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1.
Int J Nanomedicine ; 15: 6007-6018, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32884260

RESUMO

Background: Skin pharmacokinetics is an indispensable indication for studying the drug fate after administration of transdermal drug delivery systems (TDDS). However, the heterogeneity and complex skin structured with stratum corneum, viable epidermis, dermis, and subcutaneous tissue inevitably leads the drug diffusion coefficient (Kp) to vary depending on the skin depth, which seriously limits the development of TDDS pharmacokinetics in full thickness skin. Methods: A multilayer geometry skin model was established and the Kp of drug in SC, viable epidermis, and dermis was obtained using the technologies of molecular dynamics simulation, in vitro permeation experiments, and in vivo microdialysis, respectively. Besides, finite element analysis (FEA) based on drug Kps in different skin layers was applied to simulate the paeonol nanoemulsion (PAE-NEs) percutaneous dynamic penetration process in two and three dimensions. In addition, PAE-NEs skin pharmacokinetics profile obtained by the simulation was verified by in vivo experiment. Results: Coarse-grained modeling of molecular dynamic simulation was successfully established and the Kp of PAE in SC was 2.00×10-6 cm2/h. The Kp of PAE-NE in viable epidermis and in dermis detected using penetration test and microdialysis probe technology, was 1.58×10-5 cm2/h and 3.20×10-5 cm2/h, respectively. In addition, the results of verification indicated that PAE-NEs skin pharmacokinetics profile obtained by the simulation was consistent with that by in vivo experiment. Discussion: This study demonstrated that the FEA combined with the established multilayer geometry skin model could accurately predict the skin pharmacokinetics of TDDS.


Assuntos
Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Emulsões/farmacocinética , Epiderme/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Acetofenonas/administração & dosagem , Acetofenonas/farmacocinética , Animais , Emulsões/administração & dosagem , Células Epidérmicas/efeitos dos fármacos , Análise de Elementos Finitos , Masculino , Microdiálise , Modelos Biológicos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos
2.
PLoS One ; 15(9): e0239261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32991593

RESUMO

Currently, there are no registered veterinary drugs for the treatment of endocrinopathic equine laminitis, and although this form of the disease is known to be caused by prolonged hyperinsulinaemia, the mechanism of insulin toxicity is unclear. One possibility is that high concentrations of insulin activate IGF-1 receptors (IGF-1R) in lamellar tissue, leading to uncontrolled cell proliferation and epidermal lamellar dysregulation. An equinized version of a human anti-IGF-1R therapeutic monoclonal antibody (mAb11) was generated to test this theory, using a modification of the prolonged euglycaemic-hyperinsulinaemic clamp technique. Healthy Standardbred horses were infused for 48 h with 0.9% saline (negative-control, n = 6), a combination of insulin (4.5 mIU/kgBW/min) and a variable infusion of 50% glucose to maintain euglycaemia (positive-control, n = 6), or insulin and glucose, preceded by a low dose of mAb11 (20 mg), designed to treat one foot only and delivered by retrograde infusion into one forelimb (mAb-treated, n = 7). Maximum insulin concentrations were 502 ± 54.4 and 435 ± 30.4 µIU/mL in the positive-control and mAb11-treated groups, respectively (P = 0.33). While the control group remained healthy, all the insulin-treated horses developed laminitis within 30 h, as judged by clinical examination, foot radiographs and histological analysis. Some effects of insulin were not attenuated by the antibody, however, relative to the positive-control group, horses treated with mAb11 showed less sinking of the distal phalanx (P < 0.05) and milder histological changes, with markedly less elongation at the tips of the secondary epidermal lamellae (P < 0.05). These differences were apparent in both front feet and were statistically significant when the values for both feet were combined. The results confirm that IGF-1R may have a role in insulin-induced laminitis and suggest that mAb11 warrants further research as a potential agent to prevent or treat the disease.


Assuntos
Doenças dos Cavalos/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Insulina/metabolismo , Receptor IGF Tipo 1/imunologia , Animais , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/farmacologia , Anticorpos Monoclonais/farmacologia , Proliferação de Células/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Glucose/metabolismo , Doenças dos Cavalos/imunologia , Cavalos , Hiperinsulinismo/imunologia , Hiperinsulinismo/patologia , Hiperinsulinismo/veterinária , Insulina/imunologia , Receptor IGF Tipo 1/antagonistas & inibidores
3.
Chem Biol Interact ; 330: 109227, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32818478

RESUMO

The use of 3D models in various scientific applications is becoming more popular to replace traditional monolayers models. In this work, we used a three-dimensional in-house model of epidermis using HaCaT immortalized cells to evaluate the dermal toxicity induced by Basic Blue 99 and Basic Red 51, both present in commercial hair dye formulations. Our data show that cells cultured in the 3D model respond differently to those cultured in monolayer. Basic Red 51 dye induces apoptosis an DNA breaks in both models, however, these effects is more pronounced in cells cultured in monolayer. The toxic mode of action of Basic Blue 99 seems to be the induction of cell death, without genotoxic effects, but while the necrotic pathway is observed in HaCaT monolayer cell culture, was apoptosis seen in the Equivalent Human Epidermis (EHE) model. We could also confirm that cells in EHE model, an environment that could better mimic human effects, react differently to chemical stressors than the cells cultivated in 2D.


Assuntos
Técnicas de Cultura de Células/métodos , Epiderme/efeitos dos fármacos , Tinturas para Cabelo/toxicidade , Apoptose/efeitos dos fármacos , Compostos Azo/toxicidade , Técnicas de Cultura de Células/normas , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Tinturas para Cabelo/análise , Humanos , Naftoquinonas/toxicidade , Necrose/induzido quimicamente , Compostos de Amônio Quaternário/toxicidade
4.
Sci Rep ; 10(1): 13891, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807849

RESUMO

Sphingolipids are one of the major components of cell membranes and are ubiquitous in eukaryotic organisms. Ceramide 2-aminoethylphosphonate (CAEP) of marine origin is a unique and abundant sphingophosphonolipid with a C-P bond. Although molluscs such as squids and bivalves, containing CAEP, are consumed globally, the dietary efficacy of CAEP is not understood. We investigated the efficacy of marine sphingophosphonolipids by studying the effect of dietary CAEP on the improvement of the skin barrier function in hairless mice fed a diet that induces severely dry-skin condition. The disrupted skin barrier functions such as an increase in the transepidermal water loss (TEWL), a decrease in the skin hydration index, and epidermal hyperplasia were restored by CEAP dietary supplementation. Correspondingly, dietary CAEP significantly increased the content of covalently bound ω-hydroxyceramide, and the expression of its biosynthesis-related genes in the skin. These effects of dietary CAEP mimic those of dietary plant glucosylceramide. The novel observations from this study show an enhancement in the skin barrier function by dietary CAEP and the effects could be contributed by the upregulation of covalently bound ω-hydroxyceramide synthesis in the skin.


Assuntos
Ácido Aminoetilfosfônico/análogos & derivados , Organismos Aquáticos/química , Ceramidas/farmacologia , Dieta , Pele/metabolismo , Esfingolipídeos/metabolismo , Ácido Aminoetilfosfônico/farmacologia , Animais , Epiderme/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos Pelados , Pele/efeitos dos fármacos , Perda Insensível de Água/efeitos dos fármacos
5.
Pharm Res ; 37(8): 148, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681288

RESUMO

PURPOSE: Adapalene (AD) is one of the main retinoids used in the topical therapy of acne, an extremely common skin disease usually associated with psychological morbidity. However, like other retinoids, AD is frequently associated with skin irritation. To overcome the skin irritation, we proposed the encapsulation of AD in solid lipid nanoparticles (SLNs) using the ion pair strategy. METHODS: The developed SLN-AD was characterized by high-performance liquid chromatography, differential scanning calorimetry, X-ray diffraction, synchrotron small-angle X-ray scattering, and transmission electron microscopy. In vitro permeation tests using porcine skin and in vivo mice skin irritation test were performed to evaluate, respectively, the drug's skin distribution and the skin irritation. RESULTS: The characterization studies were able to demonstrate that the proposed strategy effectively provided high AD encapsulation in SLNs and its incorporation into a hydrophilic gel. Sustained release, epidermal targeting, and less skin irritation were observed for SLN-AD gel in comparison to the marketed AD gel. CONCLUSIONS: The studies demonstrated that the encapsulation of AD in SLNs through the formation of an ion pair is a valuable alternative to diminish the adverse skin reactions caused by AD and can optimize patient adherence to treatment.


Assuntos
Acne Vulgar/tratamento farmacológico , Adapaleno/farmacologia , Preparações de Ação Retardada/química , Fármacos Dermatológicos/farmacologia , Ácidos Graxos/química , Nanocápsulas/química , Aminas/metabolismo , Animais , Transporte Biológico , Fármacos Dermatológicos/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Epiderme/efeitos dos fármacos , Glicerol/química , Humanos , Íons/química , Transição de Fase , Pele , Absorção Cutânea , Suínos , Temperatura de Transição
6.
Sci Rep ; 10(1): 10154, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576871

RESUMO

Fifteen adult Soay rams were employed in this study to investigate the effect of melatonin on the scrotal skin using histological, histochemical, and morphometrical analysis. The results revealed that the melatonin treated group showed a significant increase in the thickness of the epidermis, the cross-sectional area of blood capillaries and nerve fibers compared with the control one. In addition, obvious hypertrophy and hyperplasia were detected in the sebaceous glands in association with a significant increase in the number and diameter of apocrine sweat glands with well-developed secretory activity. S100 protein and cytokeratin-19 strongly stained the basal cells of sebaceous glands in the melatonin treated group incomparable to the control group. Moreover, the nerve fibers were intensively immunoreacted for S100 and cytokeratin proteins in the melatonin treated group in contrast to the control one. A high number of telocytes (TCs) could be identified in the treated group around the nerve fibers and blood vessels in the dermis. The number of Langerhans cells showed a significant increase in the melatonin groups that were identified by MHC II and PGP 9.5 within the epidermal layer. Furthermore, a significant increase in the number of dendritic cells was identified in the melatonin group, which were distributed within the dermis, around hair follicles, sebaceous glands, and sweat glands and were strongly expressed PGP-9.5, MHC-II, VAMP, SNAP, keratin-5, and cytokeratin-19 immunoreactivity. Notably, Merkel cells showed a significant increase in the number in the melatonin group that could be stained against nestin, SNAP, and VAMP. On the other hand, the secretory granules in sweat glands were exhibited a strong positive reactivity for synaptophysin in melatonin group. The current study showed that the administration of melatonin induced a stimulatory effect on keratinocytes, non-keratinocytes, sebaceous and sweat glands, hair follicles, as well as the vascular, neuronal, and cellular constituents of the dermis.


Assuntos
Melatonina/farmacologia , Escroto , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Animais , Cruzamento , Epiderme/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Queratina-19/genética , Queratina-19/metabolismo , Queratina-5/genética , Queratina-5/metabolismo , Queratinócitos/efeitos dos fármacos , Masculino , Fibras Nervosas/efeitos dos fármacos , Glândulas Sebáceas/efeitos dos fármacos , Ovinos , Pele/inervação , Pele/metabolismo , Glândulas Sudoríparas/efeitos dos fármacos , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
7.
Toxicol Appl Pharmacol ; 401: 115078, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479919

RESUMO

Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for its ability to protect the skin against injury induced by SM in the mouse ear vesicant model. SM induced inflammation, epidermal hyperplasia and microblistering at the dermal/epidermal junction of mouse ears 24-168 h post-exposure. This was associated with upregulation of MMP-9 mRNA and protein in the skin. Dual immunofluorescence labeling showed increases in MMP-9 in the epidermis and in the adjacent dermal matrix of the SM injured skin, as well as breakdown of type IV collagen in the basement membrane. Pretreatment of the skin with BiPS reduced signs of SM-induced cutaneous toxicity; expression of MMP-9 mRNA and protein was also downregulated in the skin by BiPS. Following BiPS pretreatment, type IV collagen appeared intact and was similar to control skin. These results demonstrate that inhibiting type IV collagenases in the skin improves basement membrane integrity after exposure to SM. BiPS may hold promise as a potential protective agent to mitigate SM induced skin injury.


Assuntos
Benzopiranos/uso terapêutico , Substâncias para a Guerra Química/toxicidade , Colágeno Tipo IV/antagonistas & inibidores , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Gás de Mostarda/toxicidade , Dermatopatias/tratamento farmacológico , Animais , Benzopiranos/farmacologia , Colágeno Tipo IV/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Dermatopatias/induzido quimicamente , Dermatopatias/metabolismo , Dermatopatias/patologia
8.
Exp Mol Pathol ; 115: 104470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32445752

RESUMO

Sulfur mustard (SM), a dermal vesicant that has been used in chemical warfare, causes inflammation, edema and epidermal erosions depending on the dose and time following exposure. Herein, a minipig model was used to characterize wound healing following dermal exposure to SM. Saturated SM vapor caps were placed on the dorsal flanks of 3-month-old male Gottingen minipigs for 30 min. After 48 h the control and SM wounded sites were debrided daily for 7 days with wet to wet saline gauze soaks. Animals were then euthanized, and full thickness skin biopsies prepared for histology and immunohistochemistry. Control skin contained a well differentiated epidermis with a prominent stratum corneum. A well-developed eschar covered the skin of SM treated animals, however, the epidermis beneath the eschar displayed significant wound healing with a hyperplastic epidermis. Stratum corneum shedding and a multilayered basal epithelium consisting of cuboidal and columnar cells were also evident in the neoepidermis. Nuclear expression of proliferating cell nuclear antigen (PCNA) was contiguous in cells along the basal epidermal layer of control and SM exposed skin; SM caused a significant increase in PCNA expression in basal and suprabasal cells. SM exposure was also associated with marked changes in expression of markers of wound healing including increases in keratin 10, keratin 17 and loricrin and decreases in E-cadherin. Trichrome staining of control skin showed a well-developed collagen network with no delineation between the papillary and reticular dermis. Conversely, a major delineation was observed in SM-exposed skin including a web-like papillary dermis composed of filamentous extracellular matrix, and compact collagen fibrils in the lower reticular dermis. Although the dermis below the wound site was disrupted, there was substantive epidermal regeneration following SM-induced injury. Further studies analyzing the wound healing process in minipig skin will be important to provide a model to evaluate potential vesicant countermeasures.


Assuntos
Gás de Mostarda/toxicidade , Pele/patologia , Cicatrização , Animais , Caderinas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Epiderme/patologia , Proteínas de Membrana/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Pele/efeitos dos fármacos , Suínos , Porco Miniatura , Cicatrização/efeitos dos fármacos
9.
J Leukoc Biol ; 108(1): 267-281, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32421901

RESUMO

Psoriasis is a common, chronic multifactorial inflammatory skin disease with both genetic and environmental components. A number of studies have suggested that psoriasis episodes are often preceded by stressful life events. Nevertheless, the underline mechanisms of stress in psoriasis remain unexplored. To address this question, we established an emotional stress mouse model induced by empty bottle stimulation, and applied imiquimod (IMQ), a ligand of TLR7/8 and effective potent immune activator, on the dorsal skin to induce psoriasis-like lesions. We found that empty bottles induced emotional stress exaggerated and prolonged psoriasiform dermatitis, which appeared as more prominent epidermal hyperplasia in the emotional stress mice compared with the control mice. Higher mRNA expression of Il-1ß, Il-17a, and Il-22, as well as higher secretion of IL-1ß, IL-12p40, IL-17, and IL-22 were observed in the skin lesion of emotional stress mice. The emotional stress condition and IMQ treatment synergistically led to higher expression levels of neurotransmitters and their receptors in the skin, especially substance P (SP), we also found that SP could stimulate DCs to secrete more IL-23p40 in vitro. In addition, NK-1R antagonist partially abrogated enhanced epidermal thickness and the level of neurotransmitters in emotional stress mice. Taken together, these results indicate that stress exacerbates and prolongs psoriasiform dermatitis in mice by up-regulating IL-1ß and IL-23p40, which were related to local DCs stimulated by abnormal SP.


Assuntos
Epiderme/patologia , Imiquimode/efeitos adversos , Subunidade p40 da Interleucina-12/biossíntese , Interleucina-1beta/biossíntese , Psoríase/induzido quimicamente , Estresse Psicológico/complicações , Animais , Ansiedade/etiologia , Ansiedade/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/patologia , Dermatite/etiologia , Dermatite/patologia , Emoções , Epiderme/efeitos dos fármacos , Hiperplasia , Inflamação/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Neurotransmissores/metabolismo , Nociceptores/metabolismo , Psoríase/complicações , Psoríase/patologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Regulação para Cima/efeitos dos fármacos
10.
J Pathol ; 251(4): 420-428, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32472631

RESUMO

One of the major functions of human skin is to provide protection from the environment. Although we cannot entirely avoid, for example, sun exposure, it is likely that exposure to other environmental factors could affect cutaneous function. A number of studies have identified smoking as one such factor that leads to both facial wrinkle formation and a decline in skin function. In addition to the direct physical effects of tobacco smoke on skin, its inhalation has additional profound systemic effects for the smoker. The adverse effects on the respiratory and cardiovascular systems from smoking are well known. Central to the pathological changes associated with smoking is the elastic fibre, a key component of the extracellular matrices of lungs. In this study we examined the systemic effect of chronic smoking (>40 cigarettes/day; >5 years) on the histology of the cutaneous elastic fibre system, the nanostructure and mechanics of one of its key components, the fibrillin-rich microfibril, and the micromechanical stiffness of the dermis and epidermis. We show that photoprotected skin of chronic smokers exhibits significant remodelling of the elastic fibre network (both elastin and fibrillin-rich microfibrils) as compared to the skin of age- and sex-matched non-smokers. This remodelling is not associated with increased gelatinase activity (as identified by in situ zymography). Histological remodelling is accompanied by significant ultrastructural changes to extracted fibrillin-rich microfibrils. Finally, using scanning acoustic microscopy, we demonstrated that chronic smoking significantly increases the stiffness of both the dermis and the epidermis. Taken together, these data suggest an unappreciated systemic effect of chronic inhalation of tobacco smoke on the cutaneous elastic fibre network. Such changes may in part underlie the skin wrinkling and loss of skin elasticity associated with smoking. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Fibrilinas/efeitos dos fármacos , Envelhecimento da Pele/efeitos dos fármacos , Fumar Tabaco/efeitos adversos , Adulto , Biópsia , Derme/efeitos dos fármacos , Derme/ultraestrutura , Elasticidade/efeitos dos fármacos , Elastina/efeitos dos fármacos , Elastina/ultraestrutura , Epiderme/efeitos dos fármacos , Epiderme/ultraestrutura , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/ultraestrutura , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microfibrilas/efeitos dos fármacos , Microfibrilas/ultraestrutura , Pessoa de Meia-Idade , Pele/efeitos dos fármacos , Pele/ultraestrutura
11.
An Bras Dermatol ; 95(3): 320-325, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32291095

RESUMO

BACKGROUND: Higher skin pH in atopic dermatitis contributes to impaired epidermal barrier. A moisturizer compatible with physiological pH could improve atopic dermatitis. OBJECTIVE: To determine the effect of a physiologically compatible pH moisturizer in atopic dermatitis. METHODS: A randomized half body, double blind, controlled trial involving patients with stable atopic dermatitis was performed. pH-modified moisturizer and standard moisturizer were applied to half body for 6 weeks. RESULTS: A total of 6 (16.7%) males and 30 (83.3%) females participated. Skin pH reductions from week 0, week 2 and 6 were significant at the forearms (5.315 [0.98] to 4.85 [0.54] to 5.04 [0.78], p=0.02) and abdomen (5.25 [1.01], 4.82 [0.64], 5.01 [0.59], p=0.00) but not at the shins (5.01 [0.80], 4.76 [0.49], 4.85 [0.79], p=0.09) with pH-modified moisturizer. Transepidermal water loss (TEWL) at the forearms decreased (4.60 [2.55] to 3.70 [3.10] to 3.00 [3.55], p=0.00), abdomen (3.90 [2.90] to 2.40 [3.45] to 2.70 [2.25], p=0.046). SCORAD improved from 14.1±12.75 to 10.5±13.25 to 7±12.25, p=0.00. In standard moisturizer group, pH reductions were significant at the forearms (5.29 [0.94] to 4.84 [0.55] to 5.02 [0.70], p=0.00) and abdomen (5.25 [1.09], 4.91 [0.63], 5.12 [0.66], p=0.00). TEWL at the forearm were (4.80 [2.95], 4.10 [2.15], 4.60 [3.40], p=0.67), shins (3.80 [1.40], 3.50 [2.35], 4.00 [2.50], p=0.91) and abdomen (3.70 [2.45], 4.10 [3.60], 3.40 [2.95], p=0.80). SCORAD improved from 14.2±9.1 to 10.9±10.65 to 10.5±11, p=0.00. Reduction in pH was observed with both moisturizers while TEWL significantly improved with pH-modified moisturizer. pH-modified moisturizer resulted in greater pH, TEWL and SCORAD improvements however the differences were not significant from standard moisturizer. STUDY LIMITATION: Skin hydration was not evaluated. CONCLUSION: Moisturization is beneficial for atopic dermatitis; use of physiologically compatible pH moisturizer is promising.


Assuntos
Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/química , Fármacos Dermatológicos/uso terapêutico , Creme para a Pele/química , Creme para a Pele/uso terapêutico , Adolescente , Adulto , Criança , Método Duplo-Cego , Epiderme/química , Epiderme/efeitos dos fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Valores de Referência , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
12.
Gen Comp Endocrinol ; 293: 113470, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32234298

RESUMO

The research on impacts of environmental chemicals on crustacean molting dates back to the 1970s when ground-breaking studies investigated the disruption of molting in Crustacea by organochlorines. With the emergence of a new scientific inquiry, termed environmental endocrine disruption, in the early 1990s, increasing attention has been attracted to the possibility that environmental chemicals capable of wreaking havoc on sex steroid-regulated processes in vertebrates can also adversely affect ecdysteroid-mediated processes, e.g. molting, in crustaceans. Given the fact that many molting-disrupting chemicals accumulate in crustacean tissues and that the effect on molting is not readily visible in the field, the disruption of molting by environmental chemicals has been dubbed the invisible endocrine disruption. In recent years, much advancement has been made in both the documentation of the phenomenon of molting disruption and the search for mechanisms, by which molting disruption occurs. This review provides an overview of the current status of the field of invisible endocrine disruption, and perspectives on future directions are also presented.


Assuntos
Disruptores Endócrinos/toxicidade , Animais , Crustáceos/efeitos dos fármacos , Ecdisteroides/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Muda/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
13.
Int J Pharm ; 580: 119234, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32194205

RESUMO

The aim was to investigate the feasibility of using Er:YAG fractional laser ablation to enable topical cutaneous delivery of etanercept (ETA). Preliminary investigations into the effect of fluence on micropore depth, measured by full-field optical coherence tomography, were followed by quantitative experiments to determine ETA delivery and its cutaneous biodistribution from solution and hydrogel formulations. Visualization studies were performed using confocal laser scanning microscopy and an ETA-fluorescein conjugate. Micropore depth was linearly dependent on laser fluence. However, use of a single pulse or "pulse stacking" (i.e. multiple pulses) to apply a given fluence affected pore depth; this was accommodated mathematically by including a "stacking factor". ETA delivery into porated skin from solution and 0.8% Carbopol® formulations was equivalent: increasing ETA content in the gels from 0.5 to 1 and 2% increased ETA delivery linearly (Formulations 7-9: 5.12 ± 0.95 to 7.48 ± 1.45 and 11.2 ± 2.2 µg/cm2, respectively; 10% FAA, 89.9 J/cm2, 5 ppp); occlusion further increased ETA delivery from Formulation 9 to 23.17 ± 6.62 µg/cm2. Cutaneous biodistribution studies demonstrated that ETA was delivered in therapeutically relevant amounts to the epidermis and dermis. Topical laser-assisted delivery of ETA might expand its range of clinical indications to include recalcitrant but not widespread psoriatic plaques (clinical trial underway).


Assuntos
Etanercepte/administração & dosagem , Terapia a Laser/métodos , Absorção Cutânea/efeitos dos fármacos , Pele/efeitos dos fármacos , Administração Cutânea , Animais , Sistemas de Liberação de Medicamentos/métodos , Células Epidérmicas/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Lasers de Estado Sólido , Microscopia Confocal/métodos , Suínos , Distribuição Tecidual/fisiologia
14.
Sci Rep ; 10(1): 3970, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132628

RESUMO

Paclitaxel induces peripheral neuropathy as a side effect of cancer treatment. The underlying causes are unclear, but epidermal, unmyelinated axons have been shown to be the first to degenerate. We previously utilized an in vivo zebrafish model to show that the epidermal matrix-metalloproteinase 13 (MMP-13) induces degeneration of unmyelinated axons, whereas pharmacological inhibition of MMP-13 prevented axon degeneration. However, the precise functions by which MMP-13 is regulated and affects axons remained elusive. In this study, we assessed mitochondrial damage and reactive oxygen species (ROS) formation as possible inducers of MMP-13, and we analyzed MMP-13-dependent damage. We show that the small ROS, H2O2, is increased in basal keratinocytes following treatment with paclitaxel. Cytoplasmic H2O2 appears to derive, at least in part, from mitochondrial damage, leading to upregulation of MMP-13, which in turn underlies increased epidermal extracellular matrix degradation. Intriguingly, also axonal mitochondria show signs of damage, such as fusion/fission defects and vacuolation, but axons do not show increased levels of H2O2. Since MMP-13 inhibition prevents axon degeneration but does not prevent mitochondrial vacuolation, we suggest that vacuolization occurs independently of axonal damage. Finally, we show that MMP-13 dysregulation also underlies paclitaxel-induced peripheral neuropathy in mammals, indicating that epidermal mitochondrial H2O2 and its effectors could be targeted for therapeutic interventions.


Assuntos
Epiderme/efeitos dos fármacos , Metaloproteinase 13 da Matriz/metabolismo , Mitocôndrias/efeitos dos fármacos , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Ativação Enzimática/efeitos dos fármacos , Epiderme/metabolismo , Mitocôndrias/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Regulação para Cima/efeitos dos fármacos , Peixe-Zebra
15.
Exp Mol Pathol ; 114: 104410, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32113906

RESUMO

Nitrogen mustard (NM) is a highly reactive bifunctional alkylating agent that induces inflammation, edema and blistering in skin. An important mechanism mediating the action of NM and related mustards is oxidative stress. In these studies a modified murine patch-test model was used to analyze DNA damage and the antioxidant/stress response following NM exposure in isolated epidermis. NM (20 µmol) was applied to glass microfiber filters affixed to a shaved dorsal region of skin of CD-1 mice. NM caused structural damage to the stratum corneum as reflected by increases in transepidermal water loss and skin hydration. This was coordinate with edema, mast cell degranulation and epidermal hyperplasia. Within 3 h of NM exposure, a 4-fold increase in phosphorylated histone H2AX, a marker of DNA double-stranded breaks, and a 25-fold increase in phosphorylated p53, a DNA damage marker, were observed in the epidermis. This was associated with a 40% increase in 8-oxo-2'-deoxyguanosine modified DNA in the epidermis and a 4-fold increase in 4-hydroxynonenal modified epidermal proteins. At 12 h post NM, there was a 3-75 fold increase in epidermal expression of antioxidant/stress proteins including heme oxygenase-1, thioredoxin reductase, superoxide dismutase, glutathione reductase, heat shock protein 27 and cyclooxygenase 2. These data indicate that NM induces early oxidative epidermal injury in mouse skin leading to an antioxidant/stress response. Agents that enhance this response may be useful in mitigating mustard-induced skin injury.


Assuntos
Antioxidantes/metabolismo , Epiderme/metabolismo , Mecloretamina/farmacologia , Estresse Fisiológico/genética , Alquilantes/farmacologia , Alquilantes/toxicidade , Animais , Apoptose/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Dano ao DNA/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Glutationa Redutase/genética , Proteínas de Choque Térmico HSP27/genética , Heme Oxigenase-1/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Mecloretamina/toxicidade , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Superóxido Dismutase/genética , Tiorredoxina Dissulfeto Redutase/genética
16.
PLoS One ; 15(2): e0229613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084249

RESUMO

Mucus form H. aspersa muller has been reported to have several therapeutic proprieties, such as antimicrobial activity, skin protection and wound repair. In this study, we have analyzed H. aspersa mucus (Helixcomplex) bio-adhesive efficacy and its defensive properties against the ozone (O3) (0.5 ppm for 2 hours) exposure in human keratinocytes and reconstructed human epidermis models. Cytotoxicity, tissue morphology and cytokine levels were determined. We confirmed HelixComplex regenerative and bio-adhesive properties, the latter possibly via the characteristic mucopolysaccharide composition. In addition, HelixComplex was able to protect from O3 exposure by preventing oxidative damage and the consequent pro-inflammatory response in both 2D and 3D models. Based on this study, it is possible to suggest HelixComplex as a potentially new protective technology against pollution induced skin damage.


Assuntos
Caracois Helix/metabolismo , Muco/química , Muco/efeitos dos fármacos , Animais , Linhagem Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Muco/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
17.
Nanotoxicology ; 14(2): 263-274, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32003270

RESUMO

Suspensions of the UV filter, zinc oxide nanoparticles (ZnO NP), are widely used in sunscreen products. This paper compared the relative disposition and local cytotoxicity of ZnO NP, and zinc ions formed on its dissolution, against keratinocyte cultures and in the human epidermis (ex vivo) after application of suspensions of ZnO NP. HaCaT keratinocyte cytotoxicities were found to be related to labile intra-cellular zinc but also total zinc and extra-cellular concentrations in cell culture media and to a degree ameliorated by the presence of a zinc chelating agent. Secondly, the zinc species were then dosed onto exposed ex vivo viable human epidermis and it was found that an increase in labile zinc level correlated with a shift in the metabolic state of the viable epidermis. This study highlights that excised viable skin acts as a more relevant model for determining cutaneous toxicity over keratinocyte monolayers in vitro.


Assuntos
Epiderme/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Nanopartículas/toxicidade , Protetores Solares/toxicidade , Óxido de Zinco/toxicidade , Zinco/toxicidade , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Epiderme/metabolismo , Humanos , Íons , Queratinócitos/metabolismo , Nanopartículas/metabolismo , Absorção Cutânea/efeitos dos fármacos , Protetores Solares/metabolismo , Zinco/metabolismo , Óxido de Zinco/metabolismo
18.
Int J Mol Sci ; 21(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019183

RESUMO

The circadian rhythm regulates the physiology and behavior of living organisms in a time-dependent manner. Clock genes have distinct roles including the control over gene expression mediated by the transcriptional activators CLOCK and BMAL1, and the suppression of gene expression mediated by the transcriptional repressors PER1/2 and CRY1/2. The balance between gene expression and repression is key to the maintenance of tissue homeostasis that is disrupted in the event of an injury. In the skin, a compromised epithelial barrier triggers a cascade of events that culminate in the mobilization of epithelial cells and stem cells. Recruited epithelial cells migrate towards the wound and reestablish the protective epithelial layer of the skin. Although we have recently demonstrated the involvement of BMAL and the PI3K signaling in wound healing, the role of the circadian clock genes in tissue repair remains poorly understood. Here, we sought to understand the role of BMAL1 on skin healing in response to injury. We found that genetic depletion of BMAL1 resulted in delayed healing of the skin as compared to wild-type control mice. Furthermore, we found that loss of Bmal1 was associated with the accumulation of Reactive Oxygen Species Modulator 1 (ROMO1), a protein responsible for inducing the production of intracellular reactive oxygen species (ROS). The slow healing was associated with ROS and superoxide dismutase (SOD) production, and pharmacological inhibition of the oxidative stress signaling (ROS/SOD) led to cellular proliferation, upregulation of Sirtuin 1 (SIRT1), and rescued the skin healing phenotype of Bmal1-/- mice. Overall, our study points to BMAL1 as a key player in tissue regeneration and as a critical regulator of ROMO1 and oxidative stress in the skin.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Antioxidantes/farmacologia , Epiderme/fisiologia , Regulação da Expressão Gênica , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Ritmo Circadiano , Epiderme/efeitos dos fármacos , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
19.
Sci Rep ; 10(1): 1863, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024909

RESUMO

Exceedingly virulent pathogens and growing antimicrobial resistances require new therapeutic approaches. The zoophilic dermatophyte Trichophyton benhamiae causes highly inflammatory, cutaneous fungal infections. Recently, it could be shown that the plant-derived alkaloid tryptanthrin (TRP) exhibits strong anti-microbial activities against yeasts and dermatophytes. The aim of this study was to analyse the bioactivity of TRP under infectious conditions using an in-vitro dermatophytosis model employing fibroblasts and keratinocytes infected with T. benhamiae DSM6916. Analyses comprised determination of cell viability, effects on the innate immune response including expression and secretion of pro-inflammatory cytokines/chemokines as well as expression of various antimicrobial peptides (AMP), toll-like receptor (TLR) 2 and proliferation marker MKI67. T. benhamiae caused severe inflammation in the cutaneous cell models. TRP almost fully prevented T. benhamiae-derived damage of dermal fibroblasts and substantially reduced it in epidermal keratinocytes. A distinct down-regulation of the expression and secretion of pro-inflammatory cytokines was observed. Further, TRP promoted AMP expression, especially of HBD2 and HBD3, in keratinocytes even without fungal presence. This study provides crucial evidence that TRP is not only a strong antifungal agent but also potentially modulates the innate immune response. This makes it interesting as a natural antimycotic drug for adjuvant treatment and prevention of fungal re-infection.


Assuntos
Fibroblastos/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Quinazolinas/farmacologia , Tinha/tratamento farmacológico , Trichophyton/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/metabolismo , Linhagem Celular , Citocinas/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/microbiologia , Fibroblastos/metabolismo , Fibroblastos/microbiologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Queratinócitos/metabolismo , Queratinócitos/microbiologia , Antígeno Ki-67/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/microbiologia , Tinha/metabolismo , Tinha/microbiologia , Receptor 2 Toll-Like/metabolismo
20.
J Dermatol ; 47(4): 413-417, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31985094

RESUMO

Kakato-tsurutsuru (Kt) socks have been selling for almost 30 years in Japan. Wearers claim they improve heel dryness despite no scientific evidence. We investigated the effects of Kt socks on heel dryness by questionnaire, clinical scores and non-invasive skin measurements. In a double-blind, randomized cross-over study, 10 healthy volunteers wore control or Kt socks over 2 weeks in sequence for 4 weeks. Skin hydration and evaporation of the medial and dorsal heel were measured before and every week during the trial. Clinical evaluations of desquamation and cracked skin were scored by a dermatologist. A visual analog scale (VAS) questionnaire of comfort, sock climate humidity and skin dryness was conducted. The VAS of comfort was significantly higher in Kt than controls. Average Δskin dryness in control and Kt groups was -1.63 and 2.22, respectively, showing a significant improvement. In the clinical findings of the dorsal side of the heel, Δdesquamation and Δcracked skin scores were significantly decreased and Δstratum corneum hydration significantly increased in Kt compared with controls. Kt socks may retain evaporated sweat with components of natural moisturizing factors, supporting the water-holding ability of the heel stratum corneum. These findings suggest that Kt socks may improve heel skin dryness.


Assuntos
Vestuário , Emolientes/administração & dosagem , Epiderme/efeitos dos fármacos , Perda Insensível de Água/efeitos dos fármacos , Idoso , Estudos Cross-Over , Método Duplo-Cego , Epiderme/metabolismo , Feminino , Voluntários Saudáveis , Calcanhar , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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