Aryl Hydrocarbon Receptor as a Therapeutical Target of Environmentally Induced Skin Conditions.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, expressed in several tissues and involved in the response to environmental stressors. Studies have already associated exposure to environmental factors, such as organic air pollutants, products of the skin microbiota, and solar radiation, with the development/worsening of skin conditions, mediated by AhR. On the other hand, recent studies have shown that synthetic and natural compounds are able to modulate the activation of some AhR signaling pathways, minimizing the harmful response of these environmental stressors in the skin. Thus, AhR constitutes a new therapeutic target for the prevention or treatment of skin conditions induced by the skin exposome. Herein, an overview of potential AhR ligands and their biologic effects in environmentally induced skin conditions are presented. The literature survey pointed out divergences in the mechanism of action from a therapeutic perspective. Although most studies point to the benefits of ligand downregulation of AhR signaling, counteracting the toxic effects of environmental factors on the skin, some studies suggest the AhR ligand activation as a therapeutical mechanism for some skin conditions. Furthermore, both agonist and antagonist profiles were identified in the AhR modulation by the synthetic and natural compounds raised. Despite that, this target is still little explored, and further studies are needed to elucidate the molecular mechanisms involved and identify new AhR ligands with therapeutic potential. SIGNIFICANCE STATEMENT: The aryl hydrocarbon receptor (AhR) is involved in different skin physiological and pathological processes, including toxic mechanisms of environmental factors. Synthetic and natural AhR ligands have demonstrated therapeutic potential for skin conditions induced by these agents. Thus, a comprehensive understanding of the skin toxicity mechanisms involving the AhR, as well as the use of AhR modulators from a therapeutic perspective, provides an alternative approach to the development of new treatments for skin disorders induced by the exposome.

Modulation of skin androgenesis and sebum production by a dermocosmetic formulation.

BACKGROUND: Excessive androgenesis in the skin promotes sebaceous hyperproduction which is the onset of acne vulgaris pathogenesis. Free fatty acids and lipid accumulation in the glandular infundibulum culminates in microbiota imbalance, triggering inflammatory response and follicular hyperkeratinization. AIMS: The purpose of this work was to present an alternative cosmetic treatment for acne skin care, focusing on the prevention of sebaceous gland dysregulation. METHODS: Insulin-stimulated human sebocytes were treated with noncytotoxic concentrations of a DTRW cosmetic formulation. After 6 days of incubation, cell lysates were collected for testosterone, 5α-reductase, and dyhidrotestosterone (DHT) quantitation. In parallel, cells were stained with Oil Red O to measure sebum production. RESULTS: Human sebocytes were incubated with insulin to mimic a seborrheic microenvironment with overproduction of intracellular lipids and fatty acids. Concomitant incubation of cell cultures with DRTW was able to promote a 52.97% reduction in intracellular lipid content. The anti-androgenic properties of DRTW had been proved by the reductions of testosterone (↓59.90%), 5α reductase (↓59.34%), and DHT (↓55.98%) levels in sebocyte cultures also stimulated with insulin. CONCLUSION: The results indicate a promising action of DRTW cosmetic formulation in preventing the development of acne lesions by mechanisms involving the modulation of cutaneous androgenesis and consequently the control of sebum overproduction, considered one of the leading causes of acne.

The Ex Vivo Skin Model as an Alternative Tool for the Efficacy and Safety Evaluation of Topical Products.

The development of alternative approaches for safety and efficacy testing that avoid the use of animals is a worldwide trend, which relies on the improvement of current models and tools so that they better reproduce human biology. Human skin from elective plastic surgery is a promising experimental model to test the effects of topically applied products. As the structure of native skin is maintained, including cell population (keratinocytes, melanocytes, Langerhans cells and fibroblasts) and dermal matrix (containing collagen, elastin, glycosaminoglycans, etc.), it most closely matches the effects of substances on in vivo human skin. In this review, we present a collection of results that our group has generated over the last years, involving the use of human skin and scalp explants, demonstrating the feasibility of this model. The development of a test system with ex vivo skin explants, of standard size and thickness, and cultured at the air-liquid interface, can provide an important tool for understanding the mechanisms involved in several cutaneous disorders.

Whitening effects of cosmetic formulation in the vascular component of skin pigmentation.

BACKGROUND: Melanin plays an important role in protecting the skin against the harmful effects of solar radiation, but its abnormal accumulation may become an aesthetic problem, such as melasma and age spots. AIMS: The aim of this study was to evaluate the antiangiogenic and whitening effects of a depigmentation formulation (BLTX) using an in vitro model of human cell and skin culture. METHODS: Human fibroblasts, keratinocytes or melanocytes were treated with BLTX and subjected to oxidative stress by UV radiation or inflammatory stress with IL-1α for quantification of melanin, tyrosinase, endothelin-1, PAR-2, VEGF and iNOS. Fragments of human skin, from elective plastic surgery, were treated with BLTX and subjected to histological evaluation with hematoxylin/eosin associated with Fontana-Masson technique for melanin view. A parametric method, the one-way analysis of variance (ANOVA) followed by the Bonferroni test, was used to compare data among all groups. RESULTS: The results demonstrated that BLTX promotes a reduction in VEGF and iNOS protein synthesis in cultured dermal fibroblasts, indicating an antiangiogenic property. In relation to whitening effect, BLTX was able to reduce the production of melanin in both systems, melanocytes and human skin cultures. The depigmenting action was also revealed by decreasing the levels of endothelin-1, PAR-2 and activity of tyrosinase, when compared to cultures exposed to UV radiation. CONCLUSION: The results allow us to infer that BLTX presents an antiangiogenic effect indicating a role in the vascular component of melasma. Furthermore, the whitening property observed reinforces its use in the prevention and treatment of melasma.

Avaliação pré-clínica dos efeitos profiláticos do extrato de Pinus pinaster (Pycnogenol®) sobre a deposição cutânea de hemossiderina / Pre-clinical evaluation of the profilatic effects of Pinus pinaster extract (Pycnogenol®) on skin hemosiderin deposits

Introdução: A escleroterapia é o método mais utilizado para o tratamento de varizes dos membros inferiores tendo como complicação mais comum o aparecimento de manchas hipercrômicas na região tratada. O Pycnogenol® é conhecido há muito tempo como um flebotônico, anti-inflamatório e despigmentante da pele. Estudos já comprovaram a eficácia deste fármaco na prevenção e no tratamento da hiperpigmentação pós-inflamatória. Objetivo: Avaliar a eficácia do extrato de Pinus pinaster (Pycnogenol®; EPP) na prevenção de depósitos de hemossiderina em cultura de pele humana submetida a estresse inflamatório. Métodos: Fragmentos de pele humana foram estimulados com interleucina 1 alfa (IL-1a) para indução de uma resposta inflamatória e, concomitantemente, tratados com EPP para posterior avaliação histológica e semi-quantificação de hemossiderina. Resultados: A avaliação histológica dos fragmentos de pele expostos à IL-1alfa; revelaram uma densidade de hemossiderina 26,6% maior em comparação ao grupo controle. Por outro lado, os fragmentos de pele incubados concomitantemente com EPP mostraram reduções significativas na deposição de hemossiderina quando comparados ao grupo somente expostos ao microambiente inflamatório. Conclusões: Os resultados apresentados neste estudo apontam para um importante efeito do EPP (Pycnogenol®) na prevenção do acúmulo de hemossiderina originado pelo estresse inflamatório semelhante ao processo pós escleroterapia.

Introduction: Sclerotherapy is the most widely used method for the treatment of varicose veins of the lower limbs. The most common complication is the appearance of hyperchromic spots in the treated region. Pycnogenol® has long been known as a phlebotonic, anti-inflammatory and skin depigmenting drug. Studies have already proven the efficacy of this drug in the prevention and treatment of post inflammatory hyperpigmentation. Objective: To evaluate the effectiveness of Pinus pinaster extract (Pycnogenol®; PPE) in the prevention of hemosiderin deposits in human skin culture submitted to inflammatory stress. Methods: Fragments of human skin were stimulated with interleukin 1 alpha (IL-1 a) to induce an inflammatory response and, concurrently, treated with PPE for further histological evaluation and hemosiderin semi-quantification. Results: The histological evaluation of skin fragments exposed to IL-1 alpha revealed a 26.6% higher hemosiderin density compared with the control group. Moreover, skin fragments incubated concomitantly with PPE showed significant reductions in hemosiderin deposits when compared with the group only exposed to the inflammatory microenvironment. Conclusions: The results presented in this study showed an important effect of PPE (Pycnogenol®) in the prevention of hemosiderin accumulation caused by inflammatory stress similar to the post-sclerotherapy process.

Metodologia alternativa para o estudo dos efeitos da radiação infravermelha-A sobre a pele humana / Alternative methodology for the study of infrared-A radiation effects on human skin

Introdução: A radiação infravermelha A (IV-A) causa alterações estruturais na pele, similares àquelas provocadas pela exposição prolongada à radiação ultravioleta. A avaliação de eficácia e segurança para produtos cosméticos concentra-se em ensaios in vitro e clínicos. Uma alternativa promissora é a utilização de fragmentos de pele humana provenientes de cirurgias plasticas eletivas, para avaliar os reais beneficios os reais benefícios clínicos de um produto aplicado topicamente. Objetivo: O objetivo desta investigação foi correlacionar os efeitos da radiação IV-A, em biópsias e em fragmentos de pele ex vivo e cultura de fibroblastos humanos, pela quantificação dos mediadores MMP-1, TIMP-1 e GADD45a. Métodos: Coleta de biópsias de 15 voluntárias após aplicações de IV-A durante cinco dias consecutivos. Exposição à radiação IV-A de fragmentos de pele humana provenientes de cirurgia plástica eletiva e cultura de fibroblastos humanos. Mensuração dos mediadores MMP-1, TIMP-1 e GADD45a para posterior comparação dos resultados. Resultados: Nos três modelos utilizados a radiação IV-A induziu aumento de MMP-1, inibiu a síntese de GADD45a e não alterou os valores de TIMP-1. Conclusão: Devido à correlação positiva dos modelos estudados, pode-se sugerir o uso de pele ex vivo como ferramenta plausível e sustentável para suprir diferenças entre conhecimentos gerados a partir de experimentos in vitro e clínico.

Introduction: Infrared radiation (IR-A) causes structural changes in the skin, similar to those caused by prolonged exposure to ultraviolet radiation. Evaluation of efficacy and safety of cosmetic products concentrates in in vitro tests and clinical trials. A promising alternative is the use of fragments of human skin from elective cosmetic surgery, to evaluate the actual clinical benefits of a product applied topically. Objective: The objective of this study was to correlate IR-A radiation effects in biopsies and in ex vivo skin fragments and in human fibroblasts culture by quantifying MMP-1, TIMP-1 and GADD45a mediators. Methods: Collection of biopsies from 15 volunteers after IR-A applications for 5 consecutive days. Exposure to IR-A radiation of human skin fragments from elective cosmetic surgery, and human fibroblasts culture. Measurement of MMP-1, TIMP-1 and GADD45a mediators for further comparison of results. Results: In the three models used, the IR-A radiation induced an increase in MMP-1, inhibited the synthesis of GADD45a, and did not changed TIMP-1 values. Conclusion: Due to the positive correlation of the models studied, it may be suggested the use of ex vivo skin as plausible and sustainable tool to overcome differences between knowledge generated from in vitro and clinical experiments.

LIMIAR ANAERÓBIO EM EXERCÍCIOS RESISTIDOS: ANÁLISE DE ASPECTOS METODOLÓGICOS E HEMODINÂMICOS / ANAEROBIC THRESHOLD IN RESISTANCE EXERCISES: ANALYSIS OF METHODOLOGICAL AND HEMODINAMIC ASPECTS / UMBRAL ANAERÓBICO EN EJERCICIOS DE RESISTENCIA: ANÁLISIS DE ASPECTOS METODOLÓGICOS Y HEMODINÁMICOS

Introdução A determinação do limiar anaeróbio em exercícios resistidos tem sido tema de diversos estudos. No entanto, o impacto desta avaliação sobre os parâmetros hemodinâmicos de pressão arterial e frequência cardíaca ainda é desconhecido. Objetivo Comparar a estimativa do limiar anaeróbio (LAn) obtido em teste e reteste de protocolo incremental nos exercícios resistidos de supino reto (SR) e rosca direta (RD) e analisar o comportamento das variáveis hemodinâmicas de frequência cardíaca (FC), pressão arterial sistólica (PAS) e diastólica (PAD) durante protocolo de cargas incrementais. Métodos Oito voluntários do sexo masculino praticantes de treinamento resistido foram recrutados e realizaram quatro testes de cargas incrementais (dois no SR e dois na RD) em dias distintos para a determinação do LAn. Durante cada teste, as variáveis de lactato sanguíneo, FC, PAS e PAD foram mensuradas ao final de cada estágio. Resultados Os valores do LAn expressos em porcentagens da carga máxima (1-RM) para o SR em teste e reteste foram de 19,7±4,0% e 18,4±3,4% respectivamente e para RD de 17,7±3,4% e 19,4±3,1% respectivamente, não sendo identificadas diferenças estatísticas entre estas. No decorrer dos testes, a FC variou em média entre 90 e 135bpm para SR e entre 98 a 150bpm para RD. Apenas a PAS se alterou no decorrer dos testes, variando entre 111,8 a 123,3mmHg no SR e entre 119,4 a 141,3mmHg na RD. Conclusão Tais resultados nos sugerem que a intensidade relativa ao LAn não é diferente para SR ou RD em teste ou reteste. Não obstante, apesar de diferenças nos comportamentos hemodinâmicos entre os tipos de exercícios (SR vs. RD), os valores de FC e PAS se elevaram dentro de limites clinicamente aceitáveis, como sugerido pela literatura.

Introduction The anaerobic threshold determination in resistance exercises has been the subject of several studies. However, the impact of these evaluations over the hemodynamic parameters of blood pressure and heart rate are still unknown. Objective To compare the estimate of the anaerobic threshold (AnT) obtained during test and retest of an incremental protocol in resistance exercises of bench press (BP) and biceps curl (BC), and analyze the hemodynamic variable behavior of heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) during the incremental load protocol. Methods Eight male practitioners of resistance training volunteers have been recruited and carried out four incremental load tests (two in BP and two in BC) in distinct days for AnT determination. During each test, the variables of blood lactate, HR, SBP and DBP were measured at the end of each stage. Results The values of AnT expressed in % of maximum load (1-RM) for BP in test and retest were 19.7±4.0% and 18.4±3.4% respectively, and for BC were 17.7±3.4% and 19.4±3.1% respectively, not being found statistical differences between these. During tests, HR ranged on average between 90 and 135bpm for BP and between 98 and 150bpm for BC. Only the SBP has changed during tests, ranging between 111.8 to 123.3mmHg in BP and 119.4 to 141.3mmHg in BC. Conclusion These results suggest that the intensity related to AnT is not different for BP or BC during test or retest. Despite differences in hemodynamic behavior between exercise types (BP vs. BC), HR and SBP values had an elevation within acceptable clinical limits as suggested by literature.

Introducción La determinación del umbral anaeróbico en ejercicios de resistencia, ha sido un tema de diversos estudios, sin embargo, el impacto de esta evaluación sobre los parámetros hemodinámicos de presión arterial y frecuencia cardíaca todavía son desconocidos. Objetivo Comparar la estimación del umbral anaeróbico (LAn) obtenido en prueba y reprueba del protocolo incremental en los ejercicios de resistencia de press de banca (PB) y curl de bíceps con barra (CB) y analizar el comportamiento de las variables hemodinámicas de frecuencia cardíaca (FC), presión arterial sistólica (PAS) y diastólica (PAD) durante un protocolo de cargas incrementales. Métodos Ocho voluntarios de sexo masculino, practicantes de entrenamiento de resistencia, fueron reclutados y realizaran cuatro pruebas de cargas incrementales (dos en PB y dos en CB) en días distintos para la determinación del LAn. Durante cada prueba, las variables de lactato sanguíneo, FC, PAS y PAD fueron medidas al final de cada fase. Resultados Los valores de LAn expresados en porcentajes de carga máxima (1-RM) para el PB en prueba y reprueba fueron de 19,7±4,0% y 18,4±3,4% respectivamente y para CB de 17,7±3,4% e 19,4±3,1% respectivamente, no siendo identificadas diferencias estadísticas entre estas. En el transcurso de las pruebas, la FC varió, en promedio, entre 90 y 135bpm para PB y entre 98 a 150bpm para CB. Solamente la PAS se alteró en el transcurso de las pruebas, variando entre 111,8 a 123,3mmHg en PB y entre 119,4 a 141,3mmHg en CB. Conclusión Tales resultados nos sugieren que la intensidad relativa al LAn no es diferente para PB o CB en prueba y reprueba. No obstante, a pesar de las diferencias en los comportamientos hemodinámicos entre los tipos de ejercicios (PB vs. CB), los valores de FC y PAS aumentaron dentro de límites clínicamente aceptables como lo sugerido por la bibliografía.

PBMCs express a transcriptome signature predictor of oxygen uptake responsiveness to endurance exercise training in men.

Peripheral blood cells are an accessible environment in which to visualize exercise-induced alterations in global gene expression patterns. We aimed to identify a peripheral blood mononuclear cell (PBMC) signature represented by alterations in gene expression, in response to a standardized endurance exercise training protocol. In addition, we searched for molecular classifiers of the variability in oxygen uptake (V̇o2). Healthy untrained policemen recruits (n = 13, 25 ± 3 yr) were selected. Peak V̇o2 (measured by cardiopulmonary exercise testing) and total RNA from PBMCs were obtained before and after 18 wk of running endurance training (3 times/wk, 60 min). Total RNA was used for whole genome expression analysis using Affymetrix GeneChip Human Gene 1.0 ST. Data were normalized by the robust multiarray average algorithm. Principal component analysis was used to perform correlations between baseline gene expression and V̇o2peak. A set of 211 transcripts was differentially expressed (ANOVA, P < 0.05 and fold change > 1.3). Functional enrichment analysis revealed that transcripts were mainly related to immune function, cell cycle processes, development, and growth. Baseline expression of 98 and 53 transcripts was associated with the absolute and relative V̇o2peak response, respectively, with a strong correlation (r > 0.75, P < 0.01), and this panel was able to classify the 13 individuals according to their potential to improve oxygen uptake. A subset of 10 transcripts represented these signatures to a similar extent. PBMCs reveal a transcriptional signature responsive to endurance training. Additionally, a baseline transcriptional signature was associated with changes in V̇o2peak. Results might illustrate the possibility of obtaining molecular classifiers of endurance capacity changes through a minimally invasive blood sampling procedure.