RESUMO
Allergic march (AM) is characterized by the progression of clinical signs of atopic dermatitis (AD) to allergic asthma or rhinitis, but its pathogenesis is not completely understood. We developed mouse model of AM with three 1-week exposures (separated by 2-week interval) to an OVA or saline (control) followed by OVA challenge. The development of AM was confirmed by phenotypes of AD and allergic asthma. Increases in IL-4, IL-17, and thymic stromal lymphopoietin (TSLP) responses were associated with the progression of AM, and these responses were suppressed by treatment with Lcr35. Moreover, Lcr35 treatment led to an increase in the number of CD4(+)CD25(+) Foxp3(+) regulatory T (Treg) cells in the mesenteric lymph nodes (MLNs) of AM mice. In conclusion, the oral application of Lcr35 prevented the development of AM in this model by suppressing Th2, Th17, and TSLP responses via a mechanism that may involve CD4(+)CD25(+)Foxp3(+) Tregs in MLNs.
Assuntos
Asma/imunologia , Citocinas/imunologia , Dermatite Atópica/imunologia , Lacticaseibacillus rhamnosus/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Asma/metabolismo , Asma/patologia , Citocinas/metabolismo , Dermatite Atópica/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Mesentério , Camundongos , Neutrófilos/imunologia , Probióticos/administração & dosagem , Pele/imunologia , Pele/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Epidermal barrier abnormality due to filaggrin deficiency is an important predisposing factor in the development of atopic dermatitis (AD). In addition, the expression of thymic stromal lymphopoietin (TSLP) in keratinocytes (KCs), induced by barrier disruption, can promote type 2 helper T-cell polarization. Protease activity, including protease-activated receptor-2 (PAR-2), is also known to be involved in epidermal barrier function in AD. However, to our knowledge, the relationship between protease activity and filaggrin deficiency from the perspective of AD has not been elucidated. Flaky tail (Flg(ft)) mice, known to have a mutation in the filaggrin gene, were used to assess the role of protease in KCs in the steady state and the mite-induced AD-like skin inflammation model. In the steady state, the expression and activity levels of endogenous proteases, kallikreins 5, 7, and 14, in the skin and TSLP were higher in Flg(ft) than in control mice. In addition, activation of PAR-2 by its agonist induced the production of TSLP in KCs of Flg(ft) mice, which was abrogated by a newly developed PAR-2 antagonist. Application of the PAR-2 antagonist improved symptoms and basophil accumulation in Flg(ft) mice treated with mite extracts. These results suggest that possibly through the PAR-2 activation in KCs, filaggrin deficiency induces TSLP production and basophil accumulation, which play important roles in the establishment of AD.
Assuntos
Basófilos/metabolismo , Citocinas/biossíntese , Proteínas de Filamentos Intermediários/genética , Peptídeo Hidrolases/metabolismo , Aminoácidos/metabolismo , Animais , Dermatite Atópica/parasitologia , Dermatite Atópica/patologia , Feminino , Proteínas Filagrinas , Histidina/metabolismo , Concentração de Íons de Hidrogênio , Calicreínas/metabolismo , Queratinócitos/enzimologia , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Ácaros/fisiologia , Receptor PAR-2/agonistas , Receptor PAR-2/antagonistas & inibidores , Receptor PAR-2/metabolismo , Pele/parasitologia , Pele/patologia , Cauda , Linfopoietina do Estroma do TimoRESUMO
Prodigiosin, a red pigment produced by Hahella chejuensis, a marine-derived microorganism, has several biological functions, including antimicrobial activity and inflammatory relief. In this study, the antibacterial activity of prodigiosin against skin microorganisms was explored. Paper disc assay on skin bacterial cells revealed that Cutibacterium acnes related to acne vulgaris highly susceptible to prodigiosin. MIC (Minimal Inhibitory Concentration) and MBC (Minimal Bactericidal Concentration) were determined on Cutibacterium species. The RNA-seq analysis of prodigiosin-treated C. acnes cells was performed to understand the antibacterial mechanism of prodigiosin. Among changes in the expression of hundreds of genes, the expression of a stress-responsive sigma factor encoded by sigB increased. Conversely, the gene expression of cell wall biosynthesis and energy metabolism was inhibited by prodigiosin. Specifically, the expression of genes related to the metabolism of porphyrin, a pro-inflammatory metabolite, was significantly reduced. Therefore, prodigiosin could be used to control C. acnes. Our study provided new insights into the antimicrobial mechanism of prodigiosin against C. acnes strains.
Assuntos
Acne Vulgar , Prodigiosina , Humanos , Prodigiosina/farmacologia , Transcriptoma , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Acne Vulgar/microbiologia , Testes de Sensibilidade Microbiana , Propionibacterium acnes/genéticaAssuntos
Queratinócitos/metabolismo , Melanose/metabolismo , Receptor PAR-2/metabolismo , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Melanose/tratamento farmacológico , Camundongos , Estudos Retrospectivos , Telangiectasia/metabolismo , Regulação para CimaRESUMO
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease, and the pathogenesis is not completely understood. Although there are some mouse models of AD, it is not easy to establish model to represent the natural AD development in human. In this study, we developed an AD model based on outside-inside theory and investigated the effect of Lactobacillus rhamnosus (Lcr35), which have known as an immune modulator in allergic diseases. SKH-1 hairless mice underwent three 1-week exposures (separated by 2-week intervals) to an ovalbumin (OVA) or saline (control) patch at the same site to develop the mouse model of AD. Lcr35 (1 × 10(9) CFU) was administered orally every day from 1 week before the first sensitization until the end of the study. The AD model induced erythematous and itchy skin, increasing TEWL and increasing skin inflammation as assessed by histology in the mice. Oral Lcr35 attenuated all disease parameters previously mentioned. OVA-specific IgE and skin expression of interleukin-4 (IL-4) and thymic stromal lymphopoietin (TSLP) increased in AD mice, but were reduced in AD mice treated with Lcr35. Moreover, Lcr35 treatment led to an increase in CD4(+) CD25(+) Foxp3(+) Treg cells in the mesenteric lymph nodes of AD mice. In conclusions, based on the 'outside-inside' theory, topical allergen may induce AD without skin injury. Oral application of Lcr35 prevented the development of AD in this model by suppressing production of the inflammatory cytokines, IL-4 and TSLP in the skin via a mechanism that may involve CD4(+) CD25(+) Foxp3(+) Treg cells.
Assuntos
Dermatite Atópica/imunologia , Modelos Animais de Doenças , Lacticaseibacillus rhamnosus/imunologia , Linfonodos/imunologia , Ovalbumina/imunologia , Linfócitos T Reguladores/imunologia , Água/metabolismo , Análise de Variância , Animais , Antígenos CD4/metabolismo , Citocinas/metabolismo , Dermatite Atópica/metabolismo , Dermatite Atópica/fisiopatologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Imunoglobulina E/sangue , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-4/metabolismo , Contagem de Linfócitos , Mesentério , Camundongos , Camundongos Pelados , Permeabilidade/efeitos dos fármacos , Probióticos/farmacologia , Pele/metabolismo , Linfócitos T Reguladores/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Melanocortins have been implicated in human sebum secretion for a long time. However, the signalling pathways of α-melanocyte-stimulating hormone (α-MSH) in human sebocytes expressing melanocortin receptors (MC-Rs) are still poorly understood. Because calcium ions play a central role in MC-R signalling, we investigated whether α-MSH affects calcium signalling in the immortalized human sebocyte cell line SZ95. In addition, we investigated the impact of α-MSH on MC-1R expression and lipid synthesis in these cells. α-MSH increased intracellular calcium levels. α-MSH-mediated calcium mobilization originated from intracellular calcium stores and was mediated by inositol triphosphate. Moreover, α-MSH increased MC-1R immunoreactivity and lipid synthesis in SZ95 sebocytes in the presence of testosterone. Our data demonstrate that α-MSH in human sebocytes controls a key cellular signalling pathway, the calcium ion response, which may coordinate MC-1R-mediated sebum secretion.
Assuntos
Sinalização do Cálcio/efeitos dos fármacos , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/fisiologia , alfa-MSH/farmacologia , Linhagem Celular , Humanos , Lipídeos/biossíntese , Receptor Tipo 1 de Melanocortina/metabolismo , Glândulas Sebáceas/citologia , Sebo/efeitos dos fármacos , Sebo/metabolismo , Testosterona/farmacologiaRESUMO
Among the various adverse effects of topical corticosteroids, impairment of the epidermal permeability barrier is well-known. Decreased synthesis of the epidermal lipid consequently leads to structural defects of the stratum corneum. Recently, the beneficial effects of physiologic lipid mixtures containing pseudoceramide on the impaired epidermal permeability barrier have been reported, which suggest that physiologic lipid mixtures may reduce the topical glucocorticoid-induced barrier impairment. In this study, the effect of a pseudoceramide-containing physiologic lipid mixture as a vehicle for a mid-potency topical glucocorticoid was evaluated in an oxazolone-induced atopic dermatitis-like murine model. The changes in transepidermal water loss, hydration and skin fold thickness were measured. Inflammatory cells in the dermis, including eosinophils, were counted and Staphylococcus aureus binding assay was performed. Immunohistochemical staining for inflammatory cytokines and antimicrobial peptides were also performed. The topical steroid in physiologic lipid mixture showed a significantly decreased infiltrate of inflammatory cells (p<0.05) and a reduced number of adherent Staphylococcus aureus compared with the results of the topical steroid in polyethylene glycol/ethanol vehicle (p<0.05). In conclusion, the pseudoceramide-containing physiologic lipid mixture as a vehicle for a topical steroid enhanced the anti-inflammatory effect of the topical steroid and accelerated the skin barrier function restoration.
Assuntos
Anti-Inflamatórios/administração & dosagem , Betametasona/administração & dosagem , Ceramidas/química , Dermatite Atópica/metabolismo , Bicamadas Lipídicas/química , Metilprednisolona/análogos & derivados , Pele/efeitos dos fármacos , Adjuvantes Imunológicos/efeitos adversos , Animais , Ceramidas/administração & dosagem , Dermatite Atópica/induzido quimicamente , Emulsões , Epitélio/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Metilprednisolona/administração & dosagem , Camundongos , Camundongos Pelados , Oxazolona/efeitos adversos , Veículos Farmacêuticos , Perda Insensível de Água/efeitos dos fármacosRESUMO
BACKGROUND: Skin diseases characterized by epithelial barrier dysfunction show altered sphingolipid metabolism, which results in changes in the stratum corneum intercellular lipid components and structure. Under pathological conditions, 1-deoxysphingolipids form as atypical sphingolipids from de novo sphingolipid biosynthesis. OBJECTIVE: This study investigated the potential role of 1-deoxysphingolipids in skin barrier dysfunction secondary to X-ray and ultraviolet B (UVB) irradiation in vitro and in vivo. It was also evaluated changes in the expression of 1-deoxysphingolipids in lesional human skin of atopic dermatitis. METHODS: In this study, the changes in these 1-deoxysphingolipids levels of skin and serum samples were investigated in skin barrier dysfunction associated with X-ray and UVB irradiation in vitro and in vivo. RESULTS: Increased 1-deoxysphingolipids were observed in cultured normal human epidermal keratinocytes after X-ray irradiation. X-ray or UVB irradiation increased the production of 1-deoxysphingosine in a reconstituted 3-dimensional (3D) skin model. Interestingly, treatment with a physiological lipid mixture (multi-lamellar emulsion contained pseudoceramide), which can strengthen the epidermal permeability barrier function, resulted in decreased 1-deoxysphingosine formation in a reconstituted 3D skin model. Further investigation using a hairless mouse model showed similar preventive effects of physiological lipid mixture against 1-deoxysphingosine formation after X-ray irradiation. An increased level of 1-dexoysphingosine in the stratum corneum was also observed in lesional skin of atopic dermatitis. CONCLUSION: 1-deoxysphingosine might be a novel biomarker of skin barrier dysfunction and a physiological lipid mixture treatment could prevent 1-deoxysphingosine production and consequent skin barrier dysfunction.
RESUMO
Although several agents have been identified to provide therapeutic benefits in Huntington disease (HD), the number of conventionally used treatments remains limited and only symptomatic. Thus, it is plausible that the need to identify new therapeutic targets for the development of alternative and more effective treatments is becoming increasingly urgent. Recently, the sphingosine-1-phosphate (S1P) axis has been reported to be a valid potential novel molecular target for therapy development in HD. Modulation of aberrant metabolism of S1P in HD has been proved to exert neuroprotective action in vitro settings including human HD iPSC-derived neurons. In this study, we investigated whether promoting S1P production by stimulating Sphingosine Kinase 1 (SPHK1) by the selective activator, K6PC-5, may have therapeutic benefit in vivo in R6/2 HD mouse model. Our findings indicate that chronic administration of 0.05 mg/kg K6PC-5 exerted an overall beneficial effect in R6/2 mice. It significantly slowed down the progressive motor deficit associated with disease progression, modulated S1P metabolism, evoked the activation of pro-survival pathways and markedly reduced the toxic mutant huntingtin (mHtt) aggregation. These results suggest that K6PC-5 may represent a future therapeutic option in HD and may potentially counteract the perturbed brain function induced by deregulated S1P pathways.
RESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disease that commonly begins in childhood. K6PC-9p (N-(Ethyl dihydrogenphosphate)-2-hexyl-3-oxo-decanamide) is a synthetic ceramide derivative of PC-9S (N-Ethanol-2-mirystyl-3-oxo-staramide), which was known to be effective in atopic patients. In this study, we examined the effect of topical application of K6PC-9p on skin inflammation and AD-like skin lesions in mouse models. K6PC-9p dose-dependently inhibited phorbol ester-induced increase in ear thickness in BALB/c mice. Moreover, topical application of K6PC-9p suppressed dust mite extract-induced AD-like skin lesions in NC/Nga mice. Histopathological analysis revealed that both ear swelling and leucocyte infiltration were suppressed by K6PC-9p treatment. K6PC-9p also suppressed IL-4 and TNF-alpha expression in the ears and mast cell infiltration into the ears in NC/Nga mice. Further study demonstrated that K6PC-9p inhibited ConA-induced IL-4 secretion and LPS-induced macrophage activation. Taken together, our results showed that topical application of K6PC-9p exerts beneficial effects in animal model of skin inflammation and AD, suggesting that K6PC-9p might be a promising topical agent for the treatment of inflammatory skin diseases.
Assuntos
Ceramidas/uso terapêutico , Dermatite Atópica/prevenção & controle , Dermatite de Contato/prevenção & controle , Administração Tópica , Animais , Antígenos de Dermatophagoides/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ceramidas/química , Dermatite Atópica/patologia , Dermatite de Contato/etiologia , Dermatite de Contato/patologia , Modelos Animais de Doenças , Orelha Externa/efeitos dos fármacos , Orelha Externa/metabolismo , Orelha Externa/patologia , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Hidrocortisona/administração & dosagem , Hidrocortisona/uso terapêutico , Interleucina-4/genética , Interleucina-4/metabolismo , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Mastócitos/citologia , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Acetato de Tetradecanoilforbol/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, regulates multiple cellular responses such as Ca(2+) signaling, growth, survival, and differentiation. Because sphingosine kinase (SK) is the enzyme directly responsible for the production of S1P, many factors have been identified that regulate its activity and subsequent S1P levels. To date, there are no reports to demonstrate a chemically induced, direct activation of SK. OBJECTIVE: Here we have studied the effects of K6PC-5 as a newly synthesized SK activator on fibroblast proliferation in both human fibroblasts and aged mouse skin. To demonstrate that K6PC-5 has S1P-mediated action mechanism in fibroblasts, we have measured SK-dependent intracellular Ca(2+) signaling. METHODS: Fibroblasts were cultured primarily from human foreskin and were used to study the effect of K6PC-5 and S1P on intracellular Ca(2+) signaling and fibroblast proliferation. Changes in intracellular Ca(2+) were detected by fluorescence with fura-2/AM. To study skin anti-aging effects of K6PC-5, we used intrinsically aged hairless mice (56 weeks old). RESULTS: K6PC-5 promoted fibroblast proliferation and procollagen production in human fibroblasts significantly. K6PC-5 induced intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in human fibroblasts. Both dimethylsphingosine and dihydroxysphingosine, SK inhibitors, and the transfection of SK1-siRNA blocked the K6PC-5-induced increases in [Ca(2+)](i), an effect independent of the classical PLC/IP(3)-mediated pathway. The K6PC-5-induced [Ca(2+)](i) oscillations were dependent on thapsigargin-sensitive Ca(2+) stores and Ca(2+) entry. Topical application of K6PC-5 for 2 weeks to intrinsically aged hairless mice enhanced fibroblast proliferation, collagen production, and eventually increased dermal thickness (10%). K6PC-5 also promoted specific epidermal differentiation marker proteins, including involucrin, loricrin, filaggrin, and keratin 5, without any alterations on epidermal barrier function. CONCLUSION: These results suggest that K6PC-5 acts to regulate fibroblast proliferation through intracellular S1P production, and can further promote keratinocyte differentiation. We anticipate that the regulation of S1P levels may represent a novel approach for the treatment of skin disorders, including skin aging.
Assuntos
Envelhecimento/efeitos dos fármacos , Amidas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pele/metabolismo , Envelhecimento/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Proteínas Filagrinas , Humanos , Lisofosfolipídeos/antagonistas & inibidores , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Pelados , Modelos Animais , Pró-Colágeno/metabolismo , Pele/citologia , Pele/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inibidores , Esfingosina/metabolismoRESUMO
PC-9S (N-Ethanol-2-mirystyl-3-oxo-stearamide) is a synthetic ceramide and has been known to be effective in atopic and psoriatic patients. K112PC-5 (2-Acetyl-N-(1,3-dihydroxyisopropyl)-tetradecanamide) is a novel ceramide derivative of PC-9S. In the present study, we examined the effect of K112PC-5 on macrophage and T lymphocyte function in primary macrophages and splenocytes, respectively, as well as the effect of topical application of K112PC-5 on skin inflammation and atopic dermatitis (AD) in mouse models. K112PC-5 inhibited lipopolysaccharide-induced nitrite generation in mouse peritoneal macrophages in a dose-dependent manner. However, K112PC-5 did not affect concanavalin A-induced proliferation, interleukin (IL)-2 secretion and IL-4 secretion in mouse splenocytes. In addition, K112PC-5 significantly suppressed the increase in phorbol ester-induced ear thickness in BALB/c mice. Further study demonstrated that topical application of K112PC-5 also inhibited AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, in NC/Nga mice. Taken together, these results showed that K112PC-5 exerted an anti-inflammatory effect both in vitro and in vivo and proved to be beneficial in an animal model of AD. Our results suggest that K112PC-5 might be beneficial as a topical agent for the treatment of AD.
Assuntos
Ceramidas/farmacologia , Dermatite Atópica/prevenção & controle , Dermatite de Contato/prevenção & controle , Fármacos Dermatológicos/farmacologia , Administração Tópica , Alérgenos/toxicidade , Animais , Proliferação de Células/efeitos dos fármacos , Ceramidas/administração & dosagem , Dermatite Atópica/patologia , Dermatite de Contato/patologia , Fármacos Dermatológicos/administração & dosagem , Orelha Externa/patologia , Feminino , Interleucina-1/biossíntese , Interleucina-4/biossíntese , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Pyroglyphidae , Pele/patologia , Linfócitos T/efeitos dos fármacos , Acetato de TetradecanoilforbolRESUMO
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
RESUMO
Atopic dermatitis (AD) is a chronic inflammatory skin disease. K6PC-9 (N-Ethanol-2-hexyl-3-oxo-decanamide) is a novel synthetic ceramide derivative of PC-9S (N-Ethanol-2-mirystyl-3-oxo-stearamide), which was known to be effective in atopic and psoriatic patients. To investigate the immunomodulatory activity of K6PC-9, we examined the effect of K6PC-9 on T lymphocyte and macrophage function and the effect of topical application of K6PC-9 on skin inflammation and AD-like skin lesions in mouse models. K6PC-9 had no effect on concanavalin A-induced proliferation, interleukin (IL)-2 secretion and IL-4 secretion in mouse splenocytes. In contrast, lipopolysaccharide-induced nitrite generation was potently suppressed by K6PC-9 in mouse peritoneal macrophages. In mouse model of skin inflammation, K6PC-9 inhibited phorbol ester-induced increase in ear thickness and expression of tumor necrosis factor-alpha in the ear of BALB/c mice. Topical application of K6PC-9 also suppressed mite extract-induced AD-like skin lesions in NC/Nga mice. Increase in ear thickness was significantly inhibited by K6PC-9 in this model. K6PC-9 also blocked the infiltration of mast cells and neutrophils into the ear. Further study demonstrated that the mRNA expression of tumor necrosis factor-alpha and adhesion molecules, such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, was also suppressed by K6PC-9 in the ear of mite extract-treated NC/Nga mice. Taken together, the results presented in this report show that K6PC-9 has an anti-inflammatory potential and exerts beneficial effects in an animal model of AD, indicating that K6PC-9 might be used as a topical agent for the treatment of AD.
Assuntos
Ceramidas/administração & dosagem , Dermatite Atópica/prevenção & controle , Pyroglyphidae/imunologia , Administração Cutânea , Animais , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Feminino , Molécula 1 de Adesão Intercelular/genética , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/análise , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Acetato de Tetradecanoilforbol/toxicidade , Fator de Necrose Tumoral alfa/genética , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
The skin shows an important "epidermal permeability barrier homeostasis" in response to barrier disruption. Calcium ion (Ca(2+)), a major regulator in keratinocyte differentiation and proliferation, plays a crucial role in skin barrier homeostasis. Acute barrier disruption induces an immediate depletion of both extra- and intracellular calcium ions in the epidermis, especially in the upper granular layers, and results in the loss of normal epidermal calcium gradient. Currently, we hypothesize that the change in the intracellular calcium ion concentration triggers the barrier repair responses, such as lamellar body (LB) secretion and increased lipid synthesis in the epidermis. In this article, we suggest that PKC-delta is a signaling mediator for the changes in extracellular and intracellular calcium ion concentration.
Assuntos
Epiderme/fisiologia , Homeostase/fisiologia , Proteína Quinase C-delta/fisiologia , Animais , Cálcio/fisiologia , Permeabilidade da Membrana Celular/fisiologia , Células Epidérmicas , Humanos , Transdução de Sinais , Fenômenos Fisiológicos da PeleRESUMO
Huntington's disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.
Assuntos
Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Doença de Huntington/tratamento farmacológico , Lisofosfolipídeos/metabolismo , Terapia de Alvo Molecular , Esfingosina/análogos & derivados , Idoso , Aldeído Liases/antagonistas & inibidores , Animais , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Masculino , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/química , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingosina/metabolismoRESUMO
Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by SA-ß-gal staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.
RESUMO
Skin, as the outermost organ in the human body, continuously confronts the external environment and serves as a primary defense system. The protective functions of skin include UV-protection, anti-oxidant and antimicrobial functions. In addition to these protections, skin also acts as a sensory organ and the primary regulator of body temperature. Within these important functions, the epidermal permeability barrier, which controls the transcutaneous movement of water and other electrolytes, is probably the most important. This permeability barrier resides in the stratum corneum, a resilient layer composed of corneocytes and stratum corneum intercellular lipids. Since the first realization of the structural and biochemical diversities involved in the stratum corneum, a tremendous amount of work has been performed to elucidate its roles and functions in the skin, and in humans in general. The perturbation of the epidermal permeability barrier, previously speculated to be just a symptom involved in skin diseases, is currently considered to be a primary pathophysiologic factor for many skin diseases. In addition, much of the evidence provides support for the idea that various protective functions in the skin are closely related or even co-regulated. In this review, the recent achievements of skin researchers focusing on the functions of the epidermal permeability barrier and their importance in skin disease, such as atopic dermatitis and psoriasis, are introduced.