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Skin aging is a complex process that may be caused by factors that are intrinsic and extrinsic to the body. Ultraviolet ( UV) radiation represents one of the main sources of skin damage over the years and characterizes a process known as photoaging. Among the changes that affect cutaneous tissue with age, the loss of elastic properties caused by changes in elastin production, increased degradation and/or processing produces a substantial impact on tissue esthetics and health. The occurrence of solar elastosis is one of the main markers of cutaneous photoaging and is characterized by disorganized and non-functional deposition of elastic fibers. The occurrence of UV radiation-induced alternative splicing of the elastin gene, which leads to inadequate synthesis of the proteins required for the correct assembly of elastic fibers, is a potential explanation for this phenomenon. Innovative studies have been fundamental for the elucidation of rarely explored photoaging mechanisms and have enabled the identification of effective therapeutic alternatives such as cosmetic products. This review addresses cutaneous photoaging and the changes that affect elastin in this process. [ABSTRACT FROM AUTHOR]

Background: The rate of people with significant dermis and epidermis disorders increases linearly with age. The majority of skin changes are a consequence of cumulative exposure to environmental factors, such as chronic ultraviolet exposure. Aims and Objectives: Age-related dermatological changes include skin laxity, nails fragility, hair loss and hair breakage. This spontaneous, anecdotal observational study investigates if a dietary supplementation based on collagen, chondroitin sulfate, low-molecular weight hyaluronic acid, Pycnogenol® and coenzyme Q10 can improve age-related dermatological changes. Materials and Methods: Thirty four patients received the dietary supplement for 2 times/daily for 12 weeks. Facial skin hydration, Trans Epidermal Water Loss (TEWL) and elasticity were assessed at baseline and after 12 weeks in five selected areas. Nails hardness of the index, middle and ring fingers were also assessed at baseline and at followup by a durometer and by a nail score. The Hair Mass Index (HMI) and the Hair Breakage Index (HBI) were assessed by a mechanical device together with hair score at baseline and after 12 weeks. Results: After 12 weeks skin hydration, TEWL and elasticity significantly improved in all the tested areas (p < 0.01 and p < 0.001). Nails hardness of index, middle and ring finger significantly increased (p < 0.001) after 12 weeks. HMI and HBI were both significantly reduced (p < 0.0001) after 12 weeks. In addition, both nails and hair score improved. Conclusions: Dietary supplementation significantly improved age-related dermatological changes. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to evaluate the performances of the RHE/ IL-18 assay using the SkinEthic™ RHE model for the identification of contact sensitizers. Methods A set of 18 substances and mixtures was tested on this epidermal model, following the RHE/ IL-18 protocol. The final results of the assay were obtained following 5 interpretation schemes, to determine the optimal prediction model for this assay with this specific test system. The data were analysed with a special focus on the basal level of IL-18 release and on the performance obtained with respect to three different gold standards: LLNA, HRIPT and an integrated reference, constructed from all available results. Results No important differences were found in the performance levels depending on the three gold standards. The performances obtained with the SkinEthic™ RHE model support that this model may be considered as an alternative to different reconstructed epidermis models (Epi DERM™, Epi CS™ and VUMC- EE) for the performance of RHE/ IL-18 assays. Conclusion The prediction model to be used was refined, and more substances have to be tested in order to gather enough data for this evaluation and to determine the right criteria applicable for this assay using the SkinEthic™ RHE test system. [ABSTRACT FROM AUTHOR]

Objective Exposure to UV in humans resulting in sunburn triggers a complex series of events that are a mix of immediate and delayed damage mediation and healing. While studies on the effects of UV exposure on DNA damage and repair have been reported, changes in the oxidative modification of skin proteins are poorly understood at the molecular level, despite the important role played by structural proteins in skin tissue, and the effect of the integrity of these proteins on skin appearance and health. Proteomic molecular mapping of oxidation was here applied to try to enhance understanding of skin damage and recovery from oxidative damage and UVB exposure. Methods A redox proteomic-based approach was applied to evaluating skin protein modification when exposed to varying doses of UVB after initial oxidative stress, via tracking changes in protein oxidation during the healing process in vitro using a full-thickness reconstituted human skin tissue model. Bioassays and structural evaluation confirmed that our cultured skin tissues underwent a normal physiological response to UVB exposure. Results A set of potential skin marker peptides was generated, for use in tracking skin protein oxidative modification. Exposure to UVB after thermal oxidative stress was found to result in higher levels of skin protein oxidation than a non-irradiated control for up to seven days after exposure. Recovery of the skin proteins from oxidative stress, as assessed by the overall protein oxidation levels, was found to be impaired by UVB exposure. Oxidative modification was largely observed in skin structural proteins. Conclusion Exposure of skin proteins to UVB exacerbates oxidative damage to structural skin proteins, with higher exposure levels leading to increasingly impaired recovery from this damage. This has potential implications for the functional performance of the proteins and inter-related skin health and cosmetic appearance. [ABSTRACT FROM AUTHOR]

Objective The focus of this communication was to study phospholipid-structured emulsions whose phase behaviour is modified with monoalkyl fatty amphiphiles. Ideally, these systems would mimic key physical and structural attributes observed in human stratum corneum ( SC) so that they better alleviate xerotic skin conditions. Methods Phosphatidylcholine-structured emulsions were prepared, and their phase behaviour 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 vapour transmission rate ( WVTR) was used as a primary test to assess occlusive character. Changes in the vibrational modes observed in Fourier transform infrared ( FTIR) spectroscopy and bilayer spacing measured by X-ray diffraction ( XRD) were then applied to elucidate the lateral and lamellar microstructural characteristics in the systems. Results Water vapour transmission rate 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 dipalmitoyl and distearoylphosphatidylcholine (C18) was 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 temperature 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. [ABSTRACT FROM AUTHOR]

Objectives The present work analysed the antioxidative activity of phenol-based antioxidants 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 ( w c) relates to the amount of free radicals that can be reduced, whereas the antioxidative reactivity ( t r) relates to the reaction speed and offers a fingerprinting of the redox state of the antioxidant molecules. Fifteen phenolic molecules have been analysed. They differed in the position of the hydroxyl groups and substituents on the aromatic ring. The AP of two distinct formulations containing hydroxytyrosol is presented as well as three phenol-based antioxidants within the same formulation vehicle. Results The rate at which phenol (Ar OH) reacts with DPPH radicals, defined by the term reactivity ( t r) 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 ( w c), 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. [ABSTRACT FROM AUTHOR]

Background Sensitive skin is a poorly understood skin condition. Defects in stratum corneum ( SC) barrier function and/or extrasensory neuronal networks in the epidermis are believed to be involved in the problem. Objectives This study aimed to unravel the relationships between bleomycin hydrolase ( BH) and calpain-1 (C-1), pyrrolidone carboxylic acid ( PCA) levels, corneocyte maturation, transglutaminase ( TG) and plasmin activities on the cheeks of subjects with sensitive skin. Methods Forty-eight female Caucasian subjects, Fitzpatrick skin phototypes II- III, with self-perceived sensitive facial skin, were assessed and underwent a capsaicin reactivity test. Expert grading of skin condition was conducted as well as the measurement of transepidermal water loss ( TEWL), skin capacitance, SC cohesion and SC integrity. BH, C-1 and plasmin activities were measured as well as PCA levels, plasmin and TG activity. Differential Nile red and involucrin immunostaining was performed to assess corneocyte maturation and size. Results About 52% of the subjects reacted to capsaicin. There were no significant differences between the capsaicin-sensitive and non-capsaicin-sensitive subjects with reference to skin grading, TEWL, skin capacitance and SC cohesion. PCA levels and BH activity were lowest in the capsaicin-sensitive panel ( P < 0.05) and were correlated in non-capsaicin-sensitive subjects ( r = 0.72). The activity of TG was significantly lower (48%) in the capsaicin-sensitive subjects ( P < 0.001) and their corneocytes were less mature and smaller ( P ≤ 0.05). SC was estimated to be thinner (6.87 ± 0.28 vs. 8.68 ± 0.26 μm; P = 0.001) in the capsaicin-sensitive subjects with a corresponding shorter SC path length (83.2 ± 4.4 μm and 113.1 ± 4.5 μm; P = 0.001). Conclusions Despite the physiological similarities between the two groups of sensitive skin subjects, differences in their biochemistry were clearly evident. Lower levels of PCA, BH and TG activities together with a greater number of smaller and immature corneocytes indicate inferior SC maturation in the capsaicin-sensitive subjects. The reduced maturation of corneocytes and thinner SC likely contributes to a greater penetration of capsaicin and the associated increased skin sensitivity. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to determine how the energies supplied from a cosmetic vibrator are deeply or far transferred into organs and tissues, and how these depths or distances are influenced by tissue elasticity. Methods External vibration energy was applied to model skin surfaces through a facial cleansing vibrator, and we measured a distance- and depth-dependent energy that was transferred to model skin matrices. As model skin matrices, we synthesized hard and soft poly(dimethylsiloxane) ( PDMS) gels, as well as hydrogels with a modulus of 2.63 MPa, 0.33 MPa and 21 kPa, respectively, mostly representing those of skin and other organs. The transfer of vibration energy was measured either by increasing the separation distances or by increasing the depth from the vibrator. Results The energies were transmitted deeper into the hard PDMS than into the soft PDMS and hydrogel matrices. This finding implies that the vibration forces influence a larger area of the gel matrices when the gels are more elastic (or rigid). There were no appreciable differences between the soft PDMS and hydrogel matrices. However, the absorbed energies were more concentrated in the area closest to the vibrator with decreasing elasticity of the matrix. Softer materials absorbed most of the supplied energy around the point of the vibrator. In contrast, harder materials scattered the external energy over a broad area. Conclusions The current results are the first report in estimating how the external energy is deeply or distantly transferred into a model skins depending on the elastic moduli of the models skins. In doing so, the results would be potentially useful in predicting the health of cells, tissues and organs exposed to various stimuli. [ABSTRACT FROM AUTHOR]

Objective Human epidermis provides the body a barrier against environmental assaults. To assume this function, the epidermis needs the renewal of keratinocytes allowed by constant mitosis, which replace the exfoliating corneocytes. Keratinocyte stem cells ( KSCs) located in the basal epidermis are mitotically active, self-renewing and govern the epithelial stratification by producing renewed source of keratinocytes. Protein complex such as the chromosomal passenger complex ( CPC) allows the correct development of this process. The CPC is composed of four members: INCENP, survivin, borealin and aurora kinase B, and the disruption of the CPC during cell division induces mitotic spindle defects and improper repartition of chromosomes. The aim of our study was to investigate the implication of CRM1 and survivin in the progress of mitosis in skin keratinocytes. Methods Cultured human keratinocytes and skin biopsies were used in this study. KSCs-enriched population of keratinocytes was isolated from total keratinocytes by differential attachment to a type IV collagen matrix. Survivin and CRM1 expression levels were assessed by immunofluorescence and immunoblotting. Specific si RNAs for each CPC member and for CRM1 were used to determine the relationship between these proteins. Survivin-specific si RNA was used to induce the apparition of mitotic abnormalities in cultured keratinocytes. Results We demonstrated the ability of our compound ' IV08.009' to modulate the expression level of survivin and CRM1 in keratinocytes and in skin biopsies. We observed that members of the CPC are interdependent: si RNA-induced inhibition of one component caused a decrease in the expression of all other CPC members. Downregulation of survivin or CRM1 induced mitotic abnormalities in keratinocytes. However, decreased number of mitotic abnormalities was observed in keratinocytes after ' IV08.009' application. Conclusion Basal keratinocytes may divide frequently during skin lifespan, and signs of deterioration could appear such as loss of protein factors required for correct mitosis. Our findings suggest that mitotic abnormalities can be prevented by the modulation of CRM1 and survivin. We demonstrated the ability of compound ' IV08.009' to efficiently protect cultured keratinocytes from mitotic abnormalities. [ABSTRACT FROM AUTHOR]

Objective A state of chronic inflammation, characterized by an increased level of tumour necrosis factor-alpha ( TNF- α), is often found in the obese population. The negative effects of elevated TNF- α are not limited to systemic metabolism. It also reportedly affects skin integrity. Recently, the relationship between obesity and skin fragility was reported; however, there has been little insight into how the level of TNF- α in the skin in situ is related to the severity of obesity. In this study, we aimed to measure the level of TNF- α on the skin and to find the relationship between obesity and the level of TNF- α detected on the skin. Methods We used a novel, non-invasive method called quantitative skin blotting. Fifty-nine healthy (but some were classified as being overweight or obese) Japanese males were enrolled as subjects. The levels of TNF- α detected on the abdominal and thigh skin along with the body composition were measured, followed by a correlation analysis. Results Significant positive correlations were found between the levels of TNF- α detected on the skin and the severity of obesity such as body mass index ( BMI), body fat weight and visceral fat rating. Conclusion We found that high levels of TNF- α were detected on the skin of Japanese obese males, which implied the higher TNF- α in the skin. The elevation of skin TNF- α may be one factor related to skin fragility that is often found in obese individuals. [ABSTRACT FROM AUTHOR]

Globally, millions of men regularly remove their facial hair using an electric shaver. Over the course of several decades, the concept of an electric shaver has evolved from a relatively simple hand-powered apparatus to a technologically advanced device designed to provide the user with an optimum shaving experience. This requires a careful balance between robust removal of hair and skin comfort. By incorporating advanced scientific measurement and imaging technology into clinical testing, insights are being gained into skin comfort issues associated with hair removal practices. This study describes new research insights that have guided the development of electric shaving technology. These innovative features are designed to maximize hair removal and minimize the impact on skin health, thus enabling new levels of shaving efficacy and comfort to be attained. [ABSTRACT FROM AUTHOR]

Synopsis Objective High-frequency ultrasound is a non-invasive tool used in skin ageing research to assess dermis thickness and echogenicity. This study evaluated the reliability of a range of high-frequency ultrasound parameters and tested their correlation with age and a validated clinical scale for the assessment of forearm skin photoageing; the difference between two body sites according to environmental exposition patterns was also investigated. Methods Twenty-three volunteers aged 28-82 years were divided into three groups according to forearm photoageing degree. A 20 MHz ultrasound unit was used to obtain cross-sectional images of the skin by two trained investigators on two different sites: the dorsal forearm (chronically photoexposed skin) and the proximal medial arm (non-photoexposed skin). Several echogenicity parameters were studied for each skin compartment: total dermis, upper dermis and lower dermis, and the ratio between upper and lower dermis. Results The intraclass correlation coefficient (for complete agreement) between investigators was higher for upper and total dermis echogenicity measures compared with the lower dermis. At the non-photoexposed site, the upper and lower dermis parameter ratio was better correlated with age. At the photoexposed area, total dermis parameters demonstrated higher correlations with clinical score. Conclusion The authors discuss the choice of parameters for forearm photoageing assessment using high-frequency ultrasound. [ABSTRACT FROM AUTHOR]

Synopsis Objective Keloid scar is pathological tissue that appears after skin injury, and that is more aggressive than hypertrophic scars. Keloid scars are characterized by increased proliferation of fibroblast-like cells ( FLCs) and the accumulation of extracellular matrix, mainly collagen. Fibulin-5, a glycoprotein secreted by many cell types, is a component of the extracellular matrix. We investigated the effect of fibulin-5 on the adhesion and proliferation of FLCs derived from keloid scars and the role of integrin beta-1 in these activities. Methods Fibroblast-like cells were isolated from six keloid scars and cultured on plates coated with fibulin-5 or with gelatin. Cells were incubated for 72-96 h to examine proliferation rates and incubated for 240 min, with washings at 20, 40, 60, 90, 120, 180 min, to assess adhesion rates. To examine the role of integrin beta-1, the anti-human integrin beta-1 ( CD29) antibody was added to the culture medium. Results Fibroblast-like cells from keloids cultured on a fibulin-5-coated surface showed a significantly reduced proliferation rate and a delayed adhesion rate, compared to cells cultured on gelatin-coated dishes. Adherence of these cells to fibulin-5 pre-coated wells was significantly reduced in the presence of anti-human integrin beta-1 ( CD29) antibodies. Our current findings are similar to previously observed reduced proliferation in vascular smooth muscle cells overexpressing fibulin-5. We did not test the effects of fibulin-5 on normal fibroblasts. Conclusion This study demonstrates the pivotal role of the extracellular protein, fibulin-5, on the adhesion and proliferation of human keloid-derived cells, through binding to integrin beta-1. [ABSTRACT FROM AUTHOR]

Oxidative stress is the resultant damage that arises due to redox imbalances, more specifically an increase in destructive free radicals and reduction in protection from antioxidants and the antioxidant defence pathways. Oxidation of lipids by reactive oxygen species ( ROS) can damage cellular structures and result in premature cell death. At low levels, ROS-induced oxidative stress can be prevented through the action of antioxidants, however, when ROS are present in excess, inflammation and cytotoxicity eventually results leading to cellular oxidative stress damage. Increasing evidence for the role of oxidative stress in various diseases including neurological, dermatological, and cardiovascular diseases is now emerging. Mitochondria are the principal source (90%) of ROS in the cell, with superoxide radicals being generated when molecular oxygen is combined with free electrons. Given the key role of mitochondria in the generation of cellular oxidative stress it is worth considering this organelle and the process in more detail and to provide methods of intervention. [ABSTRACT FROM AUTHOR]

Synopsis Objective The skin melanin system is affected by ageing, resulting in dyspigmentation with associated clinical and psychosocial consequences. In dark skinned phenotypes, broad evidence is available, whereas little is known about pigmentary changes in fair-skinned Caucasians. The objective of this study was to investigate age-related changes in facial pigmentation and dyspigmentation in subjects of skin phototypes II- III and to develop and test parameters for quantifying dyspigmentation. Methods Twenty-four skin healthy female subjects were recruited in three distinct age groups (30-40, 50-60, 70-80 years). Skin colour was measured by Mexameter and Chromameter. Skin dyspigmentation was measured by clinical evaluation and newly developed image-processing parameters on the cheeks and the forehead. The reliability of the clinical evaluation was investigated by intraclass correlation coefficients between three raters, and the validity of the dyspigmentation parameters was analysed by bivariate correlations with related measures. Results Skin lightness decreased with increasing age. Clinical dyspigmentation scores showed positive associations with chronological age ranging between 0.452 and 0.606. RBX®-Brown transformation-based hyperpigmentation and hypopigmentation indices increased with age, whereas the overall pigmentation intensity decreased with age at the cheeks. The image analysis-based parameters showed strong associations with the clinical scores and related measurements. Conclusion We demonstrated age-related changes in the facial colour and dyspigmentation of fair-skinned Caucasian females. An increase in dyspigmentation was found by clinical scoring and the RBX®-Brown transformation-based pigmentation indices. The validity of hyper- and hypopigmentation indices and overall pigmentation intensity was supported. The RBX® transformation-based pigmentation indices might be applied in future studies to complement or substitute clinical evaluation. [ABSTRACT FROM AUTHOR]

Synopsis Objectives The aims of this study were to confirm the properties of selective agonist peptide (Rubixyl) contained in the spinach towards opioid receptor delta. In fact, agonist properties of both spinach peptides (Rubiscolin-5 and Rubixyl) towards opioid receptor delta were demonstrated by Zang et al., but their effects on the other opioid receptors were not studied [1]. We also studied the expression of opioid receptor delta in epidermis under normal and stress condition (inflammatory) and its role in epidermis homeostasis under stress condition in vitro and in vivo. Methods Agonist properties studies were performed using functional agonist cellular model containing human opioid receptors. Opioid receptor delta expression and epidermis homeostasis were studied on human reconstructed epidermis under normal and stress conditions (inflammatory stress) using gene expression ( RT- qPCR) and protein expression analysis (immunohistological analysis). Skin repair properties of opioid receptor delta agonist were based on the following parameters TEWL (trans epidermal water loss, hydration and wrinkle depth at periocular and perilabial area) on human volunteers having either intrinsic ageing (more than 40 years old and non-smoker group) and both intrinsic ageing and extrinsic ageing (more than 40 years old and smoker group). Results We have demonstrated that the Rubixyl peptide is a specific agonist of opioid receptor delta. We have demonstrated that opioid receptor delta expression is modulated under inflammatory condition. The agonist Rubixyl was able to block the depletion of opioid receptor delta seen under inflammatory condition in reconstructed human epidermis. Inflammatory conditions lead to the unbalanced gene and protein expressions of markers involved in epidermis integrity and barrier function properties. The treatment of human reconstructed epidermis with the agonist Rubixyl leads to the normalization of unbalanced gene and protein expressions. In vivo study has confirmed the efficiency of the agonist Rubixyl to repair damaged skin by decreasing TEWL, increasing hydration and decreasing wrinkle depth at the periocular and perilabial area. Conclusion In this research, we have demonstrated in vitro (on inflamed reconstructed human epidermis, RHE) and in vivo (on human aged volunteers) that activation by natural agonist peptide of opioid receptor delta reduces the skin inflammation thus leading to improvement in epidermis differentiation and skin barrier properties. [ABSTRACT FROM AUTHOR]

Synopsis A review of the oxidization of squalene, a specific human compound produced by the sebaceous gland, is proposed. Such chemical transformation induces important consequences at various levels. Squalene by-products, mostly under peroxidized forms, lead to comedogenesis, contribute to the development of inflammatory acne and possibly modify the skin relief (wrinkling). Experimental conditions of oxidation and/or photo-oxidation mechanisms are exposed, suggesting that they could possibly be bio-markers of atmospheric pollution upon skin. Ozone, long UVA rays, cigarette smoke... are shown powerful oxidizing agents of squalene. Some in vitro, ex vivo and in vivo testings are proposed as examples, aiming at studying ingredients or products capable of boosting or counteracting such chemical changes that, globally, bring adverse effects to various cutaneous compartments. [ABSTRACT FROM AUTHOR]

Objective A novel skin assessment tool named 'skin blotting' has been recently developed, which can easily predict the skin status to avoid its deterioration. The aim of this study was to propose a normalization method for skin blotting to compensate for individual differences that can hamper the quantitative comparisons and clinical applications. Methods To normalize individual differences, we utilized a total protein as a 'normalizer' with calibration curves. For evaluation, we performed a simple simulation experiment, in which the same concentration of a protein of interest [tumour necrosis factor ( TNF)- α] was applied at different volumes as a virtual individual difference. Moreover, to demonstrate the applicability of this normalization, male volunteers were recruited for skin blotting followed by the estimation of TNF- α with normalization. Results We obtained good calibration curves for total protein ( R2 = 0.995) and TNF- α ( R2 = 0.997), both of which were necessary for an exact quantification. In the simulation experiment, we estimated the exact concentration of TNF- α regardless of the applied volume, demonstrating the applicability of this normalization method in skin blotting. Further, skin blotting on human subjects showed a wide range of variation in the total protein content, although the normalization was thought to reduce such individual variations. Conclusion This study has proposed total protein normalization for skin blotting with calibration curves. This method may strengthen the quantitative performance of skin blotting, which may expand the applicability of this method as a skin assessment tool in broader fields, such as nursing and cosmetology. [ABSTRACT FROM AUTHOR]

Synopsis Objectives Salidroside, the predominant component of a Chinese herbal medicine, Rhodiola rosea L., becomes an attractive bio-agent due to its multifunction. Although it is well proposed that this herbal medicine may have photoprotective effect according to the folk hearsay, the direct supportive experimental evidences linking the drug with skin ageing have rarely been reported so far. The study was conducted to investigate the photoprotective role of salidrosdie and its related mechanisms in vitro. Methods First, a premature senescence model induced by UVB irradiation (250 mJ cm−2) in human dermal fibroblasts ( HDFs) was established, and senescent phenotypes were evaluated by cell morphology, cell proliferation, senescence-associated beta-galactosidase ( SA-β-gal) activity and cell cycle distribution. Then the photoprotective effect of salidroside was investigated. Cells were pre-treated with various doses of salidroside (1, 5 and 10 μM) followed by the sublethal dosage of UVB exposure and then were harvested for various detections, including senescence-associated phenotypes and molecules, alteration of oxidative stress, matrix metalloproteinase-1 ( MMP-1) secretion and inflammatory response. Results Pre-treatment of salidroside dose dependently reversed the senescent state of HDFs induced by UVB as evidenced by elevated cell viability, decreased SA-β-gal activity and relieving of G1/G0 cell cycle arrest. UVB-induced increased protein expression of cyclin-dependent kinase ( CDK) inhibitors p21 WAF1 and p16 INK4 was also repressed by salidrosdie treatment in a dose-dependent manner. Meanwhile, the increment of malondialdehyde ( MDA) level in UVB-irradiated HDFs was inhibited upon salidroside treatment. Additionally, salidroside significantly attenuated UVB-induced synthesis of MMP-1 as well as the production of IL-6 and TNF-α in HDFs. Conclusion Our data provided the evidences for the protective role of salidroside against UVB-induced premature senescence in HDFs probably via its anti-oxidative property and inhibition on production of MMP-1 and pro-inflammatory cytokines, which indicated its potential utilization as an active ingredient in the preparation of photoprotective formulation. [ABSTRACT FROM AUTHOR]

Synopsis Objective After pilot and preliminary studies aimed at identifying pertinent biochemical parameters, a multicenter clinical study was performed to evaluate the effect of pollution on human skin. Methods The clinical study was performed in collaboration with the 'Centre Régional de lutte contre le cancer de Montpellier' and the 'National Institute of Public Health of Mexico' on 96 subjects in Mexico City (exposed to pollution) and 93 subjects in Cuernavaca (less exposed to pollution). Both biochemical and clinical skin parameters were studied. Results The study demonstrated significant quantitative and qualitative modifications of parameters related to sebum excretion in Mexico City compared to Cuernavaca one: An increased level of sebum excretion rate, a lower level of vitamin E and squalene in sebum, an increase of lactic acid and a higher erythematous index on the face of the subjects. In the stratum corneum, a significant higher level of carbonylated proteins and a lower level of IL 1 α were noticed, as well as a decrease of ATP concentration with a decrease of chymotrysin like activity, without modifications of corneodesmosin content and trypsin like activity. From a clinical point of view, a higher frequency of atopic and urticarial skins, a higher frequency of red dermographism, an important seborrheic status at the forehead level and a lower level of dandruffs were noted in Mexico City population. The analysis taking into account the sex does not modify the observed results. Conclusion The study demonstrated an important impact of polluted environmental conditions on skin quality, evidencing important modifications of superficial biochemical parameters. The cause/effects relationships of these modifications remain, however, to be further assessed by a complementary in vitro/ in vivo approaches. [ABSTRACT FROM AUTHOR]

Synopsis Objective In this study, the influence of three cosmetically relevant, priorly characterized vehicles on skin hydration, sebum content and transepidermal water loss was investigated. The chosen vehicles included a liposomal pre-formulation, a multiple W/ O/ W emulsion and a microemulsion gel. The in vivo effects of these vehicles were demonstrated and compared among them. Methods The stability of the prepared vehicles was determined visually, microscopically, rheologically by pH measurements and particle size. Interactions with skin were assessed by non-invasive biophysical techniques using the Corneometer®, Aqua Flux® and Sebumeter, measuring skin hydration, TEWL and skin sebum content, respectively. Results All vehicles remained stable over an observation period of 6 weeks. The multiple emulsion increased sebum content and skin hydration. In case of the liposomes, each monitored parameter remained almost constant. In contrast, the microemulsion gel lowered skin hydration and increased TEWL values, but even 1 week after termination of the treatment TEWL decreased almost close to control levels. Conclusion All produced vehicles were proven to remain physically stable over the duration of this study. The used multiple emulsion showed very skin-friendly properties by increasing sebum and skin hydration. Likewise, the liposomal pre-formulation exhibited no negative effects. On the contrary, the investigated microemulsion gel seemed to have skin dehydrating and TEWL increasing features. However, the multiple emulsion as well as liposomes was identified to be well-tolerated vehicles for skin which might qualify them for the use in cosmetic formulations. [ABSTRACT FROM AUTHOR]

Synopsis Background Stretch marks are a common skin disorder. Pregnancy-related lesions are defined as striae gravidarum. The root cause of striae formation remains unknown. Objective The aim of this paper was to identify the risk factors associated with striae gravidarum ( SG) development. Patients and methods The study was conducted at Plastic, Reconstructive and Aesthetic Surgery Clinic and Obstetrics Outpatient Department among 299 Caucasian women maximum 6 months after the delivery, regardless of whether they were primiparas or multiparas. Results Among the women participating in the study, 71.2% (213 of 299) developed striae gravidarum at least in one site. Logistic regression analysis showed that four of the analysed factors were independent predictors of striae gravidarum occurrence: family history of SG, BMI before pregnancy, the lack of chronic diseases and birthweight ( P < 0.0001). It has been found that the presence of striae distensae on the breasts increases the risk of SG development (71.4% vs. 28.6%, P = 0.0008), whereas the presence of these lesions on the thighs decreases the risk (23% vs. 77%, P = 0.0076). Conclusion In this study, we presented a model that can help to predict the risk of SG formation, including family history of SG, BMI before pregnancy, birthweight and chronic diseases. Moreover, women with stretch marks on their breasts should know that the risk of SG development is significantly higher, whereas lesions on the thighs do not increase such a risk. [ABSTRACT FROM AUTHOR]

Abstract: ω‐Hydroxyacids are fatty acids bearing a hydroxyl group on the terminal carbon. They are found in mammals and higher plants and are often involved in providing a permeability barrier, the primary purpose of which is to reduce water loss. Some ω‐hydroxyacid derivatives may be involved in waterproofing and signalling. The purpose of this review was to survey the known natural sources of ω‐hydroxyacids. ω‐Hydroxyacids are produced by two different P450‐dependent mechanisms. The longer (30–34 carbons) ω‐hydroxyacids are produced by chain extension from palmitic acid until the chain extends across the membrane in which the extension is taking place, and then the terminal carbon is hydroxylated. Shorter fatty acids can be hydroxylated directly to produce C16 and C18 ω‐hydroxyacids found in plants and 20‐eicosatetraenoic acid (20‐HETE) by a different P450. The C16 and C18 ω‐hydroxyacids are components of polymers in plants. The long‐chain ω‐hydroxyacids are found in epidermal sphingolipids, in giant‐ring lactones from the sebum of members of the equidae, as a component of meibum and in carnauba wax and wool wax. [ABSTRACT FROM AUTHOR]

Synopsis As excessive sun exposure is tightly associated with different pathological changes of the skin, for example premature skin ageing or the development of skin cancer, an appropriate protection of the skin against UV radiation is of particular importance. Sun protection products and UV filter substances have evolved continuously in the past few decades. New developments and improved technical conditions of production have led to increasingly effective and efficient products with broadband protection ability. Accordingly, legal requirements have also changed and expanded. Although certain trends exist to harmonize the regulation of sunscreens at a global level, there are still large differences how UV absorbers are approved, which testing methods are prescribed, and which general requirements sun protection products must fulfil. Modern UV filters provide efficient protection against UVA and UVB radiation, are heat and photostable, user-friendly, cost-effective, water resistant and non-toxic. As inorganic and organic UV filters are topically applied to the skin in relatively high concentrations (up to 25%), especially the assessment of their (photo)sensitization potential is of particular importance. Accordingly, skin sensitization is a key endpoint for the legally required safety assessment of cosmetic ingredients in Europe and many other countries. This review will summarize the current regulatory status of different approved UV filters, will describe their beneficial and adverse properties and will give an overview of how the efficacy of sunscreens can be evaluated. Finally, an insight into the basic mechanism of (photo)allergic reactions and existing skin sensitization test methods will be provided. [ABSTRACT FROM AUTHOR]

Synopsis Objective Polyphenols are strong antioxidant molecules allowing prevention of skin photo-ageing damages, but their use is limited due to low solubility and toxicity towards skin cells. We postulated that enzymatic glucosylation could improve their solubility, stability and, consequently, their efficacy. The aim of this work was to study changes induced by addition of a glucose moiety on two polyphenols displaying very different chemical structures [caffeic acid ( CA), epigallocatechin-3-gallate ( EGCG) and there glucosylated form, Glc-CA and Glc-EGCG] by assessing their cytotoxic properties and their antioxidant and anti-inflammatory activities. Methods Their antioxidant effect was assessed first by the classical DPPH radical-scavenging method. Then, a panel of human skin cells (keratinocytes, melanocytes, fibroblasts and endothelial cells) was used to evaluate their effect on cell toxicity and their antioxidant activities. With this aim, a photo-ageing model based on UV irradiation of skin cells was established. Molecule activity was assessed on reactive oxygen species ( ROS) production, on superoxide dismutase (SOD) and catalase activities and, finally, on inflammatory factor production IL-6, IL-8 and IL-1β. Results In an acellular model, antioxidant activity assessed by DPPH method was strongly reduced for Glc-CA compared to CA, whereas it remained the same for Glc-EGCG compared to EGCG. Glucosylated derivatives did not display more toxic effect on various skin cells. Moreover, toxicity was even strongly reduced for caffeic acid upon glucosylation. The efficacy of glucosyl-compounds against UV-induced ROS production was preserved, both with pre- and post- UV treatments. Particularly, a better antioxidant efficacy was shown by Glc-EGCG, vs. EGCG, on keratinocytes. In addition, an induction of SOD and catalase activity was clearly observed for Glc-CA. Both glucosyl-polyphenols display the same activity as their parent molecule in decreasing inflammatory factor production. Conclusion Our results demonstrated that enzymatic glucosylation of CA and EGCG led to an improved or preserved antioxidant activity in a cellular model of UV-induced skin ageing, despite the decrease in instantaneous antioxidant properties observed for Glc-CA. Glc-EGCG is specifically more active on keratinocytes, suggesting a specific targeting. Such glucosylated polyphenols displaying improved physicochemical and biological properties should be better candidates than natural ones for use in food additives and cosmetics. [ABSTRACT FROM AUTHOR]

Synopsis Objective Organotypic skin models are powerful tools for research in development, ageing and diseases. They have become more and more complex with the use of multiple cell types. This requires a culture medium adapted to optimize the development of such in vitro skin. Foetal bovine serum ( FBS) is the most complete supplement in existence at the moment, providing at once growth factors, vitamins, hormones and other circulating compounds. However, this cocktail suffers from batch variability and its animal origin is ethically questionable. More importantly, its biological activities may interfere with the study of certain signalling pathways. Here, we present a strategy for constructing an epidermal equivalent using a defined culture medium without serum. Methods An epidermal equivalent was constructed with primary human keratinocytes cultured using an insulin-transferrin-selenium ( ITS) medium. Determination of steady-state gene expression levels and the immunohistological characterization of keratinocyte markers were performed to compare the ITS medium condition with a reference model, where keratinocytes were co-cultured with fibroblasts in the presence of FBS. Results The data show that the ITS medium promoted the expression of keratinocyte proliferation and differentiation markers at the protein and transcript levels in a similar way to that of the reference model. Conclusion We show that culture using the ITS medium appears as a viable replacement for FBS in the construction of epidermal equivalents, opening the way to signal transduction studies. [ABSTRACT FROM AUTHOR]

Synopsis Objective The stratum corneum is the outermost layer of the skin. Its components and its morphology (such as the size of its cells) play a role in sun protection, and it has been noted that the stratum corneum hydration can change these properties. Sunscreens, applied on the skin, can be more or less effective depending on the stratum corneum characteristics. We therefore propose to simulate the quality of the sun protection and the effect of the stratum corneum hydration on the sun protection. Methods We first determined the sunscreen distribution on a plastic substrate using an optical coherence tomography device. We were then able to calculate, by 2-D differential method, the extinction of several sunscreens. We modelled the hydration of the stratum corneum, by changing the substrate with corneocytes of different thicknesses. Results Our results showed that hydrated stratum corneum protects more against the UV. The benefit from changing the substrate varies depending on the sunscreen applied. Conclusion We modelled sunscreens on different substrates using electromagnetic simulations. To compare these results with measurements, we have to carefully hydrate or dehydrate the SC: the simulations did not take into account modifications of the surface (water on the surface for example) or any change in the characteristics of the stratum corneum other than the modification of the corneocytes thickness. [ABSTRACT FROM AUTHOR]

Objective Dandruff is a troubling consumer problem characterized by flaking and pruritus of the scalp and is considered a multifactorial condition with sebum, individual susceptibility and the fungus Malassezia all thought to play a part. The condition is commonly treated with shampoo products containing antifungal ingredients such as zinc pyrithione and climbazole. It is hypothesized that these ingredients may be delivering additional scalp skin benefits besides their antifungal activity helping to relieve dandruff effectively. The objective of this study was to evaluate the anti-dandruff ingredient climbazole for potential skin benefits using genomics and in vitro assays. Methods Microarray analysis was performed to profile gene expression changes in climbazole-treated primary human keratinocyte cells. Results were independently validated using qPCR and analysis of protein expression using ELISA and immunocytochemistry. Results Microarray analysis of climbazole-treated keratinocytes showed statistically significant expression changes in genes associated with the gene ontology groups encompassing epidermal differentiation, keratinization, cholesterol biosynthesis and immune response. Upregulated genes included a number encoding cornified envelope proteins such as group 3 late-cornified envelope proteins, LCE3 and group 2 small-proline-rich proteins, SPRR2. Protein analysis studies of climbazole-treated primary keratinocytes using ELISA and immunocytochemistry were able to demonstrate that the increase in gene transcripts translated into increased protein expression of these cornified envelope markers. Conclusion Climbazole treatment of primary keratinocytes results in an upregulation in expression of a number of genes including those encoding proteins involved in cornified envelope formation with further studies demonstrating this did translate into increased protein expression. A climbazole-driven increase in cornified envelope proteins may improve the scalp skin barrier, which is known to be weaker in dandruff. These studies suggest climbazole, besides its antifungal activity, is delivering positive skin benefits helping to relive dandruff symptoms effectively. [ABSTRACT FROM AUTHOR]

Synopsis Objective Outer root sheath ( ORS) cells of human hair follicles are a readily available, non-invasive source of keratinocytes for epidermis reconstruction. The aim of this study was to characterize a model of epidermis reconstructed from ORS cells ( ORS-derived model) and to evaluate its reproducibility, in comparison with native human skin and two marketed reconstructed skin models (model A, Episkin® and model B, Skinethic®). Methods Cell morphology and tissue architecture of the three models were analysed histologically and proliferation and differentiation marker expression by immunohistochemistry and m RNA quantification. Results All models displayed the same general epidermal architecture as native epidermis, but with a thicker stratum corneum in models A and B. Compared with native epidermis, Ki67 was correctly localized in epidermal basal cells in all models, as K10 in suprabasal layers. In all skin models, transglutaminase 1 ( TGM1) was prematurely expressed in suprabasal layers. However, this expression was only observed from the upper stratum spinosum in the ORS-derived model. In this model, filaggrin and loricrin were correctly located in the stratum granulosum. Filaggrin, involucrin, loricrin and TGM1 m RNAs (markers of keratinocyte terminal differentiation) were transcriptionally expressed in all models. In the ORS-derived model, transcriptional expression level was similar to that of native skin. Conclusion ORS cell-based reconstructed epidermis is a valid and reproducible model for human epidermis and it may be used to evaluate the effects of active substances and cosmetic formulations. [ABSTRACT FROM AUTHOR]

Synopsis Objective Stratum corneum ( SC) lipids are known to play an important role in barrier properties of skin by maintaining the optimal hydration levels. The disruption of SC lipids by cleanser surfactants is believed to lead to dry skin damage which can be a precursor to other skin disorders. The purpose of this study is to investigate the effects of commonly used anionic and zwitterionic surfactants sodium lauryl ether sulphate ( SLES) and cocoamidopropyl betaine ( CAPB) on the generation of drying stresses in SC and the role played by lipids. Methods Stratum corneum separated from pig skin was treated with various surfactants ( SDS, SLES and CAPB) their mixtures and solvents. The tensile response to these treatments was measured by using a dynamic mechanical thermal analyzer. A Raman spectroscopy study of the treated samples was performed to investigate the effects of lipid modification (lipid chain conformational order and lipid removal) on stress generation in SC. Results The effects of commonly used anionic and zwitterionic surfactants on the generation of drying stresses in SC were studied. Although known to be milder in comparison with SDS, both SLES and CAPB generated high drying stresses individually. In mixtures, SLES- CAPB at 4 : 1 ratio leads to lower drying stress as compared to water alone. A Raman spectroscopic study of surfactant-treated SC shows changes in lipid chain conformational order as well as a decrease in lipid-protein ratio in SC. A chloroform-methanol 2 : 1 treatment leads to the highest drying stress as well delipidization of SC. Conclusion The results show a correlation between generation of drying stress in SC and extent of lipid modification. We propose that the changes in lipid conformational order and removal of lipid components affect the stress relaxation properties of SC leading to high drying stresses. [ABSTRACT FROM AUTHOR]

Synopsis Objective Skin compartments traditionally targeted by cosmetic actives - epidermis and dermis - are anchored and nourished by the underlying hypodermis, which therefore should be a key target for skin-rejuvenating formulations. However, given the difficulty to reach even the superficial layers of the skin, and to its 'unglamorous' fatty composition, the regenerative potential of hypodermis remains largely untapped. Therefore, this study was to investigate the capacity of a cosmetic material to trigger a regenerative response in dermis and epidermis through a selective action on hypodermis. Furthermore, it aimed to establish the effect of such cosmetic material in transbuccal hypodermal delivery form, on the hypodermal precursor cells - the preadipocytes. Methods A combination of grape seed extract and soy phospholipids was formulated and standardized for elastase activity and free radical inhibition. This formulation was then used to contact the hypodermal layer of human skin biopsies and - under a transbuccal delivery vehicle form - the 3T3-L1 preadipocytes, and its effects were quantified using PCR arrays and histochemistry. Results Application of the standardized grape/soy material to the hypodermal layer of skin triggered modulation of gene expression in the upper layers of the skin and resulted in the clear morphological improvement at the dermal and epidermal levels. Furthermore, when this material was formulated in a mucoadhesive, intraoral film and applied on 3T3-L1 preadipocytes, the resulting modulation of gene expression in these cells was consistent with differentiation and detoxification effects. Conclusions These results suggest that transbuccal formulations of nutraceutical grade cosmetics have potential to induce signal transduction pathways in facial hypodermis, resulting in anti-aging effects throughout all skin compartments, including dermal and epidermal layers. [ABSTRACT FROM AUTHOR]

Synopsis Objectives Evidence is given that differences in skin physiological properties exist between men and women. However, despite an assessable number of available publications, the results are still inconsistent. Therefore, the aim of this clinical study is the first systematic assessment of gender-related differences in skin physiology in men and women, with a special focus on changes over lifetime. Methods A total of 300 healthy male and female subjects (20-74 years) were selected following strict criteria including age, sun behaviour or smoking habits. TEWL, hydration level, sebum production and pH value were measured with worldwide-acknowledged biophysical measuring methods at forehead, cheek, neck, volar forearm and dorsum of hand. Results Until the age of 50 men's TEWL is significantly lower than the water loss of women of the same age, regardless of the location. With ageing gender-related differences in TEWL assimilate. Young men show higher SC hydration in comparison with women. But, whereas SC hydration is stable or even increasing in women over lifetime, the skin hydration in men is progressively decreasing, beginning at the age of 40. Sebum production in male skin is always higher and stays stable with increasing age, whereas sebum production in women progressively decreases over lifetime. Across all localizations and age groups, the pH value in men is below 5, the pH value of female subjects is, aside from limited expectations, higher than 5. Conclusion Skin physiological distinctions between the sexes exist and are particularly remarkable with regard to sebum production and pH value. [ABSTRACT FROM AUTHOR]

Synopsis Background Cellulite refers to changes in skin relief on the thighs and buttocks of women, with a prevalence of 80-90%, causing dissatisfaction and search for treatment. Etiopathogenesis is multifactorial, as follows: herniation of the hypodermis towards the dermis, facilitated by perpendicular fibrous septa, changes in the dermal extracellular matrix, decreased adiponectin, genetic polymorphism, microcirculation alterations and inflammatory process. There are numerous therapeutic approaches, with little evidence of effectiveness. The long-wave infrared ( LWIR) radiation interacts with water, improves microcirculation and stimulates metabolic processes. To date, the use of tissues with potential reflection of LWIR radiation has not been systematically investigated as adjuvant treatment for cellulite. Objective To investigate the efficacy and safety of the treatment of cellulite through the use of compression stockings made with thread reflecting LWIR radiation. Patients and methods Clinical study of therapeutic intervention, controlled and double-blind, including 30 women, aging from 25 to 40 years, with cellulite of grades II and III on the thighs and buttocks who used compression stockings, 'pantyhose' model, made with reflector thread of LWIR radiation, on only one randomized side. Women under other treatments for cellulite and with venous and/or blood insufficiencies were excluded. Evaluation of efficacy by clinical parameters, photographs, Dermatology Life Quality Index ( DLQI), cutometry and high frequency ultrasonography and security by observation of adverse events and venous EcoDoppler recordings. Results DLQI scores showed significant reduction; the two-dimensional high-frequency ultrasonography showed an insignificant increase in dermal echogenicity as well as other efficacy parameters demonstrated no or slight improvement, with no differences between the sides exposed or not to LWIR; and there were no severe adverse events. Conclusion Compression stockings, with or without thread reflector of LWIR, showed slight effects in the appearance of cellulite, but the treatment determined a positive impact on women quality of life. [ABSTRACT FROM AUTHOR]

Synopsis Objectives Dandruff is a chronic, relapsing scalp condition that negatively impacts the quality of life of sufferers. Regular use of anti-fungal shampoos represents a proven therapeutic strategy to improve the most common symptoms of flakes and itch. Two recent approaches for enhancing the efficacy of anti-fungal shampoos are maximizing bio-availability of the active material or the addition of a second active material. Our aim is to compare the therapeutic efficacy of these two approaches - maximization of bio-availability of the zinc pyrithione ( ZPT) active material or the combination of ZPT with a secondary active material. Methods The anti-fungal potency of shampoos representing each of these approaches was evaluated in vitro using a standard microbiology method. Spatial delivery of ZPT particles in the follicular infundibulum was assessed in vivo using a novel confocal microscopy methodology. Clinical efficacy was assessed in a randomized, double-blind trial involving 620 male and female subjects using scalp flaking and epidermal histamine level as endpoints. Results The shampoo formula with maximized ZPT bio-availability known as the Potentiated ZPT formula exhibited greater anti-fungal potency than the Dual Active shampoo containing both ZPT and climbazole. The Potentiated ZPT formula also delivered more ZPT to the lower infundibulum than the Dual Active shampoo. A 4-week treatment with the Potentiated ZPT formula resulted in superior clinical efficacy compared with the Dual Active product at all 4 weekly time points for both flaking and epidermal histamine endpoints. Conclusion These results highlight the critical role that the shampoo vehicle plays in realizing full potency of active materials. By optimizing the delivery vehicle, the enhanced anti-fungal potency and the maximized spatial delivery of active materials result in greater symptomatic improvement than a product with two active materials. The therapeutic efficacy of a product based on a complex delivery vehicle such as a shampoo must be considered from a full-product perspective rather than just the active system as the non-active components of the composition will often play a significant role in the overall product pharmacology and resultant efficacy. [ABSTRACT FROM AUTHOR]