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1.
Biomed Pharmacother ; 117: 109181, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387196

RESUMO

BACKGROUND: Rosacea is a facial chronic inflammatory skin disease with dysfunction of immune and vascular system. Artemisinin (ART), an anti-malaria drug, was reported to have several effects including anti-inflammation and anti-angiogenesis activities. However, the role of ART on rosacea remains unclear. OBJECTIVES: To investigate the effects and molecular mechanism of ART on rosacea. METHOD: In rosacea-like mouse model, the phenotype of rosacea lesions was evaluated by redness score, the inflammatory biomarkers were analyzed by qPCR, and the infiltration of inflammatory cells were assessed by IHC analysis and immunofluorescence. In vitro, LL37-induced expression of inflammatory factors in HaCaT cells was detected by qPCR, potential signaling pathways were detected by Western blotting or immunofluorescence. Migration ability of human umbilical vein endothelial cells (HUVECs) was evaluated by cell scratch and transwell assays. RESULT: The skin erythema and histopathological alteration, as well as the elevated pro-inflammatory factors (IL-1ß, IL6, TNFα) and TLR2 were significantly ameliorated by ART treatment in LL37-induced rosacea-like mice. In addition, ART reduced the infiltration of CD4+ T cells, macrophages and neutrophils, and repressed the expression of immune cells related chemokines (CXCL10, CCL20, CCL2 and CXCL2) in mouse lesions. In HaCaT cells, ART significantly decreased the LL37-induced expression of inflammatory biomarkers. Moreover, we found that ART inhibited rosacea-like inflammation via NF-kB signaling pathways in HaCaT cells. Finally, for vascular dysregulation, ART repressed the angiogenesis in mouse model and inhibited the LL37-induced HUVECs migration in vitro. CONCLUSION: ART ameliorated rosacea-like dermatitis by regulating immune response and angiogenesis, indicating that it could represent an effective therapeutic option for patients with rosacea.


Assuntos
Anti-Inflamatórios/farmacologia , Artemisininas/farmacologia , Inflamação/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Rosácea/tratamento farmacológico , Animais , Biomarcadores/metabolismo , Células Cultivadas , Quimiocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Neovascularização Patológica/metabolismo , Rosácea/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo
2.
Biomed Pharmacother ; 116: 109011, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132668

RESUMO

BACKGROUND: Rosacea is a chronic inflammatory skin disorder of uncertain etiology. Evidence suggests the underlying pathogenesis is modulated by abnormal inflammatory and vascular responses. Thalidomide is a synthetic derivative acid with anti-inflammatory and anti-angiogenic properties. However, its effects on rosacea remain unknown. OBJECTIVES: To investigate the effects of thalidomide on the lesional alterations and molecular mechanisms in rosacea. METHODS: Mice were intradermally injected with LL37 to induce rosacea-like features and intraperitoneally administered with thalidomide. The severity of skin inflammation was evaluated. The mRNA levels of cytokines and chemokines associated with rosacea were assessed by qPCR. The number of CD4 positive infiltrated T helper cells and CD31 positive microvessels, and related-genes were measured by immunofluorescence, qPCR and ELISA. Moreover, the effect of thalidomide on inhibiting NF-κB activation was determined by immunofluorescence and western blot. RESULTS: Our results showed that thalidomide significantly alleviated erythema and reduced inflammatory cell infiltration in dermis of LL37-induced rosacea-like mice. The production of cytokines and chemokines induced by LL37 was decreased by thalidomide in mice skin and HaCaT keratinocytes. Particularly, we showed thalidomide reduced CD4+ T helper cell infiltration and downregulated Th1- and Th17-polarizing genes. In addition, thalidomide treatment lowered the microvessel density and vascular endothelial growth factor (VEGF) expression. We further demonstrated that thalidomide suppressed NF-κB activation in LL37-treated skin and in TNF-α-stimulated HaCaT keratinocytes in vitro. CONCLUSIONS: Our findings suggest thalidomide attenuates the inflammation and represses NF-κB activation in skin, which leads to assumptions that thalidomide may be a new therapeutic agent for rosacea.


Assuntos
Inflamação/tratamento farmacológico , Queratinócitos/metabolismo , Queratinócitos/patologia , NF-kappa B/metabolismo , Rosácea/tratamento farmacológico , Rosácea/metabolismo , Pele/patologia , Talidomida/uso terapêutico , Animais , Peptídeos Catiônicos Antimicrobianos , Linhagem Celular , Quimiocinas/biossíntese , Humanos , Inflamação/complicações , Inflamação/metabolismo , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Neovascularização Fisiológica/efeitos dos fármacos , Rosácea/complicações , Rosácea/imunologia , Pele/irrigação sanguínea , Pele/efeitos dos fármacos , Pele/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Talidomida/farmacologia
3.
Am J Ophthalmol ; 201: 72-81, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30703356

RESUMO

PURPOSE: To assess the role of nuclear factor kappa-B (NFKB) in cutaneous specimens of rosacea and unaffected tissue. METHODS: Immunohistochemical staining was performed for the activated, phosphorylated variant of NFKB (pNFKB) in eyelid specimens of rosacea (n = 12) and normal, healthy tissue (n = 12). The numbers of positively staining cells/40× microscopic field were counted across 5 consecutive fields. Additionally, quantitative Western blotting was carried out for pNFKB and NFKB in specimens of rosacea (n = 15) and normal controls (n = 14). Statistical comparisons were performed via a dedicated software package. RESULTS: The mean number of cells/40× microscopic field that stained positively for pNFKB was 18.4 (standard deviation = 15.3) for control patients and 39.3 (standard deviation = 16.9) for rosacea patients, and the difference between the 2 groups was statistically significant (P = .0024). On Western blotting, the mean ratios of pNFKB:NFKB for control and rosacea patients measured 0.58 (standard deviation = 0.81) and 3.11 (standard deviation = 3.53), respectively. The 2 groups were statistically significantly different (P = .0002). CONCLUSIONS: The activated form of NFKB is enriched in rosacea, indicating a role for this pathway in the pathogenesis of this disease. Interference with NFKB signaling may represent a novel therapy for rosacea as clinical agents become available. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.


Assuntos
Doenças Palpebrais/metabolismo , Pálpebras/metabolismo , NF-kappa B/metabolismo , Rosácea/metabolismo , Western Blotting , Doenças Palpebrais/diagnóstico , Doenças Palpebrais/etiologia , Doenças Palpebrais/terapia , Pálpebras/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Fosforilação , Rosácea/diagnóstico , Rosácea/etiologia , Rosácea/terapia
4.
Clin Exp Dermatol ; 44(4): 397-403, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30246390

RESUMO

BACKGROUND: Vitamin D has significant effects on the immune system and thereby on the pathogenesis of rosacea. However, there is a lack of information on the vitamin D status and vitamin D receptors (VDRs) of patients with rosacea. AIM: To evaluate the role of vitamin D in rosacea susceptibility. METHODS: A case-control study was conducted, enrolling patients with rosacea and healthy controls (HCs). Five VDR gene single nucleotide polymorphisms (SNPs) (Cdx2, FokI, ApaI, BsmI and TaqI) and serum 25-hydroxyvitamin D3 [25(OH)D3 ] levels were compared between patients and HCs. RESULTS: The study enrolled 60 patients (M/F: 14/46) and 60 age- and sex-matched HCs (M/F: 14/46). Age (mean ± SD) was 48 ± 11 years for both groups. The serum 25(OH)D3 levels (median ± interquartile range) were higher in patients with rosacea (12.9 ± 6.8 ng/mL) than in HCs (10.5 ± 3.7 ng/mL) (P < 0.001). Subjects with high serum 25(OH)D3 levels had a 1.36-fold increased risk of rosacea (95% CI 1.17-1.58). Heterozygous and mutant ApaI polymorphisms increased rosacea risk by 5.26-fold (95% CI 1.51-18.35) and 3.69-fold (95% CI 1.19-11.48), respectively, whereas mutant TaqI polymorphisms decreased the risk by 4.69 times (95% CI 1.37-16.67). Heterozygosity for Cdx2 alleles increased rosacea risk, whereas wildtype ApaI and mutant TaqI alleles decreased it. CONCLUSIONS: The present study suggests that an increase in vitamin D levels may contribute to the development of rosacea. ApaI and TaqI polymorphisms, and heterozygous Cdx2, wildtype ApaI and mutant TaqI alleles were significantly associated with rosacea. These results indicate a possible role of vitamin D and VDR pathways in the pathogenesis of rosacea, although causality could not be assessed.


Assuntos
Receptores de Calcitriol/genética , Rosácea/metabolismo , Vitamina D/análogos & derivados , Vitamina D/sangue , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Rosácea/diagnóstico , Rosácea/patologia , Dermatopatias/metabolismo , Dermatopatias/patologia , Vitamina D/metabolismo
5.
Ocul Immunol Inflamm ; 27(4): 632-635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29533687

RESUMO

Purpose: To evaluate the results of tear functions in acne rosacea. Methods: This prospective study includes 64 eyes of 32 acne rosacea patients without blepharitis and meibomian gland dysfunction and 90 eyes of 45 patients as control group. Tear functions of all were evaluated with ocular surface disease index (OSDI) questionnaire, and measurements of tear osmolarity were performed by using TearLab, Schirmer I tests without anesthesia and fluorescein tear break-up time (TBUT). Results: The mean Schirmer test result was 12.53 ± 6.54 in study group and 16.21 + 7.52 mm/5 min in control group (p = 0.28). The mean TBUT in study group was 8.21 ± 4.01 and in control group was 18.03 ± 6.45 s (p = 0.02). Mean tear osmolarity in study group was 304.77 ± 15.59and in control group was 275.23 + 28.52 mOsms/L (p = 0.03). Mean OSDI score in study group was 27.51 ± 16.73 and was 18.15 ± 7.05 in control group (p = 0.38). Conclusions: Our study demonstrated lower dry eye tests before the appearance of clinical signs of meibomian gland disease in acne rosacea.


Assuntos
Síndromes do Olho Seco/diagnóstico , Rosácea/diagnóstico , Lágrimas/metabolismo , Adulto , Síndromes do Olho Seco/etiologia , Feminino , Fluoresceína/farmacologia , Corantes Fluorescentes/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Estudos Prospectivos , Rosácea/metabolismo
6.
Arch Dermatol Res ; 310(9): 759-767, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30151656

RESUMO

The relationships of demodex density with systemic oxidative stress, inflammatory response, and clinical severity in rosacea are not clear. This study aimed to (a) analyze the levels of systemic oxidative stress, antioxidant capacity, inflammatory parameters, and matrix metalloproteinases (MMPs) in systemic circulation in patients with rosacea, (b) identify the relationship between mite density and both oxidative stress and inflammation, and (c) investigate the role of photoaging and sebum secretion in etiopathogenesis. Forty patients with rosacea and 40 age-, sex-, and skin phenotype-matched healthy volunteers were included in the study. Clinical disease severity of the patients was determined. Sebum levels were measured in both the groups, and photoaging was evaluated. Reflectance confocal microscopy was used to calculate demodex density. Serum total antioxidant capacity (TAC), total oxidant capacity (TOC), myeloperoxidase (MPO), MMP-1, MMP-9, arylesterase (ARES), interleukin-1ß (IL-1ß), paraoxonase-1 (PON-1), and tumor necrosis factor-α (TNF-α) levels were also analyzed. The patients with rosacea had significantly higher serum TOC and lower TAC levels (p < 0.001). The serum ARES and PON-1 levels were significantly lower (p = 0.045 and p < 0.001, respectively); however, the serum levels of MMP-1, MMP-9, IL-1ß and MPO were higher in the patient group. Demodex parameters were higher in the patient group compared to the control group. There was no significant correlation between the number of mites and disease severity. In addition, the number of mites was not correlated with the serum levels of TAC, TOC, OSI, MPO, MMP-1, MMP-9, ARES, PON-1, TNF-α, and IL-1ß. However, sebum levels were directly proportional to the number of mites. Photoaging severity was similar between the patients and control subjects. The changing sebaceous microenvironment in rosacea leads to an increase in the number of demodex mites. However, increased demodex density does not alter disease severity, level of oxidative stress, or inflammation. Although none of the patients with rosacea had any underlying systemic disease, patients' systemic oxidative stress and inflammation parameters were found high in systemic circulation. It is assumed that the patients with rosacea are more prone to systemic diseases.


Assuntos
Inflamação/complicações , Ácaros , Estresse Oxidativo , Rosácea/etiologia , Adulto , Animais , Arildialquilfosfatase/sangue , Estudos de Casos e Controles , Citocinas/sangue , Feminino , Humanos , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Rosácea/imunologia , Rosácea/metabolismo , Sebo/metabolismo , Índice de Gravidade de Doença , Envelhecimento da Pele
7.
Ophthalmic Res ; 60(2): 109-114, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29874670

RESUMO

AIMS: The purpose of this paper was to determine the lacrimal concentration of IL-1α and MMP-9 in patients with active ocular rosacea before and after systemic treatment with azithromycin or doxycycline. METHODS: After 4 weeks of therapy with azithromycin (500 mg/day, 3 days a week PO) or doxycycline (200 mg/day PO), lacrimal samples were analyzed using an enzyme-linked immunosorbent assay multiplex. RESULTS: There was a significant difference between baseline IL-1α (37.9 pg/mL) and MMP-9 (26.7 ng/mL) in rosacea eyes compared to controls (0.001 pg/mL for IL-1α and 0.2 ng/mL for MMP-9) (p < 0.001). IL-1α decreased from 47.0 pg/mL before azithromycin to 23.5 pg/mL after treatment (p = 0.024), but not after doxycycline therapy. On the contrary, baseline MMP-9 tear levels (10.28 ng/mL) decreased after treatment (8.36 pg/mL) with doxycycline (p = 0.054) but not with azithromycin. There was a strong clinical correlation of higher baseline IL-1α tear levels between patients who responded to doxycycline therapy and those who failed (p = 0.043). Patients unresponsive to azithromycin had significantly higher baseline MMP-9 levels than those with doxycycline (p = 0.040). CONCLUSIONS: While IL-1α levels decreased after azithromycin therapy, MMP-9 did so after doxycycline treatment. Baseline cytokine tear levels tend to be markedly elevated in patients with antibiotic failure, suggesting their potential role as therapeutic biomarkers for the disease.


Assuntos
Antibacterianos/uso terapêutico , Azitromicina/uso terapêutico , Doxiciclina/uso terapêutico , Interleucina-1alfa/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Rosácea/tratamento farmacológico , Lágrimas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rosácea/metabolismo
8.
Exp Dermatol ; 27(9): 1023-1029, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29873850

RESUMO

Rosacea is one of the most common dermatoses of adults. Although the detailed pathophysiology remains unknown, it is thought that rosacea is caused by a consistently aberrant, innate immune response, and that LL-37 plays an important role. However, involvement of the inflammatory cytokine IL-33 has not yet been studied. We explored the role played by IL-33 in the pathophysiology of rosacea. First, we immunohistochemically evaluated the expression of IL-33 and its receptor (ST2) in rosacea skin. Second, we exposed HaCaT cells to ultraviolet B (UVB) irradiation in the presence or absence of LL-37 and measured the expression of proinflammatory cytokines including IL-33. We also analysed VEGF (vascular endothelial growth factor) mRNA expression and protein release after costimulation of HaCaT cells by LL-37 and IL-33. Immunohistochemically, IL-33 expression was enhanced in the skin of rosacea patients, especially with erythematotelangiectatic subtype. In vitro, UVB and LL-37 synergistically increased mRNAs expression of proinflammatory cytokines, especially IL-33 and IL-1ß. IL-33 protein release was also synergistically increased by LL-37 and UVB treatment. LL-37 and IL-33 stimulated VEGF mRNA expression and VEGF release from HaCaT cells. Our findings suggest that rosacea skin with abundant LL-37 may robustly produce and release IL-33 when exposed to UV radiation. IL-33 may participate in the angiogenesis and vasodilation of rosacea skin by enhancing VEGF release.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Rosácea/metabolismo , Pele/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Peptídeos Catiônicos Antimicrobianos/farmacologia , Linhagem Celular , Feminino , Humanos , Interferon gama/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Interleucina-33/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Raios Ultravioleta , Fator A de Crescimento do Endotélio Vascular/genética , Adulto Jovem
9.
J Drugs Dermatol ; 17(6): 611-617, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29879248

RESUMO

Complementary and alternative medicine (CAM) therapies are increasing in popularity in the field of dermatology. Natural products and holistic approaches are in high demand among patients and research has begun to support their roles in acne and rosacea pathophysiology. In this article, commonly utilized biologically based complementary and alternative therapies for acne and rosacea are reviewed from an evidence-based perspective. Therapies discussed include vitamin C, nicotinamide, zinc, tea tree oil, green tea, resveratrol, curcumin, feverfew, licorice, chamomile, polypodium leucotomos, and nutrition-based approaches. J Drugs Dermatol. 2018;17(6):611-617.


Assuntos
Acne Vulgar/tratamento farmacológico , Fatores Biológicos/administração & dosagem , Terapias Complementares/tendências , Extratos Vegetais/administração & dosagem , Rosácea/tratamento farmacológico , Acne Vulgar/diagnóstico , Acne Vulgar/metabolismo , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/metabolismo , Fatores Biológicos/metabolismo , Terapias Complementares/métodos , Humanos , Fitoterapia/métodos , Fitoterapia/tendências , Extratos Vegetais/metabolismo , Rosácea/diagnóstico , Rosácea/metabolismo
10.
Mol Med Rep ; 17(6): 8385-8390, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29693177

RESUMO

Acne rosacea is a type of chronic dermatosis with the characteristics of erubescence, angiotelectasis and pustule formation. However, current treatment methods are limited due to the side effects. Artesunate demonstrated a promising therapeutic efficacy with a high safety margin. HaCaT cells were treated with antibacterial peptide LL­37 to simulate rosacea caused by Demodex folliculorum (D. folliculorum) infection. Cell Counting kit 8 and flow cytometry assays were performed to measure cellular proliferation, apoptosis, the stage of the cell cycle and reactive oxygen species generation in order to determine the level of cell damage. Then the damaged cells were treated with different concentrations of artesunate and doxycycline to determine the therapeutic effect of artesunate. Pro­inflammatory cytokines tumor necrosis factor­α (TNF­α), interleukin (IL)­6, IL­8 and C­C motif chemokine 2 (MCP­1) were measured using an ELISA, while western blotting was used to detect the expression of Janus kinase 2 (JAK2) and signal transducer and transcription activator (STAT3). As a result, LL­37 treated HaCaT cells decreased in cell viability, had an increased apoptotic rate and cell cycle arrest, indicating that cell damage caused by rosacea was simulated. In addition, upregulated concentrations of the pro­inflammatory cytokines TNF­α, IL­6, IL­8 and MCP­1 were attenuated in the artesunate group in a dose­dependent fashion, indicating the therapeutic effect of artesunate. Furthermore, higher concentrations of artesunate exhibited an improved effect compared with the doxycycline group. In addition, increased expression levels of JAK2 and STAT3 following treatment with LL­37 suggested that rosacea caused by D. folliculorum infection may lead to inflammation through the JAK/STAT signaling pathway. In conclusion, the potential mechanism by which damage occurs in rosacea was revealed and a promising therapeutic method against rosacea was demonstrated.


Assuntos
Amebicidas/farmacologia , Artemisininas/farmacologia , Janus Quinases/metabolismo , Rosácea/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Apoptose/efeitos dos fármacos , Artesunato , Linhagem Celular , Humanos , Rosácea/tratamento farmacológico , Rosácea/etiologia
11.
Exp Dermatol ; 27(7): 763-768, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29637626

RESUMO

When applied topically, oxymetazoline and brimonidine reduce the persistent facial erythema of rosacea; this effect is mediated by cutaneous vasoconstriction induced by postsynaptic activation of α-adrenoceptors. We investigated the α-adrenergic pharmacology of oxymetazoline and brimonidine. Functional activity on α-adrenoceptors was evaluated in vitro in HEK293 cells stably expressing single receptor subtypes using a fluorometric imaging plate reader Ca2+ influx assay. Oxymetazoline was an α1 -adrenoceptor agonist with partial α2 -adrenoceptor activity, whereas brimonidine was a highly selective full α2 -adrenoceptor agonist. In vivo pharmacology was investigated in a mouse model of ultraviolet B light (UVB)-induced skin erythema. To selectively inhibit α-adrenoceptor subtypes, mice were injected with prazosin (an α1 -selective antagonist) or rauwolscine (an α2 -selective antagonist) following UVB exposure. Oxymetazoline cream 1.0%, brimonidine gel 0.33% or vehicle control was applied topically, and erythema was measured using a chromameter. Oxymetazoline and brimonidine reduced UVB-induced erythema compared with vehicle control (P < .01). The effect of oxymetazoline was impaired in prazosin-pretreated but not rauwolscine-pretreated mice. Conversely, the effect of brimonidine was impaired in rauwolscine-pretreated but not prazosin-pretreated mice. These data suggest that while oxymetazoline and brimonidine produce cutaneous vasoconstriction, they do so through different α-adrenergic mechanisms, with oxymetazoline primarily acting via α1 -adrenoceptors and brimonidine acting via α2 -adrenoceptors.


Assuntos
Tartarato de Brimonidina/farmacologia , Eritema/tratamento farmacológico , Eritema/etiologia , Oximetazolina/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Eritema/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Pelados , Prazosina/farmacologia , Rosácea/tratamento farmacológico , Rosácea/etiologia , Rosácea/metabolismo , Raios Ultravioleta/efeitos adversos , Vasoconstrição/efeitos dos fármacos , Ioimbina/farmacologia
12.
Dermatol Clin ; 36(2): 81-86, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29499802

RESUMO

Rosacea is a chronic inflammatory skin disorder that is not fully understood but involves the complex interplay of genetic factors, immune dysregulation, neurovascular dysregulation, presence of microorganisms, and environmental factors. Increased activation of the immune system occurs through multiple stimuli, including increased levels of cathelicidin and kallikrein 5, Toll-like receptor 2, matrix metalloproteinases, and mast cells within the skin. Their effects are enhanced by the presence of microorganisms and external triggers, such as UV radiation.


Assuntos
Rosácea/imunologia , Rosácea/microbiologia , Canais de Receptores Transientes de Potencial/metabolismo , Humanos , Rosácea/metabolismo , Raios Ultravioleta/efeitos adversos
13.
Bioconjug Chem ; 29(4): 1060-1072, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29406699

RESUMO

The overexpression and increased activity of the serine protease Kallikrein 5 (KLK5) is characteristic of inflammatory skin diseases such as Rosacea. The use of inhibitors of this enzyme-such as 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF·HCl) or the anti-human recombinant Kallikrein 5 (anti-KLK5) antibody-in the treatment of the disease has been limited due to their low bioavailability, for which their immobilization in drug delivery agents can contribute to making serine protease inhibitors clinically useful. In this work, we synthesized gold nanoparticles (GNP) coated with a mixture of hydroxyl- and carboxyl-terminated thiolates (GNP.OH/COOH), whose carboxyl groups were used to further functionalize the nanoparticles with the serine protease inhibitor AEBSF·HCl either electrostatically or covalently (GNP.COOH AEBSF and GNP.AEBSF, respectively), or with the anti-KLK5 antibody (GNP.antiKLK5). The synthesized and functionalized GNP were highly water-soluble, and they were extensively characterized using UV-vis absorption spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Thermogravimetric Analysis (TGA). GNP.OH/COOH and their subsequent functionalizations effectively inhibited KLK5 in vitro. Internalization of fluorophore-coated GNP.OH/COOH in human keratinocytes (HaCaT cells) was proven using confocal fluorescence microscopy. Cell viability assays revealed that the cytotoxicity of free AEBSF is importantly decreased when it is incorporated in the nanoparticles, either ionically (GNP.COOH AEBSF) or, most importantly, covalently (GNP.AEBSF). The functionalized nanoparticles GNP.AEBSF and GNP.antiKLK5 inhibited intracellular KLK5 activity in HaCaT cells and diminished secretion of IL-8 under inflammatory conditions triggered by TLR-2 ligands. This study points to the great potential of these GNP as a new intracellular delivery strategy for both small drugs and antibodies in the treatment of skin diseases such as Rosacea.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Rosácea/terapia , Inibidores de Serino Proteinase/uso terapêutico , Anticorpos/imunologia , Células Cultivadas , Humanos , Interleucina-8/metabolismo , Calicreínas/imunologia , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Rosácea/metabolismo , Inibidores de Serino Proteinase/química , Solubilidade , Espectrofotometria Ultravioleta , Sulfonas/uso terapêutico , Termogravimetria
14.
Ann Pharmacother ; 52(3): 263-267, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29094614

RESUMO

OBJECTIVE: To review and summarize topical oxymetazoline's pharmacology, pharmacokinetics, efficacy, safety, cost, and place in therapy for persistent redness associated with erythematotelangiectatic rosacea. DATA SOURCES: Literature searches of MEDLINE (1975 to September 2017), International Pharmaceutical Abstracts (1975 to September 2017), and Cochrane Database (publications through September 2017) using the terms rosacea, persistent redness, α -agonist, and oxymetazoline. STUDY SELECTION AND DATA EXTRACTION: Results were limited to studies of human subjects, English-language publications, and topical use of oxymetazoline. Relevant materials from government sources, industry, and reviews were also included. DATA SYNTHESIS: Data support the efficacy of oxymetazoline for persistent facial redness. Little study beyond clinical trials cited in the drug approval process has been conducted. Current data suggest that oxymetazoline is similar in safety and efficacy to brimonidine. Head-to-head comparisons of topical α-agonists for erythema caused by rosacea are needed. CONCLUSION: The topical α-agonist, oxymetazoline, is safe and effective for reducing persistent facial redness associated with erythematotelangiectatic subtype of rosacea. Health care practitioners selecting among treatments should consider not only the subtype of rosacea but also individual patient response, preference, and cost.


Assuntos
Agonistas alfa-Adrenérgicos/administração & dosagem , Eritema/tratamento farmacológico , Oximetazolina/administração & dosagem , Rosácea/tratamento farmacológico , Administração Tópica , Agonistas alfa-Adrenérgicos/efeitos adversos , Agonistas alfa-Adrenérgicos/economia , Agonistas alfa-Adrenérgicos/farmacocinética , Interações de Medicamentos , Eritema/metabolismo , Humanos , Oximetazolina/efeitos adversos , Oximetazolina/economia , Oximetazolina/farmacocinética , Rosácea/economia , Rosácea/metabolismo , Resultado do Tratamento
15.
Lasers Med Sci ; 33(2): 393-397, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29256058

RESUMO

Long-pulsed 1064-nm neodymium: yttrium-aluminum-garnet laser (LPND) effectively treats rosacea, although the underlying mechanism is unclear, to evaluate the histological effects and molecular mechanism of LPND on LL-37-induced rosacea-like skin lesions in mice. Intradermal injection of LL-37 was performed into the dorsal skin of BALB/c mice (n = 30) twice a day for 2 days. Fifteen mice were treated with LPND. After 48 h, the excised skin sample was stained for histology and type I collagen; transforming growth factor (TGF)-ß, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase (TIMP)-1, tumor necrosis factor (TNF)-α, and interleukin (IL)-1α mRNA levels were determined by real-time RT-PCR. Intradermal injection of LL-37 induced rosacea-like clinical features. LPND treatment significantly reduced erythema and increased dermal collagen production. Levels of Type I collagen, TGF-ß, and MMP-1 mRNA were significantly higher in LPND-treated mice than in untreated mice. LPND may improve rosacea by ameliorating dermal connective tissue disorganization and elastosis through MMP-mediated dermal collagen remodeling.


Assuntos
Colágeno Tipo I/metabolismo , Lasers de Estado Sólido/uso terapêutico , Rosácea/metabolismo , Rosácea/radioterapia , Pele/patologia , Animais , Catelicidinas , Colágeno Tipo I/genética , Feminino , Camundongos Endogâmicos BALB C , Rosácea/patologia , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
16.
J Cosmet Dermatol ; 16(4): e31-e36, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28349651

RESUMO

BACKGROUND: Over the counter cosmetics sold for local treatment of slight to moderate rosacea often state the claim of actively modulating rosacea pathogenesis. Factors involved in the pathogenesis of this common yet complex skin disorder include kallikrein-related peptidase 5 (KLK5), LL-37, as well as protease-activated receptor 2 (PAR2) and vascular endothelial growth factor (VEGF). OBJECTIVE: The objective was to prove the modulating effect of the cosmetic skin care agent Dermasence Refining Gel (DRG) on factors involved in rosacea pathogenesis. METHODS: We analyzed the effect of DRG on the expression of KLK5, LL-37, PAR2, and VEGF in an in vitro skin model of human reconstituted epidermis. RESULTS: The expression of CAMP (LL-37 gene, fold change -4.19 [±0.11]), VEGFA (fold change -2.55 [±0.12]) and PAR2 (-1.33 [±0.12]) was reduced, KLK5 expression increased (fold change 2.06 (±0.08)) after 18 h of treatment with DRG in comparison to treatment with the matrix gel only. The reduction in CAMP expression was significant (P<.01). The protein expression of all four inflammatory markers was markedly reduced after 18 hours of DRG treatment in comparison to baseline (0 hour), by measure of fluorescence intensity. CONCLUSION: We show evidence explaining the anti-inflammatory effect of Dermasence Refining Gel in rosacea pathogenesis in vitro. The adjunctive use of DRG in mild to moderate rosacea as a topical cosmetic seems medically reasonable.


Assuntos
Cosméticos/farmacologia , Expressão Gênica/efeitos dos fármacos , Rosácea/genética , Rosácea/metabolismo , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Epiderme/efeitos dos fármacos , Géis , Humanos , Calicreínas/genética , Calicreínas/metabolismo , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Rosácea/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
17.
Dermatol Clin ; 35(1): 39-50, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27890236

RESUMO

Antimicrobial peptides are central effector molecules in skin immunology. The functions of antimicrobial peptides in skin diseases include the ability to act as cytokines or growth factors, driving disorders such as psoriasis and rosacea, as well as their action as natural antibiotics to control bacteria that influence diseases such as atopic dermatitis and acne.


Assuntos
Acne Vulgar/metabolismo , Peptídeos Catiônicos Antimicrobianos/metabolismo , Dermatite Atópica/metabolismo , Psoríase/metabolismo , Rosácea/metabolismo , Pele/metabolismo , Acne Vulgar/microbiologia , Dermatite Atópica/microbiologia , Humanos , Inflamação , Psoríase/microbiologia , Rosácea/microbiologia , Pele/microbiologia , Dermatopatias Bacterianas/metabolismo , Dermatopatias Bacterianas/microbiologia , beta-Defensinas/metabolismo
18.
Int J Mol Sci ; 17(9)2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27649161

RESUMO

Rosacea is a chronic cutaneous inflammatory disease that affects the facial skin. Clinically, rosacea can be categorized into papulopustular, erythematotelangiectatic, ocular, and phymatous rosacea. However, the phenotypic presentations of rosacea are more heterogeneous. Although the pathophysiology of rosacea remains to be elucidated, immunologic alterations and neurovascular dysregulation are thought to have important roles in initiating and strengthening the clinical manifestations of rosacea. In this article, we present the possible molecular mechanisms of rosacea based on recent laboratory and clinical studies. We describe the genetic predisposition for rosacea along with its associated diseases, triggering factors, and suggested management options in detail based on the underlying molecular biology. Understanding the molecular pathomechanisms of rosacea will likely aid toward better comprehending its complex pathogenesis.


Assuntos
Rosácea/patologia , Butirofilinas/genética , Predisposição Genética para Doença , Glutationa Transferase/genética , Cadeias alfa de HLA-DR/genética , Humanos , Sistema Imunitário/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Rosácea/genética , Rosácea/metabolismo , Pele/parasitologia , Pele/efeitos da radiação , Raios Ultravioleta
19.
Semin Cutan Med Surg ; 35(6 Suppl): S107-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27537212

RESUMO

Rosacea is a chronic skin disorder associated with flushing, erythema, dryness, burning and stinging, and inflammatory papules and pustules. New treatments available or in development target the inflammatory and erythematous components of the disease. These agents include the selective α2 receptor agonist brimonidine, the topical agents ivermectin cream 1% and azelaic acid foam 15%, and use of tetracyclinetype antibiotics, which affect the cathelicidin pathway. Semin Cutan Med Surg 35(supp6):S107-S109.


Assuntos
Dermatite/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Dermatoses Faciais/tratamento farmacológico , Rosácea/tratamento farmacológico , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/metabolismo , Antiparasitários/uso terapêutico , Tartarato de Brimonidina/uso terapêutico , Dermatite/metabolismo , Ácidos Dicarboxílicos/uso terapêutico , Humanos , Ivermectina/uso terapêutico , Rosácea/metabolismo
20.
Exp Dermatol ; 25(12): 956-961, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27315464

RESUMO

Cathelicidin (LL-37), Toll-like receptor 2 (TLR-2) and kallikreins (KLKs) are key inflammatory mediators in rosacea. Laser or light-based devices have been successfully used for rosacea. We investigated the effects of light-emitting diodes (LEDs) on LL-37, KLKs, TLR-2 and protease activity in cultured normal human epidermal keratinocytes (NHEKs) and rosacea-like mouse skin (RLMS). LL-37, KLK5, KLK7 and vitamin D receptor were induced by 1α, 25-dihydroxyvitamin D3 (VD3 ) and TLR-2 by Ad-CMV transfection in cultured NHEKs. NHEKs were subjected to LED irradiation at differing wavelengths (480-940 nm) and fluences (1-40 J/cm2 ). Inflammatory mediators were analysed with RT-PCR and real-time PCR and protease activity analysis and immunocytofluorescence staining were performed for NHEKs. Changes in RLMS induced by LL-37 peptide were evaluated with real-time PCR, immunohistochemical staining and enzyme-linked immunosorbent assay. In NHEKs, LED at 630 and 940 nm significantly attenuated LL37, KLK5 and TLR-2 mRNA expressions. Protease activity was significantly suppressed at 630, 850 and 940 nm. In the RLMS, LL-37, KLK5 and PAR-2 mRNA expressions significantly decreased at 24 and 48 hours after LED irradiation was performed three times at 630 and 940 nm. mCAMP and IL-8 protein levels and protease activity after LED irradiation were lower than those in RLMS control groups. LED at 630 and 940 nm downregulated TLR-2, KLK5 and LL-37 expressions and protease activity in NHEK and RLMS. Thus, LEDs may be promising for rosacea treatment. However, clinical trials are required for further study.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Calicreínas/metabolismo , Queratinócitos/efeitos da radiação , Rosácea/radioterapia , Receptor 2 Toll-Like/metabolismo , Animais , Células Cultivadas , Humanos , Interleucina-8/metabolismo , Queratinócitos/metabolismo , Camundongos Endogâmicos BALB C , Receptor PAR-2/metabolismo , Receptores de Calcitriol/metabolismo , Rosácea/metabolismo
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