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A higher concentration of calcium in breast milk than blood favors paracellular calcium absorption enabling growth during postnatal development. We aimed to determine whether suckling animals have greater intestinal calcium permeability to maximize absorption and to identify the underlying molecular mechanism. We examined intestinal claudin expression at different ages in mice and in human intestinal epithelial (Caco-2) cells in response to hormones or human milk. We also measured intestinal calcium permeability in wildtype, Cldn2 and Cldn12 KO mice and Caco-2 cells in response to hormones or human milk. Bone mineralization in mice was assessed by μCT. Calcium permeability across the jejunum and ileum of mice were 2-fold greater at 2 wk than 2 mo postnatal age. At 2 wk, Cldn2 and Cldn12 expression were greater, but only Cldn2 KO mice had decreased calcium permeability compared to wildtype. This translated to decreased bone volume, cross-sectional thickness, and tissue mineral density of femurs. Weaning from breast milk led to a 50% decrease in Cldn2 expression in the jejunum and ileum. Epidermal growth factor (EGF) in breast milk specifically increased only CLDN2 expression and calcium permeability in Caco-2 cells. These data support intestinal permeability to calcium, conferred by claudin-2, being greater in suckling mice and being driven by EGF in breast milk. Loss of the CLDN2 pathway leads to suboptimal bone mineralization at 2 wk of life. Overall, EGF-mediated control of intestinal claudin-2 expression contributes to maximal intestinal calcium absorption in suckling animals. Graphical Abstract Epidermal growth factor in milk increases the paracellular permeability to calcium across the small intestine via increasing the intestinal claudin-2 abundance in suckling mammals. [ABSTRACT FROM AUTHOR]

Intercellular lipids comprise mainly ceramides, known to enhance the barrier function of the stratum corneum. However, the activities of ceramides inside the skin have not yet been fully elucidated. Here we examined how the human ceramide mixture (HC123) functions in the dermis. We treated human skin fibroblasts with HC123-expressed fibroblast growth factor (FGF), transforming growth factor-β (TGF-β), collagen I, and fibrillin. We found that HC123 promoted the formation of collagen fibers and microfibrils (fibrillin) which affect the elasticity of the skin. We also confirmed that the gene expression of collagen and fibrillin is promoted via TGF-β and FGF2, respectively. We then investigated the permeability of HC123 for external use, in pursuit of evidence that HC123 may exert an anti-aging effect by penetrating into the dermis, activating fibroblasts, and promoting the production of collagen fibers and elastin-related microfibrils. [ABSTRACT FROM AUTHOR]

Body size dependence of metabolic rate, body surface and scale morphology complicate disentangling the contribution of these characteristics to adaptive changes in total evaporative water loss (TEWL) of reptiles. To separate adaptive changes from size‐related dependence, we compared intra‐ and interspecific scaling of several candidate traits in eyelid geckos (Eublepharidae), a group exhibiting large variation in body size and TEWL. The intraspecific allometry of TEWL of a eublepharid species fits the geometric surface–mass relationship. However, evolutionary shifts to both higher and lower evaporation were strongly correlated with habitat aridity and cannot be explained by shifts in body size alone. The intraspecific allometry of standard metabolic rate is nearly the same as the interspecific allometry. Unlike for mammals and birds, this pattern rules out respiratory water loss as a driver of the adaptive changes in TEWL among eublepharids. Scale morphology was independent of TEWL variation as well, but the correlation between cutaneous water loss and TEWL suggests a crucial role of skin permeability in adaptation to habitat aridity. Our analyses demonstrate how powerful a comparison between intra‐ and interspecific allometries can be for detecting body size‐dependent mechanisms of adaptive changes in ecophysiological traits correlated with body size. [ABSTRACT FROM AUTHOR]

In drug development, preclinical safety and pharmacokinetics assessments of candidate drugs to ensure the safety profile are a must. While in vivo and in vitro tests are traditionally used, experimental determinations have disadvantages, as they are usually time-consuming and costly. In silico predictions of these preclinical endpoints have each been developed in the past decades. However, only a few web-based tools have integrated different models to provide a simple one-step platform to help researchers thoroughly evaluate potential drug candidates. To efficiently achieve this approach, a platform for preclinical evaluation must not only predict key ADMET (absorption, distribution, metabolism, excretion and toxicity) properties but also provide some guidance on structural modifications to improve the undesired properties. In this review, we organized and compared several existing integrated web servers that can be adopted in preclinical drug development projects to evaluate the subject of interest. We also introduced our new web server, Virtual Rat, as an alternative choice to profile the properties of drug candidates. In Virtual Rat, we provide not only predictions of important ADMET properties but also possible reasons as to why the model made those structural predictions. Multiple models were implemented into Virtual Rat, including models for predicting human ether-a-go-go-related gene (hERG) inhibition, cytochrome P450 (CYP) inhibition, mutagenicity (Ames test), blood–brain barrier penetration, cytotoxicity and Caco-2 permeability. Virtual Rat is free and has been made publicly available at https://virtualrat.cmdm.tw/. [ABSTRACT FROM AUTHOR]

Although skin health is of critical importance for all horse owners, understanding of cutaneous pH and trans-epidermal water loss (TEWL) and the normal ranges of these variables is lacking. Cutaneous pH and TEWL measures provide insight into the barrier function of the epidermis and have the potential to determine the resident dermal microbiota. However, these measures have been recorded to fluctuate due to a variety of factors such as environment and anatomical locations in other species. Accordingly, the objectives of this study were to identify the impacts of anatomical location, weather, and time of day on cutaneous pH and TEWL in equines. This study utilized nine (n = 9) stock type mares, group-housed in a pasture setting at Southern Illinois University Equine Center. Researchers measured cutaneous pH and TEWL three times (6:00 AM, 12:00 PM, 6:00 PM) daily across five anatomical locations (nose, whither, heart-girth, mid-back, and base of tail) for five consecutive days. All statistical analysis was conducted using SAS On Demand for Academics (P < 0.05). Analysis of changes in variables associated with time, anatomical location, and day were conducted utilizing a PROC GLM three-way repeated measures ANOVA utilizing a Greenhouse-Geiser correction. Cutaneous pH results displayed significant main effects of day (P = 0.0052) and time (P = 0.0073) as well as a significant interaction of day and location (P = 0.0004). Mean cutaneous pH fluctuated daily, however, certain anatomical locations fluctuated more than others each day. Additionally, pH was highest in the morning (mean of 7.28) and lowest in the evening (mean 7.011). However, the mean overall pH for the study is 7.14 which is congruent with other work. TEWL measurements had significant main effects of day (P < 0.0001), time (P < 0.0001), and location (P = 0.0231), as well as a significant interaction of day, time, and location (P < 0.0001). TEWL measurements fluctuated with day, likely a result of weather changes. Mean TEWL measurements were less in the morning (mean 24.68) and greatest in the afternoons (mean 38.52). Overall mean TEWL measurement was 30.25. The results of this work indicate fluctuations in dermal barrier variables are associated with day, anatomical location, and time of day. These findings may have implications for applications of dermal treatments for horses as well as catalog the natural fluctuations which may affect future research. [ABSTRACT FROM AUTHOR]

The structure of the skin may evolve rapidly during a biological invasion, for two reasons. First, novel abiotic challenges such as hydric conditions may modify selection of traits (such as skin thickness) that determine rates of evaporative water loss. Second, invaders might benefit from enhanced rates of dispersal, with locomotion possibly facilitated by thinner (and hence more flexible) skin. We quantified thickness of layers of the skin in cane toads (Rhinella marina) from the native range (Brazil), a stepping-stone population (Hawaii), and the invaded range in Australia. Overall, the skin is thinner in cane toads in Australia than in the native range, consistent with selection on mobility. However, layers that regulate water exchange (epidermal stratum corneum and dermal ground substance layer) are thicker in Australia, retarding water loss in hot dry conditions. Within Australia, epidermal thickness increased as the toads colonized more arid regions, but then decreased in the arid Kimberley region. That curvilinearity might reflect spatial sorting, whereby mobile (thin-skinned) individuals dominate the invasion front; or the toads' restriction to moist sites in this arid landscape may reduce the importance of water-conservation. Further work is needed to clarify the roles of adaptation versus phenotypic plasticity in generating the strong geographic variation in skin structure among populations of cane toads. [ABSTRACT FROM AUTHOR]

Naphthalene, a volatile organic compound present in moth repellants and petroleum-based fuels, has been shown to induce toxicity in mice and rats during chronic inhalation exposures. Although simpler default methods exist for extrapolating toxicity points of departure from animals to humans, using a physiologically based pharmacokinetic (PBPK) model to perform such extrapolations is generally preferred. Confidence in PBPK models increases when they have been validated using both animal and human in vivo pharmacokinetic (PK) data. A published inhalation PBPK model for naphthalene was previously shown to predict rodent PK data well, so we sought to evaluate this model using human PK data. The most reliable human data available come from a controlled skin exposure study, but the inhalation PBPK model does not include a skin exposure route; therefore, we extended the model by incorporating compartments representing the stratum corneum and the viable epidermis and parameters that determine absorption and rate of transport through the skin. The human data revealed measurable blood concentrations of naphthalene present in the subjects prior to skin exposure, so we also introduced a continuous dose-rate parameter to account for these baseline blood concentration levels. We calibrated the three new parameters in the modified PBPK model using data from the controlled skin exposure study but did not modify values for any other parameters. Model predictions then fell within a factor of 2 of most (96%) of the human PK observations, demonstrating that this model can accurately predict internal doses of naphthalene and is thus a viable tool for use in human health risk assessment. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to use Gaussian process regression (GPR) methods to quantify the effect of experimental temperature (Texp) and choice of diffusion cell on model quality and performance. Methods: Data were collated from the literature. Static and flow‐through diffusion cell data were separated, and a series of GPR experiments was conducted. The effect of Texp was assessed by comparing a range of datasets where Texp either remained constant or was varied from 22 to 45 °C. Key findings: Using data from flow‐through diffusion cells results in poor model performance. Data from static diffusion cells resulted in significantly greater performance. Inclusion of data from flow‐through cell experiments reduces overall model quality. Consideration of Texp improves model quality when the dataset used exhibits a wide range of experimental temperatures. Conclusions: This study highlights the problem of collating literature data into datasets from which models are constructed without consideration of the nature of those data. In order to optimise model quality data from only static, Franz‐type, experiments should be used to construct the model and Texp should either be incorporated as a descriptor in the model if data are collated from a range of studies conducted at different temperatures. [ABSTRACT FROM AUTHOR]

An aquatic animal faces challenges not encountered by its terrestrial counterparts, promoting adaptive responses in multiple traits. For example, a thicker dermis might protect snakes when they are pushed against sharp objects by water currents, and might enable a snake to shed fouling organisms attached to its skin. We thus predicted that marine snakes should have thicker skin than terrestrial species, and that smaller sea snakes should have relatively thicker skin (because absolute, not relative, thickness determines vulnerability to fouling). Measurements of 192 snakes of 44 species supported those predictions. Many (but not all) sea snakes have skins 50% thicker than those of terrestrial and amphibious snake species, representing multiple independent evolutionary origins of thicker skin (in acrochordids, Laticauda sea kraits and both main clades of hydrophiine sea snakes). Marine snakes showed different allometries of skin thickness compared with their terrestrial counterparts; larger snakes had thicker skin within and among species of amphibious and terrestrial snakes, but larger aquatic snake species had thinner skin compared with smaller taxa. Interspecific variation in skin thickness was primarily due to increased collagen in the deep dermis, a physical barrier well suited to protecting against physical injury and to resisting penetration by epibionts. [ABSTRACT FROM AUTHOR]

Amphibians transport water, oxygen, carbon dioxide and various ions (e.g. sodium and potassium) across their skin. This cutaneous permeability is thought to affect their ability to respond to environmental change and to play a role in global population declines. Sexual dimorphism of skin anatomy has been accepted in some species, but rejected in others. The species in which such dimorphism has been detected have all been sexually dimorphic in body size, with males that are smaller and have thinner skin. It is unclear whether this difference in skin thickness manifests a functional difference or if it is related to body size alone. Skin thickness (epidermis, spongy dermis, compact dermis and total thickness) was examined in males and females of the white-lipped treefrog (Litoria infrafrenata). Although the skin of males is absolutely thinner than that of females, this difference is explained by body size differences between the sexes. Overall, we conclude that skin thickness in male and female L. infrafrenata correlates with body size dimorphism and suggest that future studies on amphibian skin anatomy include measures of body size, test the ecological significance of sexually dimorphic skin anatomy and better document the prevalence of sexually dimorphic amphibian skin anatomy. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this article was to use copaiba oil (C.O) to improve skin permeability and topical anti‐inflammatory activity of celecoxib (Cxb). Methods: Formulations containing C.O (1–50%) were associated with Cxb (2%). In vitro skin permeability studies were conducted using porcine ear skin. Histological analysis of the hairless mice skin samples after application of formulations was achieved with the routine haematoxylin/eosin technique. The anti‐inflammatory activity was assessed using the AA‐induced ear oedema mice model. Key findings: The formulation containing 25% C.O promoted the highest levels of in vitro Cxb permeation through pig ear skin, retention in the stratum corneum (SC) and epidermis/dermis of pig ear skin in vitro (~5‐fold) and hairless mice skin in vivo (~2.0‐fold), as compared with the control formulation. At 25%, C.O caused SC disorganization and increased cell infiltration and induced angiogenesis without clear signs of skin irritation. The formulation added to 25% C.O as adjuvant inhibited ear oedema and protein extravasation by 77.51 and 89.7%, respectively, and that it was, respectively, 2.0‐ and 3.4‐fold more efficient than the commercial diethylammonium diclofenac cream gel to suppress these inflammatory parameters. Conclusions: 25% C.O is a potential penetration enhancer for lipophilic drugs like Cxb that can improve cutaneous drug penetration and its anti‐inflammatory activity. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The aim of this study was to investigate how to improve predictions from Gaussian Process models by optimising the model hyperparameters. Methods: Optimisation methods, including Grid Search, Conjugate Gradient, Random Search, Evolutionary Algorithm and Hyper‐prior, were evaluated and applied to previously published data. Data sets were also altered in a structured manner to reduce their size, which retained the range, or ‘chemical space’ of the key descriptors to assess the effect of the data range on model quality. Key findings: The Hyper‐prior Smoothbox kernel results in the best models for the majority of data sets, and they exhibited significantly better performance than benchmark quantitative structure–permeability relationship (QSPR) models. When the data sets were systematically reduced in size, the different optimisation methods generally retained their statistical quality, whereas benchmark QSPR models performed poorly. Conclusions: The design of the data set, and possibly also the approach to validation of the model, is critical in the development of improved models. The size of the data set, if carefully controlled, was not generally a significant factor for these models and that models of excellent statistical quality could be produced from substantially smaller data sets. [ABSTRACT FROM AUTHOR]

This study evaluated the effects of physically effective neutral detergent fiber (peNDF), and undigested neutral detergent fiber (uNDF) on dry matter intake (DMI), eating behavior, ruminal fermentation, and total tract permeability for finishing cattle. Simmental heifers (n=6; 667.8±28.4 kg) were used in a replicated 3×3 Latin square (21-d periods) balanced for carry-over effects. Barley grain-based diets were formulated to provide treatments with: low peNDF and low uNDF (95% barley and supplement, and 0% straw; 0FOR); low peNDF but high uNDF (85% barley and supplement, 10% pelleted straw; PEL); or high peNDF with high uNDF (85% barley and supplement, 10% chopped straw; ST). Treatment did not affect DMI (P=0.93). Heifers fed 0FOR spent less (P< 0.01) time eating vs. ST, where PEL was intermediate. Time spent ruminating was greater (P=0.01) for ST than 0FOR, with PEL not differing. Heifers fed 0FOR had fewer meals/d than ST (P< 0.01) and meal size was greater for 0FOR than PEL and ST (P< 0.01). Feeding 0FOR reduced (P=0.02) mean ruminal pH (5.65 vs. 6.07) and increased (522 vs. 288 min/d, P=0.02) the duration that pH was < 5.5 relative to ST with PEL being intermediate (5.82 and 504 min/d, respectively). Heifers fed 0FOR had greater (112.5 vs. 59.9 sec, P=0.05) time between contractions and lesser (61.45 vs. 94.58 mmHg'sec, P=0.05) contraction area compared with cattle fed ST, while PEL remained intermediate (76.73 sec and 73.29 mmHg×sec, respectively). Permeability of the gastrointestinal tract to Cr-EDTA and intestine to Co-EDTA did not differ (P=0.11) among treatments. The data suggest that increasing uNDF improved ruminal function, but increasing uNDF with peNDF is needed to decrease the risk of ruminal acidosis in finishing cattle. The results further suggest that the use of uNDF and peNDF may provide useful information over NDF inclusion when evaluating fiber adequacy of finishing diets. [ABSTRACT FROM AUTHOR]

Background Atopic dermatitis ( AD) and contact dermatitis ( CD) are both T cell-mediated eczematous disorders. Interleukin ( IL)-17, expressed by T helper (Th)17 cells, is involved in recruitment of inflammatory cells into AD and CD skin. Aim In this study, we investigated whether IL-17 regulates immune dysregulation and affects skin barrier in oxazolone ( OXA)-induced AD-like and CD-like disease models in mice, by comparing IL-17 null mutant ( IL-17−/−) vs. wild-type ( WT) mouse strains in the models. Methods IL-17−/− and WT Balb/c mice were used for OXA induction of AD-like and CD-like skin diseases. Ear swelling was measured by a micrometer. Skin biopsies were obtained for RNA isolation and histology. Real-time quantitative PCR analysis was performed to quantify mRNA expression of Th2 cytokines. Skin permeability was measured by a vapometer, and structural changes in the skin were evaluated by electron and confocal microscopy. Results Both OXA-induced AD and CD responses were alleviated in IL-17−/− mice relative to WT, as demonstrated by reductions in ear swelling, inflammatory cell infiltration and levels of Th2 cytokines. These endpoints were used to characterize inflammatory dysregulation in both AD and CD models. Skin-barrier dysfunction, measured by increases in transepidermal water loss and dysfunction of lamellar bodies, and reductions in lipid distribution, were seen in both AD and CD in WT mice. In IL-17−/− mice, however, these responses were significantly diminished. Conclusions The results indicate that the IL-17 gene may play a role in modulating immune dysregulation and affecting skin barrier in OXA-induced AD-like and CD-like skin disease models in the Balb/c mouse. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to investigate skin permeation rates of a drug substance when applied in novel gel formulations with catanionic aggregates. Methods Reference gel without catanionic aggregates was compared with formulations with catanionic aggregates composed of tetracaine and either sodium dodecyl sulphate (SDS) or capric acid. Carbomer and SoftCAT were used to compare the effect of different gel types to elucidate if physically cross-linked, 'self-destructing' systems had benefits compared with classical, covalently cross-linked, gels. Key findings The rheological investigation showed that the interactions between the SoftCAT polymer and tetracaine/SDS aggregates were stronger than when the tetracaine/capric acid aggregates were used. The skin permeation was measured ex vivo in horizontal Ussing chambers and the permeation of tetracaine was significantly lower when formulations with tetracaine/SDS aggregates were applied ( P < 0.001), but not statistically different from the reference when capric acid was used. Conclusions No morphological differences could be distinguished between the skin samples exposed to the different formulations or the reference. Skin permeation was compared with silicone sheet permeation and the results indicated that silicone sheets could be used as a model of skin when using these formulations. [ABSTRACT FROM AUTHOR]

Development of risk assessment methods for skin sensitization in the absence of toxicological data generated in animals represents a major scientific and technical challenge. The first step in human skin sensitization induction is the transport of sensitizer from the applied dose on the skin surface to the epidermis, where innate immune activation occurs. Building on the previous development of a time course in vitro human skin permeation assay, new kinetic data for 10 sensitizers and 2 nonsensitizers are reported. Multicompartmental modeling has been applied to analyze the data and determine candidate dose parameters for use in integrated risk assessment methods: the area under the curve (AUC) and maximum concentration (Cmax) in the epidermis. A model with two skin compartments, representing the stratum corneum and viable skin (epidermis and dermis), was chosen following a formal model selection process. Estimates of the uncertainty, as well as average values of the epidermal disposition kinetics parameters, were made by fitting to the time course skin permeation data from individual skin donors. A potential reduced time course method is proposed based on two time points at 4 and 24 h, which gives results close to those from the full time course for the current data sets. The time course data presented in this work have been provided as a resource for development of predictive in silico skin permeation models. [ABSTRACT FROM PUBLISHER]

Dermal absorption of topically applied chemicals usually occurs from complex chemical mixtures; yet, most attempts to quantitate dermal permeability use data collected from single chemical exposure in aqueous solutions. The focus of this research was to develop quantitative structure permeation relationships (QSPR) for predicting chemical absorption from mixtures through skin using two levels of in vitro porcine skin biological systems. A total of 16 diverse chemicals were applied in 384 treatment mixture combinations in flow-through diffusion cells and 20 chemicals in 119 treatment combinations in isolated perfused porcine skin. Penetrating chemical flux into perfusate from diffusion cells was analyzed to estimate a normalized dermal absorptive flux, operationally an apparent permeability coefficient, and total perfusate area under the curve from perfused skin studies. These data were then fit to a modified dermal QSPR model of Abraham and Martin including a sixth term to account for mixture interactions based on physical chemical properties of the mixture components. Goodness of fit was assessed using correlation coefficients (r2), internal and external validation metrics (qLOO2, qL25%2, qEXT2), and applicable chemical domain determinations. The best QSPR equations selected for each experimental biological system had r2 values of 0.69–0.73, improving fits over the base equation without the mixture effects. Different mixture factors were needed for each model system. Significantly, the model of Abraham and Martin could also be reduced to four terms in each system; however, different terms could be deleted for each of the two biological systems. These findings suggest that a QSPR model for estimating percutaneous absorption as a function of chemical mixture composition is possible and that the nature of the QSPR model selected is dependent upon the biological level of the in vitro test system used, both findings having significant implications when dermal absorption data are used for in vivo risk assessments. [ABSTRACT FROM AUTHOR]

The article presents a study which determines the utility of Gaussian processes for skin permeability prediction. It states that MatLab software was utilized to evaluate the performance of Gaussian process, single linear network (SLN), and quantitative structure-permeability relationships (QSPRs) and the principal component analysis was executed to determine the nature of the dataset. Result shows that a non-linear approach was more appropriate than QSPRs and SLN of the dataset employed.

Allergic skin disorders include urticaria, angioedema, contact dermatitis and atopic dermatitis, but the model fitting most closely the systemic concept of allergy is atopic dermatitis (AD), the pathogenesis of which is linked to a complex interaction between skin barrier dysfunction and environmental factors such as allergens and microbes. In particular, an important advance was the demonstration that the mutation of the skin barrier protein filaggrin is related strictly to allergen sensitization and to the development of asthma in subjects with AD. The altered skin barrier function, caused by several factors, results in the passage of allergens through the skin and to systemic responses. A pivotal role in such a response is exerted by Langerhans cells which, via their immunoglobulin E (IgE) receptor, capture the allergens and present them to T cells. When T helper type 2 (Th2) cells are activated, the production of a proinflammatory cytokines and chemokines pattern sustains the persistence of inflammation. Known AD-related cytokines are interleukin (IL)-5, IL-13 and tumour necrosis factor (TNF)-α, with emerging importance for IL-17, which seems to drive airway inflammation following cutaneous exposure to antigens, and IL-31, which is expressed primarily in skin-homing Th2 cells. Skin-homing is another crucial event in AD, mediated by the cutaneous lymphocyte-associated antigens (CLA) receptor, which characterizes T cell subpopulations with different roles in AD and asthma. [ABSTRACT FROM AUTHOR]

The article discusses the beneficial effects of ingestion of sphingolipids in restoring skin permeability barrier damage due to ultraviolet (UV)B irradiation. It examines the preventive effects of ingesting sphingolipids, glucosylceramide (GC) and sphingomyelin (SM) on barrier dysfunction due to UVB irradiation in mice skin. It also highlights the use of skin water-evaporation recorder to measure the transepidermal water loss and the thickening of epidermis.