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2.
Br J Dermatol ; 179(2): 442-456, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29974453

RESUMO

BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.


Assuntos
Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/farmacologia , Receptores do Ácido Retinoico/agonistas , Retinoides/farmacologia , Acne Vulgar/patologia , Administração Cutânea , Animais , Biópsia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Fármacos Dermatológicos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Microssomos Hepáticos , Retinoides/uso terapêutico , Pele , Pigmentação da Pele/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Receptor gama de Ácido Retinoico
3.
Int J Obes (Lond) ; 41(11): 1693-1701, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28792489

RESUMO

OBJECTIVE: High-protein diets (HPDs) are associated with greater satiety and weight loss than diets rich in other macronutrients. The exact mechanisms by which HPDs exert their effects are unclear. However, evidence suggests that the sensing of amino acids produced as a result of protein digestion may have a role in appetite regulation and satiety. We investigated the effects of l-phenylalanine (L-Phe) on food intake and glucose homeostasis in rodents. METHODS: We investigated the effects of the aromatic amino-acid and calcium-sensing receptor (CaSR) agonist l-phenylalanine (L-Phe) on food intake and the release of the gastrointestinal (GI) hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1) and ghrelin in rodents, and the role of the CaSR in mediating these effects in vitro and in vivo. We also examined the effect of oral l-Phe administration on glucose tolerance in rats. RESULTS: Oral administration of l-Phe acutely reduced food intake in rats and mice, and chronically reduced food intake and body weight in diet-induced obese mice. Ileal l-Phe also reduced food intake in rats. l-Phe stimulated GLP-1 and PYY release, and reduced plasma ghrelin, and also stimulated insulin release and improved glucose tolerance in rats. Pharmacological blockade of the CaSR attenuated the anorectic effect of intra-ileal l-Phe in rats, and l-Phe-induced GLP-1 release from STC-1 and primary L cells was attenuated by CaSR blockade. CONCLUSIONS: l-Phe reduced food intake, stimulated GLP-1 and PYY release, and reduced plasma ghrelin in rodents. Our data provide evidence that the anorectic effects of l-Phe are mediated via the CaSR, and suggest that l-Phe and the CaSR system in the GI tract may have therapeutic utility in the treatment of obesity and diabetes. Further work is required to determine the physiological role of the CaSR in protein sensing in the gut, and the role of this system in humans.


Assuntos
Depressores do Apetite/farmacologia , Regulação do Apetite/efeitos dos fármacos , Hormônios Gastrointestinais/metabolismo , Intolerância à Glucose , Fenilalanina/farmacologia , Receptores de Detecção de Cálcio/metabolismo , Saciação/efeitos dos fármacos , Animais , Depressores do Apetite/administração & dosagem , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenilalanina/administração & dosagem , Ratos , Ratos Wistar , Receptores dos Hormônios Gastrointestinais/metabolismo
4.
Allergy ; 72(8): 1212-1221, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28052336

RESUMO

BACKGROUND: Ivermectin (IVM) is widely used in both human and veterinary medicine to treat parasitic infections. Recent reports have suggested that IVM could also have anti-inflammatory properties. METHODS: Here, we investigated the activity of IVM in a murine model of atopic dermatitis (AD) induced by repeated exposure to the allergen Dermatophagoides farinae, and in standard cellular immunological assays. RESULTS: Our results show that topical IVM improved allergic skin inflammation by reducing the priming and activation of allergen-specific T cells, as well as the production of inflammatory cytokines. While IVM had no major impact on the functions of dendritic cells in vivo and in vitro, IVM impaired T-cell activation, proliferation, and cytokine production following polyclonal and antigen-specific stimulation. CONCLUSION: Altogether, our results show that IVM is endowed with topical anti-inflammatory properties that could have important applications for the treatment of T-cell-mediated skin inflammatory diseases.


Assuntos
Alérgenos/imunologia , Dermatite Atópica/imunologia , Ivermectina/administração & dosagem , Administração Tópica , Animais , Antígenos de Dermatophagoides/imunologia , Linhagem Celular , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Modelos Animais de Doenças , ELISPOT , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Receptores Purinérgicos P2X4/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Br J Dermatol ; 150(4): 658-67, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15099361

RESUMO

BACKGROUND: For ethical and technical reasons, the in vivo biological effects of ultraviolet (UV) radiation on skin are difficult to study in human volunteers. The use of human skin grafted on to nude mice may circumvent this difficulty. OBJECTIVES: To investigate the effects of a single moderate UVB exposure on human skin grafted on to nude mice. METHODS: Modifications of epidermal differentiation markers and patterns of keratin expression were assessed from 24 h to 14 days after a physiological UVB irradiation characterized by the induction of sunburn cells. RESULTS: During the first 48 h postexposure, involucrin, loricrin, transglutaminase type I, filaggrin and keratin K2e expression were altered together with the formation of abnormal horny layers. Constitutive keratin K14 was increased while keratin K10 expression was delayed. Newly synthesized keratins K6, K16, K17 and K19 were induced in parallel with an increase in the epidermal proliferation rate. A progressive normalization of both keratinocyte proliferation and differentiation took place during the following days, reaching completion within 2 weeks. CONCLUSIONS: Exposure of human skin to a UVB dose corresponding to a mild sunburn reaction induces epidermal hyperproliferation and alterations of several constitutive differentiation markers, as well as a drastic modification in the pattern of epidermal keratins. Although these modifications were shown to be progressively reversed in a single exposure model, the data also suggest that subsequent UV exposures occurring during the recovery period may lead to potentially deleterious long-term consequences, such as photoageing and photocarcinogenesis. Grafted human skin appeared to be an attractive and promising model for investigating the biological consequences of UVB radiation in vivo.


Assuntos
Diferenciação Celular/efeitos da radiação , Queratinócitos/efeitos da radiação , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Biomarcadores/análise , Divisão Celular/efeitos da radiação , Relação Dose-Resposta à Radiação , Proteínas Filagrinas , Humanos , Proteínas de Filamentos Intermediários/análise , Queratinócitos/fisiologia , Queratinas/análise , Proteínas de Membrana/análise , Camundongos , Camundongos Nus , Precursores de Proteínas/análise , Lesões por Radiação/fisiopatologia , Transplante de Pele , Queimadura Solar/fisiopatologia , Transglutaminases/análise , Transplante Heterólogo
6.
Exp Dermatol ; 12(4): 480-9, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12930306

RESUMO

Androgens have profound effects on the physiology of the sebaceous gland. Using the hamster ear sebaceous gland model, we performed a detailed kinetic study to clarify the mechanism of androgen action on sebaceous gland function. We demonstrated that the growth of sebaceous glands observed after androgen treatment was due to both an increase in sebocyte proliferation and a parallel induction of sebocyte terminal differentiation, as evidenced by the induction of the synthesis of specific sebaceous lipids such as cholesterol esters, triglycerides, and squalene. Accordingly, the effect of androgen treatment on the mRNA expression of several key enzymes involved in the synthesis of sebaceous lipids has been studied using semi-quantitative RT-PCR. Up-regulation by androgens of mRNA expression of HMG coenzyme A synthase and reductase, acetyl coenzyme A carboxylase (ACC), glycerol 3-phosphate acyl transferase (GPAT), and FAR-17c (stearoyl coenzyme A desaturase homologous), was demonstrated. Because sterol-response element(s) (SREs) are known to be present in the promoters of these genes, we analyzed the expression by RT-PCR and the activation of the transcription factor sterol regulatory element binding protein (SREBP) using immunoblotting experiments. Our results showed that SREBP-1 was up-regulated and rapidly activated after androgen treatment. Altogether, these results demonstrate for the first time that in sebaceous glands, in vivo, androgen regulates the synthesis of sebum lipids through the SREBP pathway.


Assuntos
Androgênios/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/metabolismo , Fatores de Transcrição , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Cricetinae , Proteínas de Ligação a DNA/genética , Di-Hidrotestosterona/farmacologia , Enzimas/genética , Feminino , Hidroxicolesteróis/farmacologia , Metabolismo dos Lipídeos , Mesocricetus , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glândulas Sebáceas/citologia , Proteína de Ligação a Elemento Regulador de Esterol 1 , Regulação para Cima/efeitos dos fármacos
7.
Arch Dermatol Res ; 291(11): 591-9, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10638332

RESUMO

It has been established that human skin grafted onto the nude mouse is able to regenerate after being subjected to a full-thickness wound. In the present work, we sought to determine the cells involved in the connective tissue repair process following superficial wounding. Two months after transplantation, superficial wounds were made at the center of the graft using mechanical dermabrasion. At various times thereafter, ranging from 2 days to 6 weeks, healing grafts were harvested and processed for immunohistological study with species-specific and cross-reacting antibodies directed against human or mouse antigens. The grafted human skin regenerated according to the following series of events. First, the human dermis underneath the scab became devoid of human fibroblasts while the surrounding human dermis preserved its own characteristics. The TUNEL reaction on earlyphase healing wounds indicated that apoptosis occurred steadily within this area and could be the mechanism by which cells disappeared. Moreover, cell death was reduced when the wound was covered with an occlusive dressing. The human dermis beneath the wound was then invaded by mouse cells which deposited type I collagen on the human extracellular matrix and produced mouse granulation tissue at the surface above it. Human keratinocytes migrated over the mouse granulation tissue to reconstruct the epidermis. Eventually, the mouse granulation tissue was progressively invaded by human fibroblasts, which formed a human neodermis. The overall process appeared to depend upon several successive epithelial-mesenchymal interactions, which were not species-specific. This suggests that myofibroblasts arise from a specific subpopulation of fibroblasts, probably located at the interface between the dermis and adipose tissue, and that the granulation tissue is eventually remodeled by another population of fibroblasts present in the human dermis.


Assuntos
Transplante de Pele , Pele/citologia , Cicatrização , Animais , Apoptose , Fibroblastos/fisiologia , Humanos , Camundongos , Camundongos Nus , Vaselina/farmacologia , Coelhos , Especificidade da Espécie
8.
Br J Dermatol ; 139 Suppl 52: 3-7, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9990413

RESUMO

Adapalene, a synthetic retinoid, is a new drug proposed for the treatment of acne patients. Studies on the in vitro and in vivo pharmacology of adapalene have shown that it is very active on cell and tissue proliferation and differentiation. Furthermore, adapalene has anti-inflammatory potential as determined by its anti-AP1 activity. Adapalene interacts selectively with the nuclear receptors RAR beta and RAR gamma, and its activity on proliferation and differentiation can be blocked by a RAR beta-gamma antagonist. Because RAR beta is not expressed in human keratinocytes, the effect of adapalene on the major cell type of the epidermis is certainly mediated by its interaction with RAR gamma. The unique pharmacological properties of adapalene may explain why, when compared to tretinoin, it has an improved therapeutic ratio due to its better tolerance.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Dermatológicos/farmacologia , Naftalenos/farmacologia , Pele/efeitos dos fármacos , Acne Vulgar/tratamento farmacológico , Adapaleno , Administração Tópica , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Interações Medicamentosas , Células HeLa/efeitos dos fármacos , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Pele/citologia , Tretinoína/metabolismo
9.
Lab Anim ; 21(3): 233-40, 1987 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-3626471

RESUMO

We use a mutant hairless Sprague Dawley rat to evaluate the capacity of retinoids to inhibit the epidermal ornithine decarboxylase activity induced by sellotape stripping. In order to minimize the variability introduced by the animals in our model we decided to validate the hairless rats used. A number of animal parameters were examined using a single lot of 50 males and 50 females aged from 4 to 11 weeks and acclimatized to laboratory conditions. The body weight growth curves were established. Nude animals present two periods of hair growth, the first at 6-7 weeks and the second at about 10-11 weeks. Hair development is more pronounced in males. No histological change was observed in the stratum corneum but an increase in epidermal thickness was noted in males aged 9 weeks. Removal of the stratum corneum by sellotape stripping was more effective and reproducible in the females, as determined histologically. Sellotape-stripping induction of ornithine decarboxylase in the epidermis was higher in rats aged 5-6 weeks and reached a plateau in animals aged 6-12 weeks. Individual variations obtained were lower in females (about 5%-10% in females and 10%-20% in males). The present research suggests that female rats aged about 8 weeks provide maximum reproducibility of response and ease of use.


Assuntos
Epiderme/enzimologia , Modelos Biológicos , Ornitina Descarboxilase/biossíntese , Ratos Endogâmicos/metabolismo , Animais , Indução Enzimática , Epiderme/anatomia & histologia , Feminino , Masculino , Ratos
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