-isomer, the present findings could explain the reported differences in the concentration-effect relationship after i.v. and oral administration of racemic verapamil.

The pharmacokinetics of dextro(+)- and levo(-)-verapamil were studied in five healthy volunteers following oral administration of pseudoracemic verapamil containing equal amounts of unlabelled (-)- and dideuterated (+)-isomer. (+)-verapamil exhibited approximately five times greater Cmax (+): 240 +/- 81.1 ng/ml, (-): 46.1 +/- 15.7 ng/ml, P less than 0.0001) and AUC than (-)-verapamil. The apparent oral clearance (CLo) for (+)-verapamil was significantly smaller than that for (-)-verapamil (+): 1.72 +/- 0.57 l/min, (-): 7.46 +/- 2.16 l/min, P less than 0.001). The bioavailability of (+)-verapamil (50%) was 2.5 times greater than that of (-)-verapamil (20%), P less than 0.005). Thus following oral administration verapamil exhibited a stereoselective first-pass metabolism. Neither tmax nor the elimination t1/2,z were different between the isomers. The elimination of t1/2,z for each verapamil isomer obtained following oral administration (+): 4.03 h, (-): 5.38 h) were similar to those previously obtained following intravenous administration (+): 4.15 h, (-): 5.38 h, respectively. Whereas the (+)- to (-)-verapamil plasma concentration ratio following oral administration was 4.92 +/- 0.48, the ratio following i.v. administration was approximately 2. (-)-verapamil has been demonstrated to possess 8 to 10 times more potent negative dromotropic effect on AV conduction than (+)-verapamil. Therefore, following oral administration the same concentration of plasma verapamil consisting of a two to three times smaller proportion of the more potent (-)-isomer appeared to be less potent than that following i.v. administration with regard to the negative dromotropic effects on the AV conduction.