Autophagy Declines with Premature Skin Aging resulting in Dynamic Alterations in Skin Pigmentation and Epidermal Differentiation.

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo.

Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Because cellular senescence is a fundamental ageing mechanism, we examined the role of senescent cells in ageing pigmentation. Methods: Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16INK4A. To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analyses in senile lentigo and senescent fibroblasts. To further investigate the impact of senescent cells on ageing-related pigmentation, an intervention that targeted senescent cells using radiofrequency was performed. Results:In vivo, senescent fibroblasts accumulated at the sites of age-related pigmentation. Phenotype switching of the cells resulted in the repression of stromal-derived factor 1 (SDF1) by promoter methylation. SDF1 induced melanocyte differentiation via stromal-epithelial interactions, ultimately driving skin pigmentation. Furthermore, the elimination of senescent fibroblasts from pigmented skin using radiofrequency was accompanied by skin lightening, rendering it a potential target for treatment. Conclusion: Aged pigmented skin contains an increasing proportion of senescent fibroblasts. Cells with phenotype switching exhibited a loss of SDF1, which stimulates the melanogenic process and thereby contributes to aging pigmentation. These data may promote the development of new therapeutic paradigms, such as a stroma-targeting therapy for pigmentary disorders.

Increased blood flow and vasculature in solar lentigo.

Solar lentigo (SL) is a hallmark of ultraviolet (UV)-induced photoaged skin and growing evidence implicates blood vessels in UV-associated pigmentation. In this study, we investigated whether the vasculatures are modified in SL. Twenty-five women with facial SL were enrolled and colorimetric and blood flow studies were performed. There was a significant increase in erythema which was associated with increased blood flow in the lesional skin compared with perilesional normal skin. Immunohistochemical studies with 24 facial SL biopsies consistently revealed a significant increase in vessel density accompanied by increased levels of vascular endothelial growth factor expression. CD68 immunoreactivity was significantly higher in lesional skin suggesting increased macrophage infiltration in SL. In conclusion, SL is characterized by increased blood flow and vasculature. These findings suggest the possible influence of the characteristics of vasculature on development of SL.

Expanding Our Understanding of Human Skin Aging.

Two very different studies expand our understanding of human skin aging. In the first study, Hüls et al. show an association between nitrogen dioxide levels in outdoor air and number of lentigines on the cheek. In the second study, Bowman and Birch-Machin show that mitochondrial complex II activity in human skin fibroblasts decreases with age.

Biological processes in solar lentigo: insights brought by experimental models.

Common in ageing patient, the solar lentigo is a macular hyperpigmented skin lesion that results from chronic exposure to ultraviolet irradiations. Despite sharing numerous features with other pigmented spots, the diagnostic of this benign lesion is well characterized at the tissue level. Recent studies shed lights on several factors and their pathogenic mechanisms involved in the development of the solar lentigo. This review summarizes how diverse experimental approaches allowed the identification of several biomarkers, which contribute to a better understanding on the initiation and the maintenance of this pigmentary disorder.

Environment-induced lentigines: formation of solar lentigines beyond ultraviolet radiation.

There is no doubt that ultraviolet radiation (UVR) contributes to the generation of acquired lentigines in human skin, as indicated by the term solar lentigo. A growing number of recent epidemiological and mechanistic studies, however, strongly suggest that in addition to UVR, other environmental factors contribute to lentigines' formation as well. We therefore here introduce the term 'environment-induced lentigo' (EIL) to refer to acquired pigment spots of human skin. In this view point, we (i) summarize the existing evidence to support a role of environmental toxicants other than UVR in the pathogenesis of EILs, (ii) we argue that activation of aryl hydrocarbon receptor (AHR) signalling by UVR and environmental toxicants is critically involved in triggering and sustaining a crosstalk between melanocytes, keratinocytes and fibroblasts, which then causes the development and persistence of EILs in human skin, and (iii) we discuss clinical implications for the prevention and treatment of EILs resulting from this concept.

Black light visualized solar lentigines on the shoulders and upper back are associated with objectively measured UVR exposure and cutaneous malignant melanoma.

Previous studies on the association of solar lentigines with ultraviolet radiation (UVR) exposure have been based on retrospective questionnaires about UVR exposure. We aimed to investigate the association between solar lentigines and UVR exposure in healthy individuals using objective measurements, and to investigate the association between solar lentigines and cutaneous malignant melanoma (CMM). Forty-eight patients with CMM and 48 controls that matched the patients individually by age, sex, constitutive skin type and occupation participated. Solar lentigines on the shoulders and upper back were counted and graded into 3 categories using black light photographs to show sun damage. Current UVR exposure in healthy controls was assessed by personal electronic UVR dosimeters that measured time-related UVR and by corresponding exposure diaries during a summer season. Sunburn history was assessed by interviews. Among controls, the number of solar lentigines was positively associated with daily hours spent outdoors between noon and 3 pm on holidays (P = 0.027), days at the beach (P = 0.048) and reported number of life sunburns (P < 0.001). Compared with matched controls CMM patients had a higher number of solar lentigines (P = 0.044). There was a positive association between CMM and higher solar lentigines grade; Category III versus Category I (P = 0.002) and Category II versus Category I (P = 0.014). Our findings indicate that solar lentigines in healthy individuals are associated with number of life sunburns, as well as time spent outdoors around noon on holidays and beach trips during a summer season, most likely reflecting past UVR exposure, and that solar lentigines are a risk factor for CMM.

[Normal and abnormal skin color]. / La couleur de la peau normale ou anormale.

The varieties of normal skin color in humans range from people of "no color" (pale white) to "people of color" (light brown, dark brown, and black). Skin color is a blend resulting from the skin chromophores red (oxyhaemoglobin), blue (deoxygenated haemoglobin), yellow-orange (carotene, an exogenous pigment), and brown (melanin). Melanin, however, is the major component of skin color ; it is the presence or absence of melanin in the melanosomes in melanocytes and melanin in keratinocytes that is responsible for epidermal pigmentation, and the presence of melanin in macrophages or melanocytes in the dermis that is responsible for dermal pigmentation. Two groups of pigmentary disorders are commonly distinguished: the disorders of the quantitative and qualitative distribution of normal pigment and the abnormal presence of exogenous or endogenous pigments in the skin. The first group includes hyperpigmentations, which clinically manifest by darkening of the skin color, and leukodermia, which is characterized by lightening of the skin. Hypermelanosis corresponds to an overload of melanin or an abnormal distribution of melanin in the skin. Depending on the color, melanodermia (brown/black) and ceruloderma (blue/grey) are distinguished. Melanodermia correspond to epidermal hypermelanocytosis (an increased number of melanocytes) or epidermal hypermelanosis (an increase in the quantity of melanin in the epidermis with no modification of the number of melanocytes). Ceruloderma correspond to dermal hypermelanocytosis (abnormal presence in the dermis of cells synthesizing melanins) ; leakage in the dermis of epidermal melanin also exists, a form of dermal hypermelanosis called pigmentary incontinence. Finally, dyschromia can be related to the abnormal presence in the skin of a pigment of exogenous or endogenous origin.

[Mechanisms underlying post-inflammatory hyperpigmentation: lessons from solar lentigo]. / Mécanismes de l'hyperpigmentation post-inflammatoire: ce que le lentigo actinique nous a appris.

Hyperpigmentation of the skin is a common dermatologic condition in all skin types but most prominent in brown-skinned population. In skin of color any inflammation or injury can be accompanied by alterations in pigmentation (hyper/hypo-pigmentation). Postinflammatory hyperpigmentation (PIH) can be observed in many skin conditions including acne, eczema, and contact dermatitis. In the control of skin pigmentation, parallel to the cross-talk between keratinocytes and melanocytes, increasing evidence has underlined the crucial role exerted by the interactions between mesenchymal and epithelial cells through the release of fibroblast-derived growth factors. Among these factors, the keratinocyte growth factor (KGF), alone or in combination with interleukin-1α, induces melanin deposition in vitro and hyperpigmented lesions in vivo. Furthermore, a moderate increase of KGF and a high induction of its receptor have been shown in solar lentigo lesions, suggesting the involvement of this growth factor in the onset of the hyperpigmented spots. Several studies highlight the possible contribution of the fibroblast-derived melanogenic growth factors to the hyperpigmentated lesions, in the context of the mesenchymal - epithelial interactions modulating melanocyte functions.

Investigation by in vivo reflectance confocal microscopy: melanocytes at the edges of solar lentigines.

In vivo reflectance confocal microscopy (RCM) provides high-resolution, real-time optical sections of the skin in a non-invasive manner, allowing visualization of the skin in its native state. Highly reflective skin components including melanin, collagen and keratin appear bright (white) in RCM images. RCM examination of solar lentigines is known to show features that correlate well with histologic findings such as supranuclear melanin caps, but there are a limited number of reports on melanocyte dendrites. In this study, we utilized RCM to investigate the melanocyte dendricity and distribution within solar lentigines. Seventeen healthy Japanese females who had fairly large solar lentigines on their faces were recruited to join our clinical study, and we examined them by using RCM on their non-lesional areas, and the inside and the outer rim of the lesional areas. As a result, we discovered that dendritic melanocytes were rarely seen in the center of a solar lentigo (SL), but were seen at a very high frequency in the outer rim of a SL. The results suggest that the melanocytes are more active at the edge of a SL, produce more melanin, and often spread their dendrites widely in a horizontal direction. The findings in this report might shed light on the dynamic pathomechanisms of solar lentigines in vivo.

Mechanisms underlying post-inflammatory hyperpigmentation: lessons from solar lentigo.

Hyperpigmentation of the skin is a common dermatologic condition in all skin types but most prominent in brown-skinned population. In skin of color any inflammation or injury can be accompanied by alterations in pigmentation (hyper/hypo-pigmentation). Postinflammatory hyperpigmentation (PIH) can be observed in many skin conditions including acne, eczema, and contact dermatitis. In the control of skin pigmentation, parallel to the cross-talk between keratinocytes and melanocytes, increasing evidence has underlined the crucial role exerted by the interactions between mesenchymal and epithelial cells through the release of fibroblast-derived growth factors. Among these factors, the keratinocyte growth factor (KGF), alone or in combination with interleukin-1α, induces melanin deposition in vitro and hyperpigmented lesions in vivo. Furthermore, a moderate increase of KGF and a high induction of its receptor have been shown in solar lentigo lesions, suggesting the involvement of this growth factor in the onset of the hyperpigmented spots. Several studies highlight the possible contribution of the fibroblast-derived melanogenic growth factors to the hyperpigmentated lesions, in the context of the mesenchymal - epithelial interactions modulating melanocyte functions.

The role of keratinocyte growth factor in melanogenesis: a possible mechanism for the initiation of solar lentigines.

Solar lentigines (SLs) are hyperpigmentary lesions presented on sun-exposed areas of the skin and associated with ageing. The molecular mechanism of SL initiation is not completely understood. Ultraviolet B (UVB) stimulates keratinocytes to produce interlukin-1 alpha (IL-1α), which then induces keratinocyte growth factor (KGF) secretion; therefore, we examined their possible roles in the induction of SLs. We found that KGF increases pigment production in both pigmented epidermal equivalents and human skin explants. In addition, UVB exposure increases KGF expression, and KGF treatment induces tyrosinase (TYR) expression in primary melanocytes. The KGF-induced pigmentary changes were confirmed using pigmented Yucatan swine, and human skins grafted onto immuno-deficient mice. In both model systems, the topical treatment with KGF, alone or in combination with IL-1α, resulted in the in vivo formation of hyperpigmentary lesions with increased pigment deposition and elongated rete ridges, which resemble the histological features of human SLs. Preliminary immunohistochemical analysis of human skins showed a moderate increase in KGF, and a strong induction in KGF receptor (KGFR) in SL lesions. In summary, KGF increases pigment production and deposition in vitro and in vivo. Moreover, we show for the first time the in vivo generation of hyperpigmentary lesions with histological resemblance to human SLs and indicate the involvement of KGF/KGFR in the molecular pathology of human SLs.

The epidermal stem cell factor is over-expressed in lentigo senilis: implication for the mechanism of hyperpigmentation.

We previously reported that accentuated expression of the endothelin-1 (ET-1)/endothelin B receptor (ET(B)R) cascade is involved in the mechanism of hyperpigmentation in lentigo senilis (LS) lesions. The paracrine mechanism underlying ultraviolet B (UVB)-induced hyperpigmentation in the skin may involve the stimulation of the ET-1/ET(B)R cascade as well as the stem cell factor (SCF)/SCF receptor cascade. Therefore, we used RT-PCR and immunohistochemistry to determine whether accentuated expression of the SCF/SCF receptor cascade is also associated with the mechanism of hyperpigmentation in epidermal LS lesions. RT-PCR analysis demonstrated the increased expression of mRNA transcripts for SCF (n=7), but not for SCF receptor (n=6) or growth-related oncogene alpha (GROalpha) (n=4) in LS lesions. Immunohistochemistry revealed markedly stronger staining for SCF but not for GROalpha or basic fibroblast growth factor (bFGF) in the lesional epidermis compared with the perilesional epidermis. This increased staining for SCF was corroborated by western blotting analysis for SCF expression in the lesional epidermis. These findings suggest that in addition to the stimulated expression of the ET-1/ET(B)R cascade, the accentuated expression of SCF in lesional skin plays an important role in the mechanism involved in the epidermal hyperpigmentation of LS.

Melanoma: criterios diagnósticos en podología

La aparición cada vez más común de neoformaciones cutáneas evolutivas, con desarrollo veloz y crecimiento invasivo (como es el melanoma), proporciona al profesional sanitario y en consecuencia al podólogo la necesidad de permanecer en continua alerta ante cualquier lesión dérmica sospechosa. La necesidad por parte del podólogo de utilizar la inspección como herramienta fundamental dentro de la historia clínica del paciente, hace más frecuente el descubrimiento, muchas veces accidental, de neoformaciones cutáneas malignas. Este artículo pretende concienciar al podólogo con respecto a que, ante cualquier lesión cutánea evolutiva sospechosa, es necesario solicitar pruebas complementarias como por ejemplo la técnica del ganglio centinela, con el fin de obtener un informe oncológico y/o anatomopatológico fundamental antes de tomar cualquier decisión terapéutica (AU)

Leopard syndrome.

The Leopard syndrome is a complex of multisystemic congenital abnormalities characterised by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth and deafness (sensorineural). Hypertrophic cardiomyopathy, though not included in the mnemonic, is often associated. Although the Leopard syndrome is rare, it is important to recognise it since it can be associated with serious cardiac disease. It is advisable to follow up patients with Leopard syndrome for new onset of cardiac abnormalities and to monitor the progression of existing cardiac disease. We present a case report and review of the literature of this syndrome.

Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes.

Carney complex is a multiple endocrine neoplasia (MEN) syndrome that affects the adrenal cortex, the pituitary and thyroid glands, and the gonads. The complex is also associated with skin and mucosa pigmentation abnormalities and myxoid and other neoplasms of mesenchymal and neural crest origin. Thus, this syndrome also belongs to another group of genetic disorders, the lentiginoses (or lentigenoses), which include the Peutz-Jeghers, LEOPARD, arterial dissections and lentiginosis, and Laugier-Hunziker syndromes, Cowden disease and Ruvalcaba-Myhre-Smith (Bannayan-Zonana) syndrome and the centrofacial, benign patterned and segmental lentiginoses, all of which can be associated with a variety of developmental defects. The inheritance of Carney complex, just like that of the other MENs and the lentiginoses, is autosomal dominant. Genetic loci or genes have been identified for Carney complex, Peutz-Jeghers and Ruvalcaba-Myhre-Smith syndromes, but not for other lentiginoses. Elucidation of the molecular defects responsible for these disorders is expected to shed light on aspects of early neural crest differentiation, the regulation of pigmentation, the development of autonomous endocrine function, and endocrine and nonendocrine tumorigenesis.