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1.
PLoS One ; 19(5): e0302781, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38713650

RESUMEN

Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown. In this study, we investigated whether (S)-(-)-blebbistatin O-benzoate, a derivative of (-)-blebbistatin, improves dermatitis symptoms in a mite antigen-induced atopic dermatitis model using NC/Nga mice. The efficacy of the compound was confirmed using dermatitis scores, ear thickness measurements, serum IgE levels, histological analysis of lesions, and filaggrin expression analysis, which is important for barrier function. (S)-(-)-Blebbistatin O-benzoate treatment significantly reduced the dermatitis score and serum IgE levels compared to those in the vehicle group (p < 0.05). Furthermore, the histological analysis revealed enhanced filaggrin production and a decreased number of mast cells (p < 0.05), indicating that (S)-(-)-blebbistatin O-benzoate improved atopic dermatitis symptoms in a pathological model. In vitro analysis using cultured keratinocytes revealed increased expression of filaggrin, loricrin, involucrin, and ceramide production pathway-related genes, suggesting that (S)-(-)-blebbistatin O-benzoate promotes epidermal barrier formation. Furthermore, the effect of (S)-(-)-blebbistatin O-benzoate on type 2 alarmin cytokines, which are secreted from epidermal cells upon scratching or allergen stimulation and are involved in the pathogenesis of atopic dermatitis, was evaluated using antigens derived from mite feces. The results showed that (S)-(-)-blebbistatin O-benzoate inhibited the upregulation of these cytokines. Based on the above, (S)-(-)-blebbistatin O-benzoate has the potential to be developed as an atopic dermatitis treatment option that controls dermatitis symptoms by suppressing inflammation and improving barrier function by acting on multiple aspects of the pathogenesis of atopic dermatitis.


Asunto(s)
Benzoatos , Citocinas , Dermatitis Atópica , Epidermis , Proteínas Filagrina , Compuestos Heterocíclicos de 4 o más Anillos , Animales , Humanos , Masculino , Ratones , Antígenos Dermatofagoides/inmunología , Benzoatos/farmacología , Benzoatos/uso terapéutico , Citocinas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/patología , Proteínas Filagrina/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Inmunoglobulina E/sangre , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Alarminas/efectos de los fármacos
2.
Cell Death Dis ; 8(2): e2576, 2017 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-28151469

RESUMEN

The human skin has an important role in barrier function. Ultraviolet rays (UV) from sunlight exposure can cause cell apoptosis in the skin epidermis, resulting in the disruption of the barrier. Previously, we have demonstrated that BNIP3 stimulates autophagy in epidermal keratinocytes and has a protective effect in these cells upon UVB irradiation. In this study, we found that the accumulation of reactive oxygen species (ROS) by UVB irradiation was sufficient to trigger the activation of JNK and ERK mitogen-activated protein kinase (MAPK) in human primary epidermal keratinocytes. In turn, activated JNK and ERK MAPK mediated the upregulation of BNIP3 expression. Treatment with an antioxidant reagent or a specific inhibitor of MAPK, U0126, and a JNK inhibitor significantly attenuated the expression of BNIP3 triggered by UVB, followed by the induction of cell death by apoptosis. Furthermore, UVB-induced apoptosis was significantly stimulated by chloroquine or bafilomycin A1, an inhibitor of autophagy. Moreover, BNIP3 was required for the degradation of dysfunctional mitochondria upon UVB irradiation. These data clearly indicated that BNIP3-induced autophagy, which occurs via UVB-generated ROS-mediated JNK and ERK MAPK activation, has a crucial role in the protection of the skin epidermis against UVB irradiation.


Asunto(s)
Apoptosis/fisiología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Queratinocitos/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Rayos Ultravioleta/efectos adversos , Regulación hacia Arriba/fisiología , Animales , Antioxidantes/metabolismo , Autofagia/fisiología , Células Cultivadas , Epidermis/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo
3.
PLoS One ; 11(10): e0164799, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27736988

RESUMEN

Aloe has been used as a folk medicine because it has several important therapeutic properties. These include wound and burn healing, and Aloe is now used in a variety of commercially available topical medications for wound healing and skin care. However, its effects on epidermal keratinocytes remain largely unclear. Our data indicated that both Aloe vera gel (AVG) and Cape aloe extract (CAE) significantly improved wound healing in human primary epidermal keratinocytes (HPEKs) and a human skin equivalent model. In addition, flow cytometry analysis revealed that cell surface expressions of ß1-, α6-, ß4-integrin, and E-cadherin increased in HPEKs treated with AVG and CAE. These increases may contribute to cell migration and wound healing. Treatment with Aloe also resulted in significant changes in cell-cycle progression and in increases in cell number. Aloe increased gene expression of differentiation markers in HPEKs, suggesting roles for AVG and CAE in the improvement of keratinocyte function. Furthermore, human skin epidermal equivalents developed from HPEKs with medium containing Aloe were thicker than control equivalents, indicating the effectiveness of Aloe on enhancing epidermal development. Based on these results, both AVG and CAE have benefits in wound healing and in treatment of rough skin.


Asunto(s)
Aloe/química , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Aloe/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular , Movimiento Celular/efectos de los fármacos , Proteínas Ricas en Prolina del Estrato Córneo/genética , Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Humanos , Integrina alfa6/genética , Integrina alfa6/metabolismo , Integrina beta1/genética , Integrina beta1/metabolismo , Integrina beta4/genética , Integrina beta4/metabolismo , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Microscopía Fluorescente , Modelos Biológicos , Extractos Vegetales/química , Cicatrización de Heridas
4.
J Invest Dermatol ; 134(6): 1627-1635, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24402046

RESUMEN

Transcriptome analysis of the epidermis of Hes1(-/-) mouse revealed the direct relationship between Hes1 (hairy and enhancer of split-1) and BNIP3 (BCL2 and adenovirus E1B 19-kDa-interacting protein 3), a potent inducer of autophagy. Keratinocyte differentiation is going along with activation of lysosomal enzymes and organelle clearance, expecting the contribution of autophagy in this process. We found that BNIP3 was expressed in the suprabasal layer of the epidermis, where autophagosome formation is normally observed. Forced expression of BNIP3 in human primary epidermal keratinocytes (HPEKs) resulted in autophagy induction and keratinocyte differentiation, whereas knockdown of BNIP3 had the opposite effect. Intriguingly, addition of an autophagy inhibitor significantly suppressed the BNIP3-stimulated differentiation of keratinocytes, suggesting that BNIP3 plays a crucial role in keratinocyte differentiation by inducing autophagy. Furthermore, the number of dead cells increased in the human epidermal equivalent of BNIP3 knockdown keratinocytes, which suggests that BNIP3 is important for maintenance of skin epidermis. Interestingly, although UVB irradiation stimulated BNIP3 expression and cleavage of caspase3, suppression of UVB-induced BNIP3 expression led to further increase in cleaved caspase3 levels. This suggests that BNIP3 has a protective effect against UVB-induced apoptosis in keratinocytes. Overall, our data provide valuable insights into the role of BNIP3 in the differentiation and maintenance of epidermal keratinocytes.


Asunto(s)
Caspasa 3/metabolismo , Epidermis/metabolismo , Regulación de la Expresión Génica , Queratinocitos/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Apoptosis , Autofagia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular , Línea Celular , Regulación Enzimológica de la Expresión Génica , Proteínas de Homeodominio/genética , Homeostasis , Humanos , Queratinocitos/citología , Lisosomas/metabolismo , Ratones , Ratones Transgénicos , MicroARNs/metabolismo , Factor de Transcripción HES-1
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