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1.
J Surg Oncol ; 121(1): 100-108, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31240729

RESUMO

BACKGROUND AND OBJECTIVES: Previously, we have shown that 9-cis retinoic acid (9-cis RA) stimulates lymphangiogenesis and limits postsurgical lymphedema in animal models when administered via daily intraperitoneal injections. In this study, we investigate whether a single-use depot 9-cis RA drug delivery system (DDS) implanted at the site of lymphatic injury can mitigate the development of lymphedema in a clinically relevant mouse limb model. METHODS: Hind limb lymphedema was induced via surgical lymphadenectomy and irradiation. Animals were divided into two treatment groups: (1) 9-cis RA DDS, (2) placebo DDS. Outcomes measured included paw thickness, lymphatic clearance and density, epidermal thickness, and collagen deposition. RESULTS: Compared with control animals, 9-cis RA-treated animals had significantly less paw swelling from postoperative week 3 (P = .04) until the final timepoint at week 6 (P = .0007). Moreover, 9-cis RA-treated animals had significantly faster lymphatic clearance (P < .05), increased lymphatic density (P = .04), reduced lymphatic vessel size (P = .02), reduced epidermal hyperplasia (P = .04), and reduced collagen staining (P = .10). CONCLUSIONS: Animals receiving 9-cis RA sustained-release implants at the time of surgery had improved lymphatic function and structure, indicating reduced lymphedema progression. Thus, we demonstrate that 9-cis RA contained within a single-use depot DDS has favorable properties in limiting pathologic responses to lymphatic injury and may be an effective strategy against secondary lymphedema.


Assuntos
Alitretinoína/administração & dosagem , Excisão de Linfonodo/métodos , Linfedema/prevenção & controle , Animais , Colágeno/metabolismo , Preparações de Ação Retardada , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Membro Posterior , Hiperplasia , Excisão de Linfonodo/efeitos adversos , Sistema Linfático/efeitos dos fármacos , Sistema Linfático/metabolismo , Linfedema/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Complicações Pós-Operatórias/prevenção & controle
2.
EMBO J ; 38(23): e101982, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31633821

RESUMO

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.


Assuntos
Envelhecimento/patologia , Atrofia/patologia , Senescência Celular , Melanócitos/patologia , Pele/patologia , Telômero/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Atrofia/induzido quimicamente , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Humanos , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Comunicação Parácrina , Espécies Reativas de Oxigênio/metabolismo , Receptores CXCR4/metabolismo , Pele/metabolismo , Telômero/metabolismo , Adulto Jovem
3.
BMC Complement Altern Med ; 19(1): 286, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660950

RESUMO

BACKGROUND: Edible insects, including Oxya chinensis sinuosa Mishchenko (Oc), which is consumed as food in Asia, are considered as a human food shortage alternative, and also as a preventive measure against environmental destruction. Ultraviolet B (UVB) irradiation, which causes skin photodamage, is considered as an extrinsic skin aging factor. It reduces skin hydration, and increases wrinkle formation and reactive oxygen species (ROS) and inflammatory cytokine expression. Thus, the objective of this study was to investigate the anti-aging effects of an ethanol extract of Oc (Oc.Ex). METHODS: A UVB-irradiated hairless mouse model was used to examine relevant changes in skin hydration, wrinkle formation, and skin epidermal thickness. Also, antioxidant markers such as superoxide dismutase (SOD) and catalase (CAT) were analyzed, and Oc. Ex skin protective effects against UVB irradiation-induced photoaging were examined by determining the levels of skin hydration factors. RESULTS: Oc.Ex improved epidermal barrier dysfunctions such as increased transepidermal water loss (TEWL) and capacitance reduction in UVB-irradiated mice. It upregulated skin hydration-related markers, including hyaluronic acid (HA), transforming growth factor (TGF)-ß, and pro-collagen, in UVB-irradiated mice, compared with the vehicle control group. It also reduced UVB-induced wrinkle formation, collagen degradation, and epidermal thickness. Additionally, it remarkably suppressed the increased expression of matrix metalloproteinases (MMPs), and restored the activity of SOD and CAT in UVB-irradiated mice, compared with the vehicle control group. Furthermore, Oc. Ex treatment downregulated the production of inflammatory cytokines and phosphorylation of the mitogen-activated protein kinases (MAPKs) signaling pathway activated by UVB irradiation. CONCLUSION: This study revealed that Oc. Ex reduced skin thickness and the degradation of collagen fibers by increasing hydration markers and collagen-regulating factors in the skin of UVB-irradiated mice. It also inhibited UVB-induced antioxidant enzyme activity and inflammatory cytokine expression via MAPK signaling downregulation, suggesting that it prevents UVB-induced skin damage and photoaging, and has potential for clinical development in skin disease treatment.


Assuntos
Gafanhotos/química , Protetores contra Radiação/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Animais , Catalase/metabolismo , Colágeno/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Humanos , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Pelados , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Superóxido Dismutase/metabolismo , Raios Ultravioleta/efeitos adversos
4.
Int J Mol Sci ; 20(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480681

RESUMO

The main function of the skin is to protect the body from the external environment. The barrier function of the skin is mainly provided by the stratum corneum, which consists of corneocytes bound with the corneodesmosomes and lamellar lipids. Skin barrier proteins like loricrin and filaggrin also contribute to the skin barrier function. In various skin diseases, skin barrier dysfunction is a common symptom, and skin irritants like detergents or surfactants could also perturb skin barrier function. Many efforts have been made to develop strategies to improve skin barrier function. Here, we investigated whether the microfluidized lysates of Lactobacillus rhamnosus (LR), one of the most widely used probiotic species for various health benefits, may improve the skin barrier function in a reconstructed human epidermis, Keraskin™. Application of LR lysate on Keraskin™ increased the expression of tight junction proteins; claudin 1 and occludin as determined by immunofluorescence analysis, and skin barrier proteins; loricrin and filaggrin as determined by immunohistochemistry and immunofluorescence analysis and qPCR. Also, the cytotoxicity of a skin irritant, sodium lauryl sulfate (SLS), was alleviated by the pretreatment of LR lysate. The skin barrier protective effects of LR lysate could be further demonstrated by the attenuation of SLS-enhanced dye-penetration. LR lysate also attenuated the destruction of desmosomes after SLS treatment. Collectively, we demonstrated that LR lysate has protective effects on the skin barrier, which could expand the utility of probiotics to skin-moisturization ingredients.


Assuntos
Epiderme/efeitos dos fármacos , Lactobacillus rhamnosus/metabolismo , Modelos Biológicos , Probióticos/farmacologia , Administração Tópica , Anticorpos/farmacologia , Biomarcadores/metabolismo , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Desmossomos/efeitos dos fármacos , Desmossomos/metabolismo , Desmossomos/ultraestrutura , Epiderme/patologia , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Irritantes/toxicidade , Proteínas de Membrana/metabolismo , Permeabilidade , Rodaminas/metabolismo , Proteínas de Junções Íntimas/metabolismo
5.
Int J Nanomedicine ; 14: 5449-5475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409998

RESUMO

Purpose: We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site. Methods: To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model. Results: The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively. Conclusion: LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.


Assuntos
Diabetes Mellitus/patologia , Hidrogéis/química , Fator de Crescimento Insulin-Like I/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Oxigênio/metabolismo , Quercetina/farmacologia , Absorção Cutânea , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno/biossíntese , Modelos Animais de Doenças , Emulsões/química , Fator de Crescimento Epidérmico/farmacologia , Epiderme/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Peso Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Octanos/química , Fator de Crescimento Derivado de Plaquetas/farmacologia , Protaminas/química , Absorção Cutânea/efeitos dos fármacos
6.
Int J Mol Sci ; 20(17)2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31438472

RESUMO

Atopic dermatitis (AD) is the most common chronic and relapsing inflammatory skin disease. AD is typically characterized by skewed T helper (Th) 2 inflammation, yet other inflammatory profiles (Th1, Th17, Th22) have been observed in human patients. How cytokines from these different Th subsets impact barrier function in this disease is not well understood. As such, we investigated the impact of the canonical Th17 cytokine, IL-17A, on barrier function and protein composition in primary human keratinocytes and human skin explants. These studies demonstrated that IL-17A enhanced tight junction formation and function in both systems, with a dependence on STAT3 signaling. Importantly, the Th2 cytokine, IL-4 inhibited the barrier-enhancing effect of IL-17A treatment. These observations propose that IL-17A helps to restore skin barrier function, but this action is antagonized by Th2 cytokines. This suggests that restoration of IL-17/IL-4 ratio in the skin of AD patients may improve barrier function and in so doing improve disease severity.


Assuntos
Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Interleucina-17/farmacologia , Interleucina-4/farmacologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Células Cultivadas , Claudina-4/metabolismo , Dermatite Atópica/metabolismo , Humanos , Técnicas In Vitro , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Pele/metabolismo
7.
Skin Pharmacol Physiol ; 32(5): 254-264, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352443

RESUMO

BACKGROUND/OBJECTIVES: Ultraviolet (UV) radiation damages the stratum corneum (SC) and disrupts the skin barrier. The damaged skin changes in the molecular composition of the SC, including its water content. However, it is difficult to examine the in vivo SC changes with existing methods, so those have not been well characterized. Therefore, we investigated in vivo changes of UV-induced SC damage using confocal Raman spectroscopy. METHOD: We irradiated the volar forearm of 10 subjects with 0.5, 1, and 1.5 minimal erythemal doses of UV radiation. Then, we examined erythema, the transepidermal water loss (TEWL), the water content, the natural moisturizing factor (NMF), and the lipids of the skin. RESULTS: After UV irradiation, erythema and TEWL of the skin were both increased. The bound water content of the SC was also increased following UV irradiation. The NMF of the SC revealed different tendencies. All free amino acids (FAAs) of the NMF were increased after UV irradiation, except proline. trans-urocanic acid, pyrrolidone carboxylic acid, lactate, and urea, which are NMF components produced by the subsequent catabolism of FAAs and sweat, were decreased after UV irradiation. The amount of ceramide in the SC was also decreased after UV exposure, while cholesterol was increased. CONCLUSIONS: The bound water content of the SC was increased by UV exposure along with increasing TEWL, several NMF components, and cholesterol. These in vivo results for UV-damaged SC obtained via Raman spectroscopy could be applied to research with regard to protecting the SC from UV radiation and treating UV-damaged SC.


Assuntos
Epiderme/efeitos dos fármacos , Queratinas/metabolismo , Raios Ultravioleta , Adulto , Epiderme/metabolismo , Eritema/metabolismo , Feminino , Humanos , Masculino , Exposição à Radiação , Análise Espectral Raman , Perda Insensível de Água/efeitos da radiação , Adulto Jovem
8.
J Toxicol Sci ; 44(6): 393-403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167989

RESUMO

To predict the results of a 24-hr closed human patch test, we previously recommended the use of in vitro test with a reconstructed human epidermis (RhE) model adopted in OECD TG 439, and proposed the margin method, which includes evaluation of twice the concentration to avoid a false positive for surfactants. Therefore, in this study, we used LabCyte EPI-MODEL as a RhE model, and confirmed the reproducibility of this method using five surfactants, including benzalkonium chloride (BC), sodium lauryl sulfate (SLS), and lauryl betaine (LB), for which false negative results have previously been reported, and three different surfactants. For all surfactants, prediction of patch test results using a margin of two revealed that human tests could be performed safely, confirming the utility of the margin method. In addition, we examined the relationship with critical micellar concentration (CMC). The IC50 for cell viability in the RhE model for three types of surfactants (BC, SLS, and LB) was 2.7- to 49.7-times the CMC. Therefore, the range of concentrations in which tests were performed with the present method was within the range of concentrations with high cleansing. Furthermore, we examined the relationship between cell viability and release of the inflammatory mediator interleukin-1α (IL-1α). IL-1α release was associated with cell viability, supporting the results of the human patch test.


Assuntos
Epiderme/efeitos dos fármacos , Testes de Irritação da Pele , Tensoativos/toxicidade , Alternativas aos Testes com Animais , Compostos de Benzalcônio/toxicidade , Betaína/análogos & derivados , Betaína/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Epiderme/metabolismo , Humanos , Interleucina-1alfa/metabolismo , Testes do Emplastro , Reprodutibilidade dos Testes , Dodecilsulfato de Sódio/toxicidade
9.
Respir Res ; 20(1): 129, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31234850

RESUMO

BACKGROUND: Azithromycin (Azm) is a macrolide recognized for its disease-modifying effects and reduction in exacerbation of chronic airway diseases. It is not clear whether the beneficial effects of Azm are due to its anti-microbial activity or other pharmacological actions. We have shown that Azm affects the integrity of the bronchial epithelial barrier measured by increased transepithelial electrical resistance. To better understand these effects of Azm on bronchial epithelia we have investigated global changes in gene expression. METHODS: VA10 bronchial epithelial cells were treated with Azm and cultivated in air-liquid interface conditions for up to 22 days. RNA was isolated at days 4, 10 and 22 and analyzed using high-throughput RNA sequencing. qPCR and immunostaining were used to confirm key findings from bioinformatic analyses. Detailed assessment of cellular changes was done using microscopy, followed by characterization of the lipidomic profiles of the multivesicular bodies present. RESULTS: Bioinformatic analysis revealed that after 10 days of treatment genes encoding effectors of sterol and cholesterol metabolism were prominent. Interestingly, expression of genes associated with epidermal barrier differentiation, KRT1, CRNN, SPINK5 and DSG1, increased significantly at day 22. Together with immunostaining, these results suggest an epidermal differentiation pattern. We also found that Azm induced the formation of multivesicular and lamellar bodies in two different airway epithelial cell lines. Lipidomic analysis revealed that Azm was entrapped in multivesicular bodies linked to different types of lipids, most notably palmitate and stearate. Furthermore, targeted analysis of lipid species showed accumulation of phosphatidylcholines, as well as ceramide derivatives. CONCLUSIONS: Taken together, we demonstrate how Azm might confer its barrier enhancing effects, via activation of epidermal characteristics and changes to intracellular lipid dynamics. These effects of Azm could explain the unexpected clinical benefit observed during Azm-treatment of patients with various lung diseases affecting barrier function.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Corpos Multivesiculares/efeitos dos fármacos , Mucosa Respiratória/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem Celular , Epiderme/metabolismo , Humanos , Corpos Multivesiculares/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/metabolismo
10.
Altern Ther Health Med ; 25(5): 12-29, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31221944

RESUMO

Context: Dietary supplement manufacturers claim cutaneous anti-aging properties for their products; however, research supporting these claims remains sparse. Objectives: The study intended to determine if a correlation existed between the effects of a collagen dietary supplement and changes associated with skin aging. Design: The study was a 12-week, double-blind, placebo-controlled trial. Setting: The study took place at a clinical facility specializing in dermatological testing that could perform biophysical, instrumental analysis on the effects of proprietary supplement on human skin. Participants: Participants were 128 females, aged 39-59 (50.57 ± 5.55). Intervention: Participants were randomly assigned to an intervention or a placebo. The intervention consisted of twice daily oral administration of a supplement containing 500 mg BioCell Collagen, a chicken sternal cartilage derived dietary ingredient composed of a naturally-occurring matrix of hydrolyzed collagen type-II (≥300 mg), chondroitin sulfate (≥100 mg), hyaluronic acid (≥50 mg). Outcome Measures: The primary parameters included transepidermal water loss, viscoelasticity, hydration, (indirect) collagen content, chromophore (melanin) content and hemoglobin level, and photographic analysis. An expert visually graded participants' skin to determine the intervention's efficacy, measuring facial lines and wrinkles, crow's feet lines and wrinkles, skin texture and smoothness, and skin tone. The presence of erythema and/or dryness determined tolerance. Secondary outcome measures were tolerance and incidence of adverse events, and the participant's perception of the supplement's value. Results: For the 113 participants completing the study, the dietary supplementation compared to a placebo: (1) significantly reduced facial lines and wrinkles (P = .019) and crow's feet lines and wrinkles (P = .05), (2) increased skin elasticity (P = .008) and cutaneous collagen content (P < .001) by 12%, (3) improved indicators associated with a more youthful skin appearance based on visual grading and wrinkle width (P = .046), and (4) decreased skin dryness and erythema. No difference existed between the supplement and the placebo for skin-surface water content or retention. The supplement was well tolerated, with no reported adverse reactions. Conclusions: Dietary supplementation with chicken, sternal cartilage extract supports the accumulation of types-I/III collagen in skin to promote increased elasticity and reduced skin wrinkling.


Assuntos
Galinhas , Colágeno Tipo II/administração & dosagem , Cartilagem Costal/química , Epiderme/efeitos dos fármacos , Envelhecimento da Pele/efeitos dos fármacos , Esterno/química , Adulto , Animais , Colágeno Tipo II/farmacologia , Método Duplo-Cego , Face/irrigação sanguínea , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Mol Carcinog ; 58(10): 1715-1725, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31254372

RESUMO

Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65- to 100-fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B-induced epidermal hyperplasia and hyperproliferation in SKH-1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell-specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan-FGFR inhibitor; AZD4547 significantly decreased cSCC cell-cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR-mediated effects. To further bolster the in vitro studies, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle-only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.


Assuntos
Benzamidas/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Piperazinas/farmacologia , Pirazóis/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Cutâneas/tratamento farmacológico , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Epiderme/efeitos dos fármacos , Epiderme/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Queratinócitos/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
12.
J Dermatol ; 46(6): 457-465, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31106905

RESUMO

The pH of the skin surface increases with age and thus reduces epidermal barrier function. Aged skin needs appropriate skin care to counterbalance age-related pH increase and improve barrier function. This confirmatory randomized study investigated the efficacy of water-in-oil (w/o) emulsions with either pH 4 or pH 5.8 in 20 elderly subjects after 4 weeks of treatment. After the treatment, the skin was challenged with a sodium dodecyl sulphate (SDS) solution in order to analyze barrier protection properties of both formulations. The pH 4 w/o emulsion resulted in a significantly lower skin pH compared with the pH 5.8 w/o emulsion and an improved skin hydration after 4-week treatment. Further, the pH 4 emulsion led to more pronounced improvements in length of intercellular lipid lamellae, lamellar organization as well as lipid levels than the pH 5.8 emulsion. Following SDS-induced barrier damage to the skin, the pH of all test areas increased, but the area treated with the pH 4 emulsion showed the lowest increase compared with baseline. In addition, even after the SDS challenge the skin area treated with the pH 4 emulsion still maintained a significantly increased length of intercellular lipid lamellae compared with the beginning of the study. This study provides evidence that topical application of a w/o emulsion with pH 4 reacidifies the skin in elderly and has beneficial effects on skin moisturization, regeneration of lipid lamellae and lipid content. Application of a pH 4 emulsion can improve the epidermal barrier as well as the stratum corneum organization in aged skin.


Assuntos
Cosméticos/administração & dosagem , Epiderme/metabolismo , Envelhecimento da Pele/efeitos dos fármacos , Perda Insensível de Água/efeitos dos fármacos , Administração Cutânea , Idoso , Método Duplo-Cego , Emulsões , Epiderme/efeitos dos fármacos , Epiderme/ultraestrutura , Espaço Extracelular/diagnóstico por imagem , Espaço Extracelular/metabolismo , Feminino , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Óleos/química , Permeabilidade/efeitos dos fármacos , Envelhecimento da Pele/fisiologia , Dodecilsulfato de Sódio/farmacologia , Resultado do Tratamento , Água/química
13.
Aquat Toxicol ; 212: 88-97, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31077970

RESUMO

Ionocytes are specialized cells in the epidermis of embryonic zebrafish (Danio rerio) that play important roles in ion homeostasis and have functional similarities to mammalian renal cells. Here, we examined whether these cells might also share another functional similarity with renal cells, which is the presence of efflux transporter activities useful for elimination of toxic small molecules. Xenobiotic transporters (XTs), including the ATP-Binding Cassette (ABC) family, are a major defense mechanism against diffusible toxic molecules in aquatic embryos, including zebrafish, but their activity in the ionocytes has not previously been studied. Using fluorescent small molecule substrates of XT, we observed that specific populations of ionocytes uptake and efflux fluorescent small molecules in a manner consistent with active transport. We specifically identified a P-gp/ABCB1 inhibitor-sensitive efflux activity in the H+-ATPase-rich (HR) ionocytes, and show that these cells exhibit enriched expression of the ABCB gene, abcb5. The results extend our understanding of the functional significance of zebrafish ionocytes and indicate that these cells could play an important role in protection of the fish embryo from harmful small molecules.


Assuntos
Embrião não Mamífero/citologia , Embrião não Mamífero/metabolismo , Xenobióticos/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Animais , Ânions , Transporte Biológico , Epiderme/efeitos dos fármacos , Corantes Fluorescentes/metabolismo , Mitocôndrias/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Proteínas de Peixe-Zebra/genética
14.
Biomed Res Int ; 2019: 9068314, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143777

RESUMO

Background: Malar melasma has a chronic and recurrent character that may be related to epigenetic changes. Objective: To recognize the expression and DNA methylation of DNA methyltransferases (DNMTs) in malar melasma and perilesional skin, as well as the changes in DNMTs after their treatment with sunscreen in combination with 4% niacinamide, 0.05% retinoic acid, or placebo. Methods: Thirty female patients were clinically evaluated for the expression of DNMT1 and DNMT3b using real-time PCR and immunofluorescence. These initial results were compared to results after eight weeks of treatment with sunscreen in combination with niacinamide, retinoic acid, or placebo. Results: The relative expression of DNMT1 was significantly elevated in melasma compared with unaffected skin in all subjects, indicating DNA hypermethylation. After treatment, it was decreased in all groups: niacinamide (7 versus 1; p<0.01), retinoic acid (7 versus 2; p<0.05), and placebo (7 versus 3; p<0.05), which correlates with clinical improvement. DNMT3b was not overexpressed in lesional skin but reduced in all groups. Conclusions: We found DNA hypermethylation in melasma lesions. Environmental factors such as solar radiation may induce cellular changes that trigger hyperpigmentation through the activation of pathways regulated by epigenetic modifications. However, limiting or decreasing DNA methylation through sunscreen, niacinamide, and retinoic acid treatments that provide photoprotection and genetic transcription can counteract this.


Assuntos
Metilases de Modificação do DNA/metabolismo , Melanose/tratamento farmacológico , Melanose/enzimologia , Niacinamida/uso terapêutico , Protetores Solares/uso terapêutico , Tretinoína/uso terapêutico , 5-Metilcitosina/metabolismo , Adulto , Metilação de DNA , Metilases de Modificação do DNA/genética , Epiderme/efeitos dos fármacos , Epiderme/patologia , Feminino , Fluorescência , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Placebos , Protetores Solares/farmacologia
15.
Daru ; 27(1): 283-293, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31129807

RESUMO

BACKGROUND: Atopic dermatitis is a multifactorial immune-mediated skin disorder characterized by an alteration of epidermal barrier function and onset of skin lesions, which range from mild erythema to severe lichenification. Treatment consists in hydration with possible use of topical or immunomodulatory corticosteroids, which, however sometimes showed side effects. Recently, the interest in natural compounds has grown significantly and among these, hydroxytyrosol (HT) plays a pivotal role due to its strong and well-known anti-inflammatory activity. OBJECTIVES: The aim of this study was to investigate the safety and efficacy of Fenolia® Eudermal Cream 15 (HT-based formulation) on epidermal barrier impaired as consequence of skin injury. METHODS: Whit this purpose, morphologic and structural as well as anti-inflammatory evaluations, after treatment with pro-inflammatory mediators (PBS 1 X and LPS) and HT-based formulation on reconstructed human epidermis (RHE) were carried out by qualitative (hematoxylin/eosin- and immunostaining) and quantitative (MTT assay, IL-1α and IL-8 release by ELISA) techniques. Furthermore, HT absorption through the epidermal barrier was evaluated by RP-LC-DAD analysis. RESULTS: A rise in the thickness of the epidermis as well as an appropriate maturation and protein expression (Loricrin, Fillagrin, E-Cadherin and Cytokeratins 5&6) were detected in treated RHE samples. In particular, the HT-based formulation was found to stimulate cell proliferation, as evidenced by the significant increase in Ki67 expression, which suggests the involvement of repair mechanisms, increasing epithelial regeneration and differentiation and improving the epidermal barrier effect. Furthermore, HT-based formulation showed a statistically significant anti-inflammatory activity by reducing both IL-1α and IL-8 release by RHE tissues, greater than the reference drug dexamethasone. Finally, excellent transcutaneous absorption values were found for HT, demonstrating how this new formulation increases the availability of the bioactive compound. CONCLUSIONS: In light of these results, Fenolia® Eudermal Cream 15 could be an effective agent to counteract atopic dermatitis. Graphical abstract Safety and efficacy of hydroxytyrosol-based formulation on skin inflammation: in vitro evaluation on reconstructed human epidermis model.


Assuntos
Dermatite/prevenção & controle , Epiderme/imunologia , Lipopolissacarídeos/efeitos adversos , Álcool Feniletílico/análogos & derivados , Administração Tópica , Sobrevivência Celular/efeitos dos fármacos , Dermatite/imunologia , Composição de Medicamentos , Epiderme/efeitos dos fármacos , Humanos , Modelos Biológicos , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Absorção Cutânea , Creme para a Pele
16.
Free Radic Res ; 53(7): 737-747, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31130017

RESUMO

Dermal exposure to cumene hydroperoxide (CumOOH) during manufacturing processes is a toxicological issue for the industry. Its genotoxicity, mutagenic action, ability to promote skin tumour, capacity to induce epidermal hyperplasia, and aptitude to induce allergic and irritant skin contact dermatitis are well known. These toxic effects appear to be mediated through the activation to free radical species such as hydroxyl, alkoxyl, and alkyl radicals characterised basically by electron paramagnetic resonance (EPR) and spin-trapping (ST) techniques. To be a skin sensitiser CumOOH needs to covalently bind to skin proteins in the epidermis to form the antigenic entity triggering the immunotoxic reaction. Cleavage of the O-O bond allows formation of unstable CumO•/CumOO• radicals rearranging to longer half-life specific carbon-centred radicals R• proposed to be at the origin of the antigen formation. Nevertheless, it is not still clear which R• is precisely formed in the epidermis and thus involved in the sensitisation process. The aim of this work was to elucidate in conditions closer to real-life sensitisation which specific R• are formed in a 3D reconstructed human epidermis (RHE) model by using 13C-substituted CumOOH at carbon positions precursors of potentially reactive radicals and EPR-ST. We demonstrated that most probably methyl radicals derived from ß-scission of CumO• radicals occur in RHE through a one-electron reductive pathway suggesting that these could be involved in the antigen formation inducing skin sensitisation. We also describe a coupling between nitroxide radicals and ß position 13C atoms that could be of an added value to the very few examples existing for the coupling of radicals with 13C atoms.


Assuntos
Derivados de Benzeno/uso terapêutico , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Epiderme/efeitos dos fármacos , Radicais Livres/química , Detecção de Spin/métodos , Derivados de Benzeno/farmacologia , Humanos
17.
Mol Neurobiol ; 56(10): 7144-7158, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30989631

RESUMO

Current strategies to enhance regeneration of peripheral neurons involve broad activation of sensory, autonomic, and motor axons. Peripheral neuron regeneration is limited in persons with damage or disease of peripheral axons. Here, we provide evidence that subtoxic activation of TRPV1 channels in sensory neurons is associated with activation of growth and subtle changes in skin reinnervation. We identify a bidirectional, dose-related impact of capsaicin, a TRPV1 agonist, on sensory neurons and their axons with rises in their outgrowth plasticity at low doses and toxic neurodegeneration at high doses. Moreover, its impact on growth added to that of preconditioning. Neither outcome was observed in TRPV1 null neurons. We confirmed that low dose activation was associated with rises in neuronal calcium, as well as rises in TRPV1 mRNA transcripts. In mice with a sciatic nerve crush followed by a single application of capsaicin directly to the injury site, there was no impact on motor or myelinated axon recovery but there was evidence of better recovery of thermal sensation toward baseline with hyperalgesia. Moreover, skin reinnervation by epidermal axons approached contralateral levels. TRPV1 null mice displayed loss of thermal sensation during later recovery. In sensory axons innervating the pinna of the ear, local capsaicin rendered early axon loss followed by later hyperinnervation. Taken together, TRPV1 activation alters the regenerative behavior of adult neurons and their axons both in vitro and during epidermal reinnervation in vivo. The findings identify a selective manipulation that augments cutaneous innervation by thermosensitive axons.


Assuntos
Axônios/metabolismo , Ativação do Canal Iônico , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Axônios/efeitos dos fármacos , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Capsaicina/farmacologia , Citosol/metabolismo , Epiderme/efeitos dos fármacos , Epiderme/inervação , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Regeneração Nervosa/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Remielinização/efeitos dos fármacos , Células Receptoras Sensoriais/efeitos dos fármacos , Temperatura Ambiente
18.
J Pharm Biomed Anal ; 172: 94-102, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31029804

RESUMO

The molecular organization of stratum corneum (SC) lipids is important for maintaining the barrier properties of the skin. The majority of intercellular lipids are in a solid state at normal humidity (RH) and ambient temperature; however, several studies indicate that a small fraction exist in a fluid state. In a previous work, a preferential solubilization of fluid skin lipids by acetone (Ac) was envisaged. A different change in the skin permeability related to the different lipid structures of the extracted lipids was suggested. To increase the knowledge of the specific role of different lipids on skin structure, a selective lipid modification is proposed. This study assess the effect of Ac on skin barrier lipids in-depth. Synchrotron based Fourier-transform infrared microspectroscopy (FTIR), which is used to study SC lipid organization, revealed a more ordered lipid organization after Ac treatment. In vitro experiments using Franz cells, which were selected to follow the SC barrier function capability, demonstrated that Ac-treated skin retained caffeine and ibuprofen on the SC with very low permeation of both compounds into the deeper skin layers. In vitro transepidermal water loss (TEWL) measurements revealed the ability of Ac to induce a less water permeated skin. Although an important lipid fraction has been removed, Ac skin treatment brings to a skin where the remaining lipids promote an improved barrier function. These results could lead to a better understanding of the role of different lipid components in skin structure.


Assuntos
Acetona/administração & dosagem , Epiderme/metabolismo , Solventes/administração & dosagem , Perda Insensível de Água/efeitos dos fármacos , Administração Cutânea , Animais , Cafeína/administração & dosagem , Cafeína/farmacocinética , Epiderme/efeitos dos fármacos , Ibuprofeno/administração & dosagem , Ibuprofeno/farmacocinética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/análise , Lipídeos/química , Modelos Animais , Permeabilidade/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Sus scrofa
19.
Skin Res Technol ; 25(3): 251-257, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30937980

RESUMO

BACKGROUND: Two clinical methods of assessing a moisturizer's effect on stratum corneum (SC) barrier repair were evaluated in female subjects with dry skin, to identify an assessment method for future studies. METHODS: In this single-centre, split-body study, women with dry skin applied moisturizer before (method A) or after (method B) SC barrier perturbation using D-Squame® stripping discs. Transepidermal water loss (TEWL) and residual protein on D-Squame discs were assessed over 14 days. RESULTS: Twenty-four subjects were included. For method A, the mean slope values of plots of 1/TEWL vs cumulative protein removed decreased over time for both treated and untreated areas, indicating improved SC barrier quality. There were no significant differences between treated and untreated areas, although a trend to a more negative slope was observed by Day 14 in the treated areas (P = 0.082), suggesting treatment improved barrier quality. For method B, using pre- and post-stripping as covariates, no statistical differences/trends were observed between treated and untreated areas for change in TEWL from post-stripping to any evaluation from Days 3-14. TEWL values returned towards pre-stripping values for treated and untreated areas by the initial Day 3 evaluation. CONCLUSION: For method A, there were trends suggesting the moisturizing treatment improved SC barrier quality. For method B, there were no significant differences/trends between treated and untreated areas. Further assessment with different methodologies is warranted to design appropriate clinical protocols for evaluating accelerated skin barrier repair. These data are insufficient to conclude whether the product or methodology was responsible for the results.


Assuntos
Emolientes/farmacologia , Epiderme/fisiologia , Creme para a Pele/farmacologia , Perda Insensível de Água/efeitos dos fármacos , Adulto , Água Corporal/fisiologia , Epiderme/efeitos dos fármacos , Feminino , Humanos , Pessoa de Meia-Idade , Estado de Hidratação do Organismo/efeitos dos fármacos , Adulto Jovem
20.
J Immunol Res ; 2019: 5143635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944833

RESUMO

Ideal agents for the topical treatment of skin wounds should have antimicrobial efficacy without negative influence on wound healing. Octenidine (OCT) has become a widely used antiseptic in professional wound care, but its influence on several components of the wound healing process remains unclear. In the present study, we have used a superficial wound model using tape stripping on human full-thickness skin ex vivo to investigate the influence of OCT on epidermal Langerhans cells (LCs) and cytokine secretion pattern of skin cells during wound healing in a model without disruption of the normal skin structure. Histological and immunofluorescence studies showed that OCT neither altered human skin architecture nor the viability of skin cells upon 48 hours of culture in unwounded or wounded skin. The epidermis of explants and LCs remained morphologically intact throughout the whole culture period upon OCT treatment. OCT inhibited the upregulation of the maturation marker CD83 on LCs and prevented their emigration in wounded skin. Furthermore, OCT reduced both pro- and anti-inflammatory mediators (IL-8, IL-33, and IL-10), while angiogenesis and growth factor mediators (VEGF and TGF-ß1) remained unchanged in skin explant cultures. Our data provide novel insights into the host response to OCT in the biologically relevant environment of viable human (wounded) skin.


Assuntos
Anti-Infecciosos/farmacologia , Citocinas/genética , Epiderme/efeitos dos fármacos , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/imunologia , Piridinas/farmacologia , Cicatrização/efeitos dos fármacos , Adulto , Citocinas/imunologia , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/imunologia , Humanos , Pessoa de Meia-Idade , Modelos Biológicos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Fita Cirúrgica , Cicatrização/imunologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/imunologia , Adulto Jovem
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