A chronic pro-inflammatory environment contributes to the physiopathology of actinic lentigines.

Actinic lentigines (AL) or age spots, are skin hyperpigmented lesions associated with age and chronic sun exposure. To better understand the physiopathology of AL, we have characterized the inflammation response in AL of European and Japanese volunteers. Gene expression profile showed that in both populations, 10% of the modulated genes in AL versus adjacent non lesional skin (NL), i.e. 31 genes, are associated with inflammation/immune process. A pro-inflammatory environment in AL is strongly suggested by the activation of the arachidonic acid cascade and the plasmin pathway leading to prostaglandin production, along with the decrease of anti-inflammatory cytokines and the identification of inflammatory upstream regulators. Furthermore, in line with the over-expression of genes associated with the recruitment and activation of immune cells, immunostaining on skin sections revealed a significant infiltration of CD68+ macrophages and CD4+ T-cells in the dermis of AL. Strikingly, investigation of infiltrated macrophage subsets evidenced a significant increase of pro-inflammatory CD80+/CD68+ M1 macrophages in AL compared to NL. In conclusion, a chronic inflammation, sustained by pro-inflammatory mediators and infiltration of immune cells, particularly pro-inflammatory M1 macrophages, takes place in AL. This pro-inflammatory loop should be thus broken to normalize skin and improve the efficacy of age spot treatment.

A precise analysis of the relative contribution of UVA1 and visible light colour domains in solar light-induced skin pigmentation.

BACKGROUND: Solar light induces or aggravates hyperpigmentation issues. The contribution of UVA1, as well as visible light (VL), especially high-energy blue-violet visible (HEV) light, is now clearly established. OBJECTIVES: This work aimed at determining the relative contribution of UVA1, HEV and VL wavelength bands and their sub-domains in pigmentation induction. METHODS: Two clinical studies using solar simulators equipped with specific bandpass physical filters were carried out. Volunteers (FSPT III-IV) were exposed on the back to UVA1 + HEV (350-450 nm), UVA1 (350-400 nm), HEV (400-450 nm) or part of UVA1 + HEV (370-450 nm) in Study 1 (n = 27) and to VL (400-700 nm), HEV (400-450 nm), Blue (400-500 nm), Green (500-600 nm) and Green+Red (500-700 nm) domains in Study 2 (n = 25). Pigmentation level was assessed by visual scoring and colorimetry at different time points postexposure, up to Day 43. RESULTS: Induced pigmentation was detected in all exposed conditions, peaking at 2 h and thereafter progressively decreasing but remaining persistent up to Day 43. In Study 1, UVA1 showed an additive effect with HEV, with a significant contribution coming from the Longest UVA1 rays (370-400 nm). Study 2 demonstrated that 24 h postexposure, the Blue domain accounted for 71% of VL-induced pigmentation, the HEV one for 47%, the Green one for 37% and the Green+Red one for 36%, confirming no significant effect for Red light. CONCLUSIONS: Altogether, these results underline the need for UVA1 photoprotection up to 400 nm and highlight the importance of protecting the skin from solar VL wavelengths and especially from HEV, Blue and Green light, to limit induced pigmentation.

Actinic lentigines from Japanese and European volunteers share similar impaired biological functions.

BACKGROUND: Hyperpigmented spots develop earlier and with a higher incidence in Asian individuals compared with Europeans. Although actinic lentigines (AL) are very common, the biological events underlying their formation remain ill-defined. OBJECTIVE: AL from Japanese volunteers were characterized through morphological and gene expression analyses. Data were then compared with published data on European volunteers. METHODS: AL on hands were selected through dermoscopic imaging and pattern scoring in Japanese women. Skin biopsies of AL and adjacent non-lesional (NL) skin were processed for histology and gene expression profiling. Japanese and European studies were compared after harmonizing the data using the same mathematical and statistical methods. RESULTS: Histologically, AL from Japanese individuals revealed deep epidermal invaginations with melanin accumulation in the depth of epidermal rete ridges. Transcriptomic data identified 245 genes differentially expressed in AL versus NL skin samples, associated with the different skin compartments and multiple functional families and biological processes, such as epidermal homeostasis, extracellular matrix organization and ion binding/transmembrane transport. Strikingly, melanogenesis-related genes were not significantly modulated in AL compared with NL skin. Comparison of the molecular profiles of Japanese and European AL showed that a huge majority of genes were modulated in the same way, recapitulating the overall biological alterations. CONCLUSION: AL from Japanese volunteers exhibited morphological and molecular alterations of the whole skin structure with impairment of multiple biological functions similar to that found in European women. These findings will contribute to the development of efficient treatments of AL lesions.

In-Vivo Tape Stripping Study with Caffeine for Comparisons on Body Sites, Age and Washing.

PURPOSE: Assessing the percutaneous absorption of cosmetic ingredients using in-vitro human skin reveals certain limitations, such as restricted anatomical sites and repeated exposure, and to overcome these issues, in-vivo studies are required. The aim of the study is to develop a robust non-invasive in-vivo protocol that should be applicable to a wide range of application. METHODS: A robust tape stripping protocol was therefore designed according to recent recommendations, and the impact of two different washing procedures on caffeine distribution in tape strips was investigated to optimise the protocol. The optimised protocol was then used to study the effect of age and anatomical area on the percutaneous absorption of caffeine, including facial areas which are not readily available for in-vitro studies. RESULTS: With tape stripping, a difference between the percutaneous absorption on the face (forehead, cheek) and the volar forearm was observed. No obvious difference was observed between percutaneous absorption in young and post-menopausal women, but this could be due to the limited number of subjects. CONCLUSION: This tape stripping protocol is now to be deployed to address many other factors, such as percutaneous absorption in other anatomical areas (e.g. abdomen, axilla, etc.), impact of repeated applications and effect of formulation.

Multi-omics analysis to decipher the molecular link between chronic exposure to pollution and human skin dysfunction.

Environmental pollution is composed of several factors, namely particulate matter (PM2.5, PM10), ozone and Ultra Violet (UV) rays among others and first and the most exposed tissue to these substances is the skin epidermis. It has been established that several skin disorders such as eczema, acne, lentigines and wrinkles are aggravated by exposure to atmospheric pollution. While pollutants can interact with skin surface, contamination of deep skin by ultrafine particles or Polycyclic aromatic hydrocarbons (PAH) might be explained by their presence in blood and hair cortex. Molecular mechanisms leading to skin dysfunction due to pollution exposure have been poorly explored in humans. In addition to various host skin components, cutaneous microbiome is another target of these environment aggressors and can actively contribute to visible clinical manifestation such as wrinkles and aging. The present study aimed to investigate the association between pollution exposure, skin microbiota, metabolites and skin clinical signs in women from two cities with different pollution levels. Untargeted metabolomics and targeted proteins were analyzed from D-Squame samples from healthy women (n = 67 per city), aged 25-45 years and living for at least 15 years in the Chinese cities of Baoding (used as a model of polluted area) and Dalian (control area with lower level of pollution). Additional samples by swabs were collected from the cheeks from the same population and microbiome was analysed using bacterial 16S rRNA as well as fungal ITS1 amplicon sequencing and metagenomics analysis. The level of exposure to pollution was assessed individually by the analysis of polycyclic aromatic hydrocarbons (PAH) and their metabolites in hair samples collected from each participant. All the participants of the study were assessed for the skin clinical parameters (acne, wrinkles, pigmented spots etc.). Women from the two cities (polluted and less polluted) showed distinct metabolic profiles and alterations in skin microbiome. Profiling data from 350 identified metabolites, 143 microbes and 39 PAH served to characterize biochemical events that correlate with pollution exposure. Finally, using multiblock data analysis methods, we obtained a potential molecular map consisting of multi-omics signatures that correlated with the presence of skin pigmentation dysfunction in individuals living in a polluted environment. Overall, these signatures point towards macromolecular alterations by pollution that could manifest as clinical sign of early skin pigmentation and/or other imperfections.

Keratinocytic Malfunction as a Trigger for the Development of Solar Lentigines.

INTRODUCTION: Solar lentigines (SL) affect chronically UV-radiated skin. Treatment is often refractory. Deeper knowledge on its pathogenesis might improve therapeutic effects. MATERIAL AND METHODS: Morphological characterization of 190 SL was performed and epidermal thickness, pigment distribution, dendricity, and cornification grade were measured. Immunoreactivity was investigated using Melan A, Tyrosinase, MITF, p53, and CD20, as well as Notch1 using immunofluorescence. RESULTS: We found 2 groups of histological patterns, i.e., either acanthotic or atrophic epidermis. Lesions with basket-woven cornification and atrophic epidermis were observed in 6 out of 9 and 14 out of 16 cases from the face, respectively. Consistency of areas with a high pigmentation was observed in 96-97% of the cases. Hyperpigmentation grade and acanthosis or cornification disorders correlated positively in 88.5% of the cases. Overexpressed of p53 was found in 19 out of 20 lesions, presenting in a scattered distribution. A significant correlation of p53 and acanthosis (p = 0.003) and cornification grade (p = 0.0008) was observed. Notch1 was expressed in all SL, with the highest immunoreactivity in atrophic facial lesions. Lesions from the hands expressed Notch1 mainly in acanthotic areas with elongated rete ridges and less compact cornification. DISCUSSION: We suggest that Notch1-dependent keratinocytic malfunction causes the development of SL. Consequently, hyperpigmentation would be a result and not the primary cause of the pathogenesis. Confirmation of these findings might have clinical implications as hitherto treatment has mainly focused on melanocytes and pigmentation and not on the proliferation/differentiation balance of keratinocytes.

Skin Hyperpigmentation in Indian Population: Insights and Best Practice.

Skin pigmentation is one of the most strikingly variable phenotypes in humans, therefore making cutaneous pigmentation disorders frequent symptoms manifesting in a multitude of forms. The most common among them include lentigines, postinflammatory hyperpigmentation, dark eye circles, and melasma. Variability of skin tones throughout the world is well-documented, some skin tones being reported as more susceptible to pigmentation disorders than others, especially in Asia and India. Furthermore, exposure to ultraviolet radiation is known to trigger or exacerbate pigmentation disorders. Preventive strategies for photoprotection and treatment modalities including topical and other medical approaches have been adopted by dermatologists to mitigate these disorders. This review article outlines the current knowledge on pigmentation disorders including pathophysiology, molecular profiling, and therapeutic options with a special focus on the Indian population.

Skin complexion and pigmentary disorders in facial skin of 1204 women in 4 Indian cities.

BACKGROUND: The color of Indian skin shows great diversity and pigmentary disorders are a major concern of Indian women. Despite great variations in climate, diet, and social parameters within India, studies of the range of skin types have been rather scarce. AIMS: This study was aimed at characterizing the color of Indian skin in various geographical locations, its characteristics in terms of overall skin complexion and pigmentary disorders, and the impact of age on these features. METHODS: An extensive descriptive study, including skin color parameters (objective measurements and evaluations by dermatologists, clinically or from photographs) was carried out involving 1,204 female volunteers of different ages living in four different Indian cities. RESULTS: Important differences in skin complexion according to the geographical location were observed. Age seemed to have little impact on complexion. Hyperpigmented spots were frequent and were noted at early stages and many lentigines were found. Melasma affected about 30% of middle-aged women, but many other ill defined, pigmented macules were also observed. Additionally, we found pigmented lip corners associated with marionette lines, and linear nasal pigmentation. CONCLUSIONS: Indian skin color is diverse and pigmentary disorders are common. Skin complexion is not greatly affected by age. Some hyperpigmented disorders occur at early stages and increase with age, contributing to overall unevenness of facial color.

Effects of topical DHEA on aging skin: a pilot study.

OBJECTIVES: Dehydroepiandrosterone (DHEA) is a steroid hormone involved in physiological aging. When administered by oral route, it has been shown to positively affect skin condition on aged people. The purpose of this pilot study was to observe the in vivo effects on skin aging of topical DHEA (1%). METHODS: The DHEA formulation (1%) or the vehicle was topically applied for 4 months to facial and hand skin, in two groups of 20 post-menopausal women. The efficacy of the treatment was evaluated on the basis of clinical and biophysical signs linked to skin aging. RESULTS: We showed that DHEA treatment increased the rate of sebum, which was perceived rather positively by a menopausal population usually affected with a declining sebum level. Topical DHEA tends to improve skin brightness, to counteract papery appearance of skin and epidermal atrophy, a characteristic feature of hormone-related skin aging. Topical DHEA could also act on skin process related to wrinkles, but this result remains to be confirmed. CONCLUSIONS: This pilot study showed beneficial effects on skin characteristics that are rarely provided by topical treatments. It raised some interesting clues towards the treatment of skin aging.

Age-related changes of the cutaneous microcirculation in vivo.

BACKGROUND: The architectural frameworks of the skin microcirculation are rather complex and change continuously with aging. But these changes are yet poorly documented in vivo. OBJECTIVES: Using non-invasive methods belonging to the field of biometrology, the study aimed to investigate quantitatively the changes of the cutaneous microvasculature in different anatomic sites with age. METHODS: Measurements were performed on crow's feet, forehead, volar forearm and dorsum of hand in 50 women (aged 20-74 years who consisted of 10 probands in each live decades). The superficial vascular plexus was scanned by videocapillaroscopy and assessed with the software Capilab Toolbox. The subpapillary vascular plexus was explored with laser Doppler flowmetry. The skin color a* was analyzed by chromametry. RESULTS: A marked site and age effect on the skin microcirculation has been demonstrated. The density of capillary loops in the eldest group decreased by about 40-70% compared with the youngest group whereas the vascular length increased by 35-156%. The capillary density in the back of the hand was 4 times higher than in the crow's feet. The vascular length in the crow's feet was 3 times longer than in the back of the hand. Both blood flow and skin redness (a*) increased also with age. CONCLUSION: Both morphology and quantification of the cutaneous microvasculature showed changes with site and age. Videocapillaroscopy associated to an image processing and laser Doppler flowmetry revealed different vascular layers. So the combination of both instruments offers an easy way to observe the architectural frameworks in vivo.

Age-related changes in skin topography and microcirculation.

Skin topography and microvasculature undergo characteristic changes with age. Although several non-invasive bioengineering methods are currently available to measure them quantitatively, few publications have referred to their relationship with age in different anatomical sites. This study was carried out to observe the age-related changes of the skin topography and skin microcirculation. The microrelief was assessed with special processing software from scanning by interference fringe profilometry of silicone replicas performed on two sites (volar forearm and back of hand) on 50 female volunteers (aged 20-74 years who consisted of ten probands in each decade). The superficial vascular network of both sites was assessed by videocapillaroscopy, and the subpapillary vascular plexus was studied with laser Doppler flowmetry. Skin color, which is affected by blood flow, was observed by colorimeter. The skin roughness and the mean height between peak and valley increased with age. There were statistically significant differences between the evaluated sites. This study also shows that the capillary loops in the dermal papillae decrease but the subpapillary plexus increase with age. The interference fringe profilometry associated with videocapillaroscopy may be useful and accurate to measure the efficacy of medical or cosmetic products to delay skin aging.